Indian Patents. 277165:"PHENOXY ACETIC ACIDS AS PPAR DELTA ACTIVATORS"

Title of Invention	"PHENOXY ACETIC ACIDS AS PPAR DELTA ACTIVATORS"
Abstract	The present invention describes phenoxy-acetic acids and pharmaceutical compositions containing the same and methods of using the same. The phenoxy-acetic acids are activators of PPAR-8 and should be useful for treating conditions mediated by the same.

Full Text	NOVEL COMPOUNDS, THEIR PREPARATION AND USE FIELD OF THE INVENTION [0001] The present invention relates to novel phenoxy-acetic acids, Pharmaceuticals comprising the same, and methods of using the same. The phenoxy-acetic acids are activators of peroxisome proliferator-activated receptors (PPAR)-5. BACKGROUND OF THE INVENTION [0002] Coronary artery disease (CAD) is the major cause of death in Type 2 diabetic and metabolic syndrome patients (i.e., patients that fall within the 'deadly quartet' category of impaired glucose tolerance, insulin resistance, hypertriglyceridaemia and/or obesity). [0003] The hypolipidaemic fibrates and antidiabetic thiazolidinediones separately display moderately effective triglyceride-lowering activities, although they are neither potent nor efficacious enough to be a single therapy of choice for the dyslipidaemia often observed in Type 2 diabetic or metabolic syndrome patients. The thiazolidinediones also potently lower circulating glucose levels of Type 2 diabetic animal models and humans. However, the fibrate class of compounds are without beneficial effects on glycaemia. Studies on the molecular actions of these compounds indicate that thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased and decreased expression of specific enzymes and apol-ipoproteins respectively, both key-players in regulation of plasma triglyceride content. [0004] PPAR-5 activation was initially reported not to be involved in modulation of glucose or triglyceride levels. (Berger et al., JBiol. Chem. 1999,274, 6718-6725). Later it was shown that PPAR-8 activation leads to increased levels of HDL cholesterol in db/db mice (Leibowitz et al., FEBS letters 2000,473, 333-336). Further, a PPAR-5 agonist when dosed to insulin-resistant middle-aged obese rhesus monkeys caused a dramitic dose-dependent rise in serum HDL cholesterol while lowering the levels of small dense LDL, fasting triglycerides and fasting insulin (Oliver et al., PNAS 2001, 98,5306-5311). The same paper also showed that PPAR-8 activation increased the reverse cholesterol transporter ATP-binding cassette Al and induced apolipoprotein Al-specific cholesterol efflux. The involvement of PPAR-5 in fatty acid oxidation in muscles was further substantiated in PPAR-a knock-out mice. Muoio et a\. (J. Biol. Chem. 2002,277,26089-26097) showed that the high levels of PPAR-8 in skeletal muscle can compensate for deficiency in PPAR-a. In addition to the effects on cholesterol homeostasis, PPAR5 treatment was observed to lower plasma glucose and insulin and improve insulin sensitivity in diabetic ob/ob and db/db mice and high fat diet induced insulin resistant mice (PNAS 2003, 700,15924-15929; PNAS 2006,103, 3444-3449).Taken together these observations suggest that PPAR-8 activation is useful in the treatment and prevention of Type 2 diabetes, cardiovascular diseases and conditions including atherosclerosis, hypertriglyceridemia, and mixed dyslipidaemia (WO 01/00603). A number of PPAR-8 compounds have been reported to be useful in the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia (WO 02/59098, WO 01/603, WO 01/25181, WO 02/14291, WO 01/79197, WO 99/4815, WO 97/28149, WO 98/27974, WO 97/28115, WO 97/27857, WO 97/28137, and WO 97/27847). WO 2004093879, WO 2004092117, WO 2004080947, WO 2004080943, WO 2004073606.WO 2004063166, WO 2004063165, WO 2003072100, WO 2004060871, WO 2004005253, WO 2003097607, WO 2003035603, WO 2004000315, WO 2004000762, WO 2003074495, WO 2002070011, WO 2003084916, US 20040209936, WO 2003074050, WO 2003074051, WO 2003074052, JP 2003171275, WO 2003033493, WO 2003016291, WO 2002076957, WO 2002046154, WO 2002014291, WO 2001079197, WO 2003024395, WO 2002059098, WO 2002062774, WO 2002050048, WO 2002028434, WO 2001000603, WO 2001060807, WO 9728149, WO 2001034200, WO 9904815, WO 200125226, WO 2005097098; WO 2005097762; WO 2005097763. [0005] Glucose lowering as a single approach does not overcome the macrovascular complications associated with Type 2 diabetes and metabolic syndrome. Novel treatments of Type 2 diabetes and metabolic syndrome must therefore aim at lowering both the overt hypertriglyc-eridaemia associated with these syndromes as well as alleviation of hyperglycaemia. This indicates that research for compounds displaying various degree of PPAR-8 activation should lead to the discovery of efficacious triglyceride and/or cholesterol and/or glucose lowering drugs that have great potential in the treatment of diseases such as type 2 diabetes, dyslipide- mia, syndrome X (including the metabolic syndrome, i.e., impaired glucose tolerance, insulin resistance, hypertrigyceridaemia and/or obesity), cardiovascular diseases (including atherosclerosis) and hypercholesteremia. SUMMARY OF THE INVENTION [0006] In an aspect, the present invention provides novel phenoxy-acetic acids or pharma- ceutically acceptable salts thereof that are useful as PPAR-8 activators. [0007] In another aspect, the present invention provides novel pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof. [0008] In another aspect, the present invention provides a novel method of treating type 2 diabetes comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof. [0009] In another aspect, the present invention provides a novel method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the disease is selected from dyslipidemia, syndrome X (including the metabolic syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity), cardiovascular diseases (e.g., atherosclerosis, coronary artery disease, and myocardial ischemia), hyperglycemia, hyperlipidemia, and hypercholesterolemia. [0010] In another aspect, the present invention provides a novel method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the disease is selcted from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes, decreasing apoptosis in mammalian cells (e.g., beta cells of Islets of Langer-hans), renal diseases (e.g., glomerulonephritis, glomerulosclerosis, nephrotic syndrome, and hypertensive nephrosclerosis), improving cognitive functions in dementia, treating diabetic complications, psoriasis, polycystic ovarian syndrome (PCOS), prevention and treatment of •orosis), and lowering the bio-markers of atherosclerosis (e.g., c-reactivei, and IL-6). pect, the present invention provides novel compounds for use in ther- pect, the present invention provides the use of novel compounds for the icament for the treatment of type 2 diabetes. her objects, which will become apparent during the following detailed i achieved by the inventors' discovery that compounds of formula I: R; R2 (Formula Removed) I itically acceptable salts thereof, are PPAR-8 activators. HE INVENTION odiment, the present invention provides a novel compound of formula I: (Formula Removed) [0016] or a pharmaceutically acceptable salt thereof, wherein: [0017] X is selected from O, S, OCH2, and SCH2; [0018] X'is O or S; [0019] R1 is selected from H, C1-8 alkyl, C2-8alkenyl, aryl, heteroaryl,C3-10 cycloalkyl, and a heterocyclyl, wherein each R1 group is substituted with 0-4 Rla; [0020] Rla, at each occurrence, is selected from S substituted with 0-1 Rlb, 0 substituted with 0-1 Rlb, halogen, NH2 substituted with 0-2 RIb, -CN, NO2, Ci.6 alkyl substituted with 0-3 Rlb, C2.6 alkenyl substituted with 0-2 Rlb, C2.6 alkynyl substituted with 0-2 Rlb, aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3.io cycloalkyl substituted with 0-2 Rlb, and heterocycle substituted with 0-2 Rlb; [0021] Rlb, at each occurrence, is selected from S substituted with 0-1 Rlc, O substituted with 0-1 Rlc, halogen, methanesulfonyl, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-6 alkyl substituted with 0-3 Rlc, C2.6 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3-1o cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc; [0022] Rlc, at each occurrence, is selected from S substituted with 0-1 Rld, O substituted with 0-1 Rld, halogen, NH2 substituted with 0-2 Rld, -CN, N02, d.6 alkyl substituted with 0-2 RId, C2.6 alkenyl substituted with 0-2 Rld, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3-10cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; [0023] Rld, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, Q. 6alkyl, C2-6 alkenyl, aryl, CF3, and OCF3; [0024] R2 is selected from -C=C-R2a, -CH=CH-R2a, aryl substituted with 0-3 R2a, and het-eroaryl substituted with 0-3 R2a; [0025] R2a, at each occurrence, is selected from S substituted with 0-1 R2b, O substituted with 0-1 R2b, halogen, NH2 substituted with 0-2 R2b, -CN, NO2, C1-6alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, heteroaryl substituted with 0-2 R2b, Cs-io cycloalkyl substituted with 0-2 R2b, and a heterocycle substituted with 0-2; [0026] R2b, at each occurrence, is selected from S substituted with 0-1 R20,0 substituted with 0-1 R20, halogen, methanesulfonyl, NH2 substituted with 0-2 R20, -CN, NO2, Ci.6alkyl substituted with 0-2 R20, C2.6 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R2c, heteroaryl substituted with 0-2 R20, C3-10 cycloalkyl substituted with 0-2 R20, and a heterocycle substituted with 0-2 R20; [0027] R20, at each occurrence, is selected from S substituted with 0-1 R2d, O substituted with 0-1 RM, halogen, NH2 substituted with 0-2 R2d, -CN, NO2, Chalky! substituted with 0-2 R24, C2-6 alkenyl substituted with 0-2 RM, aryl substituted with 0-2 R24, heteroaryl substituted with 0-2 R2d, Cs-io cycloalkyl substituted with 0-2 R2d, and a heterocycle substituted with 0-2 R2d [0028] R2d, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, Q. 6alkyl, C2.6 alkenyl, aryl, CF3, and OCF3; [0029] R3 is selected from halogen and Ci-6 alkyl substituted with 0-2 R3a; [0030] R3a, at each occurrence, is selected from OH, 0, S, halogen, C(O)NH2, C(O)NH-d.4 alkyl, and C(O)N(d.4 alkyl)2; [0031] alternatively, R3 and R5c combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; [0032] R4a, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R4d; [0033] R4d, at each occurrence, is selected from OH, 0, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 alkyl)2; [0034] R4b, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R4c; [0035] R4, at each occurrence, is selected from OH, O, halogen, NH2, NH-d-4 alkyl, and N(C,.4 alkyl)2; [0036] R4c, at each occurrence, is selected from H, halogen, and C\.6 alkyl substituted with 0-2 R4f; [0037] R4f, at each occurrence, is selected from OH, O, halogen, NH2, NH-Ci.4 alkyl, and N(C1-4alkyl)2; [0038] R5a, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; [0039] R5b, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; [0040] R5c, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; [0041] R5d, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; and, [0042] R5e, at each occurrence, is selected from H, halogen, CH3, and CH2CH3. [0043] In another embodiment, the present invention provides a novel compound of formula I or a pharmaceutically acceptable salt thereof, wherein: [0044] X is selected from O, S, OCH2, and SCH2; [0045] X'isOorS; [0046] R1 is selected from H, Q.g alkyl, C2.g alkenyl, aryl, 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CMO cycloaikyl, and a 3-8 membered heterocycle consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2, wherein each R1 group is substituted with 0-4 Rla; [0047] Rla, at each occurrence, is selected from OH substituted with 0-1 Rlb, SH substituted with 0-1 Rlb, S, O, halogen, NH2 substituted with 0-2 Rlb, -CN, NO2, d.6 alkyl substituted with 0-3 Rlb, C2.6 alkenyl substituted with 0-2 Rlb, C2.6 alkynyl substituted with 0-2 Rlb, aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CMO cycloaikyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 RIb and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2; [0048] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, S, O, halogen, methanesulfonyl, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-6 alkyl substituted with 0-3 Rlc, C2.6 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 Rlc, and a 3-8 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-z; [0049] Rlc, at each occurrence, is selected from OH substituted with 0-1 Rld, SH substituted with 0-1 Rld, S, 0, halogen, NH2 substituted with 0-2 Rld, -CN, N02, d.6 alkyl substituted with 0-2 Rld, C2.6 alkenyl substituted with 0-2 Rld, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from 0, N, and S(O)o-2, C3.10 cycloalkyl substituted with 0-2 Rld, and a 3-8 membered heterocycle substituted with 0-2 RId and consisting of carbon atoms and 1-3 heteroatoms selected from 0, N, and S(O)0.2; [0050] Rld, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, C,. 6 alkyl, C2.6 alkenyl, aryl, CF3, and OCF3; [0051] R2 is selected from -C=C-R2a, -CH=CH-R2a substituted with 0-2 R2a, aryl substituted with 0-3 R2", and 5-10 membered heteroaryl substituted with 0-3 R2a and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2; [0052] R2a, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, S, O, halogen, NH2 substituted with 0-2 R2b, -CN, NO2, Ci-6 alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3-10 cycloalkyl substituted with 0-2 R2b, and a 3-8 membered heterocycle substituted with 0-2 R2b and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2; [0053] R2b, at each occurrence, is selected from OH substituted with 0-1 R2c, SH substituted with 0-1 R20, S, O substituted with 0-1 R2c, halogen, methanesulfonyl, NH2 substituted with 0-2 R2, -CN, NO2, C1-6 alkyl substituted with 0-2 R20, C2.6 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R20,5-10 membered heteroaryl substituted with 0-2 R20 and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.10 cycloalkyl substituted with 0-2 R20, and a 3-8 membered heterocycle substituted with 0-2 R20 and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2; [0054] R2, at each occurrence, is selected from OH substituted with 0-1 R2d, SH substituted with 0-1 R2d, S, 0, halogen, NH2 substituted with 0-2 R2d, -CN, N02, C1.6alkyl substituted with 0-2 R2d, C2.6 alkenyl substituted with 0-2 R2d, aryl substituted with 0-2 R2d, 5-10 membered heteroaryl substituted with 0-2 R2d and consisting of carbon atoms and 1-4 heteroatoms selected from 0, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 R2d, and a 3-8 membered heterocycle substituted with 0-2 R2d and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2; [0055] Ru, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, C1_ 6alkyl, C2.6 alkenyl, aryl, CF3, and OCF3; [0056] R3 is selected from halogen and Ci-e alkyl substituted with 0-2 R3a; [0057] R3a, at each occurrence, is selected from OH, O, S, halogen, C(O)NH2> C(O)NH-Ci.4 alkyl, and C(O)N(C1-4 alkyl)2; [0058] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; [0059] R4a, at each occurrence, is selected from H, halogen, and C1-6alkyl substituted with 0-2 R4d; [0060] R4d, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-44 alkyl, and N(C1-4alkyl)2; [0061] R4b, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R46; [0062] R4, at each occurrence, is selected from OH, 0, halogen, NH2, NH-C1-4alkyl, and N(C1-4 alkyl)2; [0063] R4", at each occurrence, is selected from H, halogen, and Ci-e alkyl substituted with 0-2 R4f; [0064] R4f, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 alkyl)2; [0065] R5a, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; [0066] R5b, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; [0067] R5c, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; [0068] R5d, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; and, [0069] R5e, at each occurrence, is selected from H, halogen, CH3, and CH2CH3. [0070] In another embodiment, the present invention provides a novel compound of formula I or a pharmaceutically acceptable salt thereof, wherein: [0071] X is selected from O, S, OCH2, and SCH2; [0072] X'is O or S; [0073] R1 is selected from H, C1-8 alkyl, C2.8 alkenyl, aryl, 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o_2, C3-10 cycloalkyl, and a 3-8 membered heterocycle consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2, wherein each R1 group is substituted with 0-4 Rla; [0074] Rla, at each occurrence, is selected from OH substituted with 0-1 Rlb, SH substituted with 0-1 Rlb, S, O, halogen, NH2 substituted with 0-2 Rlb, -CN, NO2, Ci.6 alkyl substituted with 0-2 Rlb, C2-a alkenyl substituted with 0-2 Rlb, C2.6 alkynyl substituted with 0-2 Rlb, aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CMO cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2; [0075] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, S, O, halogen, NH2 substituted with 0-2 Rlc, -CN, NO2l,C1-4alkyl substituted with 0-2 Rlc, C2.6 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CMO cycloalkyl substituted with 0-2 Rlc, and a 3-8 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2; [0076] Rlc, at each occurrence, is selected from OH substituted with 0-1 Rld, SH substituted with 0-1 Rld, S, 0, halogen, NH2 substituted with 0-2 Rld, -CN, NO2, d.6 alkyl substituted with 0-2 Rld, C2-6 alkenyl substituted with 0-2 Rld, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CMO cycloalkyl substituted with 0-2 Rld, and a 3-8 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0-2; [0077] Rld, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, d. 6 alkyl, C2-6 alkenyl, aryl, CF3, and OCF3; [0078] R2 is selected from -C=C-R2a, -CH=CH-R2a substituted with 0-2 R2a, aryl substituted with 0-3 R2a, and 5-10 membered heteroaryl substituted with 0-3 R2a and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0.2; [0079] R2, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, S, O, halogen, NH2 substituted with 0-2 R2b, -CN, NO2, d.6 alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CMO cycloalkyl substituted with 0-2 R2b, and a 3-8 membered heterocycle substituted with 0-2 R2b and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2; [0080] R2b, at each occurrence, is selected from OH substituted with 0-1 R20, SH substituted with 0-1 R20, S, O, halogen, NH2 substituted with 0-2 R2, -CN, NO2> C1-6 alkyl substituted with 0-2 R20, C2-6 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R2c, 5-10 membered heteroaryl substituted with 0-2 R20 and consisting of carbon atoms and 1-4 heteroatoms selected from 0, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 R2c, and a 3-8 membered heterocycle substituted with 0-2 R20 and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2; [0081] R20, at each occurrence, is selected from OH substituted with 0-1 R2d, SH substituted with 0-1 R2d, S, O, halogen, NH2 substituted with 0-2 R2", -CN, NO2, C1-6alkyl substituted with 0-2 RM, C2-6 alkenyl substituted with 0-2 R2"1, aryl substituted with 0-2 R2, 5-10 membered heteroaryl substituted with 0-2 R2d and consisting of carbon atoms and 1-4 heteroatoms selected from 0, N, and S(O)o-2, C3.10 cycloalkyl substituted with 0-2 R2d, and a 3-8 mem- bered heterocycle substituted with 0-2 RM and consisting of carbon atoms and 1-3 heteroa-toms selected from O, N, and S(0)o-2; [0082] RM, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2> Q. 6alkyl, C2-6 alkenyl, aryl, CF3, and OCF3; [0083] R3 is selected from halogen and C1-6 alkyl substituted with 0-2 R3a; [0084] R3a, at each occurrence, is selected from OH, O, S, halogen, C(O)NH2, C(0)NH-Ci.4 alkyl, and C(O)N(C1-4 alkyl)2; [0085] alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5c; [0086] R4a, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R4d; [0087] R4d, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(C,.4alkyl)2; [0088] R4b, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R46; [0089] R46, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(C,.4alkyl)2; [0090] R40, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R4f; [0091] R4f, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 alkyl)2; [0092] R5a, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; [0093] R5b, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; [0094] R5c, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; [0095] R5d, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; and, [0096] R5e, at each occurrence, is selected from H, halogen, CH3, and CH2CH3. [0097] In a embodiment, the present invention provides a novel compound of formula la: (Formula Removed) [0098] or a pharmaceutically acceptable salt thereof. [0099] In another embodiment, the present invention provides a novel compound of formula II: (Formula Removed) [00100] or a pharmaceutically acceptable salt thereof, wherein: [00101] R1 is H, C1-8alkyl, heteroaryl, and C3-10 cycloalkyl, wherein each R1 group is substituted with 0-4 Rla; [00102] Rla, at each occurrence, is selected from Ci.6 alkyl substituted with 0-3 Rlb; C2.6 al-kynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3.io cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb; [00103] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, N02, methanesulfonyl, C1-4 alkyl substituted with 0-3 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3.6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc; [00104] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld and, C3.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; [00105] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2-4 alkenyl; [00106] R2a is selected from C1-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and heteroaryl substituted with 0-2 R2b; [00107] R2b, at each occurrence, is selected from OH substituted with 0-1 R2, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R20, -CN, NO2, methanesulfonyl, C1-4 alkyl substituted with 0-2 R20, C2.4 alkenyl substituted with 0-2 R2, aryl substituted with 0-2 R7c, heteroaryl substituted with 0-2 R20, C3.6 cycloalkyl substituted with 0-2 R20, and a heterocycle substituted with 0-2 R20; [00108] R26, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 alkenyl, aryl substituted with 0-2 RM, and heteroaryl substituted with 0-2 R2d; [00109] R24, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2-4 alkenyl; [00110] R3 is selected from Cl, F, CH3, and CH2CH3; [00111] alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5c; [00112] R4a, at each occurrence, is selected from H, Cl, F, and CH3; [00113] R4b, at each occurrence, is selected from H, Cl, F, and CH3; [00114] R4c, at each occurrence, is selected from H, Cl, F, and CH3; [00115] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00116] R5b, at each occurrence, is selected from H, Cl, F, and CH3; [00117] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00118] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00119] R5c, at each occurrence, is selected from H, Cl, F, and CH3. [00120] In another embodiment, the present invention provides a novel compound of formula II or a pharmaceutically acceptable salt thereof, wherein: [00121] R1 is H, C1-8 alkyl, 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, and C3-10cycloalkyl, wherein each R1 group is substituted with 0-4 Rla; [00122] Rla, at each occurrence, is selected from d.6 alkyl substituted with 0-3 Rlb; C2.6 al-kynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(0)o-2; [00123] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, methanesulfonyl, CM alkyl substituted with 0-3 Rlc, C2-4 alkenyl substituted with 0-2 Ru, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0.2, C3.6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00124] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, N02, CM alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0.2, C3.6 cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 R!d and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00125] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2> C,.4alkyl, and C2.4 alkenyl; [00126] R2a is selected from d.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2; [00127] R2b, at each occurrence, is selected from OH substituted with 0-1 R20, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R2, -CN, NO2, methanesulfonyl, C1-4 alkyl substituted with 0-2 R20, C2-4 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R20, 5-10 membered heteroaryl substituted with 0-2 R2c and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.6 cycloalkyl substituted with 0-2 R20, and a 3-6 membered heterocycle substituted with 0-2 R20 and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00128] R20, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2> C1-4 alkyl, C2.4 alkenyl, aryl substituted with 0-2 R2d, and 5-10 membered heteroaryl substituted with 0-2 RM and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2; [00129] R2d, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl; [00130] R3 is selected from Cl, F, CH3, and CH2CH3; [00131] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o_2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5c; [00132] R4a, at each occurrence, is selected from H, Cl, F, and CH3; [00133] R4b, at each occurrence, is selected from H, Cl, F, and CH3; [00134] R40, at each occurrence, is selected from H, Cl, F, and CH3; [00135] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00136] R5b, at each occurrence, is selected from H, Cl, F, and CH3; [00137] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00138] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00139] R5c, at each occurrence, is selected from H, Cl, F, and CH3. [00140] In another embodiment, the present invention provides a novel compound of formula Ilor a pharmaceutically acceptable salt thereof, wherein: [00141] R1 is H or C1-4 alkyl substituted with 1-4 Rla; [00142] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-10 mem-bered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 Rlb, and a 3-8 mem-bered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from 0, N, and S(O)o-2; [00143] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3.6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2; [00144] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2-4 alkenyl, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with G-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.6 cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00145] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and Ca-4 alkenyl; [00146] R21 is selected from C1-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2; [00147] R2b, at each occurrence, is selected from OH substituted with 0-1 R20, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R20, -CN, N02, C1-4 alkyl substituted with 0-2 R20, C2-4 alkenyl substituted with 0-2 R2c, aryl substituted with 0-2 R2c, 5-10 membered heteroaryl substituted with 0-2 R26 and consisting of carbon atoms and 1 -4 heteroatoms selected from O, N, and S(O)0.2, C3.6 cycloalkyl substituted with 0-2 R20, and a 3-6 membered hetero-cycle substituted with 0-2 R20 and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00148] R2", at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 alkenyl, aryl substituted with 0-2 R2d, and 5-10 membered heteroaryl substituted with 0-2 RM and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2; [00149] RM, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2-4 alkenyl; [00150] R3 is selected from Cl, F, CH3, and CH2CH3; [00151] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; [00152] R4a, at each occurrence, is selected from H, Cl, F, and CH3; [00153] R4b, at each occurrence, is selected from H, Cl, F, and CH3; [00154] R40, at each occurrence, is selected from H, Cl, F, and CH3; [00155] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00156] R5b, at each occurrence, is selected from H, Cl, F, and CH3; [00157] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00158] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00159] R5c, at each occurrence, is selected from H, Cl, F, and CH3. [00160] In another embodiment, the present invention provides a novel compound of formula Ha: (Formula Removed)Ha [00161] or a pharmaceutically acceptable salt thereof, wherein: [00162] R is H, C1-6 alkyl, aryl, heteroaryl, and C3-10 cycloalkyl, wherein each R group is substituted with 0-1 Rla; [00163] Ru, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 Rlb; C2-6 al-kynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb and, C5.6 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb and; [00164] Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, methanesul-fonyl, CM alkyl substituted with 0-3 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C5-6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc; [00165] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2-4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C5.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; [00166] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl; [00167] R2a is selected from d.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and heteroaryl substituted with 0-2 R2b; [00168] R2b, at each occurrence, is selected from OH substituted with 0-1 R20, SH, Cl, F, NH2, -CN, NO2, methanesulfonyl, C1-4 alkyl, C2.4 alkenyl, aryl, heteroaryl, C5.6 cycloalkyl, and a heterocycle; [00169] R20, at each occurrence, is CM alkyl; [00170] R3 is selected from Cl, F, CH3, and CH2CH3; and, [00171] alternatively, R3 and R5c combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e. [00172] In another embodiment, the present invention provides a novel compound of formula IIa or a pharmaceutically acceptable salt thereof, wherein: [00173] R1 is H, Ci-6 alkyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, and C3-10 cycloalkyl, wherein each R1 group is substituted with 0-1 Rla; [00174] Rla, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 RIb; C2-6 al-kynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, 5-6 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(0)o-2, C$-6 cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00175] Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, methanesul-fonyl, CM alkyl substituted with 0-3 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, Cs-6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2', [00176] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2-4 alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 Rld, and a 5-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(0)o-2; [00177] RId, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2-4 alkenyl; [00178] R2a is selected from C1-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00179] R2b, at each occurrence, is selected from OH substituted with 0-1 R20, SH, Cl, F, NH2, -CN, N02, methanesulfonyl, d1-4 alkyl, C2-4 alkenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2,, C5.6 cycloalkyl, and a 5-6 membered heterocycle and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; [00180] R20, at each occurrence, is CM alkyl; [00181] R3 is selected from Cl, F, CH3, and CH2CH3; and, [00182] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)0-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e. [00183] In another embodiment, the present invention provides a novel compound of formula Ha or a pharmaceutically acceptable salt thereof, wherein: [00184] R1 is H or C1-4 alkyl substituted with 1 Ru; [00185] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-6 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00186] Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5.6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00187] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 Rld, and a 5-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00188] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2> CM alkyl, and C2-4 alkenyl; [00189] R2a is selected from C,.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1 -2 heteroatoms selected from O, N, and S(O)o-2; [00190] R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, N02, CM alkyl, C2-4 alkenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2,, Cs-e cycloalkyl, and a 5-6 membered heterocycle and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(0)o-2; [00191] R3 is selected from Cl, F, CH3, and CH2CH3; and, [00192] alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e. [00193] In another embodiment, the present invention provides a novel compound of formula IIa or a pharmaceutically acceptable salt thereof, wherein: [00194] R1 is H, C1-6 alkyl, aryl, heteroaryl, C3-10 cycloalkyl, wherein each R1 group is substituted with 0-1 Rla; [00195] Rla, at each occurrence, is selected from CM alkyl substituted with 0-3 Rlb; C2.6 al-kynyl substituted with 0-1 Rlb, aryl substituted with 0-1 Rlb, heteroaryl substituted with 0-1 Rlb, C5.6 cycloalkyl substituted with 0-1 Rlb, and a heterocycle substituted with 0-1 Rlb; [00196] Rlb, at each occurrence, is selected from Cl, F, methanesulfonyl, and CM alkyl substituted with 0-3 Rlc, and; [00197] Rlc, at each occurrence, is selected from Cl, F and a heterocycle ; [00198] R2a is selected from d.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and heteroaryl substituted with 0-2 R2b; [00199] R2b, at each occurrence, is selected from OH optionally substituted with CM alkyl, Cl, F, methanesulfonyl, aryl, heteroaryl, C5-6cycloalkyl, and a heterocycle ; [00200] R3 is selected from Cl, F, CH3, and CH2CH3.. [00201] In another embodiment, the present invention provides a novel compound of formula Ila or a pharmaceutically acceptable salt thereof, wherein: [00202] R1 is H, C1-6 alkyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from O and N; C3-10 cycloalkyl, wherein each R1 group is substituted with O-lRla; [00203] Rla, at each occurrence, is selected from CM alkyl substituted with 0-3 Rlb; C2-6 al-kynyl substituted with 0-1 Rlb aryl substituted with 0-1 Rlb, 5-6 membered heteroaryl substituted with 0-1 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O and N, C5.6 cycloalkyl substituted with 0-1 Rlb, and a 5-6 membered heterocycle substituted with 0-1 Rlb; [00204] Rlb, at each occurrence, is selected from Cl, F, methanesulfonyl, and CM alkyl substituted with 0-3 Rlc, and; [00205] Rlc, at each occurrence, is selected from Cl, F and a 5-6 membered heterocycle consisting of carbon atoms and 1-2 heteroatoms selected from 0 and N; [00206] R2a is selected from d.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from 0 and N; [00207] R2b, at each occurrence, is selected from OH optionally substituted with CM aiky), Cl, F, methanesulfonyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from 0 and N, C5_6 cycloalkyl, and a 5-6 membered heterocycle consisting of carbon atoms and 1-2 heteroatoms selected from O and N; [00208] R3 is selected from Cl, F, CH3, and CH2CH3. [00209] In another embodiment, the present invention provides a novel compound of formula IIb (Formula Removed)libor a pharmaceutically acceptable salt thereof. [00210] In another embodiment, the present invention provides a novel compound of formula lib, wherein R1 is Ci.g alkyl. [00211] In another embodiment, the present invention provides a novel compound of formula IIb, wherein R2a is CM alkyl substituted with a heterocycle. [00212] In another embodiment, the present invention provides a novel compound of formula IIb, wherein R2a is CM alkyl substituted with morpholinyl. [00213] In another embodiment, the present invention provides a novel compound of formula IIb, wherein R3 is selected from Cl and CH3. [00214] In another embodiment, the present invention provides a novel compound of formula IIb, wherein X is selected from S and SCH2 [00215] In another embodiment, the present invention provides a novel compound of formula IIb, wherein X is S. [00216] In another embodiment, the present invention provides a novel compound of formula IIb, wherein X is SCH2. [00217] In another embodiment, the present invention provides a novel compound of formula IIb, wherein X1 is O. [00218] In another embodiment, the present invention provides a novel compound of formula IIb, wherein X1 is S. [00219] In another embodiment, the present invention provides a novel compound of formula IIb, wherein: R1 is aryl substituted with 0-1 Rla; wherein Rla, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-64 alkyl. [00220] In another embodiment, the present invention provides a novel compound of formula IIb, wherein R1 is C1-6 alkyl substituted with Rla; and wherein Rla is aryl substituted with 0-1 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-64 alkyl. [00221] In another embodiment, the present invention provides a novel compound of formula IIb, wherein: R1 is C1-6 alkyl substituted with Rla, wherein Rla is heteroaryl substituted with 0- 1 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4alkyl. [00222] in another embodiment, the present invention provides a novel compound of formula IIb, wherein: R1 is C1-6 alkyl substituted with Rla, wherein Rla is heterocyclyl substituted with 0-1 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl. [00223] In another embodiment, the present invention provides a novel compound of formula lib, wherein: R1 is C1-6 alkyl substituted with Rla, wherein Rla is C5.6 cycloalkyl substituted with 0-2 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2, -CN, NO2> CM alkyl. [00224] In another embodiment, the present invention provides a novel compound of formula lib, wherein: R2ais aryl substituted with R2b; wherein R2b is selected from OH, SH, Cl, F, NH2,-CN,NO2, CM alkyl. [00225] In another embodiment, the present invention provides a novel compound of formula lib, wherein: R2ais C1-6 alkyl substituted with R2b; wherein R2b is selected from aryl substituted with R20; and wherein R20 is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alky!. [00226] In another embodiment, the present invention provides a novel compound of formula lib, wherein: R2a is C1-6 alkyl substituted with R2b; wherein R2b is selected from heteroaryl substituted with R2c; and wherein R is selected from OH, SH, Cl, F, NH2, -CN, N02, CM alkyl. [00227] In another embodiment, the present invention provides a novel compound selected from: [00228] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-l-yl-propoxy)-phenyl- sulfanyl]-phenoxy} -acetic acid; [00229] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]- phenoxy}-acetic acid; [00230] {2-Chloro-4- [3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl- sulfanyl]-phenoxy}-acetic acid; [00231] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)- phenylsulfanyl]-phenoxy}-aceticacid; [00232] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(l-methyl-piperidin-4-ylmethoxy)- phenylsulfanyl]-phenoxy }-acetic acid; [00233] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1 -ynyl)-phenyl- sulfanyl]-phenoxy}-acetic acid; [00234] {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2- methyl-phenoxy)-acetic acid; [00235] {4-[3-Cyclohexylmemoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2- methyl-phenoxy}-acetic acid; [00236] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid; [00237] {4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2- methyl-phenoxy} -acetic acid; [00238] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}- acetic acid; [00239] {4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid; [00240] {2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]- phenoxy}-acetic acid; [00241] {2-Chloro-4-[3-(3-methoxy-prop-l-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl- sulfanyl]-phenoxy}-acetic acid; [00242] {2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-l-ynyl-phenylsulfanyl]- phenoxy)-acetic acid; [00243] {2-Methyl-4-[3-(3-moipholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-benzyl- sulfanyl]-phenoxy}-acetic acid; [00244] {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-lynyl)-benzylsulfanyl]-2- methyl-phenoxy)-acetic acid; and, [00245] {2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-l-ynyl)-benzyl- sulfanyl]-phenoxy}-acetic acid; [00246] or a pharmaceutically acceptable salt thereof. [00247] In another embodiment, the present invention provides a novel compound selected from: [00248] {4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2- methyl-phenoxy}-acetic acid; [00249] [4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2- methyl-phenoxy} -acetic acid; [00250] {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid; [00251] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenyl- salfanyl]-2-methyl-phenoxy}-aceticacid; [00252] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl- sulfanyl]-2-methyl-phenoxy}-acetic acid; [00253] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenyl- sulfanyl]-2-methyl-phenoxy}-acetic acid; [00254] {4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid; [00255] [4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid; [00256] {4-[3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]- 2-methyl-phenoxy}-acetic acid; [00257] [4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]- acetic acid; [00258] {4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}- acetic acid; [00259] {4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyi- phenoxy)-acetic acid; [00260] {4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid; [00261] {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2- methyl-phenoxy} -acetic acid; [00262] {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2- methyl-phenoxyj-acetic acid; [00263] {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsuifanyl]-2- methyl-phenoxy }-acetic; [00264] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl- phenoxy}-acetic acid; [00265] [4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid; [00266] {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl- phenoxy}-acetic acid; [00267] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)- phenylsulfanyl]-2-methyl-phenoxy }-acetic acid; [00268] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)- phenylsulfanyl]-2-methyl-phenoxy}-aceticacid; [00269] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-pyridin 2 yloxy)-phenylsulfanyl]-phenoxy}-aceticacid; [00270] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(5-trifluoromethyl-pyridin-2- yloxy)-phenylsulfanyl]-phenoxy}-aceticacid; [00271] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-phenoxy)- phenylsulfanyl]-phenoxy}-aceticacid; [00272] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenyl- sulfanyl]-2-methyl-phenoxy}-acetic acid; and [00273] {2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl- sulfanyl]-phenoxy}-acetic acid, [00274] or a pharmaceutically acceptable salt thereof. [00275] In another embodiment, the present invention provides a novel compound of formula III: [00276] or a pharmaceutically acceptable salt thereof, wherein: [00277] R1 is CM alkyl substituted with 1-2 Rla; [00278] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3-10 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb; [00279] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3.6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 R1'; [00280] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; [00281] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, N02, CM alkyl, and C2.4 alkenyl; [00282] R23 is selected from aryl substituted with 0-2 R2b and heteroaryl substituted with 0-2 R2b; [00283] R2b, at each occurrence, is selected from OH substituted with 0-1 R20, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R2", -CN, NO2, C,.4 alkyl substituted with 0-2 R20, C2.4 alkenyl substituted with 0-2 R2c, aryl substituted with 0-2 R2c, heteroaryl substituted with 0-2 R2c, C3.6 cycloalkyl substituted with 0-2 R2c, and a heterocycle substituted with 0-2 R; [00284] R20, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 alkenyl, aryl substituted with 0-2 R2d, and heteroaryl substituted with 0-2 R2d; [00285] R2d, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl; [00286] R3 is selected from Cl, F, CH3, and CH2CH3; [00287] alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; [00288] R4a, at each occurrence, is selected from H, Cl, F, and CH3; [00289] R4b, at each occurrence, is selected from H, Cl, F, and CH3; [00290] R40, at each occurrence, is selected from H, Cl, F, and CH3; [00291] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00292] R5b, at each occurrence, is selected from H, Cl, F, and CH3; [00293] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00294] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00295] R5e, at each occurrence, is selected from H, Cl, F, and CH3. [00296] In another embodiment, the present invention provides a novel compound of formula HI or a pharmaceutically acceptable salt thereof, wherein: [00297] R1 is CM alkyl substituted with 1-2 Rla; [00298] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00299] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2l CM alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered hev-eroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3-6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered hetero-cycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2; [00300] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, €3-6 cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 RId and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2; [00301] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2> CM alkyl, and C2-4 alkenyl; [00302] R2a is selected from aryl substituted with 0-2 R2b and 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and 8(0)0.2; [00303] R2b, at each occurrence, is selected from OH substituted with 0-1 R2c, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R2, -CN, NO2, C1-4alkyl substituted with 0-2 R20, C2.4 alkenyl substituted with 0-2 R2c, aryl substituted with 0-2 R2c, 5-10 membered heteroaryl substituted with 0-2 R26 and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, Cs-6 cycloalkyl substituted with 0-2 R20, and a 3-6 membered heterocycle substituted with 0-2 R20 and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2; [00304] R20, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, CM alkenyl, aryl substituted with 0-2 R2d, and 5-10 membered heteroaryl substituted with 0-2 R24 and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0.2; [00305] RM, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and £2^ alkenyl; [00306] R3 is selected from Cl, F, CH3, and CH2CH3; [00307] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)0-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; [00308] R4a, at each occurrence, is selected from H, Cl, F, and CH3; [00309] R4b, at each occurrence, is selected from H, Cl, F, and CH3; [00310] R40, at each occurrence, is selected from H, Cl, F, and CH3; [00311] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00312] R5b, at each occurrence, is selected from H, Cl, F, arid CH3; [00313] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00314] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00315] R5e, at each occurrence, is selected from H, Cl, F, and CH3. [00316] In another embodiment, the present invention provides a novel compound of formula Ilia (Formula Removed) [00317] or a pharmaceutically acceptable salt thereof, wherein: [00318] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C5_6 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb; [00319] Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4alkyl substituted with 0-2 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C5-6cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc; [00320] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; [00321] R2a is selected from aryl substituted with 0-2 R2b and heteroaryl substituted with 0-2 R2b and; and, [00322] R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4alkyl, C2-4 alkenyl, aryl, heteroaryl, C5-6 cycloalkyl, and a heterocycle. [00323] In another embodiment, the present invention provides a novel compound of formula Ilia or a pharmaceutically acceptable salt thereof, wherein: [00324] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-6 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00325] Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alky! substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, Cs-6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00326] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2_4 alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2, C$.6 cycloalkyl substituted with 0-2 Rrd, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00327] R2a is selected from aryl substituted with 0-2 R2b and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2l and, [00328] R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2_4 alkenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from 0, N, and S(O)o-2, C5.6 cycloalkyl, and a 5-6 membered heterocycle and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2. [00329] In another embodiment, the present invention provides a novel compound of formula la, wherein: [00330] R1 is CM alkyl substituted with 1-2 Rla; [00331] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3-10cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb; [00332] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, N02, C1-4 alkyl substituted with 0-2 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3.6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc; [00333] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; [00334] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and €2-4 alkenyl; [00335] R2 is aryl substituted with 0-3 R2a or heteroaryl substituted with 0-2 R2a; [00336] R2a, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, Cl, F, NH2 substituted with 0-2 R2b, -CN, NO2, CM alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, heteroaryl substituted with 0-2 R2b, C3.6 cycloalkyl substituted with 0-2 R2b, and a heterocycle substituted with 0-2 R2b; [00337] R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and, C2_4 alkenyl; [00338] R3 is selected from Cl, F, CH3, and CH2CH3; [00339] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; [00340] R4a, at each occurrence, is selected from H, Cl, F, and CH3; [00341] R4b, at each occurrence, is selected from H, Cl, F, and CH3; [00342] R4, at each occurrence, is selected from H, Cl, F, and CH3; [00343] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00344] R5b, at each occurrence, is selected from H, Cl, F, and CH3; [00345] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00346] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00347] R5c, at each occurrence, is selected from H, Cl, F, and CH3. [00348] In another embodiment, the present invention provides a novel compound of formula la, wherein: [00349] R1 is CM alkyl substituted with 1-2 Rla; [00350] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-10 mem-bered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3-10cycloalkyl substituted with 0-2 Rlb, and a 3-8 mem-bered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00351] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, CM alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3.6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; [00352] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2-4 alkenyl, aryl substituted with 0-2 RId, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from 0, N, and S(O)o-2, C3.6 cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00353] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, N02, CM alkyl, and C2-4 alkenyl; [00354] R2 is aryl substituted with 0-3 R2a or 5-10 membered heteroaryl substituted with 0-2 R2a and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(0)o-2; [00355] R23, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, Cl, F, NH2 substituted with 0-2 R2b, -CN, NO2, C1-4alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1 -4 heteroatoms selected from O, N, and S(O)0-2, C3.6 cycloalkyl substituted with 0-2 R2b, and a 3-6 membered hctero-cycle substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; [00356] R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4alkyl, and, C2-4 alkenyl; [00357] R3 is selected from Cl, F, CH3, and CH2CH3; [00358] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; [00359] R4a, at each occurrence, is selected from H, Cl, F, and CH3; [00360] R4b, at each occurrence, is selected from H, Cl, F, and CH3; [00361] R4', at each occurrence, is selected from H, Cl, F, and CH3; [00362] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00363] R5b, at each occurrence, is selected from H, Cl, F, and CH3; [00364] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00365] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00366] R5c, at each occurrence, is selected from H, Cl, F, and CH3. [00367] In another embodiment, the present invention provides a novel compound of formula Ib: j I\. (Formula Removed) [00368] or a pharmaceutically acceptable salt thereof, wherein: [00369] R1 is C1-4 alkyl substituted with 1 Rla; [00370] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-6 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2, C5.6 cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00371] Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o_2, C$-6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00372] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and €2^ alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, Cj.e cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from 0, N, and S(O)0.2; [00373] R2 is aryl substituted with 0-2 R2a or 5-6 membered heteroaryl substituted with 0-2 R2a and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2; and, [00374] R2a, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, Cl, F, NH2 substituted with 0-2 R2b, -CN, NO2, C1-4 alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-6 membered het- eroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, Cs-6 cycloalkyl substituted with 0-2 R2b, and a 5-6 membered hetero-cycle substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2. [00375] In another embodiment, the present invention provides a novel compound pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of the present invention or a pharmaceutically acceptable salt thereof. [00376] In another embodiment, the present invention provides a novel method of treating type 2 diabetes, comprising: administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. [00377] In another embodiment, the present invention provides a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the disease is selected from dyslipidemia, syndrome X (including the metabolic syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity), cardiovascular diseases (e.g., atherosclerosis and related diseases, including mortality reduction, coronary artery diseases, coronary heart diseases, heart attack, myocarc'ial ischemia, myocardial infarct, coronary infarct, transient ischemic attack (TIA), and stroke), hyperglycemia, hyperlipidemia, hypercholesterolemia, and hyperinsulinemia. [00378] In another embodiment, the present invention provides a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the disease is selcted from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes, decreasing apoptosis in mammalian cells (e.g., beta cells of Islets of Langerhans), renal diseases (e.g., glomerulonephritis, glomerulosclerosis, nephrotic syndrome, and hypertensive nephrosclerosis), improving cognitive functions in dementia, treating diabetic complications, psoriasis, polycystic ovarian syndrome (PCOS), prevention and treatment of bone loss (e.g. osteoporosis), and lowering the bio-markers of atherosclerosis (e.g., c-reactive protein (CRP), TNF-ct, and IL-6). [00379] In another embodiment, the present invention provides a novel process for the preparation of the compounds of the present invention or stereoisomers or pharmaceutically acceptable salts thereof. [00380] In another embodiment, the present compounds are administered in combination with one or more further pharmacologically active substances selected from antiobesity agents, appetite regulating agents, antidiabetics, antihypertensive agents, agents for the treatment of complications resulting from or associated with diabetes, and agents for the treatment of complications and disorders resulting from or associated with obesity. [00381] Suitable additional substances may be selected from CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, uro-cortin agonists, P3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR (retinoid X receptor) modulators or TR P agonists. [00382] Suitable antiobesity agents include leptin, dexamphetamine, amphetamine, fenflura-mine, dexfenfluramine, sibutramine, orlistat, mazindol, and phentermine. [00383] Suitable antidiabetics include insulin, orally active hypoglycaemic agents, and GLP-1 (glucagon like peptide-1) derivatives (see WO 98/08871). [00384] Orally active hypoglycaemic agents preferably include sulphonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists (see WO99/01423), GLP-1 agonists, potassium channel openers (see WO 97/26265 and WO 99/03861), DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeo-genesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism (e.g., antihyperlipidemic agents and antilipidemic agents), compounds lowering food intake, RXR agonists, agents acting on the ATP-dependent potassium channel of the P-cells, and thiazolidinediones (e.g., troglitazone, ciglitazone, pioglitazone and rosiglitazone). [00385] Agents to be administered in combination with compounds of the present invention also include sulphonylureas (e.g., tolbutamide, glibenclamide, glipizide, and glicazide), biguanides (e.g., metformin), meglitinides (e.g., repaglinide and senaglinide), a-glucosidase inhibitors (e.g., miglitol and acarbose), an agent acting on the ATP-dependent potassium channel of the p-cells (e.g., the above sulphonylureas and repaglinide), and nateglinide. [00386] Antihyperlipidemic or antilipidemic agents include apolipoprotein A-I Milano, cho-lestyramine, colestipol, clofibrate, gemfibrozil, fenoflbrate, bezafibrate, tesaglitazar, muragli-tazar, EML-4156, LY-518674, LY-519818, MK-767, torcetrapib, atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, cerivastin, rosuvastatin, pitavastatin, acipimox, ezetimibe, probucol, dextrothyroxine and nicotinic acid. [00387] In another embodiment the present compounds are administered in combination with more than one of the above-mentioned compounds (e.g, in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, or insulin and lovastatin). [00388] Examples of ntihypertensive agents include p-blockers (e.g, alprenolol, atenolol, ti-molol, pindolol, propranolol, and metoprolol), ACE (angiotensin converting enzyme) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril), calcium channel blockers (e.g., nifedipine, felodipine, nicardipine, isradipine, nimodipine, dilti-azem and verapamil), and a-blockers (e.g., doxazosin, urapidil, prazosin and terazosln). [00389] It should be understood that any suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and optionally one or more further pharmacologically active substances are considered to be within the scope of the present invention. [00390] It is preferred that the compounds of the present invention have a solubility in water of at least 0.1 mg/L as determined at 25°C and pH 7.0. More preferably the solubility is at least 0.5 mg/L. Even more preferably the solubility is at least 1 mg/L. Still more preferably, the solubility is at least 2 mg/L. Further preferably the solubility is at least 10 mg/L. Even further preferably the solubility is at least 50 mg/L. Still further preferably the solubility is at least 200 mg/L. [00391] It is preferred that compounds of the present invention have an ICso value of less than 5 Jim as determined by the PPAR transient transactivation assay. More preferably the ICso value is less than 1 /im. Even more preferably the ICso value is less than 500 nM. Still more preferably the ICso value is less than 100 nM. Further preferably the ICso value is less than 50 nM. Even further preferably the ICso value is less than 25 nM. Still further preferably the IC50 value is less than 10 nM. Even still further preferably the IC5o value is less than 5 nM. [00392] It is preferred that the compounds of the present invention have a molecular weight of less than 10CO g/mol. More preferably the molecular weight is less than 750 g/mol. Even more preferably the molecular weight is less than 600 g/mol. Still more preferably, the molecular weight is less than 550 g/mol. Further preferably the molecular weight is less than 500 g/mol. Even further preferably the molecular weight is less than 400 g/mol. [00393] It is preferred that compounds of the present invention are ionized at pH 7.4. [00394] It is preferred that the compounds of the present invention have only one ionized carboxylic acid group at a pH of from 5.5-9. More preferably the compounds have only one ionized carboxylic acid group at a pH of from 6-8. Even more preferably the compounds have only one ionized carboxylic acid group at a pH of from 6.5-7.5. Still more preferably, the compounds have only one ionized carboxylic acid group at pH 7.4. [00395] It is preferred that the compounds of the present invention are zwitter-ionic with one ionized amine group and one ionized carboxylic acid group at a pH of from 5.5-9. More preferably the compounds are zwitter-ionic with one ionized amine group and one ionized carboxylic acid group at a pH of from 6-8. Even more preferably the compounds are zwitter-ionic with one ionized amine group and one ionized carboxylic acid group at a pH of from 6.5-7.5. Still more preferably, the compounds are zwitter-ionic with one ionized amine group and one ionized carboxylic acid group at pH 7.4. PHARMACEUTICAL COMPOSITIONS [00396] The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions of the present invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The compositions may appear in conventional forms, which include capsules, tablets, aerosols, solutions, suspensions, andtopical applications. [00397] Typical compositions include a compound of the present invention a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient, which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier, which can be in the form of a capsule, sachet, paper, or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, ac?.cia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. [00398] The pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds. [00399] The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, trans-dermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred. [00400] If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution. [00401] For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes. [00402] For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxyiated castor oil. [00403] Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed. [00404] If desired, the pharmaceutical composition of the invention may comprise a compound of the present invention in combination with further pharmacologically active substances such as those described in the foregoing. [00405] The compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of diseases related to the regulation of blood sugar. Mammals also include animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife. [00406] The compounds of the present invention are expected to be effective over a wide dosage range. A typical oral dosage is hi the range of from about 0.001 to about 100 ifig/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art. [00407] The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg. DEFINITIONS [00408] All references described herein are incorporated in there entirety by reference. [00409] "Substituted" signifies that one or more hydrogen atoms are replaced by the designated substituent. Only pharmaceutically stable compounds are intended to be covered. [00410] When examples of definitions are provided, the definition is not meant to be limited to the specific examples. [00411] The present invention includes all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14. [00412] When O or S is listed as a substituent, oxo and sulfo, respectively, it is intended that a carbon atom be replaced by either the O or S. For example if alkyl were substituted by O, then an ether would be formed. Preferably heteroatom-heteroatom bonds such as O-O, O-S, O-N, S-S, and S-N are not formed. [00413] "Alkyl" includes both straight chain and branched alkyl groups having the designated number of carbon atoms (e.g., 1, 2, 3,4,5, 6, 7, or 8). Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, 2-methyl-butyl, and 2-ethyl-butyl. [00414] "Alkenyl" includes both straight chain and branched alkenyll groups having the designated number of carbon atoms (e.g., 2, 3,4,5, 6,7, or 8). Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 2-methyl-butenyl. [00415] "Alkynyl" includes both straight chain and branched alkynyl groups having the designated number of carbon atoms (e.g., 2, 3,4,5, 6, 7, or 8). Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 2-methyl-butynyl. [00416] "Aryl" includes phenyl, naphthyl, fluorene, anthracene, phenanthrenyl, azulenyl, and a partially saturated bicyclic carbocyclic ring. The partially saturated bicyclic carbocyclic ring consists of 8,9,10,11, or 12 carbon atoms, preferably 8,9, or 10 carbon atoms. Examples of partially saturated bicyclic carbocyclic rings include 1,2,3,4-tetrahydronaphthyl, in-danyl, indenyl, l,2,4a,5,8,8ot-hexahydronaphtyl, and l,3a-dihydropentalene. A preferred aryl group is phenyl. [00417] "Cycloalkyl" means a ring having the number of designated carbon atoms and having only single bonds between the carbon atoms. Examples of cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Preferred cycloalkyl groups are cyclopentyl and cyclohexyl. [00418] "Heteroaryl" signifies a mono-, bi-, or tricyclic ring consisting of carbon atoms and from one heteroatom to 5, wherein the heteroatom is selected from oxygen, nitrogen, and sulphur. If sulphur is present, then it can be mono- or di-oxidized. If a nitrogen is present, then it can be N, NH, or substituted N. The heterocycle can be attached via a carbon or nitrogen atom, unless linking the nitrogen atom would lead to a quaternary nitrogen. If the heteroaryl is bicyclic, then one or both of the rings may have a heteroatom(s) present. If the heteroaryl is tricyclic, then one, two, or all three of the rings may have a heteroatom(s) present. If the net-erocycle is monocyclic, then this ring is aromatic (e.g., fully unsaturated). If the heteroaryl is bicyclic or tricyclic, then at least one ring is aromatic. [00419] Examples of "heteroaryl" are pyrrolyl (e.g. pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl), fu-ranyl (e.g. furan-2-yl, furan-3-yl), thienyl (e.g. thien-2-yl, thien-3-yl), oxazolyl (e.g. oxazol-2-yl, oxazol-4-yl, oxazol-5-yl), thiazolyl (e.g. thiazol-2-yl, thiazol-4-yl, thiazol-5-yl), imidazolyl (e.g. imidazol-2-yl, imidazol-4-yl, imidazol-5-yl), pyrazolyl (e.g. pyrazol-1-yl, pyrazol-3-yl, pyrazol-5-yl), isoxazolyl (e.g. isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl), isothiazolyl (e.g. isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl), 1,2,3-triazolyl (e.g. 1,2,3-triazol-l-yl, 1,2,3-triazol-4-yl, l,2,3-triazol-5-yl), 1,2,4-triazolyl (e.g. 1,2,4-triazol-l-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl), 1,2,3-oxadiazolyl (e.g. 1,2,3-oxadiazol-4-yl, l,2,3-oxadiazol-5-yl), 1,2,4-oxa-diazolyl (e.g. l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl), 1,2,5-oxadiazolyl (e.g. 1,2,5-oxa-diazol-3-yl, l,2,5-oxadiazol-4-yl), 1,3,4-oxadiazolyl (e.g. l,3,4-oxadiazol-2-yl, 1,3,4-oxadia-zol-5-yl), l,2,3-thiadiazolyl(e.g. l,2,3-thiadiazol-4-yl, l,2,3-thiadiazol-5-yl), 1,2,4-thiadia-zolyl(e.g. l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl), 1,2,5-thiadiazolyl (e.g. 1,2,5-thiadia-zol-3-yl, l,2,5-thiadiazol-4-yl), 1,3,4-thiadiazolyl (e.g. l,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl), tetrazolyl (e.g. tetrazol-1-yl, tetrazol-5-yl), pyranyl (e.g. pyran-2-yl), pyridinyl (e.g. pyridine-2-yl, pyridine-3-yl, pyridine-4-yl), pyridazinyl (e.g. pyridazin-2-yl, pyridazin-3-yl), pyrimidinyl (e.g. pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl), pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, thiadiazinyl, azepinyl, azecinyl, indolyl (e.g. indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), isoindolyl, benzofuranyl (e.g. benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo[b]furan-5-yl, benzo[c]furan-2-yl, benzo[c]furan-3-yl, benzo[c]furan-5-yl), benzo-thienyl (e.g. benzotb]thien-2-yl, benzo[b]thien-3-yl, benzo[b]thien-5-yl, benzo[c]thien-2-yl, benzo[c]thien-3-yl, benzo[c]thien-5-yl), indazolyl (e.g. indazol-1-yl, indazol-3-yl, indazol-5-yl), indolizinyl (e.g. indolizin-1-yl, indolizin-3-yl), benzopyranyl (e.g. benzo[b]pyran-3-yl, benzo[b]pyran-6-yl, benzo[c]pyran-l-yl, benzo[c]pyran-7-yl), benzimidazolyl (e.g. benzimi-dazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzothiazolyl (e.g. benzothiazol-?-yl, benzothiazol-5-yl), benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotria- zolyl, naphthyridinyl (e.g. l,8-naphthyridin-2-yl, 1,7-naphthyridin-2-yl, 1,6-naphthyridin-2-yl), phthalazinyl (e.g. phthalazin-1-yl, phthalazin-5-yl), pteridinyl, purinyl (e.g. purin-2-yl, purin-6-yl, purin-7-yl, purin-8-yl, purin-9-yl), quinazolinyl (e.g. quinazolin-2-yl, quinazolin-4-yl, quinazolin-6-yl), cinnolinyl, quinoliny (e.g. quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl), isoquinolinyl (e.g. isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl), qui-noxalinyl (e.g. quinoxalin-2-yl, quinoxalin-5-yl), pyrrolopyridinyl (e.g. pyrrolo[2,3-b]pyridi-nyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl), furopyridinyl (e.g. furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-c]pyridinyl), thienopyridinyl (e.g. thieno[2,3-b]pyridinyl, thi-eno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl), imidazopyridinyl (e.g. imidazot4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, imidazo[l,5-a]pyridinyl, imidazo[l,2-a]pyridinyl), imidazopyrimidi-nyl (e.g. imidazo[l,2-a]pyrimidinyl, imidazo[3,4-a]pyrimidinyl), pyrazolopyridinyl (e.g. pyra-zolot3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[l,5-a]pyridinyl), pyrazolopyrimidi-nyl (e.g. pyrazolo[l,5-a]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl), thiazolopyridinyl (e.g. thi-azolo[3,2-d]pyridinyl), thiazolopyrimidinyl (e.g. thiazolo[5,4-d]pyrimidinyl), imdazojhiazoly) (e.g. imidazo[2,l-b]thiazolyl), triazolopyridinyl (e.g. triazolo[4,5-b]pyridinyl), triazolopyrimi-dinyl (e.g. 8-azapurinyl), carbazolyl (e.g. carbazol-2-yl, carbazol-3-yl, carbazol-9-yl), phen-oxazinyl (e.g. phenoxazin-10-yl), phenazinyl (e.g. phenazin-5-yl), acridinyl (e.g. acridin-9-y1, acridin-10-yl), phenothiazinyl (e.g. phenothiazin-10-yl), carbolinyl (e.g. pyrido[3,4-b]indol-l-yl, pyrido[3,4-b]indol-3-yl), phenanthrolinyl (e.g. phenanthrolin-5-yl), pyrrolinyl, pyrazolinyl, imidazolinyl (e.g. 4,5-dihydroimidazol-2-yl, 4,5-dihydroimidazol-l-yl), indolinyl (e.g. 2,3-dihydroindol-1-yl, 2,3-dihydroindol-5-yl), dihydrobenzofuranyl (e.g. 2,3-dihydrobenzo-[b]furan-2-yl, 2,3-dihydrobenzo[b]furan-4-yl), dihydrobenzothienyl (e.g. 2,3-dihydrobenzo-[b]thien-2-yl, 2,3-dihydrobenzo[b]thien-5-yl), 4,5,6,7-tetrahydrobenzo[b]furan-5-yl), dihy-drobenzopyranyl (e.g. 3,4-dihydrobenzo[b]pyran-3-yl, 3,4-dihydrobenzo[b]pyran-6-yl, 3,4-dihydrobenzo[c]pyran-l-yl, dihydrobenzo[c]pyran-7-yl), oxazolinyl (e.g. 4,5-dihydrooxazol-2-yl, 4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl), isoxazolinyl, oxazepinyl, tetralwdro-indazolyl (e.g. 4,5,6,7-tetrahydroindazol-l-yl, 4,5,6,7-tetrahydrouidazol-3-yl, 4,5,6,7-teirahy-droindazol-4-yl, 4,5,6,7-tetrahydroindazol-6-yl), tetrahydrobenzimidazolyl (e.g. 4,5,6,7-tetrahydrobenzimidazol-1-yl, 4,5,6,7-tetrahydrobenzimidazol-5-yl), tetrahydroimidazo[4,5-c]pyridyl (e.g. 4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-l-yl, 4,5,6,7-tetrahydroimidazo[4,5- ]pyrid-5-yl, 4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-6-yl), tetrahydroquinolinyl (e.g. 1,2,3,4-tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinolinyl), tetrahydroisoquinolinyl (e.g. 1,2,3,4-tetre hydroisoquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinoxalinyl (e.g. 1,2,3,4-te-trahydroquinoxalinyl, 5,6,7,8-tetrahydroquinoxaliriyl), spiro[isoquinoline-3,l'-cyclohexan]-l-yl, spiro[piperidine-4,1' -benzo[c]thiophen]-1 -yl, spiro[piperidine-4,1' -benzo[c]furan]- 1-yl, spiro[piperidine-4,3'-benzo[b]furan]-l-yl, spiro[piperidine-4,3'-coumarin]-l-yl. A preferred heteroaryl is pyridinyl. [00420] Other examples of "heteroaryl" are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, tri-azolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl, oxazolyl, oxa-diazolyl, thiadiazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinnyl, indolyl, benzimida-zolyl, benzofuranyl, benzothienyl, pteridinyl and purinyl. [00421] "Heterocyclyl" or "heterocycle" (heterocycle) signifies a mono-, bi-, or tricydic ring consisting of carbon atoms and from one heteroatom to 4, wherein the heteroatom is selected from oxygen, nitrogen, and sulphur. If sulphur is present, then it can be S, S(O), or S(O)2. If nitrogen is present, then it can be N, NH, substituted N, or N-oxide. The heterocycle is a saturated or partially saturated ring. From 0-2 CH2 groups of the heterocycle can be replaced by C(O). The heterocycle can be attached via a carbon or nitrogen atom, unless linking the nitrogen atom would lead to a quaternary nitrogen. If the heterocycle is bicyclic, then one or both of the rings may have a heteroatom(s) present. If the heterocycle is tricyclic, then one, two, or all three of the rings may have a heteroatom(s) present. [00422] Examples of "heterocycle" are aziridinyl (e.g. aziridin-1-yl), azetidinyl (e.g. azetidin-1-yl, azetidin-3-yl), oxetanyl, pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), imidazolidinyl (e.g. imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl), oxazolidinyl (e.g. oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl), thiazolidinyl (e.g. thiazolidin 2-yl, thiazolidin-3-yl, thiazolidin-4-yl), isothiazolidinyl, piperidinyl (e.g. piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), homopiperidinyl (e.g. homopiperidin-1-yl, homopiperi-din-2-yl, homopiperidin-3-yl, homopiperidin-4-yl), piperazinyl (e.g. piperazin-1-yl, piperazin-2-yl), morpholinyl (e.g. morpholin-2-yl, morpholin-3-yl, morpholin-4-yl), thiomorpholinyl (e.g. thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl), 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, tetrahydrofuranyl (e.g. tetrahydrofuran-2-yl, tetrahydrofuran-3- yl), tetrahydrothienyl, tetrahydro-l,l-dioxothienyl, tetrahydropyranyl (e.g. 2-tetrahydropyra-nyl), tetrahydrothiopyranyl (e.g. 2-tetrahydrothiopyranyl), 1,4-dioxanyl, 1,3-dioxanyl, octa-hydroindolyl (e.g. octahydroindol-1-yl, octahydroindol-2-yl, octahydroindol-3-yl, octahydro-indol-5-yl), decahydroquinolinyl (e.g. decahydroquinolin-1-yl, decahydroquinolin-2-yl, deca-hydroquinolin-3-yl, decahydroquinolin-4-yl, decahydroquinolin-6-yl), decahydroquinoxalinyl (e.g. decahydroquinoxalin-1-yl, decahydroquinoxalin-2-yl, decahydroquinoxalin-6-yl), 3-aza-bicyclo[3.2.2]nonyl, 2-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.0]hexyl, 2,5-diazabicyclo-[2.2.1]heptyl, atropinyl, tropinyl, quinuclidinyl, l,4-diazabicyclo[2.2.2]octanyl, 1,4-dioxa-spiro[4.5]decanyl (e.g. l,4-dioxaspiro[4.5]decan-2-yl, l,4-dioxaspiro[4.5]decan-7-yl), 1,4-dioxa-8-azaspiro[4.5]decanyl (e.g. l,4-dioxa-8-azaspiro[4.5]decan-2-yl, l,4-dioxa-8-aza-spiro[4.5]decan-8-yl), 8-azaspiro[4.5]decanyl (e.g. 8-azaspiro[4.5]decan-l-yl, 8-azaspiio-[4.5]decan-8-yl), 2-azaspiro[5.5]undecanyl (e.g. 2-azaspiro[5.5]undecan-2-yl), 2,8-diaza-spiro[4.5]decanyl (e.g. 2,8-diazaspiro[4.5]decan-2-yl, 2,8-diazaspiro[4.5]decan-8-yl), 2,8-diazaspiro[5.5]undecanyl (e.g. 2,8-diazaspiro[5.5]undecan-2-yl), l,3,8-triazaspiro[4.5]decanyl (e.g. l,3,8-triazaspiro[4.5]decan-l-yl, l,3,8-triazaspiro[4.5]decan-3-yl, and 1,3,8-triazaspi-ro[4.5]decan-8-yl). [00423] Preferred examples of "heterocycle" are pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, imidzolidinyl, imidazolinyl, pyra-zolidinyl, pyrazolinyl, oxazolidinyl, oxazoline, isoxazolidinyl, isoxazoline, thioxazolidinyl, thioxazoline, isothioxazolidinyl, isothioxazoline, triazolidinyl, triazolinyl, tetrazolidinyl, tetrazolinyl, tetrahydropyranyl, dihydropyranyl, pyran, piperidinyl, piperazinyl, homcniperaz-inyl, morpholinyl. Preferred heterocycle groups are piperidinyl and morpholinyl. [00424] "Therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to activate glucokinase. [00425] 'Treating" or "treatment" cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, e.g., arresting or slowing its develop- ment; and/or (c) relieving the disease-state, e.g., causing regression of the disease state itself or some symptom of the disease state. [00426] Pharmaceutically acceptable include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts, and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include, hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, and nitric acids. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, man-delic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluene-sulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hy-droxynaphthoates, glycerophosphates, and ketoglutarates. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium, zinc, and calcium salts. Examples of amines and organic amines include ammonium, methylamine, dimethylarnine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine, tetramethylamii;e, etha-nolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N-methyl-D-glucamine, and guanidine. Examples of cationic amino acids include lysine, arginine, and histidine. [00427] The pharmaceutically acceptable salts are prepared by reacting the compound of formula I with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, and magnesium hydroxide, in solvents such as ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases such as lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, and tartaric acid in solvents such as ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used. [00428] The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, enzymatic resolution, resolving the diastereo-meric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, and lactic acid wherever applicable or chiral bases such as brucine, (R$)- or (S)-phenyl-ethylamine, cinchona alkaloids and their derivatives. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). More specifically a compound of the present invention may be converted to a 1:1 mixture of diastereomeric amides by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatog-raphy and the stereoisomers of compound of formula I may be prepared by hydrolysincr the pure diastereomeric amide. [00429] The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into a compound of the present invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. [00430] This invention will be better understood from the following examples, which are for purposes of illustration and are not intended to limit the invention defined in the claims which follow thereafter.EXAMPLES [00431] All reactions involving air-sensitive reagents were performed under nitrogen using syringe-septum cap techniques. The glassware was dried by heating with a heat-gun. MgSO4 was used to dry solutions. Solvents were removed in vacua by rotary evaporation. Melting points were recorded on a Biichi 535. Bruker AMX 400 and Bruker DRX 300 instruments were used to record H NMR spectra at 400 and 300 MHz, respectively, with tetramethylsi-lane (TMS) as internal standard. Coupling constants (J) are given in Hz. [00432] Materials [00433] Test compounds were synthesized or when commercially available they were purchased from Aldrich, Specs, Maybridge, or Bionet. For the synthesized compounds, the procedure for synthesis and measured characteristics of the compound are stated in the example. All compounds for which no synthesis procedure is stated in the examples are commercially available and have been purchased or were prepared by standard methods described in the literature. [00434] A general procedure may be as follows: (scheme Removed) [00435] The synthetic intermediate of formula I with Rl = H, R2 =Br and a carboxylic ester group e.g. [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acetate can be converted via a classical Mitsunobu reaction or a reaction can be performed between the phenol and an alkyl halides (or an alkyle mesylate, triflate, tosylate or alike) to a new intermediate of formula I where X1-R1 forms a ether or thioether group and R = Br. The new intermediate can be converted via a classical Sonogashira, Heck or Suzuki coupling protocol to a new intermediate where R2 is -OC-R2", -CH=CH-R2a or a substituted or non substituted aryl or heteroaryl. It is also possible to perform the reaction in the opposite way by first performing the Sonogashira, Heck or Suzuki coupling followed by the ether forming reaction as described above. The claimed compounds can also be performed as described for [4-(3-Bromo-5-cyclopropylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester by condensing e.g. l,3-dibromo-5-cyclopropylmethoxy-benzene or another substituted dibromo • phenyle ether with (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester or another substituted mercaptobezene. The intermediates formed can be converted to the claimed compounds by a classical ester hydrolyses reaction from the respective esters of I (scheme 1-3). [00436] General procedure (A) [00437] HPLC systems [00438] HPLC method A [00439] The RP-purification was performed on a Gilson system (4 Gilson 306 pumps, Gilson 155 detector, Gilson reodyne manual injection, Gilson 811C mixer and a Gilson 202 fraction collector) using a Phenomenex RP synergi-MAX column (3µm, 30 mm x 250 mm) with gradient elution, 5 % to 100 % solvent B (acetonitrile) in solvent A (water) within 40 min, 60 mL/min, detection at 210 nm, room temperature. The pooled fractions were either evaporated to dryness in vacua, or evaporated in vacua until the MeCN is removed, and then frozen and freeze dried. [00440] HPLC method B [00441] The RP-purification was performed on a Gilson system (3 Gilson 306 pumps, Gilson 170 DAD detector and a Gilson 215 liquid-handler) using a Waters X-terra RP (10 /mi, .30 mm x 150 mm) with gradient elution, 5% to 95% solvent B (0.05% TFA in acetonitrile) in solvent A (0.05% TFA in water) within 15 min, 40 mL/min, detection at 210 nm, room temperature. The pooled fractions were either evaporated to dryness in vacua or evaporated in vacua until the MeCN is removed and then frozen and freeze dried. [00442] HPLC-MS (System 1) [00443] The RP-analysis was performed on an Agilent HPLC system (1100 degasser, 1100 pump, 1100 injector and a 1100 DAD) fitted with an Agilent MS detector system Model VL (MW 0-1000) and a S.E.D.E.R.E Model Sedex 55 ELS detector system using a Waters X-terra MS CIS column (5 /im, 3.0 mm x 50 mm) with gradient elution, 5% to 95% solvent B (0.05% TFA in acetonitrile) in solvent A (0.05% TFA in water) within 3 min, 2.7 mL/min. [00444] Thin layer chromatography was performed on Merck DC-Alufolien, silica gel 60 F254 and components were visualized by UV254. Flash chromatography was performed using silica gel Merck 60 size 0.04-0-063 mm and a Quad 12/25 flash system. 3,5-dibromophenol was prepared as described by Yang, et al., Synth Commun; 2003,33,19, 3317-3326. [00445] Intermediates [00446] [4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (Formula Removed) [00447] Step A: tert-Butyl-(3,5-dibromo-phenoxy)-dimethyl-silane (Formula Removed) [00448] 3,5-Dibromophenol (59.6 mmol; 15 g) and imidazole (65.5 mmol; 4.5 g) were dissolved in dichloromethane (150 mL) and terf-butyl-dimethylsilylchloride (65,5 mmol; 9,9 g) was added. The reaction mixture was stirred at room temperature for 16 hours, diluted with diethyl ether, and filtered. The organic solution was washed with saturated ammonium chloride, saturated sodium hydrogen carbonate, and water and dried and evaporated to dryness. Yield: 22 g. HPLC-MS: m/z: 366.9 (M+); Rt: 3.09 min. [00449] Step B: 3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde(Formula Removed) H [00450] tert-Butyl-(3,5-dibromo-phenoxy)-dimethyl-silane (22 g; 60.08 mmol) was dissolved in THF (200 mL) in a dried reaction flask under an atmosphere of nitrogen. The mixture was cooled to -78°C and n-BuLi (1.6 N in hexane; 41.25 mL; 66.09 mmol) was added while the temperature was kept between -60 and -78°C. The mixture was stirred for 15 min. and DMF (4.83 g; 66.08 mmol) was added. The reaction mixture was stirred for 1 h and methanol (5 mL) followed by saturated ammonium chloride was added. Etyl acetate (200 mL) was added and the organic phase was separated from the aqueous phase. The organic phase was washed with water, dried, and evaporated to dryness. The crude product was purified by flash chro-matography (heptane: dichloromethane (1:1). Yield 7 g. HPLC-MS: m/z: 317.0 (M+l); Rt: 2.7 min. [00451] Step C: [3-Bromo-5-(tret-butyl-dimethyl-silanyloxy)-phenyl]-methanol (Formula Removed) [00452] 3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde (7 g, 22.2 mmol) was dissolved in THF and sodium borohydride (0.92 g; 24.4 mmol) waas added. The reaction mixture was stirred at room temperature for 2 h and water was added, and the reaction mixture was partly avaporated to strip off THF. Ethyl acetate was added and the phases separated. The organic phase was washed with water, dried, and evaporated to dryness. Yield: 6.4 ^, HPLC-MS: m/z: 317.0 (M+); Rt: 2.37 min. [00453] Step D: {4-[3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (Formula Removed) [00454] [3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-phenyl]-methanol (6.4 g; 20.17 mmol) and (4-mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (5.02 g; 22.19 mmol) were dissolved inTHF (200 mL). Tributylphosphine (8.15 g; 40.34 mmol) and l,l'-(azodicarbonyl)-dipiperidine (10.17 g; 40.34 mmol) were added, and the reaction mixture was stirred for 14 h at room temperature. Water and ethyl acetate were added to the reaction mixture. The phases were separated. The organic phase was washed with water, dried, and evaporated. The crude product was purified by flash chromatography (heptane: dichloromethane (1:1)). Yield: 8 g; 80%. HPLC-MS: m/z: 527.0 (M+l); Rt: 3.10 min. [00455] Step E: [4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (Formula Removed) [00456] {4-[3-Bromo-5-(ferf-butyl-dimethyl-silanyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester 7 g, 13.3 mmol) was dissolved in THF under an atmosphere of nitrogen. Tetrabutylammonium fluoride 1 N in THF (15 mL) was added, and the reaction mixture was stirred at 60°C for 2h. Saturated sodium carbonate and water were added t.o- gether with ethyl acetate, and the organic phase was separated. The organic phase was washed with water, dried, and evaporated to dryness. Yield: 3.2 g. HPLC-MS: m/z: 435.4 (M+Na); Rt: 2.22 min. [00457] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-chloro-phenoxy]-acetic acid ethyl acetate (Formula Removed) [00458] (2-Chloro-4-mercapto-phenoxy)-acetic acid ethyl ester (3 g; 12,16 mmol), dibromo-phenol (3,67 g; 14,59 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.45 g; 0.49 mmol), and l,r-bis-(diphenylphosphineo)ferrocenE (0.40 g; 0.73 mmol) were added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (6,74 mL, 48,64 mmol) and NMP (10 mL) were added, and the reaction mixture was stirred in a microwave oven for 1 h at 100°C. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate phase was washed twice with a 5% aqueous citric acid solution. The organic phase was dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (dichloromethane → dichlormethane: ethyl acetate (1:1)). Yield 1.8 g. HPLC-MS: m/z: 441.2 (M+Na); Rt: 2.34 min. [00459] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acetate (Formula Removed) [00460] (2-Methyl-4-mercapto-phenoxy)-acetic acid ethyl ester (6 g; 26,51 mmol), dibromo-phenol (8,68 g; 34,47 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.97 g; 1,06 mmol), and l,l'-bis-(diphenylphosphineo)ferrocene (0.88 g; 1,59 mmol) were added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (10.73 mL, 106 mmol) and NMP (20 mL) were added, and the reaction mixture was stirred in a microwave oven for 1 h at 105 °C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4 X 100 mL). The pooled organic phases were washed twice with water (30 mL), dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (heptane: ethyl acetate (10:1→ 7:3). Yield 6,5 g. HPLC-MS: m/z: 397.3 (M+); Rt: 2,33 min. [00461] {4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-acetic acid ethyl ester (Formula Removed) [00462] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-chloro-phenoxy]-acetic acid ethy! acetate (1.7 g; 4.07 mmol), N-(3-hydroxypropyl)morpholine (0.59 g; 4.07 mmol) and tributyl-phosphine (1.8 g; 7.33 mmol) were dissolved in THF (100 mL) in a dried reaction flask under an atmosphere of nitrogen. l,l'-(Azodicarbonyl)dipiperidine (1.85 g; 7,33 mmol) dissolved in THF (50 mL) was added to the reaction mixture, which was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and purified by flash chromatography (ethyl acetate: heptane). Yield: 1.1 g. HPLC-MS: m/z: 544.0 (M+); Rt: 1.78 min. [00463] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (Formula Removed) [00464] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-chloro-phenoxy]-acetic acid ethyl acetate (1.1 g; 2.63 mmol), 4-chlorophenylacetylene (1.08 g; 7.9 mmol), bis(triphenylphosphine)-palladium (II) chloride (0.15 g; 0.21 mmol) and copper iodide (0.03 g; 0.16 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (5 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100°C for Ih. The reaction mixture was evaporated to dryness and portioned between 5% aqueous citric acid and ethyl acetate. The organic phase was dried and evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate: heptane 1:3). Yield: 1.1 g. HPLC-MS: m/z: 473.3 (M+); Rt: 2.76 min. [00465] [4-(3-hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (Formula Removed) [00466] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acetate (3 g; 7.55 mmol), 3-phenyl-l-propyn (2.63 g; 22.65 mmol), bis(triphenylphosphine)palladium (II) chloride (0.42 g; 0.60 mmol) and copper iodide (0.086 g; 0.45 mmol) were dissolved in a mixture of triethylamine (3 mL) and DMF (6 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100 °C for 1 Ih. The reaction mixture was evaporated to dryness, and portioned between 5% aqueous citric acid and ethyl acetate. The organic phase was dried and evaporated to dryness. The crude product was purified by preparative HPLC method A. Yield: 1.4 g. HPLC-MS: m/z: 433.3 (M+); Rt: min. [00467] [4-(3-Hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (Formula Removed) [00468] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acetate (2.3 g; 5.79 mmol), phenylacetylene (1.9 mL; 17.4 mmol), bis(triphenylphosphine)palladivun (II) chloride (0.33 g; 0.46 mmol) and copper iodide (0.07 g; 0.35 mmol) were dissolved in a mixture of triethylamine (7 mL) and DMF (8 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100 °C for Ih. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid and ethyl acetate was added. The organic phase was separated, dried and evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate: heptane 1:10→ 1:3). Yield: 1.2 g. HPLC-MS: ni/z: 419 (M+); Rt: 2.52 min. [00469] {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (Formula Removed) [00470] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acsiate (3 g; 7.55 mmol), 4-prop-2-ynyl-morpholine (2.8 g; 22.65 mmol), bis(triphenylphosphine)- palladium (II) chloride (0.42 g; 0.60 mmol) and copper iodide (0.09 g; 0.45 mmol) were dissolved in a mixture of triethylamine (7 mL) and DMF (8 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100 °C for 1.5 h. The reaction mixture was purified by preparative HPLC (method A). Yield: 1.4 g. HPLC-MS: m/z: 442.4 (M+);Rt: 1.54 min. [00471] {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester(Formula Removed) [00472] [4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester 20 (2.3 g; 5.6 mmol), 4-prop-2-ynyl-morpholine (2.1 g; 16.8 mmol), bis(triphenylphosphine)- palladium (II) chloride (0.31 g; 0.45 mmol) and copper iodide (0.06 g; 0.34 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (10 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100 °C for Ih. The reaction mixture was purified by preparative HPLC (method A). Yield: 0.9 g. HPLC-MS: m/z: 456.1 (M+);Rt: 1.53min. [00473] (4-[3-Hydroxy-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (Formula Removed) [00474] [4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (2 g; 4.9 mmol), 3-phenyl-l-propyn (1.7 g; 14.6 mmol), bis(triphenylphosphine)palladium (II) chloride (0.27 g; 0.39 mmol) and copper iodide (0.056 g; 0.29 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (10 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100°C for Ih. Further 3-phenyl-l-propyn (1.7 g; 14.6 mmol) was added and the reaction mixture was reacted in a microwave oven at 100°C for further Ih. The reaction mixture was purified by preparative HPLC (method A). Yield: 0.8 g. HPLC-MS: m/z: 434.6 (M+l); Rt: 2.43 min. [00475] {4-[3-Bromo-5-cyclohexylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (Formula Removed) [00476] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acetate ester (0.23 g; 0.58 mmol), cyclohexyl-methanol (80 /il; 0.64 mmol) and tributylphosphine (0.21 mL; 0.87 mmol) were dissolved in THF (10 mL) in a dried reaction flask under an atmosphere of nitrogen. l,r-(Azodicarbonyl)dipiperidine (0.22 g; 0,87 mmol) dissolved in THF (10 mL) was added to the reaction mixture, which was stirred at room temperature for 2 days. The reaction mixture was filtered, evaporated to dryness and purified by flash chroma-tography (ethyl acetate: heptane 1:1). Yield: 100 mg. HPLC-MS: m/z: 493.4 (M)+; Rt: 3.17 min. [00477] {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (Formula Removed) [00478] 1,3-Dibromo-5-cyclopentylmethoxy-benzene. [00479] 3,5-Dibromophenol (5.0 g; 19.8 mmol), cyclopentane-methanol (2.0 g; 19.9 mmol) and tributylphosphine (8.8 mL; 35.7 mmol) were dissolved in dry THF (250 mL) in a dried reaction flask under an atmosphere of nitrogen. l,l'-(Azodicarbonyl)dipiperidine (9.01 g; 35.7 mmol) dissolved in dry THF (150 mL) was added to the reaction mixture, which was stirred at room temperature for 16 hours. The reaction mixture was filtered, evaporated to dryness and purified by flash chromatography (heptane -> ethyl acetate: heptane 2:3). Yield: 5.68 g; 86 %. [00480] [4-(3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. [00481] l,3-Dibromo-5-cyclopentylmethoxy-benzene (2.9 g; 8.6 rnmol), (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (1.5 g; 6.6 rnmol), tris(dibenzylideneacetone)-dipalladium(O) (0.18g, 0.20 rnmol) and l,l'-bis(diphenylphosphino)-ferrocen (0.22 g; 0.40 mmol) was added to a dried microwave flask under an atmosphere of nitrogene. The reaction flask was sealed and dry NMP (10 mL) and TEA (3,7 mL; 26.5 mmol) was added through the septum. The reaction flask was reacted in a microwave oven at 140°C for Ih. Ethyl acetate (30 mL) and aqueous 5% citric acid (30 mL) was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with ethyl acetate (30 mL X 2) and the pooled organic phases were dried (MgSO4) and evaporated to dryness. The reaction mixture was purified by flash chromatography (heptane→ heptane: ethyl acetate (Q.-l1/2i). Yield: 1.45 g (46%). HPLC-MS: m/z: 479.8 (M)+; Rt: 3.18 min. [00482] {4-[3-Bromo-5-isobutoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (Formula Removed) [00483] {4-[3-Bromo-5-isobutoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester was prepared as described for {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. Yield: 45%. HPLC-MS: m/z:. 454.8 (M+H)+; Rt: 3.07 min. [00484] (4- {3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-acetic acid ethyl ester (Formula Removed) [00485] (4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-acetic acid ethyl ester was prepared as described for {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. Yield: 25%. HPLC-MS: m/z:.537.1 (M+2); Rt: 3.11 min. [00486] {4-[3-Bromo-5-(2-ethyl-butoxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester (Formula Removed) [00487] {4-[3-Bromo-5-(2-ethyl-butoxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester was prepared as described for {4-[3-Bromo-5-cyclopentylmethoxy-phenyi sulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. Yield: 63%. HPLC-MS: m/z:. 481.0 (M); Rt: 3.20 min. [00488] [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (Formula Removed) [00489] [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester was prepared as described for {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2- methyl-phenoxyj-acetic acid ethyl ester. Yield: 51%. HPLC-MS: m/z:.565.0 (M)+; Rt: 3.04 min. [00490] {4-[3-Bromo-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid ethyl ester (Formula Removed) [00491] {4-[3-Bromo-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester was prepared as described for {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. Yield: 9%. HPLC-MS: m/z: 565.2 (M)+; Rt: 2.58 min. [00492] {4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aciuc acid ethyl ester (Formula Removed)[00493] {4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester was prepared as described for {4-[3-Bromo-5-cyclopentylmethoxy-pheny!-sulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. Yield: 51%. HPLC-MS: m/z:. 508.R (M+H)+; Rt: 3.33 min. [00494] {4-[3-Bromo-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester (Formula Removed) [00495] 2-(3,5-Dibromo-phenoxy)-3-trifluoromethyl-pyridine. [00496] 3,5-Dibromophenol (2.0 g; 7.9 mmol), 2-chloro-3-triflouropyridine (1.4 g; 7.9 mmol), potassium hydroxide (0.45 g; 7.9 mmol) and DMSO (40 mL) was added to a reaction flask under an atmosphere of nitrogen. The reaction mixture was reacted at 110 °C for 6 h. The reaction mixture was cooled to room temperature and ethyl acetate (30 ml) and water (120 mL) was added. The organic phase was separated form the aqueous phase and the aqueous phase was extracted with ethyl acetate (30 mL X 4). The combined organic phases were dried, evaporated to dryness and purified by flash chromatography (heptane -» ethyl acetate: heptane 1:8). Yield: 2.23 g; 71 %. HPLC-MS: m/z: 397.9 (M)+; Rt: 2.58 min. [00497] {4-[3-Bromo-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester [00498] 2-(3,5-Dibromo-phenoxy)-3-trifluoromethyl-pyridine (2.05 g; 5.17 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.9 g; 4.0 mmol) was condensed to give the title product applying the procedure described for {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. The crude product was purified by flash chromatography (heptane → ethyl acetate: heptane 2:9). Yield 1.26 g (58%). HPLC-MS: m/z: 544.3 (M+2); Rt: 2.77 min. [00499] {4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (Formula Removed) [00500] 2-(3,5-Dibromo-phenoxy)-5-trifluoromethyl-pyridine. [00501] The title product was prepared as described for 2-(3,5-Dibromo-phenoxy)-3-tri- fluoromethyl-pyridine Yield: 70%; HPLC-MS: m/z: 397.7 (M)+; Rt 2.60 min. [00502] {4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00503] 2-(3,5-Dibromo-phenoxy)-5-trifluoromethyl-pyridine (2.5 g; 6.3 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (1.1 g; 4.9 mmol) was condensed to give the title product applying the procedure described for (4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. The crude product was purified by flash chromatography (heptane → ethyl acetate: heptane 2:9). Yield 1.4 g (53%). HPLC-MS: m/z: 544.3 (M+2); Rt: 2.80 min. [00504] {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester(Formula Removed)[00505] 1,3-Dibromo-5-(3-trifluorornethyl-phenoxy)-benzene. [00506] 3,5-Dibroraophenol (4.1 g; 16.2 mmol), 3-(triflouromethyl)-phenylboronic acid (6.2 g; 32.4 mmol), Cu(II) acetate (2.9 g; 16.2 mmol), TEA (5.6 mL; 40.5 mmol) and dichloro-methane (150 mL) and molecular sieves (2 ml) was added to a reaction flask the reaction mixture was stirred for 7 days. Further 3-(triflouromethyl)-phenylboronic acid (6.2 g; 32.4 mmol) was added and the reaction mixture stirred for 1 day. Further 3-(triflouromethyl)-phenyl-boronic acid (6.2 g; 32.4 mmol) and TEA (5.6 mL; 40.5 mmol) was added and the reaction mixture stirred for 1 day. 5% Aqueous citric acid (150 mL) was added and the two phases were separated. The aqueous phase was extracted with dichloromethane (50 mL X 2) and the organic phases were pooled, dried and evaporated to dryness. The crude product purified by flash chromatography (heptane → ethyl acetate: heptane 1:9). Yield: 1.86 g; HPLC-MS: m/z: 397. (M+H)+; Rt: 2.78 min. [00507] {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00508] l,3-Dibromo-5-(3-trifluoromethyl-phenoxy)-benzene (1.35 g; 3.4 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.7 g; 3.1 mmol) was condensed to give the title product applying the procedure described for {4-[3-Bromo-5-cyclopentylmethoxy- phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. The crude product was purified by preparative HPLC (Method A) followed by flash chromatography (dichloromethane: heptane 3:7). Yield 0.5 g. HPLC-MS: m/z: 541.3 (M)+; Rt: 3.03 min. [00509] [4-(3-Bromo-5-cyclopropylmethoxy-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (Formula Removed) [00510] [4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (1.0 g; 2.43 mmol), cyclopropylcarbinol (175 mg; 2.43 mmol) and tributylphosphine (1.07 mL; 4.38 mmol) was dissolved in THF (100 mL) in a dried reaction flask under an atmosphere of nitrogen. l,l'-(Azodicarbonyl)dipiperidine (1.1 g; 4,38 mmol) dissolved in THF (20 mL) was added to the reaction mixture, which was stirred at room temperature for 16 hours. The reaction mixture was filtered, evaporated to dryness and purified by flash chromatography (ethyl acetate: heptane 1:9→ 2:3). Yield: 980 mg; 86%; HPLC-MS: m/z: 465.0(M)+; Rt: 2.74 min. [00511] [4-(3-Bromo-5-cyclopropylmethoxy-phenylsulfanyl)-2-tnethyl-phenoxy]-acetic acid ethyl ester [00512] Step A: l,3-Dibromo-5-cyclopropylmethoxy-benzene [00513] 3,5-Dibromo-phenol (5g; 19.9 mmol), cyclopropylcarbinol (1.4 g; 19.9 mmol) and tributylphosphine (8.8 mL; 35.7 mmol) were dissolved in THF (500 mL) in a dried reaction flask under an atmosphere of nitrogen. l,l'-(Azodicarbonyl)dipiperidine (9.0 g; 35,7 mmol) dissolved in THF (100 mL) was added to the reaction mixture, which was stirred at room temperature for 16 hours. The reaction mixture was partly evaporated, filtered, evaporated to dryness and purified by flash chromatography (ethyl acetate: heptane 0:1→ 1:10). Yield: 545 g; 90%. [00514] Step B: [4-(3-Bromo-5-cyclopropylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester [00515] l,3-Dibromo-5-cyclopropylmethoxy-benzene (5.27 g; 17,23 mmol), (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (3g; 13.26 mmol), tris(dibenzylideneacetone)dipal-ladium (0) (0.36 g; 0,40 mmol), and l,r-bis-(diphenylphosphineo)ferrocene (0.44 g; 0,80 mmol) was added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (7.45 mL) and NMP (8 mL) was added, and the reaction mixture was stirred in a microwave oven for 1 h at 140 °C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4 X 100 mL). The pooled organic phases were dried and evaporated hi vacuo. The crude reaction product was purified by flash chromatography (heptane: ethyl acetate (20:1 -» 7:3). Yield 2.8 g; 47%). HPLC-MS: m/z: 451.0 (M+); Rt: 2.85 min [00516] [4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-acetic acid ethyl ester (Formula Removed) [00517] StepAl: l,3-Dibromo-5-isobutoxy-benzene [00518] Potassium hydroxide (15.9g; 284 mmol) was dissolved in water (300 ml) and 3,5-dibromo-phenol (47g; 188.5 mmol) was added. Benzyl tributylammoniumchloride (17.7g; 56.8 mmol) and toluene (200 ml) was added and the reaction mixture was heated to 85 °C. Bromoethylpropan (32.3 g; 325.7 mmol) was added over 5 hours and the reaction mixture was stirred at 85 °C for additional 16 h. The reaction mixture was cooled to room temperature and the phases were separated. Toluene (100 ml) was added to the organic phase which waa washed with 0.2 N aqueous HC1 (200 ml X 2) and water (200 ml X 2). The organic phase was evaporated to give the crude product which was purified by distillation (0.7.mm Hg; Bp: 98 °C); Yield: 43 g (colourless oil). [00519] Step A2: (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester [00520] (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester was prepared as described for 2,6-difluoro-4-mercapto-phenoxy)acetic acid methyl ester (compound 21) in Eur. J. Med. Chem, 1995, 30, 403 (Kawashima, M. S.) except that (4-chlorosulfonyl-2,5-dimethyl-phenoxy)-acetic acid ethyl ester was reduced with 4 eq. of zn (dust) in a mixture of konc. sul-furic acid and ethanol at 80 °C. [00521] Step B: [4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-acttic acid ethyl ester [00522] 1,3-Dibromo-5-isobutoxy-benzene (1.66 g; 5.4 mmol), (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester (1.0 g; 4.1 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.11 g; 0,12 mmol), and l,l'-bis-(diphenylphosphineo)ferrocene (0.14 g; 0,25 mmol) were added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (2.3 mL) and NMP (10 mL) was added, and the reaction mixture was stirred in a microwave oven for 1 h at 140 °C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4 X 100 mL). The pooled organic phases were dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (hep- tane: ethyl acetate (10:1 → 1:1). Yield: 1.3 g; 67%. HPLC-MS: m/z: 467.0 (M+); Rt: 3.10 min [00523] [4-(3-Bromo-5-isobutoxy-phenoxy)-2-methyl-phenoxy]-acetic acid methyl ester (Formula Removed) [00524] Step A: 3-Bromo-5-isobutoxy-phenylboronic acid [00525] l,3-Dibromo-5-isobutoxy-benzene (1. g; 3.3 mmol) was dissolved in dry THF (30 ml) in a dry reaction under stirring. The reaction mixture was cooled to -70 °C and n-BuLi (2M; 2.44 ml) was added. The reaction mixture was stirred for 15 min. and triisobutylborate (1.50 ml; 6.5 mmol) was added at -70 °C. The temperature was raised to -30 °C and stirred for l'/2 hour followed by a temperature increase to room temperature. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate (about 3 ml) and evaporated to dryness. The crude product was purified by prep HPLC (method B). Yield: 430 mg; 49 %. HPLC-MS: m/z: 272.9 (M+); Rt: 2.08 min [00526] Step B: [4-(3-Bromo-5-isobutoxy-phenoxy)-2-methyl-phenoxy]-acetic acid methyl ester [00527] (4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (215 mg; 1.1 mmol), 3- Bromo-5-isobutoxy-phenylboronic acid (523.4; 1.9 mmol), copper(II) acetate (199 mg; 1.1 mmol), crushed molsieves (about Ig) and triethylamine (0.46 ml; 3.3 mmol) was dissolved in dichloromethane (40 ml) and stirred over night. The reaction mixture was filtered through celite and evaporated to dryness. The crude product was purified by preperative HPLC (method B). Yield: 300 mg; 65%. HPLC-MS: m/z: 423.5 (M+); Rt: 2.71 min [00528] Example 1 [00529] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-l-yl-propoxy)-phenyl- sulfanyl]-phenoxy} -acetic acid (Formula Removed) [00530] Step A: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-l-yl-propoxy)-phenylsulfanyl]-phenoxy} -acetic acid ethyl ester [00531] [{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (0.4 g; 0.85 mmol), 3-piperidin-l-yl-propan-l-ol (0.12 g; 0.85 mmol) and tributylphosphine (0.37 mL; 1.5 mmol) were dissolved in THF (50 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1' -(Azodicarbonyl)dipiperidine (0.38 g; 1,5 mmol) dissolved in THF (25 mL) was added to the reaction mixture, which was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and 5% aqueous citric acid and ethyl acetate was added. The organic phase was separated, dried, evaporated to dryness, and purified by prep HPLC (method A). Yield: 275 mg. HPLC-MS: m/z: 598.0 (M+); Rt: 2.3 min. [00532] Step B: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-l-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic acid [00533] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-l-yl-propoxy)-phenyl-sulfanyl]-phenoxy}-acetic acid ethyl ester (275 mg; 0.46 mmol) was dissolved in ethanol (15 mL) and aqueous IN sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with 5% aqueous citric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 200 mg. HPLC-MS: m/z: 570.0 (M+); Rt: 2.07 min. [00534] Example 2 [00535] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]- phenoxy)-acetic acid (Formula Removed) [00536] Step A: {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenyl-sulfanyl]-phenoxy }-acetic acid ethyl ester [00537] [4-(3-Hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (0.25 g; 0.60 mmol), 3-morpholin-4-yl-propan-l-ol (0.12 g; 0.84 mmol) arrl oibu-tylphosphine (0.27 mL; 1.08 mmol) were dissolved in THF (20 mL) in a dried reaction flask under an atmosphere of nitrogen. l,l'-(Azodicarbonyl)dipiperidine (0.27 g; 1,08 mmol) dissolved in THF (10 mL) was added to the reaction mixture, which was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness, acetonitrile added, and the mixture filtered. The solution was purified by prep HPLC (method A). Yield: 150mg. HPLC-MS: m/z: 546.6 (M+H); Rt: 2.08 min. [00538] Step B: {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenyl-sulfanyl]-phenoxy}-acetic acid [00539] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy} -acetic acid ethyl ester (150 mg; 0.28 mmol) was dissolved in ethanol (15 mL), and aqueous IN sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with IN aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 110 mg. HPLC-MS: m/z: 518.1 (M+H); Rt: 1.86 min. [00540] Example 3(Formula Removed) [00541] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-sulfanyl]-phenoxy} -acetic acid [00542] Step A: {2-Chloro-4-[3-(4-chloro-phenylemynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester [00543] [{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (293 mg; 0.62 mmol) was dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 3-morpholin-4-yl-propan-l-ol (75 mg; 0.52 nanoi) and tributylphosphine (0.23 mL; 0.93 mmol) was added followed by l,l'-(Azodicarboayl)-dipiperidine (0.38 g; 1,5 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 16 h, filtered and evaporated in vacuo. The crude product was purified by prep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 600.4 (M+); Rt: 2.2 min. [00544] Step B: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy }-acetic acid [00545] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-sulfanylj-phenoxy) -acetic acid ethyl ester (200 mg; 0.33 mmol) was dissolved in ethanol (10 mL), and aqueous 1N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness, and purified by prep. HPLC (method A). Yield: 46 mg. HPLC-MS: m/z: 572.3 (M+); Rt: 2.03 min. [00546] Example 4 [00547] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)- phenylsulfanyl] -phenoxy} -acetic acid (Formula Removed) [00548] Step A: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl- benzyloxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester [00549] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}- acetic acid ethyl ester (274 mg; 0.58 mmol) was dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. (4-Morpholin-4-ylmethyl-phenyl)-methanol (IOC mg; 0.48 mmol) and tributylphosphine (0.21 mL; 0.87 mmol) was added followed by l,l'-(Azodi- carbonyl)dipiperidine (0.22 g; 0.87 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 5 h, filtered and evaporated in vacuo. The crude product was purified by prep. HPLC (method A). Yield: 250 mg. HPLC-MS: m/z: 663.0 (M+H); Rt: 2.47 min. [00550] Step B: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl- ben7yloxy)-phenylsulfanyl]-phenoxy}-acetic acid [00551] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)- phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (250 mg; 0.38 mmol) was dissolved in etha- nol (10 mL), and aqueous IN sodium hydroxide (5 mL) was added. The reaction mixture was stirred for 16 h, acidified with IN aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep. HPLC (method A). Yield: 32 mg. HPLC-MS: m/z: 634.5 (M+); Rt: 2.21 min. [00552] Example 5 [00553] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(l-methyl-piperidin-4-ylmethoxy)- phenylsulfanyl] -phenoxy} -acetic acid (Formula Removed) [00554] Step A: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(l-methyl-piperidin-4-yl-methoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester [00555] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxyl-phenylsullfanyl]-phenoxy}•• acetic acid ethyl ester (274 mg; 0.58 mmol) was dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. l-(Methyl-piperidin-4-yl)-methanol (100 mg; 0.48 mmol) and tributylphosphine (0.21 mL; 0.87 mmol) were added followed by l,l'-(Azodi-carbonyl)dipiperidine (0.22 g; 0.87 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 5 h, filtered, and evaporated in vacuo. The crude product was purified by prep. HPLC (method B). Yield: 250 mg. HPLC-MS: m/z: 663.0 (M+H); Rt: 2.47 min. [00556] Step B: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(l-methyl-piperidin-4-ylmethoxy)-phenylsulfanyl]-phenoxy }-acetic acid [00557] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(l-methyl-piperidin-4-ylmethoxy)-phenylsulfanyl]-phenoxy)-acetic acid ethyl ester (60 mg; 0.10 mmol) was dissolved in etha-nol (7 mL), and aqueous 1N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep. HPLC (method B). Yield: 20 mg. HPLC-MS: m/z: 556.5 (M+); Rt: 2.10 min. [00558] Example 6 [00559] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1 -ynyl)-phenyl- sulfanylj-phenoxy} -acetic acid (Formula Removed) [00560] Step A: {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-phenylsulfanylj-phenoxy)-acetic acid ethyl ester [00561] {4-[3-Hydroxy-5-(3-phenyl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.46 mmol), 3-morpholin-4-yl-propan-l-ol (101 mg; 0.69 mmol), tributylphosphine (0.28 mL; 1.39 mmol) and l,l'-(azodicarbonyl)dipiperidine (0.35 g; 1.39 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 1 h the reaction mixture was purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 560.5 (M+H); Rt: 2.07 min. [00562] Step B: {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-phenylsulfanyl]-phenoxy}-acetic acid [00563] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-phenyl-sulfanylj-phenoxy }-acetic acid ethyl ester (200 mg; 0.36 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 150 mg. HPLC-MS: m/z: 532.1 (M+);Rt: 1.87 min. [00564] Example 7 [00565] {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2- methyl-phenoxy}-acetic acid (Formula Removed) [00566] Step A: {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00567] {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.45 mmol), 4-flourobenzylalcohol (85.7 mg; 0.68 mmol), tributylphosphine (0.27 mL; 1.36 mmol) and l,l'-(azodicarbonyl)dipiperidine (0.34 g; 1.36 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 1 h the reaction mixture was purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 550.3 (M+H); Rt: 2.00 min. [00568] Step B: {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid [00569] {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy)-acetic acid ethyl ester (200 mg; 0.36 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 170 mg. HPLC-MS: m/z: 522.1 (M+);Rt: 1.77 min. [00570] Example 8 [00571] {4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2- methyl-phenoxyj-acetic acid (Formula Removed) [00572] Step A: {4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl- sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00573] {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl phenoxy}-acetic acid ethyl ester (200 mg; 0.45 mmol), cyclohexylmethanol (77.6 mg; 0.68 mmol), tributylphosphine (0.27 mL; 1.36 mmol) and l,l'-(azodicarbonyl)dipiperidine (0.34 g; 1.36 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 1 h the reaction mixture was purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 538.1 (M+H); Rt: 2.24 min. [00574] Step B: {4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl- sulfanyl] -2-methyl-phenoxy} -acetic acid [00575] {4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2- methyl-phenoxy }-acetic acid ethyl ester (200 mg; 0.37 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 180 mg. HPLC-MS: m/z: 510.1 (M+);Rt: 1.98 min. [00576] Example 9 [00577] {4-[3-Isobutoxy-5-(3-moipholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid (Formula Removed) [00578] Step A: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester [00579] {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.57 mmol), 2-methyl-propan-l-ol (0.078 mL; 0.85 mmol) and tributylphosphine (0.31 mL; 1.25 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1' -(Azodicarbonyl)dipiperidine (0.31 g; 1.25 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After stirring for 16 h the reaction mixture was evaporated to dryness and purified by prep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 498.1 (M+); Rt: 2.03 min [00580] Step B: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid [00581] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy)-acetic acid ethyl ester (140 mg; 0.28 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 130 mg. HPLC-MS: m/z: 470.0 (M+); Rt: 1.76 min. 8H(400 MHz; CDC13) 1.00 (d, 6H), 1.98-2.09 (m, 1H), 2.27 (s, 3H), 3.13-3.29 (m, 2H), 3.43-3.57 (m, 2H), 3.66 (d, 2H), 3.92-4.09 (m, 4H), 4.12 (s, 2H), 4.71 (s, 2H), 6.55 (m, 1H), 6.71-6.75 (m, 2H), 6.79 (m, 1H), 7.25-7.29 (m, 1H), 7.30 (m, 1H). [00582] Example 10 [00583] {4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid (Formula Removed) [00584] Step A: {4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester [00585] 4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.57 mmol), 4-(chloro-phenyl)-methanol (0.12 mg; 0.85 mmol) and tributylphosphine (0.31 mL; 1.25 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1' -(Azodicarbonyl)dipiperidine (0.31 g; 1.25 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After storing for 16 h the reaction mixture was evaporated to dryness and purified by prep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 566.1 (M+); Rt: 2.13 min. [00586] Step B: {4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy} -acetic acid {4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (140 mg; 0.28 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 180 mg. HPLC-MS: m/z: 538.0 (M+); Rt: 1.84 min. δH(400 MHz; CDC13) 2.27 (s, 3H), 3.15-3.30 (m, 2H), 3.45 (d, 2H), 3.99-4.06 (m, 2H), 4.13-4.22 (m, 4H), 4.73 (s, 2H), 4.96 (s, 2H), 6.57-6.60 (m, 1H), 6.74 (d, 1H), 6.76-6.81 (m, 2H), 7.25-7.31 (m, 4H), 7.32-7.36 (m, 2H). [00587] Example 11 [00588] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}- acetic acid (Formula Removed) [00589] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (50 mg; 0.11 mmol) was dissolved in ethanol (6 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep. HPLC (method B). Yield: 36 mg. HPLC-MS: m/z: 445.1 (M+); Rt: 2.44 min. [00590] Example 12 [00591] {4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid (Formula Removed) [00592] Step A: {4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2 methyl-phenoxy}-acetic acid ethyl ester [00593] 4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.57 mmol), 2-butyn-l-ol (0.064 mL; 0.85 mmol) and tributylphosphine (0.31 mL; 1.25 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1' -(Azodicarbonyl)dipiperidine (0.31 g; 1.25 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After stirring for 16 h the reaction mixture was evaporated to dryness and purified by prep. HPLC (method B). Yield: 150 mg. HPLC-MS: m/z: 494.0 (M+); Rt: 1.87 min. [00594] Step B: {4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid [00595] {4- [3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2-methyl-phenoxy)-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 140 mg. HPLC-MS: m/z: 466.0 (M-i-); Rt: 1.60 min. [00596] Example 13 [00597] {2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]- phenoxy}-acetic acid (Formula Removed) [00598] Step A: {2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenyl-sulfanyl]-phenoxy} -acetic acid ethyl ester [00599] [4-(3-Hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.48 mmol), 2-morpholin-4-yl-ethanol (0.22 g; 0.67 mmol) and tributylphosphine (0.24 mL; 0.96 mmol) were dissolved in THF (15 mL) in a dried reaction flask un- der an atmosphere of nitrogen. l,1-(Azodicarbonyl)dipiperidine (0.24 g; 0.96 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After stirring for 16 h the reac tion mixture was evaporated to dryness and purified by flash chromatography (ethyl acetate: heptane (1:3 -» 1:9). Yield: 150 mg. HPLC-MS: m/z: 532.6 (M+H); Rt: 2.07 min. [00600] Step B: {2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-acetic acid [00601] {2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 140 mg. HPLC-MS: m/z: 504.1 (M+); Rt: 1.80 min. [00602] Example 14 [00603] {2-Chloro-4-[3-(3-methoxy-prop-l-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl- sulfanyl]-phenoxy}-acetic acid (Formula Removed)[00604] Step A: {2-Chloro-4-[3-(3-methoxy-prop-l-ynyl)-5-(3-morpholin-4-yl-propcxy)-phenylsulfanylj-phenoxy} -acetic acid ethyl ester [00605] {4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-acetic acid ethyl ester (0.2 g; 0.37 mmol), 3-methoxy-propyne (0.10 g; 1.47 mmol), bis(triphenylphosphine) palladium (II) chloride (21 mg; 0.029 mmol) and copper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 150°C for Ih. The reaction mixture was evaporated to dryness and extracted with ethyl acetate from a aqueous 5% citric acid solution. The crude product was dried, evaporated to dryness and purified by preparative HPLC (method B). Yield: 160 mg. HPLC-MS: m/z: 534.1 (M+); Rt: 1.79min. [00606] Step B: {2-Chloro-4-[3-(3-methoxy-prop-l-ynyl)-5-(3-morpholin-4-yl-propoxy)- phenylsulfanyl]-phenoxy} -acetic acid [00607] {2-Chloro-4-[3-(3-methoxy-prop-l-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-sulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethaaol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture wa;. stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, and evaporated to dryness and purified by preparative HPLC (method B). Yield: 50 mg. HPLC-MS: m/z: 506.0 (M+); Rt: 1.56 min. δH(400 MHz; CDC13) 2.06-2.15 (m, 2H), 2.82-2.92 (m, 2H), 3.15-3.23 (m, 2H), 3.45 (s, 3H), 3.56 (d, 2H), 3.78(t, 2H), 3.95-4.03 (m, 4H), 4.30 (s, 2H), 4.89 (s, 2H), 5.91-5.94(m, 1H), 6.63-6.66 (m, 1H), 6.93 (d, 1H), 7.01-7.03 (m, 1H), 7.40 (dd,1H), 7.58 (d, 1H). [00608] Example 15 [00609] {2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-l-ynyl-phenylsulfanyl]- phenoxy}-acetic acid (Formula Removed) [00610] Step A: {2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-l-ynyl-phenylsulfanyl]- phenoxy}-acetic acid ethyl ester [00611] {4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyI]-2-chloro-phenoxy}- acetic acid ethyl ester (0.2 g; 0.37 mmol), 1-pentyne (0.10 g; 1.47 mmol), bis(triphenyl- phosphine)palladium (II) chloride (21 mg; 0.029 mmol) and copper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 150 °C for Ih. The reaction mixture was evaporated to dryness and extracted with ethyl acetate from a aqueous 5% citric acid solution. The crude product was dried, evaporated to dryness and purified by preparative HPLC (method B). Yield: 120 mg. HPLC-MS: m/z: 532.0 (M+); Rt: 2.02 min. [00612] Step B: {2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-l-ynyl-phenylsulfany!]-phenoxy)-acetic acid [00613] {2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent- 1-ynyl-phenylsulfanyl]-phenoxy)-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, and evaporated to dryness and purified by preparative HPLC (method B). Yield: 70 mg. HPLC-MS: m/z: 504.1 (M+); Rt: 1.81 min. [00614] Example 16 [00615] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1 -ynyl)-benzyl- sulfanyl]-phenoxy} -acetic acid (Formula Removed) [00616] Step A: {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-phenoxy}-acetic acid ethyl ester [00617] {4-[3-Hydroxy-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.45 mmol), 3-morpholin-4-yl-propan-l-ol (97.6 mg; 0.67 mmol), tributylphosphine (0.27 mg; 1.34 mmol) and l,r-(Azodicarbonyl)dipiperidine (0.34 g; 1.34 mmol) were dissolved in THF (20 mL) in a dried reaction flask under an atmosphere of nitrogen. The reaction mixture was stirred for Ih and purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 574.3 (M+H); Rt: 2.07 min. [00618] Step B: (2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-phenoxy}-acetic acid [00619] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-benzyl-sulfanyl]-phenoxy} -acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 190 mg. HPLC-MS: m/z: 546. • (M+);Rt: 1.85 min. [00620] Example 17 [00621] {4-[3-(4-Ruoro-benzyloxy)-5-(3-morpholin-4-yl-prop-lynyl)-benzylsulfanyl]-2- methyl-phenoxy} -acetic acid (Formula Removed) [00622] Step A: {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-lynyl)-benzyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00623] {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1 -ynyl)-benzylsulfanyl]-2-methyl-phenoxy)-acetic acid ethyl ester (250 mg; 0.55 mmol), l-fluoro-4-methoxymethyl-benzene (103.8 mg; 0.82 mmol), tributylphosphine (0.33 mg; 1.65 mmol) and l,l'-(azodicarbonyl)-dipiperidine (0.414 g; 1.65 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. The reaction mixture was stirred for 16h and purified by prep. HPLC (method A). Yield: 160 mg. HPLC-MS: m/z: 564.1 (M+H); Rt: 1.99 min. [00624] Step B: (4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-lynyl)-benzyl-sulfanyl]-2-methyl-phenoxy} -acetic acid [00625] {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-lynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 190 mg. HPLC-MS: m/z: 536.1 (M+);Rt: 1.76 min. [00626] Example 18 [00627] {2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-l-ynyl)-benzyl- sulfanyl]-phenoxy}-acetic acid (Formula Removed) [00628] Step A: {2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-phenoxy}-acetic acid ethyl ester [00629] {4-[3-Hydroxy-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.56 mmol), 3-morpholin-4-yl-propan-l-ol (110.1 mg; 0.84 mmol), tributylphosphine (0.34 mL; 1.68 mmol) and l,r-(azodicarbonyl)dipiperidine (0.42 g; 1.68 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 2 h the reaction mixture was purified by prep. HPLC (method A). Yield: 50 mg. HPLC-MS: m/z: 560.2 (M+H); Rt: 2.03 min. [00630] Step B: {2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-l-ynyl)-benzyl- sulfanyl]-phenoxy}-acetic acid [00631] {2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-l-ynyl)-benzyl-sulfanyl]-phenoxy }-acetic acid ethyl ester (50 mg; 0.09 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (2 mL) was added. The reaction mixture was stirred for 16 h, acidified with 1 N aqueous hydrochloric acid and extracted with dichloromethane. The organic phase was dried and evaporated to dryness. Yield: 45 mg. HPLC-MS: m/z: 532.1 (M+);Rt: 1.79 min. [00632] Example 19 [00633] {4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2- methyl-phenoxy}-acetic acid(Formula Removed) [00634] Step A: {4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00635] [4-(3-Bromo-5-cyclohexylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl acetate (0.1 g; 0.203 mmol), 1-Ethynyl-4-methanesulfonyl-benzene (0.109 g; 0.6; mmol), bis(triphenylphosphine)palladium (II) chloride (11.4 mg; 0.016 mmol) and copper :o-dide (2.3 mg; 0.06 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 120°C for Ih. Water and dichloromethane was added to the reaction mixture and the phases were separated and washed with water. The organic phase was dried and evaporated to dryness. The crude product was purified by prep. HPLC (Metode A). Yield: 90 mg. HPLC-MS: m/z: 593.5 (M+H)+; Rt: 3.04 min. [00636] Step B: {4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid [00637] {4- [3-Cyclohexylmethoxy-5 -(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester (120 mg; 0.202 mmol) was dissolved in ethanol (50 mL), and aqueous 1 N sodium hydroxide (2 mL) was added. The reaction mixture was stirred for 30 min, acidified with 1 N aqueous hydrochloric acid and extracted with dichloromethane. The organic phase was dried and evaporated to dryness. Yield: 90 mg. HPLC-MS: m/z: 565.3 (M+H)+;Rt:2.81 min. [00638] Example 20 [00639] {4-[3-Cyclopentylmethoxy-5-(4-methanesuhconyl-phenylethynyl)-phenylsulfanyl]-2- methyl-phenoxy}-acetic acid (Formula Removed) [00640] Step A: {4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00641] [4-(3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl acetate (0.24 g; 0.50 mmol), 1-Ethynyl-4-methanesulfonyl-benzene (0.271 g; 1.5 mmol), bis(triphenylphosphine)palladium (II) chloride (28.11 mg; 0.04 mmol) and copper iodide (5.7 mg; 0.03 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (5 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 120°C for Ih. Water and dichloromethane was added to the reaction mixture and the phases were separated and washed with water. The organic phase was dried and evaporated to dryness. The crude product was purified by prep. HPLC (Metode A). Yield: 180 mg. HPLC-MS: m/z: 579.4 (M+H)+; Rt: 3.00 min. [00642] Step B: {4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid [00643] {4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanylJ-2-methyl-phenoxy}-acetic acid ethyl ester (120 mg; 0.202 mmol) was dissolved in ethanol (50 mL), and aqueous 1 N sodium hydroxide (2 mL) was added. The reaction mixture was stirred for 30 min, acidified with 1 N aqueous hydrochloric acid and extracted with dichloromethane. The organic phase was dried and evaporated to dryness. Yield: 100 mg. HPLC-MS: m/z: 551.5(M+H)+;Rt:2.69min. [00644] Example 21 [00645] {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl- phenoxy} -acetic acid (Formula Removed) [00646] Step A: {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2- methyl-phenoxy} -acetic acid ethyl ester [00647] The title product was prepared as described for {4-[3-Cyclopentylmethoxy-5-(4- methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by prep. HPLC (method B). Yield: 52%. HPLC-MS: m/z: 552.7 (M)+; Rt: 2.88 min. [00648] Step B: {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2- methyl-phenoxy}-acetic acid [00649] {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid ethyl ester (190 mg; 0.34 mmol) was dissolved in ethanol (10 mL), ai?.d aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 110 mg (61%). HPLC-MS: m/z: 525.1 (M+H)+; Rt: 2.55 min. [00650] Example 22 [00651] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)- phenylsulfanyl]-2-methyl-phenoxy} -acetic acid (Formula Removed) [00652] Step A: {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00653] The title product was prepared as described for {4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl estei. The crude product was purified by prep. HPLC (method B). Yield: 64 %. HPLC-MS: m/z: 635.4 (M+H)+; Rt: 2.92 min. [00654] Step B: {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid [00655] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (190 mg; 0.30 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 160 mg (89%). HPLC-MS: m/z: 607.1 (M+H)+; Rt: 2.82 mm. [00656] Example 23 [00657] {4-[3-[2-(4-Chloro-phenyl)-emoxy]-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyi- sulfanyl]-2-methyl-phenoxy} -acetic acid (Formula Removed) [00658] Step A: {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00659] (4- {3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl }-2-methyl-phenoxy)-acetic acid ethyl ester (300 mg; 0.56 mmol), 4-prop-2-ynyl-morpholine (280,4 mg; 2.2 mnol), bis(triphenylphosphine) palladium (II) chloride (31.4 mg; 0.045 mmol) and copper iodide (6.4 mg; 0.034 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 110 °C for 1.5 h. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid (30 mL) and ethyl acetate (30 mL) was added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were dried and evaporated to dryness and purified by preparative HPLC (method B). Yield: 300 mg; 92%. HPLC-MS: m/z: 580.7 (M+H)+; Rt: 2.16 min. [00660] Step B: {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (190 mg; 0.30 mmol) was dissolved in ethano! (25 mL), and aqueous 1 N sodium hydroxide (5 mL) was added. The reaction mixture wf s stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. Tne organic phase was dried and evaporated to dryness, redissolved in dichloromethane and evaporated to dryness. Yield: 250 mg (87%). HPLC-MS: m/z: 552.8 (M+H)+; Rt: 1.90 min. [00661] Example 24 [00662] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenyl- sulfanyl]-2-methyl-phenoxy}-acetic acid (Formula Removed) [00663] Step A: {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00664] (4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-acetic acid ethyl ester (270 mg; 0.46 mmol), (4-ethynyl-phenyl)-methanol (296 mg; 2.2 mmol), bis(triphenylphosphine) palladium (II) chloride (31.4 mg; 0.045 mmol) and copper iodide (6.4 mg; 0.034 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 niL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 110 °C for 1.5 h. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid (30 mL) and ethyl acetate (30 mL) was added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were dried and evaporated to dryness and purified by preparative HPLC (method B). Yield: 270 mg (83%). HPLC-MS: m/z: 587.1 (M+H)+; Rt: 2.96 min. [00665] Step B: {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynv!) phenylsulfanyl]-2-methyl-phenoxy }-acetic acid [00666] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep HPLC (method B). Yield: 218 mg (85%). HPLC-MS: m/z: 559.1 (M+H)+; Rt: 2.61 min. [00667] Example 25 [00668] {4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid(Formula Removed) [00669] Step A: {4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy)-acetic acid ethyl ester [00670] The title product was prepared from {4-[3-Bromo-5-(2-ethyl-butoxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.42 mmol), (phenyl acetylene (170 mg; 1.66 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 170 mg (82%). HPLC-MS: m/z: 502.9 (M)+; Rt: 3.32 min. [00671] Step B: {4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phen-oxy}-acetic acid [00672] {4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N so dium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep HPLC (method B). Yield: 128 mg (80%). HPLC-MS: m/z: 475.1 (M+H)+; Rt: 3.06 min. [00673] Example 26 [00674] [4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid (Formula Removed) [00675] Step A: [4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester [00676] The title product was prepared from [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (250 mg; 0.54 mmol), (phenyl acetylene (110 mg; 1.07 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 186 mg (70%). HPLC-MS: m/z: 487.1 (M+H)+; Rt: 3.17 min. [00677] Step B: [4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid [00678] {[4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep HPLC (method B). Yield: 120 mg (69%). HPLC-MS: m/z: 459.1 (M+H)+; Rt: 2.86 min. [00679] Example 27 [00680] {4- [3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]- 2-methyl-phenoxy}-acetic acid (Formula Removed) [00681] Step A: {4-[3-(4-Huoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00682] The title product was prepared from {4-[3-Bromo-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (335 mg; 0.59 mmol), l-ethynyl-4-fluorobenzene (142.3 mg; 1.19 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 140 mg (39%). HPLC-MS: m/z: 605.5 (M+H)+; Rt: 2.80 min. [00683] Step B: {4-[3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid [00684] {4- [3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep HPLC (method B). Yield: 113 mg (85%). HPLC-MS: m/z: 599.4 (M+Na); Rt: 2.50 min. [00685] Example 28 [00686] [4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]- acetic acid (Formula Removed) [00687] Step A: [4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester [00688] The title product was prepared from [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.63 mmol), phenylacetylen (191.7 mg; 1.88 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 200 mg (64%). HPLC-MS: m/z: 500.8 (M)+; Rt: 3.30 min. [00689] Step B: [4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid [00690] {[4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.40 mmol) was dissolved in THF (2 mL), ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 146 mg (78%). HPLC-MS: m/z: 472.9 (M)+; Rt: 3.03 min. [00691] Example 29 [00692] {4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}- acetic acid (Formula Removed) [00693] Step A: {4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00694] The title product was prepared from {4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester (300 mg; 0.58 mmol), phenylace-tylen (181.1 mg; 1.8 mmol) applying the procedure described for {4-[3-[2-(4-ChIoro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 110 mg (33%). HPLC-MS: m/z: 529.6 (M+H)+; Rt: 3.38 min. [00695] Step B: {4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid [00696] {4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (110 mg; 0.208 mmol) was dissolved in THF (2 mL), ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 105 mg. HPLC-MS: m/z: 500.1 (M)+; Rt: 3.20 min. [00697] Example 30 [00698] {4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2 methyl- phenoxy}-acetic acid(Formula Removed) [00699] Step A: {4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00700] The title product was prepared from 4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.42 mmol) and 4-prop-2-ynyl-morpho-line (156,0 mg; 1,26 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 210 mg (95%). HPLC-MS: m/z: 526.2 (M+H)+; Rt: 2.23 min [00701] Step B: {4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}- acetic acid [00702] {4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (210 mg; 0.40 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yie'.d. 144 mg (73%). HPLC-MS: m/z: 498.2 (M+H)+; Rt: 1.97 min. [00703] Example 31 [00704] {4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid (Formula Removed) [00705] Step A: {4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2- methyl-phenoxyj-acetic acid ethyl ester [00706] The title product was prepared from [4-(3-Bromo-5-cyclopentyloxy-phenylsuifanyl)- 2-methyl-phenoxy]-acetic acid ethyl ester (250 mg; 0.54 mmol) and 4-prop-2-ynyl-moipho- line (134.48 mg; 1.07 mmol) applying the procedure described for {4-[3-[2-(4-Chloro- phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}- acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 210 mg (95%). HPLC-MS: m/z: 510.2 (M+H)+; Rt: 2.03 min [00707] Step B: (4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2- methyl-phenoxy} -acetic acid [00708] {4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid ethyl ester (160 mg; 0.31 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 105 mg (70%). HPLC-MS: m/z: 482.2 (M+H)+; Rt: 1.77 min. [00709] Example 32 [00710] {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-y 1-prop-1 -ynyl)-phenylsulfanyl]-2- methyl-phenoxy} -acetic acid (Formula Removed) [00711] Step A: {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester [00712] The title product was prepared from {4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (300 mg; 0.59 mmol) and 4-prop-2-ynyl-morpholine (222.0 mg; 1.77 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy] -5 - (4-hydroxymethy l-phenylethynyl)-phenylsulfanyl] -2-methyl-phenoxy} -acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 200 mg (30%). HPLC-MS: m/z: 551.8 (M)+; Rt: 2.35 min [00713] Step B: {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid [00714] {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester (200 mg; 0.36 mmol) was dissolved in THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 107 mg (57%). HPLC-MS: m/z: 523.9 (M)+; Rt: 2.06 min. [00715] Example 33 [00716] {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2- methyl-phenoxy}-acetic acid [00717] Step A: {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00718] The title product was prepared from {4-[3-Bromo-5-cyclopentylmethoxy-phenyl-sulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (260 mg; 0.54 mmol) and 4-prop-2-ynyl-morpholine (203.6 mg; 1.63 mmol) applying the procedure described for (4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 80 mg (28%). HPLC-MS: m/z: 523.9 (M)+; Rt: 2.19 min [00719] Step B: {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid [00720] {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (80 mg; 0.15 mmol) was dissolved in THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 43 mg (57%). HPLC-MS: m/z: 495.8 (M)+; Rt: 1.92 min. [00721] Example 34 [00722] {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2- methyl-phenoxy} -acetic (Formula Removed)[00723] Step A: {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic ethyl ester [00724] The title product was prepared from {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop 1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (350 mg; 0.77 mmol), cyclohexylmethanol (131.6 mg; 1.15 mmol), tributylphosphine (0.465 mg; 2.31 mmol) and l,r-(azodicarbonyl)dipiperidine (0.581 g; 2.31 mmol) were dissolved in THF (50 mL) in a dried reaction flask under an atmosphere of nitrogen. The reaction mixture was stirred for 16h and purified by column chromatography; ethyl acetate: heptane (5:1). Yield: 120 mg. HPLC-MS: m/z: 552.1 (M+H)+; Rt: 2.19 min. [00725] Step B: {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic [00726] {4-[3-Cydopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic ethyl ester (120 mg; 0.22 mmol) was dissolved in THF (2 mL) and ethanol (8 mL), and aqueous 1 N sodium hydroxide (2 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 110 mg (90%). HPLC-MS: m/z: 524.2 (M+H)+; Rt: 1.97 min. [00727] Example 35 [00728] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl- phenoxy}-acetic acid [00729] Step A: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}- acetic acid ethyl ester The title product was prepared from [4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.64 mmol) and 4-prop-2-ynyl-morpholine (221 mg; 2.6 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 140 mg (44%). HPLC-MS: m/z: 511.9 (M)+; Rt: 2.00 min. [00730] Step B: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid {{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (140 mg; 0.27 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acie;fiec! with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness, redissolved in dichloromethane and evaporated to dryness. Yield: 113 mg (86%). HPLC-MS: m/z: 484.9 (M+H)+; Rt: 1.70 min. δH(400 MHz; CDC13) 1.03 (d, 6H), 2.04-2.12 (m, 1H), 2.24 (s, 3H), 2.90-3.30 (m, 2H), 3.40-3.70 (m, 2H), 3.71 (d, 2H), 3.74 (s, 2H), 3.95-4.05 (m, 4H), 4.17 (s, 2H), 4.69 (s, 2H), 6.14 (m, 1H), 6.53 (d, 1H), 6.77(dd, 1H), 6.81 (m, 1H), 6.89 (m, 1H), 7.23 (d, 1H). [00731] Example 36 [00732] [4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid (Formula Removed) [00733] Step A: [4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester [00734] The title product was prepared from [4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2- methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.64 mmol) and phenylacetylen (262 mg; 2.6 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4- hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 130 mg (45%). HPLC-MS: m/z: 489.1 (M+H)+; Rt: 3.01 min [00735] Step B: [4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid [00736] [4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (130 mg; 0.27 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness, redissolved in dichloromethane and evaporated to dryness. Yield: 120 mg (97%). HPLC-MS: m/z: 461.7 (M+H)+; Rt: 2.82 min. [00737] Example 37 [00738] {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl- phenoxy}-acetic acid (Formula Removed) [00739] Step A: [{4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxy } -acetic acid ethyl ester [00740] The title product was prepared from [4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.64 mmol) and l-Ethynyl-4-methane-sulfonyl-benzene (347.0 mg; 1.93 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy } -acetic acid ethyl ester. The crude product was purified by preparative HPLC (method A). Yield: 260 mg (72%). HPLC-MS: m/z: 567.6 (M+H)+; Rt: 2.77 min [00741] Step B: {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxy} -acetic acid. [00742] {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxy) -acetic acid ethyl ester (130 mg; 0.27 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness, redissolved in dichloromethane and evaporated to dryness. Yield: 230 mg (%). HPLC-MS: m/z: 539.5 (M+H)+; Rt: 2.49 min. [00743] Example 38 [00744] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)- phenylsulfanyl]-2-methyl-phenoxy }-acetic acid (Formula Removed) [00745] Step A: {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00746] The title product was prepared from {4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester (250 mg; 0.46 mmol) and l-Ethynyl-4-methanesulfonyl-benzene (249.2 mg; 1.38 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 168 mg (57%). HPLC-MS: m/z: 642.1 (M+H)+; Rt: 2.75 min [00747] Step B: {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid. [00748] {{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester (168 mg; 0.26 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by prep -rative HPLC (method B). Yield: 120 mg (75%). HPLC-MS: m/z: 614.1 (M+H)+; Rt: 2.45 min. [00749] Example 39[00750] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)- phenylsulfanyl]-2-methyl-phenoxy }-acetic acid (Formula Removed) [00751] Step A: {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester [00752] The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-pvridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester (250 mg; 0.46 mmol) and l-Ethynyl-4-methanesulfonyl-benzene (249.2 mg; 1.38 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 197 mg (67%). HPLC-MS: m/z: 642.4 (M+H)+; Rt: 2.73 min [00753] Step B: {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid. [00754] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester (197 mg; 0.31 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 150 mg (80%). HPLC-MS: m/z: 614.4 (M+H)+; Rt: 2.42 min. [00755] Example 40 [00756] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-1 -ynyl)-5-(3-trifluoromethyl-pyridin-2- yloxy)-phenylsulfanyl]-phenoxy} -acetic acid (Formula Removed) [00757] Step A: {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy} -acetic acid ethyl ester [00758] The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester (250 mg; 0.46 mmol) and 4-prop-2-ynyl-morpholine (173.09 mg; 1.38 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 262 mg (97%). HPLC-MS: m/z: 587.5 (M+H)+; Rt: 2.03 min [00759] Step B: {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy} -acetic acid. [00760] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-pyridm-2-yloxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (262 mg; 0.45 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 178 mg (72%). HPLC-MS: m/z: 559.5 (M+H)+; Rt: 1.78 min. [00761] Example 41 [00762] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(5-trifluoromethyl-pyridin-2- yloxy)-phenylsulfanyl]-phenoxy}-acetic acid (Formula Removed) [00763] Step A: {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy} -acetic acid ethyl ester [00764] The title product was prepared from {4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.46 mmol) and 4-prop-2-ynyl-morpholine (173.09 mg; 1.38 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 270 mg (100%). HPLC-MS: m/z: 587.5 (M+H)+; Rt: 2.03 min [00765] Step B: {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy} -acetic acid. [00766] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy} -acetic acid ethyl ester (262 mg; 0.45 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 174 mg (68%). HPLC-MS: m/z: 559.5 (M+H)+; Rt: 1.81 min. [00767] Example 42 [00768] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-phenoxy)- phenylsulfanyl] -phenoxy} -acetic acid (Formula Removed) [00769] Step A: {2-Memyl-4-[3-(3-morpholm-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl- phenoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester [00770] The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)- phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (230 mg; 0.43 mmol) and 4-prop- 2-ynyl-morpholine (159.5 mg; 1.28 mmol) applying the procedure described for {4-[3-[2-(4- Chloro-phenyl)-etlioxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl- phenoxy} -acetic acid ethyl ester. The crude product was purified by preparative HPLC (method A). Yield: 160 mg. HPLC-MS: m/z: 586.5 (M+H)+; Rt: 2.18 min [00771] Step B: {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl- phenoxy)-phenylsulfanyl]-phenoxy} -acetic acid. [00772] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (160 mg; 0.27 mmol) was dissolved in etha nol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 128 mg (84%). HPLC-MS: m/z: 558.4 (M+H)+; Rt: 1.91 min.δH(400 MHz; CDC13) 2.26 (s, 3H), 3.05-3.55 (m, 4H), 3.91-4.04 (m, 4H), 4.11 (s, 2H), 4.70 (s, 2H), 6.71-6.78 (m, 3H), 6.81-6.84 (m, 1H), 7.11-7.16 (m, 1H), 7.19-7.23 (m, 1H), 7.27-7.33 (m, 2H), 7.37-7.41 (m, 1H), 7.43-7.49 (m, 1H). [00773] Example 43 (Formula Removed) [00774] (4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid [00775] Step A: {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester [00776] The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester (230 mg; 0.43 mmol) and 1-Ethynyl-4-methanesulfonyl-benzene (229.7 mg; 1.28 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method A). Yield: 140 mg. HPLC-MS: m/z: 641.5 (M+H)+; Rt: 2.89 min [00777] Step B: {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid. [00778] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (140 mg; 0.22 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 100 mg (75%). HPLC-MS: m/z: 635.1 (M+Na); Rt: 2.62 min. [00779] Example 44 [00780] {2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl- sulfanyl]-phenoxy} -acetic acid (Formula Removed) [00781] Step A: {2-Methyl-4-[3-phenylemynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)- phenylsulfanylj-phenoxy} -acetic acid ethyl ester [00782] The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)- phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (300 mg; 0.55 mmol) and phenylacetylene (113 mg; 1.11 mmol) applying the procedure described for {4-[3-[2-(4- Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl- phenoxy} -acetic acid ethyl ester. The crude product was purified by preparative HPLC (method A). Yield: 150 mg. HPLC-MS: m/z: 564.5 (M+H)+; Rt: 3.00 min [00783] Step B: {2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)- phenylsulfanyl]-phenoxy}-acetic acid. [00784] {2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)- phenylsulfanyl]-phenoxy} -acetic acid ethyl ester (150 mg; 0.266 mmol) was dissolved in THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1/2h. acidified with 5% aqueous citric acid and extracted with ethyl acetate, dried and evaporated to dryness. Yield: 100 mg (75%). HPLC-MS: m/z: 535.7 (M)+; Rt: 2.78 min. [00785] Example 45 [00786] {4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2- methyl-phenoxy)-acetic acid (Formula Removed) [00787] Step A: {4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzyl-sulfanyl]-2-methyl-phenoxy}-acetic acid acid ethyl ester [00788] The title product was prepared from [4-(3-Bromo-5-cyclopropylmethoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.43 mmol) and 4-prop-2-ynyl-morpholine (161 mg; 1.3 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 173 mg; 79%. HPLC-MS: m/z: 510.1 (M)+; Rt: 1.9 min. [00789] Step B: {4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid [00790] (4-[3-Cydopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy)-acetic acid acid ethyl ester (173 mg; 0.34 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 107 mg; 66%. HPLC-MS: m/z: 482.0 (M+H)+; Rt: 1.62 min. [00791] Example 46 [00792] _{4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2- methyl-phenoxy)-acetic acid [00793] Step A: {4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00794] The title product was prepared from [4-(3-Bromo-5-cyclopropylmethoxy-phenyl-sulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (250 mg; 0.55 mmol) and 4-prop-2-ynyl-morpholine (208 mg; 1.7 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 205 mg; 75%. HPLC-MS: m/z: 496.1 (M+H)+; Rt: 2.04 min. [00795] Step B: {4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid [00796] {4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (205 mg; 0.41 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 160 mg; 83%. HPLC-MS: m/z: 468.1(M+H)+;Rt: 1.78 min. [00797] Example 47 [00798] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2,5-dimethyl- phenoxy}-acetic acid (Formula Removed) [00799] Step A: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2,5-dimethyl-phenoxy} -acetic acid ethyl ester [00800] The title product was prepared from [4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-acetic acid ethyl ester (400 mg; 0.86 mmol) and 4-prop-2-ynyl-morpholine (321.3 mg; 2.6 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 350 mg; 80%. HPLC-MS: m/z: 512.2 (M+H)+; Rt: 2.09 min. [00801] Step B: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2,5-dimethyl-phenoxy}-acetic acid [00802] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2,5-dimethyl-phenoxy}-acetic acid ethyl ester (350 mg; 0.68 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 250 mg; 76%. HPLC-MS: m/z: 484.6 (M+H)+; Rt: 1.87 min. [00803] Example 48 {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenoxy]-2-methyl-phenoxy}-acetic acid (Formula Removed) [00804] Step A: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenoxy]-2-methyl-phenoxy}-acetic acid ethyl ester [00805] The title product was prepared from [4-(3-Bromo-5-isobutoxy-phenylsulfanyl> 2,5-dimethyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.71 mmol) and 4-prop-2-ynyl-morpholine (266.1 mg; 2.1 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 260 mg; 79%. HPLC-MS: m/z: 468.7 (M+H)+; Rt: 1.94 min [00806] Step B: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenoxy]-2-methyl-phenoxy}-acetic acid [00807] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenoxy]-2-methyl-phenoxy}-acetic acid ethyl ester (260 mg; 0.56 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 180 mg; 72%. HPLC-MS: m/z: 454.6 (M+H)+; Rt: 1.77 min. 6H(400 MHz; CDC13) 1.01 (d, 6H), 2.02-2.10 (m, 1H), 2.28 (s, 3H), 3.10-3.55 (m, 4H), 3.68 (d, 2H), 3.93-4.07 (m, 4H), 4.10 (s, 2H), 4.67 (s, 2H), 6.47 (m, 1H), 6.57-6.59 (m, 1H), 6.66-6.69 (m, 1H), 6.71 (d, 1H), 6.79 (dd, 1H), 6.86 (d, 1H). PHARMACOLOGICAL METHODS IN VITRO PPAR-8 ACTIVATION ACTIVITY [00808] The PPAR transient transactivation assay is based on transient transfection into human HEK293 cells of two plasmids encoding a chimeric test protein and a reporter protein respectively. The chimeric test protein is a fusion of the DNA binding domain (DBD) from the yeast GAL4 transcription factor to the ligand binding domain (LBD) of the human PPAR proteins. The PPAR-LBD moiety harbored in addition to the ligand binding pocket also the native activation domain (activating function 2 = AF2) allowing the fusion protein to function as a PPAR ligand dependent transcription factor. The GAL4 DBD will direct the chimeric protein to bind only to Gal4 enhancers (of which none existed in HEK293 cells). The reporter plasmid contained a Gal4 enhancer driving the expression of the firefly luciferase protein. After transfection, HEK293 cells expressed the GAL4-DBD-PPAR-LBD fusion protein. The fusion protein will in turn bind to the Gal4 enhancer controlling the luciferase expression, and do nothing in the absence of ligand. Upon addition to the cells of a PPAR ligand luciferase protein will be produced in amounts corresponding to the activation of the PPAR protein. The amount of luciferase protein is measured by light emission after addition of the appropriate substrate. CELL CULTURE AND TRANSFECTION [00809] HEK293 cells were grown in DMEM + 10% PCS. Cells were seeded in 96-well plates the day before transfection to give a confluency of 50-80 % at transfection. A total of 0,8 ng DNA containing 0,64 ug pMlo/LBD, 0,1 ug pCMVßGal, 0,08 ug pGL2(Ga!4)5 and 0,02 ug pADVANTAGE was transfected per well using FuGene transfection reagent according to the manufacturers instructions (Roche). Cells were allowed to express protein for 48 h followed by addition of compound. [00810] Plasmids: Human PPAR-8 was obtained by PCR amplification using cDNA synthesized by reverse transcription of mRNA from human liver, adipose tissue and plancenta respectively. Amplified cDNAs were cloned into pCR2.1 and sequenced. The ligand binding domain (LBD) of each PPAR isoform was generated by PCR (PPAR6: aa 128 - C-terminus) and fused to the DNA binding domain (DBD) of the yeast transcription factor GAL4 by sub- cloning fragments in frame into the vector pMl (Sadowski et al. (1992), Gene 118,137) generating the plasmids pMlaLBD, pMlyLBD and pM18. Ensuing fusions were verified by sequencing. The reporter was constructed by inserting an oligonucleotide encoding five repeats of the GAL4 recognition sequence (5 x CGGAGTACTGTCCTCCG(AG)) (Webster et al. (1988), Nucleic Acids Res. 16, 8192) into the vector pGL2 promoter (Promega) generating the plasmid pGL2(GAL4)5. pCMVßGal was purchased from Clontech and pADVANTAGE was purchased from Promega. IN VITRO TRANSACTIVATION ASSAY [00811] Compounds: All compounds were dissolved in DMSO and diluted 1:1000 upon addition to the cells. Compounds were tested in quadruple in concentrations ranging from O.OO1 to 300 uM. Cells were treated with compound for 24 h followed by luciferase assay. Each compound was tested in at least two separate experiments. [00812] Luciferase assay: Medium including test compound was aspirated and 100 µl PBS incl.1mM Mg++ and Ca++ were added to each well. The luciferase assay was performed using the LucLite kit according to the manufacturer's instructions (Packard Instruments). Light emission was quantified by counting on a Packard LumiCounter. To measure 0-galactosidase activity 25µl supernatant from each transfection lysate was transferred to a new microplate. ß-Galactosidase assays were performed in the microwell plates using a kit from Promega and read in a Labsystems Ascent Multiscan reader. The p-galactosidase data were used to normalize (transfection efficiency, cell growth etc.) the luciferase data. STATISTICAL METHODS [00813] The activity of a compound is calculated as fold induction compared to an untreated sample. For each compound the efficacy (maximal activity) is given as a relative activity compared to Wy 14,643 for PPARa, Rosiglitazone for PPAR and Carbacyclin for PPAR8. The EC50 is the concentration giving 50% of maximal observed activity. EC50 values were calculated via non-linear regression using GraphPad PRISM 3.02 (GraphPad Software, San Diego, Ca). [00814] While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications, and substitutions can be made therein without departing from the spirit and scope of the present invention. For example, effective dosages other than the preferred dosages as set forth herein may be applicable as a consequence of variations in the responsiveness of the mammal being treated for PPAR-5 mediated disease(s). Likewise, the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. Accordingly, the invention is not to be limited as by the appended claims. [00815] The features disclosed in the foregoing description and/or in the claims may both separately ans in any combination thereof be material for realising the invention in diverse forms thereof. or a pharmaceutically acceptable salt thereof, wherein: X is selected from O, S, OCH2, and SCH2; 125 [00816] Preferred features of the invention: [00817] 1. A compound of formula I: (Formula Removed) X1 is O or S; R1 is selected from H, C1-8 alkyl, C2.8 alkenyl, aryl, heteroaryl ,C3-10 cycloalkyl, and a hetero-cyclyl, wherein each R1 group is substituted with 0-4 Rla; Rla, at each occurrence, is selected from S substituted with 0-1 Rlb, O substituted with G-l Rlb, halogen, NH2 substituted with 0-2 Rlb, -CN, NO2, C,.6 alkyl substituted with 0-3 Rlb, C2.6 alkenyl substituted with 0-2 Rlb, C2.6 alkynyl substituted with 0-2 Rlb, aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3-10cycloalkyl substituted with 0-2 Rlb, and het-erocycle substituted with 0-2 Rlb; Rlb, at each occurrence, is selected from S substituted with 0-1 Rlc, O substituted with 0-1 Rlc, halogen, methanesulfonyl, NH2 substituted with 0-2 Rlc, -CN, NO2, d1-6 alkyl substituted with 0-3 Rlc, C2-6 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3-10 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc; Rlc, at each occurrence, is selected from S substituted with 0-1 Rld, O substituted with 0-1 Rld, halogen, N42 substituted with 0-2 Rld, -CN, NO2, C1-6 alkyl substituted with 0-2 Rld, C2.6 alkenyl substitu'ed with 0-2 Rld, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3.io cycle; Ikyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; Rld, at each occ'irrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, C1-6 alkyl, C2.6 alkenyl, ary 1, CF3) and OCF3; R2 is selected from -C=C-R2a, -CH=CH-R2a, aryl substituted with 0-3 R2a, and heteroaryl substituted with 0-3 R2a; R2a, at each occurrence, is selected from S substituted with 0-1 R2b, O substituted with 0-1 R2b, halogen, NH2 substituted with 0-2 R2b, -CN, NO2, C1-6 alkyl substituted with 0-2 R2b, C2.6 alkenyl substitu'ed with 0-2 R2b, aryl substituted with 0-2 R2b, heteroaryl substituted with 0-2 R2b, C3-10 cyclo; Ikyl substituted with 0-2 R2b, and a heterocycle substituted with 0-2; R2b, at each occ'irrence, is selected from S substituted with 0-1 R2c, O substituted with 0-1 R20, halogen, methanesulfonyl, NH2 substituted with 0-2 R2c, -CN, NO2, Ci.6alkyl substituted with 0-2 R20, C2-6 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R20, heteroaryl substituted with 0-2 R25, CMO cycloalkyl substituted with 0-2 R20, and a heterocycle substituted with 0-2 R20; R2c, at each occurrence, is selected from S substituted with 0-1 R2d, O substituted with 0-1 R2d, halogen, NH2 substituted with 0-2 R2d, -CN, NO2, C,.6 alkyl substituted with 0-2 R2d, C2.6 alkenyl substitu'ed with 0-2 RM, aryl substituted with 0-2 R2d, heteroaryl substituted with 0-2 R2d, C3-10 cyckv.lkyl substituted with 0-2 R2d, and a heterocycle substituted with 0-2 R2d R2d, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, Ci.6 alkyl, C2.6 alkenyl, aryl, CF3, and OCF3; R3 is selected from halogen and C1-66 alkyl substituted with 0-2 R3a; R3a, at each occurrence, is selected from OH, O, S, halogen, C(0)NH2, C(O)NH-CM alkyl, and C(O)N(CM alkyl)2; alternatively, R3 and R5c combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)0.2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; R4a, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R4d; R4d, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N'C1-4 al-kyl)2; R4b, at each occurrence, is selected from H, halogen, and C1-6alkyl substituted with 0-2 R4"; R46, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 al-kyl)2; R40, at each occurrence, is selected from H, halogen, and Ci-6 alkyl substituted with 0-2 R4f, R4f, at each occurrence, is selected from OH, 0, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 al-kyl)2; R5a, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; R5b, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; R5c, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; R5d, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; and, R5c, at each occurrence, is selected from H, halogen, CH3, and CH2CH3. [00818] 2. A compound of clause 1 wherein: X is selected from O, S, OCH2, and SCH2; X'isOorS; R1 is selected from H, C1-8g alkyl, C2.8 alkenyl, aryl, 5-10 membered heteroaryl consisting of carbon atoms ard 1-4 heteroatoms selected from O, N, and S(O)0.2> C3-10 cycloalkyl, and a 3-8 membered heterocycle consisting of carbon atoms and 1-3 heteroatoms selected from 0, N, and S(O)o-2, wherein each R1 group is substituted with 0-4 Rla; Rla, at each occurrence, is selected from OH substituted with 0-1 Rlb, SH substituted with 0-1 Rlb, S, O, halogen, NH2 substituted with 0-2 Rlb, -CN, NO2, C1-6alkyl substituted with 0-3 Rlb, C2-6 alkenyl substituted with 0-2 Rlb, C2-6 alkynyl substituted with 0-2 Rlb, aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1 -3 heteroatoms selected from O, N, and S(0)0.2; Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, S, O, halogen, methanesulfonyl, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-6alkyl substituted with 0-3 Rlc, C2.6 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 R!c, 5 10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 beteroa-toms selected from O, N, and S(O)0.2, C3.10 cycloalkyl substituted with 0-2 Rlc, and a 3-8 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0.2; Rlc, at each occ>.irrence, is selected from OH substituted with 0-1 Rld, SH substituted with 0-1 Rld, S, O, halogen, NH2 substituted with 0-2 Rld, -CN, NO2, Ci.6alkyl substituted with 0-2 Rld, C2.6 alkenyl substituted with 0-2 Rld, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0.2, C3-10 cycloalkyl substituted with 0-2 Rld, and a 3-8 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0.2; Rld, at each occ irrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, C1-6 a'kyi, C2.6 alkenyl, ary 1, CF3, and OCF3; R2 is selected from -OC-R2a, -CH=CH-R2a substituted with 0-2 R2a, aryl substituted with 0-3 R2a, and 5-10 numbered heteroaryl substituted with 0-3 R2a and consisting of carbon atoms and 1-4 heteroa'oms selected from O, N, and S(0)o-2; R2a, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, S, O, halogen, NH2 substituted with 0-2 R2b, -CN, NO2, C\|.6alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3.10 cycloalkyl substituted with 0-2 R2b, and a 3-8 membered hetero-cycle substituted with 0-2 R2b and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0-2; R2b, at each occurrence, is selected from OH substituted with 0-1 R2c, SH substituted with 0-1 R2, S, O substituted with 0-1 R2c, halogen, methanesulfonyl, NH2 substituted with 0-2 R2c, -CN, NO2, C!.6a!kyl substituted with 0-2 R2c, C2.6 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R2c, 5-10 membered heteroaryl substituted with 0-2 R2c and consisting of carbon atoms and 1 -4 heteroatoms selected from O, N, and S(O)0-2, C3-10 cycloalkyl substituted with 0-2 R20, and a 3-8 membered heterocycle substituted with 0-2 R20 and consisting of carbon atoms and 1 -3 heteroatoms selected from O, N, and S(O)0-2; P.20, at each occurrence, is selected from OH substituted with 0-1 R2d, SH substituted with 0-1 R2d, S, O, halogen, NH2 substituted with 0-2 R2d, -CN, NO2, C1-6alkyl substituted with 0-2 R2d, C2.6 alkenyl substituted with 0-2 R2d, aryl substituted with 0-2 R2d, 5-10 membered heteroaryl substituted with 0-2 R2d and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3-10 cycloalkyl substituted with 0-2 R2d, and a 3-8 membered hete>-o-cycle substituted with 0-2 R2d and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0.2; RM, at each occ'irrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, C1-6alkyl, C2-6 alkenyl, an 1, CF3, and OCF3; R3 is selected from halogen and C1-6 alkyl substituted with 0-2 R "; R3a, at each occ irrence, is selected from OH, O, S, halogen, C(O)NH2, C(O)NH-C1-4 alkyl, and C(O)N(CM alkyl)2; alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; R4a, at each occ'irrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R4d; R4d, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4alkyl, and N(C1-4 al-kyl)2; R4b, at each occ'irrence, is selected from H, halogen, and C1-8 alkyl substituted with 0-2 R4e; R4", at each occurrence, is selected from OH, O, halogen, NH2, NH-Ci-4 alkyl, and N(C1-4 al-kyl)2; R40, at each occurrence, is selected from H, halogen, and C1-4 alkyl substituted with 0-2 R4f; R4f, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 al-kyl)2; R5a, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; R5b, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; R5c, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; R5d, at each occ>irrence, is selected from H, halogen, CH3, and CH2CH3; and, R5e, at each occurrence, is selected from H, halogen, CH3, and CH2CH3. [00819] 3. A compound of clause 1 or 2 wherein: X is selected from O, S, OCH2, and SCH2; X'isOorS; R1 is selected from H, C1-8 alkyl, C2-8 alkenyl, aryl, 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.io cycloalkyl, and a 3-8 membered heteiocycle consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o_2, wherein each R1 group is substituted with 0-4 Rla; Rla, at each occurrence, is selected from OH substituted with 0-1 Rlb, SH substituted with 0-1 Rlb, S, O, halogen, NH2 substituted with 0-2 Rlb, -CN, NO2, C1-6alkyl substituted with 0-2 Rlb, C2.6 alkenyl substituted with 0-2 Rlb, C2.6 alkynyl substituted with 0-2 Rlb, aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting vl carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.io cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 Rlb and consisting of cat-bon atoms and 1 -3 heteroatoms selected from O, N, and S(O)o-2; Rlb, at each occ'irrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, S, O, halogen, NH2 substituted with 0-2 Rlc, -CN, NO2, d-6 alkyl substituted with 0-2 Rlc, C2-6 alkeny! substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3-10 cycloalkyl substituted with 0-2 Rlc, and a 3-8 membered hetero- cycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0-2; Rlc, at each occurrence, is selected from OH substituted with 0-1 Rld, SH substituted with 0-1 Rld, S, O, halogen, NH2 substituted with 0-2 Rld, -CN, NO2, C1-6alkyl substituted with 0-2 Rld, C2_6 alkenyl substituted with 0-2 Rld, aryl substituted with 0-2 Rld, 5-10 membererf het-eroaryl substituied with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2,C3.10 cycloalkyl substituted with 0-2 Rld, and a 3-8 membered hetero-cycle substituted with 0-2 Rld and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0.2; Rld, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2) C1-6alkyl, C2.6 alkenyl, arty 1, CF3, and OCF3; R2 is selected from -OC-R2", -CH=CH-R2a substituted with 0-2 R2a, aryl substituted with 0-3 R2a, and 5-10 numbered heteroaryl substituted with 0-3 R2aand consisting of carbon atoms and 1-4 heteroaioms selected from O, N, and S(O)o-2; R2a, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, S, O, halogen, NH2 substituted with 0-2 R2b, -CN, NO2, C1-6alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-10 membered heteroaryl substituied with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.io cycloalkyl substituted with 0-2 R2b, and a 3-8 membered hetero-cycle substituted with 0-2 R2b and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0.2; R2b, at each occ'irrence, is selected from OH substituted with 0-1 R2c, SH substituted with 0-1 R20, S, O, halogen, NH2 substituted with 0-2 R2c, -CN, NO2, C1-6 alkyl substituted with 0-2 R20, C2.6 alkenyl substituted with 0-2 R2c, aryl substituted with 0-2 R2c, 5-10 membered heteroaryl substituied with 0-2 R2c and consisting of carbon atoms and 1-4 heteroatoms relucted from O, N, and S(O)0-2, C3-10cycloalkyl substituted with 0-2 R2c, and a 3-8 membered hetero-cycle substituted with 0-2 R2" and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0-2; R20, at each occurrence, is selected from OH substituted with 0-1 R2d, SH substituted with 0-1 R2d, S, O, halog-n, NH2 substituted with 0-2 R2d, -CN, NO2, C1-6 alkyl substituted with 0-2 R2d, C2-6 alkenyl substituted with 0-2 R2d, aryl substituted with 0-2 R2d, 5-10 membered het-eroaryl substituted with 0-2 R2d and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CB-IO cycloalkyl substituted with 0-2 R2d, and a 3-8 membered hetero-cycle substituted with 0-2 R2d and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0-2; R2d, at each occ'irrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, C1-6alkyl, C2.6 alkenyl, ary 1, CF3, and OCF3; R3 is selected from halogen and Ci.6 alkyl substituted with 0-2 R3a; R3a, at each occurrence, is selected from OH, O, S, halogen, C(O)NH2, C(O)NH-C1-4 alkyl, and C(O)N(C1-4alkyl)2; alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heieroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; R4a, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R4d; R4d, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(CM alkyl).; R4b, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R46; R46, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4alkyl, and N(C1-4 al-kyl)2; R40, at each occurrence, is selected from H, halogen, and C1-4 alkyl substituted with 0-2 R4f; R4f, at each occurrence, is selected from OH, 0, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 al-kyl)2; R5a, at each occtirrence, is selected from H, halogen, CH3, and CH2CH3; R5b, at each occ'irrence, is selected from H, halogen, CH3, and CH2CH3; R5c, at each occ'irrence, is selected from H, halogen, CH3, and CH2CH3; R5d, at each occ'irrence, is selected from H, halogen, CH3, and CH2CH3; and, R5e, at each occurrence, is selected from H, halogen, CH3, and CH2CH3. [00820] 4. A compound of any of the preceding clauses 1-3, wherein the compound is of formula la: (Formula Removed) pharmaceu! ically acceptable salt thereof. [00821] 5. A compound of clause 1, wherein the compound is of formula II: (Formula Removed) II or a pharmaceui ically acceptable salt thereof, wherein: R1 is H, C1-8 alkyl, heteroaryl, and C3-10cycloalkyl, wherein each R1 group is substituted with 0-4 Rla; Rla, at each occiirrence, is selected from C1-6 alkyl substituted with 0-3 Rlb; C2.6 alkynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3.i0 cycloalkyl subsiituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb; Rlb, at each occiirrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, methanesulfonyl, C1-4 alkyl substituted with 0-3 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3-6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc; alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld and, C3-6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; Rld, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl; R2a is selected f om d.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and liet-eroaryl substituted with 0-2 R2b; R2b, at each occ'.irrence, is selected from OH substituted with 0-1 R2c, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R2", -CN, NO2, methanesulfonyl, Ci.4 alkyl substituted with 0-2 R20, C2.4 alkenyl substituted with 0-2 R2", aryl substituted with 0-2 R2c, heteroaryl substituted with 0-2 R20, C3.e cycloalkyl substituted with 0-2 R20, and a heterocycle substituted with 0-2 R20; R20, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 alkenyl, aryl substituted with 0-2 R2d, and heteroaryl substituted with 0-2 R2d; R2d, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2-4 alkenyl; R3 is selected from Cl, F, CH3, and CH2CH3; alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5c; R4a, at each occirrence, is selected from H, Cl, F, and CH3; R4b, at each occ'irrence, is selected from H, Cl, F, and CH3; R4c, at each occ'irrence, is selected from H, Cl, F, and CH3; R5a, at each occurrence, is selected from H, Cl, F, and CH3; R5b, at each occurrence, is selected from H, Cl, F, and CH3; R5c, at each occurrence, is selected from H, Cl, F, and CH3;, R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, R5e, at each occurrence, is selected from H, Cl, F, and CH3. [00822] 6. A compound of clause 5 wherein: R1 is H, C1-8alkyl, 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, and C3.10 cycloalkyl, wherein each R1 group is substituted with 0-4 Rla; Rla, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 Rlb; C2-6 alkynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from 0, N, and S(O)o-2; Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, methanesulfonyl, CM alkyl substituted with 0-3 Rlc, C24 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 mem- bered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3.6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1.4 alkyl, and C2-44 alkenyl, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of ca1 bon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, Cs.g cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of ca'bon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; Rld, at each occ'.irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl; R2" is selected f-om C1-6alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-10 membered heteioaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2; R2b, at each occurrence, is selected from OH substituted with 0-1 R^, SH substituted -v'ith 0-1 R20, Cl, F, NH2 substituted with 0-2 R2c, -CN, NO2, methanesulfonyl, CM alkyl substituted with 0-2 R2, C2-4 alkenyl substituted with 0-2 R2c, aryl substituted with 0-2 R2c, 5-10 membered heteroaryl substituted with 0-2 R2* and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.e cycloalkyl substituted with 0-2 R2, and a 3-6 membered heterocycle substituted with 0-2 R2c and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; R2, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 alkenyl, aryl subs ituted with 0-2 R2d, and 5-10 membered heteroaryl substituted with 0-2 R2d and consisting c f carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0.2; R2d, at each occ'.irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl; R3 is selected from Cl, F, CH3, and CH2CH3; alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)0.2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; R4a, at each occ'.irrence, is selected from H, Cl, F, and CH3; R4b, at each occ'irrence, is selected from H, Cl, F, and CH3; R40, at each occ'irrence, is selected from H, Cl, F, and CH3; R5a, at each occurrence, is selected from H, Cl, F, and CH3; R5b, at each occ'irrence, is selected from H, Cl, F, and CH3; R5c, at each occurrence, is selected from H, Cl, F, and CH3; R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, R5', at each occ'irrence, is selected from H, Cl, F, and [00823] 7. A compound of clause 5 or 6, wherein: R1 is H or CM alkyl substituted with 1-4 Rla; u, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-10 membered het-eroaryl substituied with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3-10 cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered hetero-cycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2; Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 P.lc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2-4 alkenyl substiUred with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2,C3.6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; R'c, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.., alkenyl, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of ca bon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C$.6 cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl; R2a is selected f, om C1-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-10 membered heteioaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heterca-toms selected from O, N, and S(O)o-2; R2b, at each occ'jrrence, is selected from OH substituted with 0-1 R2", SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R20, -CN, NO2,C1-4 alkyl substituted with 0-2 R2c, C2.4 alkenyl substitu'ed with 0-2 R20, aryl substituted with 0-2 R20,5-10 membered heteroaryl sub- stituted with 0-2 R20 and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-6, cycloalkyl substituted with 0-2 R20, and a 3-6 membered heterocycle substituted with 0-2 R2c and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; R26, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2-4 al-kenyl, aryl substituted with 0-2 R2d, and 5-10 membered heteroaryl substituted with 0-2 R2d and consisting c f carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2; R21, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, N02, C1-4 alkyl, and C2.4 alkenyl; R3 is selected from Cl, F, CH3, and CH2CH3; alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; R4a, at each occurrence, is selected from H, Cl, F, and CH3; R4b, at each occurrence, is selected from H, Cl, F, and CH3; R40, at each occ1 irrence, is selected from H, Cl, F, and CH3; R5a, at each occ'irrence, is selected from H, Cl, F, and CH3; R5b, at each occurrence, is selected from H, Cl, F, and CH3; R5c, at each occurrence, is selected from H, Cl, F, and CH3; Ria, at each occurrence, is selected from H, Cl, F, and CHs; and, R5e, at each occurrence, is selected from H, Cl, F, and CH3. [00824] 8. A compound of clause 5, wherein the compound is of formula Ha: (Formula Removed) or a pharmaceutically acceptable salt thereof, wherein: R1 is H, C1-6 alkyl, aryl, heteroaryl, and C3-10 cycloalkyl, wherein each R1 group is substituted withO-lRla; Rla, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 Rlb; C2-6 alkynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb and, C5. 6 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb and; Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, methanesulfonyl, d 4alkyl substituted with 0-3 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted w.th C-2 Rlc, heteroaryl substituted with 0-2 Rlc, C5.6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc; Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, d.4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C5.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; Rld, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl; R2a is selected from d.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and heteroaryl substituted with 0-2 R2b; R2b, at each occ irrence, is selected from OH substituted with 0-1 R20, SH, Cl, F, NH2, -CN, NO2, methanesi Ifonyl, CM alkyl, C2.4 alkenyl, aryl, heteroaryl, C5.6 cycloalkyl, and a hetero-cycle; R20, at each occurrence, is CM alkyl; R3 is selected from Cl, F, CH3, and CH2CH3; and, alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e. [00825] 9. A compound of clause 8 wherein: R1 is H, Cj-e alkyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected fnm O, N, and S(O)o-2, and C3-10 cycloalkyl, wherein each R1 group is substituted with 0-1 Rla; Rla, at each occurrence, is selected from C1-.6 alkyl substituted with 0-3 Rlb; C2-6 alkynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, 5-6 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5.6 cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(0)o-2; Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, methanesulfonyl, C,. 4 alkyl substituted with 0-3 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and .1 -2 heteroatoms sel ;cted from O, N, and S(O)o-2. C5-6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5.6 cycloalkyl substituted with 0-2 Rld, and a 5-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; Rld, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2, alkenyl; R2a is selected from Ci-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; R2b, at each occ'irrence, is selected from OH substituted with 0-1 R20, SH, Cl, F, NH2, -CN, NO2> methanesi Ifonyl, CM alkyl, C2-4 alkenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms ai d 1-2 heteroatoms selected from O, N, and S(O)o_2,, C5-6 cycloalkyl, and a 5-6 membered heterocycle and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(0)0.2; R20, at each occurrence, is CM alkyl; R3 is selected from Cl, F, CH3, and CH2CH3; and, alternatively, R3 and R5c combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5c. [00826] 10. A compound of clause 8 or 9 wherein: R1 is H or C1-4alky! substituted with 1 Rla; Rla, at each occ'irrence, is selected from aryl substituted with 0-2 Rlb, 5-6 membered het-eroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered hetero-cycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; Rlb, at each occirrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2, C5.6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle sub ;tituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, Ci-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of ca bon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5.5 cycloal-kyl substituted with 0-2 Rld, and a 5-6 membered heterocycle substituted with 0-2 Rld and consisting of ca:bon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2; Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl; R2a is selected f/om C1-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1 -2 heteroatoms selected from O, N, and S(O)o-2; R2b, at each occ irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 al-kenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2,, C5-6 cycloalkyl, and a 5-6 membered heterocycle and consisting of carbon atoms ard 1-2 heteroatoms selected from O, N, and S(O)o-2; R3 is selected from Cl, F, CH3, and CH2CH3; and, alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbun atoms and 0-2 heieroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e. 100827] 11. A compound of clause 8 wherein: R1 is H, Ci.6 alkyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from O and N; C3-10 cycloalkyl, wherein each R1 group is substituted with 0-1 Rla; Rla, at each occ'irrence, is selected from C1-4 alkyl substituted with 0-3 Rlb; C2-6 alkyiiyl substituted with 0-1 Rlb aryl substituted with 0-1 Rlb, heteroaryl substituted with 0-1 Rlb, C5.6 cycloalkyl substituted with 0-1 Rlb, and a heterocycle substituted with 0-1 Rlb; Rlb, at each occ;irrence, is selected from Cl, F, methanesulfonyl, and CM alkyl substituted with 0-3 Rlc, and; Rlc, at each occurrence, is selected from Cl, F and a heterocycle ; R2" is selected f/ora C1.6alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and het- eroaryl substituted with 0-2 R2b; R2b, at each occ irrence, is selected from OH optionally substituted with CM alkyl, Cl, F, methanesulfonyl, aryl, heteroaryl, C5_6 cycloalkyl, and a heterocycle ; R3 is selected from Cl, F, CH3, and CH2CH3.. [00828] 12. A compound of clause 11 wherein: R1 is H, C1-6 alkyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroa-toms selected from O and N; C3-10 cycloalkyl, wherein each R1 group is substituted with 0-1 R"; Rla, at each occurrence, is selected from CM alkyl substituted with 0-3 Rlb; C2-6 alkynyl substituted with 0-1 Rlb aryl substituted with 0-1 Rlb, 5-6 membered heteroaryl substituted with 0-1 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O and N, C5_6 cycloalkyl substituted with 0-1 Rlb, and a 5-6 membered heterocycle substituted with 0-1 Rlb; Rlb, at each occ'irrence, is selected from Cl, F, methanesulfonyl, and CM alkyl substituted with 0-3 Rlc, and; Rlc, at each occurrence, is selected from Cl, F and a 5-6 membered heterocycle consisting of carbon atoms ard 1-2 heteroatoms selected from O and N; R2" is selected f-om C1-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-6 membered heteioaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O and N; R2b, at each occurrence, is selected from OH optionally substituted with C1-4 alkyl, Cl, F, methanesulfonyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroa-toms selected from O and N, C5.6 cycloalkyl, and a 5-6 membered heterocycle consisting of carbon atoms ai d 1-2 heteroatoms selected from O and N; R3 is selected from Cl, F, CH3, and CH2CH3. [00829] 13. A compound of clause 12 wherein R is CM alkyl substituted with 1 R11 [00830] 14. A compound of clause 5, wherein the compound is of of formula lib (Formula Removed) or a pharmaceutically acceptable salt thereof. [00831] 15. A compound of clause 14 wherein R2a is selected from aryl substituted witn 0-2 R2t> and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2- [00832] 16. A compound of clause 14, wherein R1 is C1-6 alkyl. [00833] 17. A compound of clause 14, wherein R2a is C1-4 alkyl substituted with a heterocycle. [00834] 18. A compound of clause 14, wherein the R2" is CM alkyl substituted with mor-pholinyl. [00835] 19. A compound of clause 14, wherein R3 is selected from Cl and CH3. [00836] 20. A compound of clause 14, wherein X is selected from S and SCH2 [00837] 21. A compound of clause 14, wherein X is S. [00838] 22. A compound of clause 14, wherein X is O. [00839] 23. A compound of clause 14, wherein X is SCH2. [00840] 24. A compound of clause 14, wherein X1 is O. [00841] 25. A compound of clause 14, wherein R1 is aryl substituted with 0-1 Rla; wherein Rla, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2) CM alkyl. [00842] 26. A compound of clause 14, wherein ein R1 is Ci.6 alkyl substituted with Pla, and wherein Rla is aryl substituted with 0-1 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2,-CN,NO2, C1-4 alkyl. [00843] 27. A compound of clause 14, wherein R1 is C1-4 alkyl substituted with Rla, wherein Rla is heteroary! substituted with 0-1 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2,-CN, NO2. C1-4alkyl. [00844] 28. A compound of clause 14, wherein R1 is C1-6 alkyl substituted with Rla, wherein Rla is heterocyclyl substituted with 0-1 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2,-CN, NO2> C1-4alkyl. [00845] 29. A compound of clause 14, wherein R1 is C1-6 alkyl substituted with Rla, v.herein Rla is C5.6 cyclcalkyl substituted with 0-2 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2,-CN, N02, C1-4 alkyl. [00846] 30. A compound of clause 14, wherein R2ais aryl substituted with R2b; whereir- R2'J is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl. [00847] 31. A compound of clause 14, wherein R2ais Ci-6 alkyl substituted with R2b; wherein R2b is selected from aryl substituted with R2c; and wherein R2* is selected from OH, SH, Cl, F, NH2,-CN, NO2, C1-4 alkyl. [00848] 32. A compound of clause 14, wherein R2a is C1-6 alkyl substituted with R2b; wherein R2b is selected from heteroaryl substituted with R20; and wherein R2c is selected from OH, SH, Cl, F, NH2, -CN, N02, CM alkyl. • [00849] 33. A compound of clause 1, wherein the compound is selected from:. {2-Chloro-4-[3-(4-chloro-phenylemynyl)-5-(3-piperidin-l-yl-propoxy)-phenylsulfanyl]- phenoxy}-acetic acid; {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}- acetic acid; {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]- phenoxy)-acetic acid; {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)-phenyl- sulfanyl]-phenoxy} -acetic acid; {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(l-methyl-piperidin-4-ylmethoxy)-phenyl- sulfanyl]-phemxy} -acetic acid; {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-phenylsulfanyl]- phenoxy}-acetic acid; {4-[3-(4-Fluoro benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-meihyl- phenoxy}-acetic acid; {4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid; {4-[3-Isobutoxy-5 -(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2-methyl-phenoxy} - acetic acid; {4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid; {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid; {4-[3-But-2-yn\loxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}- acetic acid; {2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-acetic acid; {2-Chloro-4-[3-(3-methoxy-prop-l-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]- phenoxy}-acetic acid; {2-Chloro-4- [3- (3 -morpholin-4-y l-propoxy)-5-pent-1 -ynyl-phenylsulfanyl] -phenoxy} -acetic acid; {2-Methyl-4-[3 (3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]- phenoxy}-acetic acid; {4-[3-(4-Fluoro benzyloxy)-5-(3-morpholin-4-yl-prop-1 ynyl)-benzyIsulfanyl]-2-methyl- phenoxy}-acetic acid; and, {2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]- phenoxy)-acetic acid; or a pharmacem ically acceptable salt thereof. [00850] 34. A compound of clause 1, wherein the compound is selected from:. {4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-metliyl- phenoxy}-acetic acid; {4-[3-Cyclopen!.ylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid; {4-[3-Isobutoxj-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}- acetic acid; {4-[3-[2-(4-Chl )ro-plienyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2- methyl-phenoxy}-acetic acid; {4-[3-[2-(4-Chl )ro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2- methyl-phenox)} -acetic acid; {4-[3-[2-(4-Chl )ro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2- methyl-phenoxy} -acetic acid; {4-[3-(2-Ethyl-hutoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid; [4-(3-Cyclopeniyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid; {4-[3-(4-Fluoro phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl- phenoxy)-acetic acid; [4-(3-Cyclopeniylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid; {4-[3-(2-Cyclol exyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetir acid; {4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid; {4-[3-Cyclopen'yloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid; {4-[3-(2-Cyclol exyl-ethoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid; {4-[3-Cyclopen!ylmethoxy-5-(3-moq)holin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic acid; {4-[3-Cyclopen'ylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl- phenoxy}-acetic; {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid; [4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid; {4-[3-Isobutoxy-5-(4-raethanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxyj- acetic acid; {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)- phenylsulfanyl] 2-methyl-phenoxy{-acetic acid; {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)- phenylsulfanyl] -2-methyl-phenoxy }-acetic acid; {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)- phenylsulfanyl] phenoxy} -acetic acid; {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)- phenylsulfanyl] phenoxy}-acetic acid; {2-Methyl-4-[3 (3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-phenoxy)- phenylsulfanyl] phenoxy}-acetic acid; {4-[3-(4-Methauesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]- methyl-phenoxy} -acetic acid; and {2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]- phenoxy}-acetic acid, or a pharmaceuucally acceptable salt thereof. [00851] 35. A compound of clause 1, wherein the compound is of formula formula III: (Formula Removed) or a pharmaceuiically acceptable salt thereof, wherein: R1 is CM alkyl substituted with 1-2 Rla; with 0-2 Rlb, C3-10 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, heteroaryl substituted vith Rlb; Rlb, at each occ irrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2-4 alkenyl substitu'ed with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3.6 cycloa'kyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc; Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; Rld, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl; R2a is selected f-om aryl substituted with 0-2 R2b and heteroaryl substituted with 0-2 P2b; R2b, at each occ1 irrence, is selected from OH substituted with 0-1 R2c, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R20, -CN, NO2, C1-4 alkyl substituted with 0-2 R2c, C2.4 alkenyl substitu'ed with 0-2 R20, aryl substituted with 0-2 R20, heteroaryl substituted with 0-2 R20, C3.6 cycloa'kyl substituted with 0-2 R2*, and a heterocycle substituted with 0-2 R20; R20, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 alkenyl, aryl subs:ituted with 0-2 R2d, and heteroaryl substituted with 0-2 R2d; RM, at each occ•irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl; R3 is selected fr 3m Cl, F, CH3, and CH2CH3; alternatively, R3 and R5c combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heieroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; R4a, at each occ-irrence, is selected from H, Cl, F, and CH3; R4b, at each occurrence, is selected from H, Cl, F, R40, at each occurrence, is selected from H, Cl, F, and CH3; R5a, at each occurrence, is selected from H, Cl, F, and CH3; R5b, at each occurrence, is selected from H, Cl, F, and CH3; RSc, at each occurrence, is selected from H, Cl, F, and CH3; R5d, at each occ1 irrence, is selected from H, Cl, F, and CH3; and, R5e, at each occurrence, is selected from H, Cl, F, and [00852] 36. A compound of clause 35, wherein: R1 is C1-4 alkyl substituted with 1-2 Rla; Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-10 membered het-eroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered hetero-cycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0 1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2) Ci.4 alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-64 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and 8(0)0-2; Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 R'd and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-6cyyclor.l-kyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl; R2a is selected from aryl substituted with 0-2 R2b and 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and 8(0)0.2; R2b, at each occurrence, is selected from OH substituted with 0-1 R2", SH substituted with 0 1 R20, Cl, F, NH2 substituted with 0-2 R2c, -CN, NO2, CM alkyl substituted with 0-2 R2', C2.4 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R20, 5-10 membered heteroaryl substituted with 0-2 R20 and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-6 cycloalkyl substituted with 0-2 R20, and a 3-6 membered heterocycle substituted with 0-2 R2c and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2; R20, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, C2-4 al-kenyl, aryl substituted with 0-2 R2d, and 5-10 membered heteroaryl substituted with 0-2 R2d and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2; R2d, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2-4 alkenyl; R3 is selected from Cl, F, CH3) and CH2CH3; alternatively, R3 and R5c combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from 0, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; R4a, at each occurrence, is selected from H, Cl, F, and CH3; R4b, at each occurrence, is selected from H, Cl, F, and CH3; R40, at each occurrence, is selected from H, Cl, F, and CH3; R5a, at each occurrence, is selected from H, Cl, F, and CH3; R5b, at each occurrence, is selected from H, Cl, F, and CH3; R5c, at each occurrence, is selected from H, Cl, F, and CH3; R5 , at each occurrence, is selected from H, Cl, F, and CH3; and, R5e, at each occurrence, is selected from H, Cl, F, and CH3. [00853] 37. A compound of clause 35, wherein the compound is of formula formula Ilia (Formula Removed) Ilia or a pharmaceutically acceptable salt thereof, wherein: Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C5.6 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb; Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C5.6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc; Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, d1-4 alkyl, and C2-4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3.6 cycloa:ky! substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; R2" is selected from aryl substituted with 0-2 R2b and heteroaryl substituted with 0-2 R2b and-and, R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, C2.4 alkenyl, aryl, heteroaryl, C5-6 cycloalkyl, and a heterocycle. [00854] 38. A compound of clause 37 wherein: Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-6 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5.6 cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered hetero-cycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms seiscted from O, N, and S(O)o-2; Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o_2; Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C^ cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; R2" is selected from aryl substituted with 0-2 R2b and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2; and, R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2) C1-4 alkyl, C2.4 alkenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2, C5_6 cycloalkyl, and a 5-6 membered heterocycle and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2. [00855] 39. A compound of clause 4, wherein: R1 is Ci.4 alkyl substituted with 1-2 Rla; Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3-10 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb; Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3.6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc; Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rl d, heteroaryl substituted with 0-2 Rl d, C3.6 cycloalkyl substituted with 0-2 Rl d, and a heterocycle substituted with 0-2 Rl d; Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4alkyl, and C2.^ alkenyl; R2 is aryl substituted with 0-3 R2a or heteroaryl substituted with 0-2 R2a; R2", at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, Cl, F, NH2 substituted with 0-2 R2b, -CN, NO2, C1-4 alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, heteroaryl substituted with 0-2 R2b, C3-6 cycloalkyl substituted with 0-2 R2b, and a heterocycle substituted with 0-2 R2b; R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and, C2.4 alkenyl; R3 is selected from Cl, F, CH3, and CH2CH3; alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and RSe; R4a, at each occurrence, is selected from H, Cl, F, and CH3; R4b, at each occurrence, is selected from H, Cl, F, and CH3; R40, at each occurrence, is selected from H, Cl, F, and CH3; R5a, at each occurrence, is selected from H, Cl, F, and CH3; R5b, at each occurrence, is selected from H, Cl, F, and CH3; R5c, at each occurrence, is selected from H, Cl, F, and CH3; R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, R5c, at each occurrence, is selected from H, Cl, F, and CH3. [00856] 40. A compound of clause 39, wherein: R1 is CM alkyl substituted with 1-2 Rla; Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-10 membered het-eroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3_io cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered hetero-cycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, CM alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3.6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2-4 alkenyl, aryl substituted with 0-2 R l d, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-6 cycloalkyl substituted with 0-2 Rl d, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl; R2 is aryl substituted with 0-3 R2a or 5-10 membered heteroaryl substituted with 0-2 R2a anil consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2; R , at each occurrence, is selected from OH substituted with 0-1 R , SH substituted with 0-1 R2b, Cl, F, NH2 substituted with 0-2 R2b, -CN, NO2, C1-4 alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-6 cycloalkyl substituted with 0-2 R2b, and a 3-6 membered heterocycle substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o.2; R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, N02, C1-4 alkyl, ar-d, C2_4 alkenyl; 3 is selected from Cl, F, CH3, and CH2CH3; alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; R4a, at each occurrence, is selected from H, Cl, F, and CH3; R4b, at each occurrence, is selected from H, Cl, F, and CHs; R4c, at each occurrence, is selected from H, Cl, F, and CH3; R5a, at each occurrence, is selected from H, Cl, F, and CH3; R5b, at each occurrence, is selected from H, Cl, F, and CH3; R5c, at each occurrence, is selected from H, Cl, F, and CH3; R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, R5e, at each occurrence, is selected from H, Cl, F, and CH3. [00857] 41. A compound of clause 40, wherein the compound is of formula Ib: (Formula Removed) or a pharmaceutically acceptable salt thereof, wherein: la, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-6 membered het-eroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2, C5-6cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered hetero-cycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2; Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, Ci.4 alkyl, and C2-4 alkenyl, aryl substituted with 0-2 Rl d, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C3-6 cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rl d and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; R2 is aryl substituted with 0-2 R2a or 5-6 membered heteroaryl substituted with 0-2 R2a and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; and. R2a, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, Cl, F, NH2 substituted with 0-2 R2b, -CN, NO2, C1-4 alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from 0, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 R2b, and a 5-6 membered heterocycle substi- tuted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from 0, N, and S(O)0-2. [00858] 42. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of one of clauses 1 -41 or a pharmaceutically acceptable salt. [00859] 43. A pharmaceutical composition for treating type 2 diabetes, comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients, [00860] 44. A pharmaceutical composition for treating dyslipidemia, syndrome X (including the metabolic syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity), cardiovascular diseases (e.g., atherosclerosis and related diseases, including mortality reduction, coronary artery diseases, coronary heart diseases, heart attack, myocardial ischemia, myocardial infarct, coronary infarct, transient ischemic attack (TIA), and stroke), hyperglycemia, hyperlipidemia, hypercholesterolemia, and hyperinsulinemia, comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients. [00861] 45. A pharmaceutical composition for treating dyslipidemia comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients. [00862] 46. A pharmaceutical composition for treating syndrome X (including the p syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity), comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients. [00863] 47. A pharmaceutical composition for treating cardiovascular diseases (e.g., atherosclerosis and related diseases, including mortality reduction, coronary artery diseases, coronary heart diseases, heart attack, myocardial ischemia, myocardial infarct, coronary infarct, transient ischemic attack (TIA), and stroke), comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients [00864] 48. A pharmaceutical composition for treating hyperglycemia comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients. [00865] 49. A pharmaceutical composition for treating hyperlipidemia comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients. [00866] 50. A pharmaceutical composition for treating hypercholesterolemia comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients [00867] 51. A pharmaceutical composition for treating hyperinsulinemia comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients [00868] 52. A pharmaceutical composition according to any one of the clauses 42-51 for oral, nasal, transdermal, pulmonal or parenteral administration. [00869] 53. Use of a compound according to any one of the clauses 1-41 as a pharmaceutical composition. [00870] 54. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating type 2 diabetes. [00871] 55. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating dyslipidernia, syndrome X (including the metabolic syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity), cardiovascular diseases (e.g., atherosclerosis and related diseases, including mortality reduction, coronary artery diseases, coronary heart diseases, heart attack, myocardial ischemia, myocardial infarct, coronary infarct, transient ischemic attack (TIA), and stroke), hyperglycemia, hyperlipidemia, hypercholesterolemia, and hyperinsulinemia. [00872] 56. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating dyslipidernia. [00873] 57. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating syndrome X (including the metabolic syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyce .iaemia, and obesity). [00874] 58. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating cardiovascular diseases (e.g., atherosclerosis and related diseases, including mortality reduction, coronary artery diseases, coronary heart diseases, heart attack, myocardial ischemia, myocardial infarct, coronary infarct, transient ischemic attack (TIA), and stroke). [00875] 59. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating hyperglycemia. [00876] 60. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating hyperlipidemia. [00877] 61. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating hypercholesterolemia. [00878] 62. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating hyperinsulinemia [00879] 63. A method of treating type 2 diabetes, comprising: administering a therapeutically effective amount of a compound of one of clauses 1-41 or a pharmaceutically acceptable salt. [00880] 64. A method of treating a disease, comprising: administering a therapeutically effective amount of a compound of one of clauses 1-41 or a pharmaceutically acceptable salt, wherein the disease is selected from dyslipidemia, syndrome X (including the metabolic syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity), cardiovascular diseases (e.g., atherosclerosis and related diseases, including mortality reduction, coronary artery diseases, coronary heart diseases, heart attack, myocardial ischemia, myocardial infarct, coronary infarct, transient ischemic attack (TIA), and stroke), hyperglycemia, hyperlipidemia, hypercholesterolemia, and hyperinsulinemia. [00881] 65. A compound of one of clauses 1-41 or a pharmaceutically acceptable salt thereof, wherein the compound has a solubility in water of at least 0.1 mg/L as determined at 25°C and pH7.0. [00882] 66. The compound of clause 65, wherein the compound has a solubility in water of at least 0.5 mg/L. [00883] 67. The compound of clause 66, wherein the compound has a solubility in water of at least 1 mg/L. [00884] 68. The compound of clause 67, wherein the compound has a solubility in water of at least 2 mg/L. [00885] 69. The compound of clause 68, wherein the compound has a solubility in water of at least 10 mg/L. [00886] 70. The compound of clause 69, wherein the compound has a solubility in water of at least 50 mg/L. [00887] 71. The compound of clause 70, wherein the compound has a solubility in water of at least 200 mg/L. [00888] 72. A compound of one of clauses 1-41 or a pharmaceutically acceptable salt thereof, wherein the compound has an ICso value of less than 1/tm as determined by the PPAR transient transactivation assay. [00889] 73. The compound of clause 72, wherein the compound has an IC50 value of less than 500 nm. [00890] 74. The compound of clause 73, wherein the compound has an ICso value of less than 100 nm. [00891] 75. The compound of clause 74, wherein the compound has an ICso value of less than 50 nm. [00892] 76. The compound of clause 75, wherein the compound has an ICso value of less than 25 nm. [00893] 77. The compound of clause 76, wherein the compound has an ICso value of less than 10 nm. [00894] 78. The compound of clause 77, wherein the compound has an ICso value of less than 5 nm. [00895] 79. A compound of one of clauses 1-41, wherein the compound has a molecular weight of less than 750 g/mol. [00896] 80. The compound of clause 79, wherein the compound has a molecular weight of less than 600 g/mol. [00897] 81. The compound of clause 80, wherein the compound has a molecular weight of less than 550 g/mol. [00898] 82. The compound of clause 81, wherein the compound has a molecular weight of less than 500 g/mol. [00899] 83. The compound of clause 82, wherein the compound has a molecular weight of less than 400 g/mol. [00900] 84. A compound of one of clauses 1-41, wherein the compound is ionized at a pH of from 5.5-9. [00901] 85. The compound of clause 84, wherein the compound has only one ionized car-boxylic acid group at a pH of from 6-8. [00902] 86. The compound of clause 85, wherein the compound has only one ionized car-boxylic acid group at a pH of from 6.5-7.5. [00903] 87. The compound of clause 86, wherein the compound has only one ionized car-boxylic acid group at pH 7.4. [00904] 88. A compound of one of clauses 1-41, wherein the compound is a z witter-ion with one ionized amine group and one ionized carboxylic acid group at a pH of from 5.5-9. [00905] 89. The compound of clause 88, wherein the compound is a zwitter-ion with one ionized amine group and one ionized carboxylic acid group at a pH of from 6-8. [00906] 90. The compound of clause 89, wherein the compound is a zwitter-ion with one ionized amine group and one ionized carboxylic acid group at a pH of from 6.5-7.5 [00907] 91. The compound of clause 90, wherein the compound is a zwitter-ion with one ionized amine group and one ionized carboxylic acid group at pH 7.4. We Claim: 1. A compound of formula IIb or a pharmaceutically acceptable salt thereof: (Formula Removed) wherein: X is S or SCH2; X1 is O; R1 is C1-6 alkyl; R2 is -OC-R2a; R2a is C1-4 alkyl substituted with morpholinyl; and R3 is chloro or methyl. 2. The compound as claimed in claim 1, wherein X is SCH2. 3. The compound as claimed in claim 1, wherein X is S. 4. The compound as claimed in claim 1 wherein the compound is {4-[3-isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid or a pharmaceutically acceptable salt thereof. 5. A compound as claimed in claim 1, wherein the compound is {4-[3-isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid or a pharmaceutically acceptable salt thereof.

Full Text

NOVEL COMPOUNDS, THEIR PREPARATION AND USE
FIELD OF THE INVENTION
[0001] The present invention relates to novel phenoxy-acetic acids, Pharmaceuticals comprising the same, and methods of using the same. The phenoxy-acetic acids are activators of peroxisome proliferator-activated receptors (PPAR)-5.
BACKGROUND OF THE INVENTION
[0002] Coronary artery disease (CAD) is the major cause of death in Type 2 diabetic and metabolic syndrome patients (i.e., patients that fall within the 'deadly quartet' category of impaired glucose tolerance, insulin resistance, hypertriglyceridaemia and/or obesity). [0003] The hypolipidaemic fibrates and antidiabetic thiazolidinediones separately display moderately effective triglyceride-lowering activities, although they are neither potent nor efficacious enough to be a single therapy of choice for the dyslipidaemia often observed in Type 2 diabetic or metabolic syndrome patients. The thiazolidinediones also potently lower circulating glucose levels of Type 2 diabetic animal models and humans. However, the fibrate class of compounds are without beneficial effects on glycaemia. Studies on the molecular actions of these compounds indicate that thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased and decreased expression of specific enzymes and apol-ipoproteins respectively, both key-players in regulation of plasma triglyceride content. [0004] PPAR-5 activation was initially reported not to be involved in modulation of glucose or triglyceride levels. (Berger et al., JBiol. Chem. 1999,274, 6718-6725). Later it was shown that PPAR-8 activation leads to increased levels of HDL cholesterol in db/db mice (Leibowitz et al., FEBS letters 2000,473, 333-336). Further, a PPAR-5 agonist when dosed to insulin-resistant middle-aged obese rhesus monkeys caused a dramitic dose-dependent rise in serum HDL cholesterol while lowering the levels of small dense LDL, fasting triglycerides and fasting insulin (Oliver et al., PNAS 2001, 98,5306-5311). The same paper also showed that PPAR-8 activation increased the reverse cholesterol transporter ATP-binding cassette Al and induced apolipoprotein Al-specific cholesterol efflux. The involvement of PPAR-5 in
fatty acid oxidation in muscles was further substantiated in PPAR-a knock-out mice. Muoio et a\. (J. Biol. Chem. 2002,277,26089-26097) showed that the high levels of PPAR-8 in skeletal muscle can compensate for deficiency in PPAR-a. In addition to the effects on cholesterol homeostasis, PPAR5 treatment was observed to lower plasma glucose and insulin and improve insulin sensitivity in diabetic ob/ob and db/db mice and high fat diet induced insulin resistant mice (PNAS 2003, 700,15924-15929; PNAS 2006,103, 3444-3449).Taken together these observations suggest that PPAR-8 activation is useful in the treatment and prevention of Type 2 diabetes, cardiovascular diseases and conditions including atherosclerosis, hypertriglyceridemia, and mixed dyslipidaemia (WO 01/00603).
A number of PPAR-8 compounds have been reported to be useful in the treatment of hyperglycemia, hyperlipidemia and hypercholesterolemia (WO 02/59098, WO 01/603, WO 01/25181, WO 02/14291, WO 01/79197, WO 99/4815, WO 97/28149, WO 98/27974, WO 97/28115, WO 97/27857, WO 97/28137, and WO 97/27847). WO 2004093879, WO 2004092117, WO 2004080947, WO 2004080943, WO 2004073606.WO 2004063166, WO 2004063165, WO 2003072100, WO 2004060871, WO 2004005253, WO 2003097607, WO 2003035603, WO 2004000315, WO 2004000762, WO 2003074495, WO 2002070011, WO 2003084916, US 20040209936, WO 2003074050, WO 2003074051, WO 2003074052, JP 2003171275, WO 2003033493, WO 2003016291, WO 2002076957, WO 2002046154, WO 2002014291, WO 2001079197, WO 2003024395, WO 2002059098, WO 2002062774, WO 2002050048, WO 2002028434, WO 2001000603, WO 2001060807, WO 9728149, WO 2001034200, WO 9904815, WO 200125226, WO 2005097098; WO 2005097762; WO 2005097763.
[0005] Glucose lowering as a single approach does not overcome the macrovascular complications associated with Type 2 diabetes and metabolic syndrome. Novel treatments of Type 2 diabetes and metabolic syndrome must therefore aim at lowering both the overt hypertriglyc-eridaemia associated with these syndromes as well as alleviation of hyperglycaemia. This indicates that research for compounds displaying various degree of PPAR-8 activation should lead to the discovery of efficacious triglyceride and/or cholesterol and/or glucose lowering drugs that have great potential in the treatment of diseases such as type 2 diabetes, dyslipide-
mia, syndrome X (including the metabolic syndrome, i.e., impaired glucose tolerance, insulin resistance, hypertrigyceridaemia and/or obesity), cardiovascular diseases (including atherosclerosis) and hypercholesteremia.
SUMMARY OF THE INVENTION
[0006] In an aspect, the present invention provides novel phenoxy-acetic acids or pharma-
ceutically acceptable salts thereof that are useful as PPAR-8 activators.
[0007] In another aspect, the present invention provides novel pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof.
[0008] In another aspect, the present invention provides a novel method of treating type 2 diabetes comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof.
[0009] In another aspect, the present invention provides a novel method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the disease is selected from dyslipidemia, syndrome X (including the metabolic syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity), cardiovascular diseases (e.g., atherosclerosis, coronary artery disease, and myocardial ischemia), hyperglycemia, hyperlipidemia, and hypercholesterolemia.
[0010] In another aspect, the present invention provides a novel method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the disease is selcted from non-insulin requiring Type 2 diabetes to insulin requiring
Type 2 diabetes, decreasing apoptosis in mammalian cells (e.g., beta cells of Islets of Langer-hans), renal diseases (e.g., glomerulonephritis, glomerulosclerosis, nephrotic syndrome, and hypertensive nephrosclerosis), improving cognitive functions in dementia, treating diabetic complications, psoriasis, polycystic ovarian syndrome (PCOS), prevention and treatment of
•orosis), and lowering the bio-markers of atherosclerosis (e.g., c-reactivei, and IL-6).
pect, the present invention provides novel compounds for use in ther-
pect, the present invention provides the use of novel compounds for the icament for the treatment of type 2 diabetes.
her objects, which will become apparent during the following detailed i achieved by the inventors' discovery that compounds of formula I: R*; R2
(Formula Removed)
I itically acceptable salts thereof, are PPAR-8 activators.
HE INVENTION
odiment, the present invention provides a novel compound of formula I:
(Formula Removed)

[0016] or a pharmaceutically acceptable salt thereof, wherein: [0017] X is selected from O, S, OCH2, and SCH2; [0018] X'is O or S;
[0019] R1 is selected from H, C1-8 alkyl, C2-8alkenyl, aryl, heteroaryl,C3-10 cycloalkyl, and a heterocyclyl, wherein each R1 group is substituted with 0-4 Rla; [0020] Rla, at each occurrence, is selected from S substituted with 0-1 Rlb, 0 substituted with 0-1 Rlb, halogen, NH2 substituted with 0-2 RIb, -CN, NO2, Ci.6 alkyl substituted with 0-3 Rlb, C2.6 alkenyl substituted with 0-2 Rlb, C2.6 alkynyl substituted with 0-2 Rlb, aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3.io cycloalkyl substituted with 0-2 Rlb, and heterocycle substituted with 0-2 Rlb;
[0021] Rlb, at each occurrence, is selected from S substituted with 0-1 Rlc, O substituted with 0-1 Rlc, halogen, methanesulfonyl, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-6 alkyl substituted with 0-3 Rlc, C2.6 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3-1o cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc;
[0022] Rlc, at each occurrence, is selected from S substituted with 0-1 Rld, O substituted with 0-1 Rld, halogen, NH2 substituted with 0-2 Rld, -CN, N02, d.6 alkyl substituted with 0-2 RId, C2.6 alkenyl substituted with 0-2 Rld, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3-10cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld;
[0023] Rld, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, Q. 6alkyl, C2-6 alkenyl, aryl, CF3, and OCF3;
[0024] R2 is selected from -C=C-R2a, -CH=CH-R2a, aryl substituted with 0-3 R2a, and het-eroaryl substituted with 0-3 R2a;
[0025] R2a, at each occurrence, is selected from S substituted with 0-1 R2b, O substituted with 0-1 R2b, halogen, NH2 substituted with 0-2 R2b, -CN, NO2, C1-6alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, heteroaryl substituted with 0-2 R2b, Cs-io cycloalkyl substituted with 0-2 R2b, and a heterocycle substituted with 0-2; [0026] R2b, at each occurrence, is selected from S substituted with 0-1 R20,0 substituted with 0-1 R20, halogen, methanesulfonyl, NH2 substituted with 0-2 R20, -CN, NO2, Ci.6alkyl substituted with 0-2 R20, C2.6 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R2c, heteroaryl substituted with 0-2 R20, C3-10 cycloalkyl substituted with 0-2 R20, and a heterocycle substituted with 0-2 R20;
[0027] R20, at each occurrence, is selected from S substituted with 0-1 R2d, O substituted with 0-1 RM, halogen, NH2 substituted with 0-2 R2d, -CN, NO2, Chalky! substituted with 0-2 R24, C2-6 alkenyl substituted with 0-2 RM, aryl substituted with 0-2 R24, heteroaryl substituted with 0-2 R2d, Cs-io cycloalkyl substituted with 0-2 R2d, and a heterocycle substituted with 0-2
R2d
[0028] R2d, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, Q. 6alkyl, C2.6 alkenyl, aryl, CF3, and OCF3;
[0029] R3 is selected from halogen and Ci-6 alkyl substituted with 0-2 R3a; [0030] R3a, at each occurrence, is selected from OH, 0, S, halogen, C(O)NH2, C(O)NH-d.4 alkyl, and C(O)N(d.4 alkyl)2;
[0031] alternatively, R3 and R5c combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e;
[0032] R4a, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R4d;
[0033] R4d, at each occurrence, is selected from OH, 0, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 alkyl)2;
[0034] R4b, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with
0-2 R4c;
[0035] R4*, at each occurrence, is selected from OH, O, halogen, NH2, NH-d-4 alkyl, and
N(C,.4 alkyl)2;
[0036] R4c, at each occurrence, is selected from H, halogen, and C\.6 alkyl substituted with
0-2 R4f;
[0037] R4f, at each occurrence, is selected from OH, O, halogen, NH2, NH-Ci.4 alkyl, and
N(C1-4alkyl)2;
[0038] R5a, at each occurrence, is selected from H, halogen, CH3, and CH2CH3;
[0039] R5b, at each occurrence, is selected from H, halogen, CH3, and CH2CH3;
[0040] R5c, at each occurrence, is selected from H, halogen, CH3, and CH2CH3;
[0041] R5d, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; and,
[0042] R5e, at each occurrence, is selected from H, halogen, CH3, and CH2CH3.
[0043] In another embodiment, the present invention provides a novel compound of formula I or a pharmaceutically acceptable salt thereof, wherein: [0044] X is selected from O, S, OCH2, and SCH2; [0045] X'isOorS;
[0046] R1 is selected from H, Q.g alkyl, C2.g alkenyl, aryl, 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CMO cycloaikyl, and a 3-8 membered heterocycle consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2, wherein each R1 group is substituted with 0-4 Rla; [0047] Rla, at each occurrence, is selected from OH substituted with 0-1 Rlb, SH substituted with 0-1 Rlb, S, O, halogen, NH2 substituted with 0-2 Rlb, -CN, NO2, d.6 alkyl substituted with 0-3 Rlb, C2.6 alkenyl substituted with 0-2 Rlb, C2.6 alkynyl substituted with 0-2 Rlb, aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CMO cycloaikyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 RIb and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2;
[0048] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, S, O, halogen, methanesulfonyl, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-6 alkyl substituted with 0-3 Rlc, C2.6 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 Rlc, and a 3-8 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-z;
[0049] Rlc, at each occurrence, is selected from OH substituted with 0-1 Rld, SH substituted with 0-1 Rld, S, 0, halogen, NH2 substituted with 0-2 Rld, -CN, N02, d.6 alkyl substituted with 0-2 Rld, C2.6 alkenyl substituted with 0-2 Rld, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from 0, N, and S(O)o-2, C3.10 cycloalkyl substituted with 0-2 Rld, and a 3-8 membered heterocycle substituted with 0-2 RId and consisting of carbon atoms and 1-3 heteroatoms selected from 0, N, and S(O)0.2;
[0050] Rld, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, C,. 6 alkyl, C2.6 alkenyl, aryl, CF3, and OCF3;
[0051] R2 is selected from -C=C-R2a, -CH=CH-R2a substituted with 0-2 R2a, aryl substituted with 0-3 R2", and 5-10 membered heteroaryl substituted with 0-3 R2a and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2;
[0052] R2a, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, S, O, halogen, NH2 substituted with 0-2 R2b, -CN, NO2, Ci-6 alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3-10 cycloalkyl substituted with 0-2 R2b, and a 3-8 membered heterocycle substituted with 0-2 R2b and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2;
[0053] R2b, at each occurrence, is selected from OH substituted with 0-1 R2c, SH substituted with 0-1 R20, S, O substituted with 0-1 R2c, halogen, methanesulfonyl, NH2 substituted with 0-2 R2*, -CN, NO2, C1-6 alkyl substituted with 0-2 R20, C2.6 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R20,5-10 membered heteroaryl substituted with 0-2 R20 and consisting of
carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.10 cycloalkyl substituted with 0-2 R20, and a 3-8 membered heterocycle substituted with 0-2 R20 and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2;
[0054] R2*, at each occurrence, is selected from OH substituted with 0-1 R2d, SH substituted with 0-1 R2d, S, 0, halogen, NH2 substituted with 0-2 R2d, -CN, N02, C1.6alkyl substituted with 0-2 R2d, C2.6 alkenyl substituted with 0-2 R2d, aryl substituted with 0-2 R2d, 5-10 membered heteroaryl substituted with 0-2 R2d and consisting of carbon atoms and 1-4 heteroatoms selected from 0, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 R2d, and a 3-8 membered heterocycle substituted with 0-2 R2d and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2;
[0055] Ru, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, C1_ 6alkyl, C2.6 alkenyl, aryl, CF3, and OCF3;
[0056] R3 is selected from halogen and Ci-e alkyl substituted with 0-2 R3a; [0057] R3a, at each occurrence, is selected from OH, O, S, halogen, C(O)NH2> C(O)NH-Ci.4 alkyl, and C(O)N(C1-4 alkyl)2;
[0058] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e;
[0059] R4a, at each occurrence, is selected from H, halogen, and C1-6alkyl substituted with 0-2 R4d;
[0060] R4d, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-44 alkyl, and N(C1-4alkyl)2;
[0061] R4b, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R46;
[0062] R4*, at each occurrence, is selected from OH, 0, halogen, NH2, NH-C1-4alkyl, and N(C1-4 alkyl)2;
[0063] R4", at each occurrence, is selected from H, halogen, and Ci-e alkyl substituted with 0-2 R4f;
[0064] R4f, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 alkyl)2;
[0065] R5a, at each occurrence, is selected from H, halogen, CH3, and CH2CH3;
[0066] R5b, at each occurrence, is selected from H, halogen, CH3, and CH2CH3;
[0067] R5c, at each occurrence, is selected from H, halogen, CH3, and CH2CH3;
[0068] R5d, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; and,
[0069] R5e, at each occurrence, is selected from H, halogen, CH3, and CH2CH3.
[0070] In another embodiment, the present invention provides a novel compound of formula I or a pharmaceutically acceptable salt thereof, wherein: [0071] X is selected from O, S, OCH2, and SCH2; [0072] X'is O or S;
[0073] R1 is selected from H, C1-8 alkyl, C2.8 alkenyl, aryl, 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o_2, C3-10 cycloalkyl, and a 3-8 membered heterocycle consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2, wherein each R1 group is substituted with 0-4 Rla; [0074] Rla, at each occurrence, is selected from OH substituted with 0-1 Rlb, SH substituted with 0-1 Rlb, S, O, halogen, NH2 substituted with 0-2 Rlb, -CN, NO2, Ci.6 alkyl substituted with 0-2 Rlb, C2-a alkenyl substituted with 0-2 Rlb, C2.6 alkynyl substituted with 0-2 Rlb, aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CMO cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2;
[0075] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, S, O, halogen, NH2 substituted with 0-2 Rlc, -CN, NO2l,C1-4alkyl substituted with 0-2 Rlc, C2.6 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CMO cycloalkyl substituted with 0-2 Rlc, and a 3-8 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2;
[0076] Rlc, at each occurrence, is selected from OH substituted with 0-1 Rld, SH substituted with 0-1 Rld, S, 0, halogen, NH2 substituted with 0-2 Rld, -CN, NO2, d.6 alkyl substituted
with 0-2 Rld, C2-6 alkenyl substituted with 0-2 Rld, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CMO cycloalkyl substituted with 0-2 Rld, and a 3-8 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0-2;
[0077] Rld, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, d. 6 alkyl, C2-6 alkenyl, aryl, CF3, and OCF3;
[0078] R2 is selected from -C=C-R2a, -CH=CH-R2a substituted with 0-2 R2a, aryl substituted with 0-3 R2a, and 5-10 membered heteroaryl substituted with 0-3 R2a and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0.2;
[0079] R2*, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, S, O, halogen, NH2 substituted with 0-2 R2b, -CN, NO2, d.6 alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CMO cycloalkyl substituted with 0-2 R2b, and a 3-8 membered heterocycle substituted with 0-2 R2b and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2;
[0080] R2b, at each occurrence, is selected from OH substituted with 0-1 R20, SH substituted with 0-1 R20, S, O, halogen, NH2 substituted with 0-2 R2*, -CN, NO2> C1-6 alkyl substituted with 0-2 R20, C2-6 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R2c, 5-10 membered heteroaryl substituted with 0-2 R20 and consisting of carbon atoms and 1-4 heteroatoms selected from 0, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 R2c, and a 3-8 membered heterocycle substituted with 0-2 R20 and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o-2;
[0081] R20, at each occurrence, is selected from OH substituted with 0-1 R2d, SH substituted with 0-1 R2d, S, O, halogen, NH2 substituted with 0-2 R2", -CN, NO2, C1-6alkyl substituted with 0-2 RM, C2-6 alkenyl substituted with 0-2 R2"1, aryl substituted with 0-2 R2*, 5-10 membered heteroaryl substituted with 0-2 R2d and consisting of carbon atoms and 1-4 heteroatoms selected from 0, N, and S(O)o-2, C3.10 cycloalkyl substituted with 0-2 R2d, and a 3-8 mem-
bered heterocycle substituted with 0-2 RM and consisting of carbon atoms and 1-3 heteroa-toms selected from O, N, and S(0)o-2;
[0082] RM, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2> Q. 6alkyl, C2-6 alkenyl, aryl, CF3, and OCF3;
[0083] R3 is selected from halogen and C1-6 alkyl substituted with 0-2 R3a; [0084] R3a, at each occurrence, is selected from OH, O, S, halogen, C(O)NH2, C(0)NH-Ci.4 alkyl, and C(O)N(C1-4 alkyl)2;
[0085] alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5c;
[0086] R4a, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R4d;
[0087] R4d, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(C,.4alkyl)2;
[0088] R4b, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R46;
[0089] R46, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(C,.4alkyl)2;
[0090] R40, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R4f;
[0091] R4f, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 alkyl)2;
[0092] R5a, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; [0093] R5b, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; [0094] R5c, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; [0095] R5d, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; and, [0096] R5e, at each occurrence, is selected from H, halogen, CH3, and CH2CH3.
[0097] In a embodiment, the present invention provides a novel compound of formula la:
(Formula Removed)

[0098] or a pharmaceutically acceptable salt thereof.
[0099] In another embodiment, the present invention provides a novel compound of formula II:
(Formula Removed)
[00100] or a pharmaceutically acceptable salt thereof, wherein:
[00101] R1 is H, C1-8alkyl, heteroaryl, and C3-10 cycloalkyl, wherein each R1 group is substituted with 0-4 Rla;
[00102] Rla, at each occurrence, is selected from Ci.6 alkyl substituted with 0-3 Rlb; C2.6 al-kynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3.io cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb; [00103] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, N02, methanesulfonyl, C1-4 alkyl substituted with 0-3 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3.6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc;
[00104] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld and, C3.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; [00105] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2-4 alkenyl;
[00106] R2a is selected from C1-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and heteroaryl substituted with 0-2 R2b;
[00107] R2b, at each occurrence, is selected from OH substituted with 0-1 R2*, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R20, -CN, NO2, methanesulfonyl, C1-4 alkyl substituted with 0-2 R20, C2.4 alkenyl substituted with 0-2 R2*, aryl substituted with 0-2 R7c, heteroaryl substituted with 0-2 R20, C3.6 cycloalkyl substituted with 0-2 R20, and a heterocycle substituted with 0-2 R20;
[00108] R26, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 alkenyl, aryl substituted with 0-2 RM, and heteroaryl substituted with 0-2 R2d; [00109] R24, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2-4 alkenyl;
[00110] R3 is selected from Cl, F, CH3, and CH2CH3;
[00111] alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5c; [00112] R4a, at each occurrence, is selected from H, Cl, F, and CH3; [00113] R4b, at each occurrence, is selected from H, Cl, F, and CH3;
[00114] R4c, at each occurrence, is selected from H, Cl, F, and CH3; [00115] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00116] R5b, at each occurrence, is selected from H, Cl, F, and CH3; [00117] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00118] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00119] R5c, at each occurrence, is selected from H, Cl, F, and CH3.
[00120] In another embodiment, the present invention provides a novel compound of formula II or a pharmaceutically acceptable salt thereof, wherein:
[00121] R1 is H, C1-8 alkyl, 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, and C3-10cycloalkyl, wherein each R1 group is substituted with 0-4 Rla;
[00122] Rla, at each occurrence, is selected from d.6 alkyl substituted with 0-3 Rlb; C2.6 al-kynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(0)o-2;
[00123] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, methanesulfonyl, CM alkyl substituted with 0-3 Rlc, C2-4 alkenyl substituted with 0-2 Ru, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0.2, C3.6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00124] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, N02, CM alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0.2, C3.6 cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 R!d and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00125] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2> C,.4alkyl, and C2.4 alkenyl;
[00126] R2a is selected from d.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2;
[00127] R2b, at each occurrence, is selected from OH substituted with 0-1 R20, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R2*, -CN, NO2, methanesulfonyl, C1-4 alkyl substituted with 0-2 R20, C2-4 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R20, 5-10 membered heteroaryl substituted with 0-2 R2c and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.6 cycloalkyl substituted with 0-2 R20, and a 3-6 membered heterocycle substituted with 0-2 R20 and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00128] R20, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2> C1-4 alkyl, C2.4 alkenyl, aryl substituted with 0-2 R2d, and 5-10 membered heteroaryl substituted with 0-2 RM and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2; [00129] R2d, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl;
[00130] R3 is selected from Cl, F, CH3, and CH2CH3;
[00131] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o_2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5c; [00132] R4a, at each occurrence, is selected from H, Cl, F, and CH3; [00133] R4b, at each occurrence, is selected from H, Cl, F, and CH3; [00134] R40, at each occurrence, is selected from H, Cl, F, and CH3; [00135] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00136] R5b, at each occurrence, is selected from H, Cl, F, and CH3; [00137] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00138] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00139] R5c, at each occurrence, is selected from H, Cl, F, and CH3.
[00140] In another embodiment, the present invention provides a novel compound of formula Ilor a pharmaceutically acceptable salt thereof, wherein: [00141] R1 is H or C1-4 alkyl substituted with 1-4 Rla;
[00142] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-10 mem-bered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 Rlb, and a 3-8 mem-bered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from 0, N, and S(O)o-2;
[00143] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3.6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2;
[00144] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2-4 alkenyl, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with G-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.6 cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00145] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and Ca-4 alkenyl;
[00146] R21 is selected from C1-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2;
[00147] R2b, at each occurrence, is selected from OH substituted with 0-1 R20, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R20, -CN, N02, C1-4 alkyl substituted with 0-2 R20, C2-4 alkenyl substituted with 0-2 R2c, aryl substituted with 0-2 R2c, 5-10 membered heteroaryl substituted with 0-2 R26 and consisting of carbon atoms and 1 -4 heteroatoms selected
from O, N, and S(O)0.2, C3.6 cycloalkyl substituted with 0-2 R20, and a 3-6 membered hetero-cycle substituted with 0-2 R20 and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00148] R2", at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 alkenyl, aryl substituted with 0-2 R2d, and 5-10 membered heteroaryl substituted with 0-2 RM and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2; [00149] RM, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2-4 alkenyl;
[00150] R3 is selected from Cl, F, CH3, and CH2CH3;
[00151] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; [00152] R4a, at each occurrence, is selected from H, Cl, F, and CH3; [00153] R4b, at each occurrence, is selected from H, Cl, F, and CH3; [00154] R40, at each occurrence, is selected from H, Cl, F, and CH3; [00155] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00156] R5b, at each occurrence, is selected from H, Cl, F, and CH3; [00157] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00158] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00159] R5c, at each occurrence, is selected from H, Cl, F, and CH3.
[00160] In another embodiment, the present invention provides a novel compound of formula Ha:
(Formula Removed)Ha [00161] or a pharmaceutically acceptable salt thereof, wherein:
[00162] R is H, C1-6 alkyl, aryl, heteroaryl, and C3-10 cycloalkyl, wherein each R group is substituted with 0-1 Rla;
[00163] Ru, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 Rlb; C2-6 al-kynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb and, C5.6 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb and;
[00164] Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, methanesul-fonyl, CM alkyl substituted with 0-3 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C5-6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc;
[00165] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2-4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C5.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; [00166] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl;
[00167] R2a is selected from d.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and heteroaryl substituted with 0-2 R2b;
[00168] R2b, at each occurrence, is selected from OH substituted with 0-1 R20, SH, Cl, F, NH2, -CN, NO2, methanesulfonyl, C1-4 alkyl, C2.4 alkenyl, aryl, heteroaryl, C5.6 cycloalkyl, and a heterocycle;
[00169] R20, at each occurrence, is CM alkyl; [00170] R3 is selected from Cl, F, CH3, and CH2CH3; and,
[00171] alternatively, R3 and R5c combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e.
[00172] In another embodiment, the present invention provides a novel compound of formula IIa or a pharmaceutically acceptable salt thereof, wherein:
[00173] R1 is H, Ci-6 alkyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, and C3-10 cycloalkyl, wherein each R1 group is substituted with 0-1 Rla;
[00174] Rla, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 RIb; C2-6 al-kynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, 5-6 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(0)o-2, C$-6 cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00175] Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, methanesul-fonyl, CM alkyl substituted with 0-3 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, Cs-6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2',
[00176] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2-4 alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 Rld, and a 5-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(0)o-2; [00177] RId, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2-4 alkenyl;
[00178] R2a is selected from C1-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00179] R2b, at each occurrence, is selected from OH substituted with 0-1 R20, SH, Cl, F, NH2, -CN, N02, methanesulfonyl, d1-4 alkyl, C2-4 alkenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2,, C5.6 cycloalkyl, and a 5-6 membered heterocycle and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2;
[00180] R20, at each occurrence, is CM alkyl; [00181] R3 is selected from Cl, F, CH3, and CH2CH3; and,
[00182] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)0-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e.
[00183] In another embodiment, the present invention provides a novel compound of formula Ha or a pharmaceutically acceptable salt thereof, wherein: [00184] R1 is H or C1-4 alkyl substituted with 1 Ru;
[00185] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-6 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00186] Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5.6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00187] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 Rld, and a 5-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00188] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2> CM alkyl, and C2-4 alkenyl;
[00189] R2a is selected from C,.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1 -2 heteroatoms selected from O, N, and S(O)o-2;
[00190] R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, N02, CM alkyl, C2-4 alkenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2,, Cs-e cycloalkyl, and a 5-6 membered heterocycle and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(0)o-2; [00191] R3 is selected from Cl, F, CH3, and CH2CH3; and,
[00192] alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e.
[00193] In another embodiment, the present invention provides a novel compound of formula IIa or a pharmaceutically acceptable salt thereof, wherein:
[00194] R1 is H, C1-6 alkyl, aryl, heteroaryl, C3-10 cycloalkyl, wherein each R1 group is substituted with 0-1 Rla;
[00195] Rla, at each occurrence, is selected from CM alkyl substituted with 0-3 Rlb; C2.6 al-kynyl substituted with 0-1 Rlb, aryl substituted with 0-1 Rlb, heteroaryl substituted with 0-1 Rlb, C5.6 cycloalkyl substituted with 0-1 Rlb, and a heterocycle substituted with 0-1 Rlb; [00196] Rlb, at each occurrence, is selected from Cl, F, methanesulfonyl, and CM alkyl substituted with 0-3 Rlc, and;
[00197] Rlc, at each occurrence, is selected from Cl, F and a heterocycle ; [00198] R2a is selected from d.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and heteroaryl substituted with 0-2 R2b;
[00199] R2b, at each occurrence, is selected from OH optionally substituted with CM alkyl, Cl, F, methanesulfonyl, aryl, heteroaryl, C5-6cycloalkyl, and a heterocycle ; [00200] R3 is selected from Cl, F, CH3, and CH2CH3..
[00201] In another embodiment, the present invention provides a novel compound of formula
Ila or a pharmaceutically acceptable salt thereof, wherein:
[00202] R1 is H, C1-6 alkyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2
heteroatoms selected from O and N; C3-10 cycloalkyl, wherein each R1 group is substituted
with O-lRla;
[00203] Rla, at each occurrence, is selected from CM alkyl substituted with 0-3 Rlb; C2-6 al-kynyl substituted with 0-1 Rlb aryl substituted with 0-1 Rlb, 5-6 membered heteroaryl substituted with 0-1 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O and N, C5.6 cycloalkyl substituted with 0-1 Rlb, and a 5-6 membered heterocycle substituted with 0-1 Rlb;
[00204] Rlb, at each occurrence, is selected from Cl, F, methanesulfonyl, and CM alkyl substituted with 0-3 Rlc, and;
[00205] Rlc, at each occurrence, is selected from Cl, F and a 5-6 membered heterocycle consisting of carbon atoms and 1-2 heteroatoms selected from 0 and N; [00206] R2a is selected from d.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from 0 and N;
[00207] R2b, at each occurrence, is selected from OH optionally substituted with CM aiky), Cl, F, methanesulfonyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from 0 and N, C5_6 cycloalkyl, and a 5-6 membered heterocycle consisting of carbon atoms and 1-2 heteroatoms selected from O and N; [00208] R3 is selected from Cl, F, CH3, and CH2CH3.
[00209] In another embodiment, the present invention provides a novel compound of formula IIb
(Formula Removed)libor a pharmaceutically acceptable salt thereof.
[00210] In another embodiment, the present invention provides a novel compound of formula lib, wherein R1 is Ci.g alkyl.
[00211] In another embodiment, the present invention provides a novel compound of formula
IIb, wherein R2a is CM alkyl substituted with a heterocycle.
[00212] In another embodiment, the present invention provides a novel compound of formula
IIb, wherein R2a is CM alkyl substituted with morpholinyl.
[00213] In another embodiment, the present invention provides a novel compound of formula
IIb, wherein R3 is selected from Cl and CH3.
[00214] In another embodiment, the present invention provides a novel compound of formula
IIb, wherein X is selected from S and SCH2
[00215] In another embodiment, the present invention provides a novel compound of formula
IIb, wherein X is S.
[00216] In another embodiment, the present invention provides a novel compound of formula
IIb, wherein X is SCH2.
[00217] In another embodiment, the present invention provides a novel compound of formula
IIb, wherein X1 is O.
[00218] In another embodiment, the present invention provides a novel compound of formula
IIb, wherein X1 is S.
[00219] In another embodiment, the present invention provides a novel compound of formula
IIb, wherein: R1 is aryl substituted with 0-1 Rla; wherein Rla, at each occurrence, is selected
from OH, SH, Cl, F, NH2, -CN, NO2, C1-64 alkyl.
[00220] In another embodiment, the present invention provides a novel compound of formula
IIb, wherein R1 is C1-6 alkyl substituted with Rla; and wherein Rla is aryl substituted with 0-1
Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-64 alkyl.
[00221] In another embodiment, the present invention provides a novel compound of formula
IIb, wherein: R1 is C1-6 alkyl substituted with Rla, wherein Rla is heteroaryl substituted with 0-
1 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4alkyl.
[00222] in another embodiment, the present invention provides a novel compound of formula
IIb, wherein: R1 is C1-6 alkyl substituted with Rla, wherein Rla is heterocyclyl substituted with
0-1 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl.
[00223] In another embodiment, the present invention provides a novel compound of formula lib, wherein: R1 is C1-6 alkyl substituted with Rla, wherein Rla is C5.6 cycloalkyl substituted with 0-2 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2, -CN, NO2> CM alkyl. [00224] In another embodiment, the present invention provides a novel compound of formula lib, wherein: R2ais aryl substituted with R2b; wherein R2b is selected from OH, SH, Cl, F, NH2,-CN,NO2, CM alkyl.
[00225] In another embodiment, the present invention provides a novel compound of formula lib, wherein: R2ais C1-6 alkyl substituted with R2b; wherein R2b is selected from aryl substituted with R20; and wherein R20 is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alky!. [00226] In another embodiment, the present invention provides a novel compound of formula lib, wherein: R2a is C1-6 alkyl substituted with R2b; wherein R2b is selected from heteroaryl substituted with R2c; and wherein R* is selected from OH, SH, Cl, F, NH2, -CN, N02, CM alkyl.
[00227] In another embodiment, the present invention provides a novel compound selected
from:
[00228] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-l-yl-propoxy)-phenyl-
sulfanyl]-phenoxy} -acetic acid;
[00229] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]-
phenoxy}-acetic acid;
[00230] {2-Chloro-4- [3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-
sulfanyl]-phenoxy}-acetic acid;
[00231] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)-
phenylsulfanyl]-phenoxy}-aceticacid;
[00232] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(l-methyl-piperidin-4-ylmethoxy)-
phenylsulfanyl]-phenoxy }-acetic acid;
[00233] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1 -ynyl)-phenyl-
sulfanyl]-phenoxy}-acetic acid;
[00234] {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-
methyl-phenoxy)-acetic acid;
[00235] {4-[3-Cyclohexylmemoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-
methyl-phenoxy}-acetic acid;
[00236] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid;
[00237] {4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-
methyl-phenoxy} -acetic acid;
[00238] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-
acetic acid;
[00239] {4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid;
[00240] {2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-
phenoxy}-acetic acid;
[00241] {2-Chloro-4-[3-(3-methoxy-prop-l-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-
sulfanyl]-phenoxy}-acetic acid;
[00242] {2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-l-ynyl-phenylsulfanyl]-
phenoxy)-acetic acid;
[00243] {2-Methyl-4-[3-(3-moipholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-benzyl-
sulfanyl]-phenoxy}-acetic acid;
[00244] {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-lynyl)-benzylsulfanyl]-2-
methyl-phenoxy)-acetic acid; and,
[00245] {2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-l-ynyl)-benzyl-
sulfanyl]-phenoxy}-acetic acid;
[00246] or a pharmaceutically acceptable salt thereof.
[00247] In another embodiment, the present invention provides a novel compound selected
from:
[00248] {4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-
methyl-phenoxy}-acetic acid;
[00249] [4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-
methyl-phenoxy} -acetic acid;
[00250] {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid;
[00251] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenyl-
salfanyl]-2-methyl-phenoxy}-aceticacid;
[00252] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-
sulfanyl]-2-methyl-phenoxy}-acetic acid;
[00253] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenyl-
sulfanyl]-2-methyl-phenoxy}-acetic acid;
[00254] {4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic
acid;
[00255] [4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic
acid;
[00256] {4-[3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-
2-methyl-phenoxy}-acetic acid;
[00257] [4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-
acetic acid;
[00258] {4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-
acetic acid;
[00259] {4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyi-
phenoxy)-acetic acid;
[00260] {4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid;
[00261] {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2-
methyl-phenoxy} -acetic acid;
[00262] {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-
methyl-phenoxyj-acetic acid;
[00263] {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsuifanyl]-2-
methyl-phenoxy }-acetic;
[00264] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-
phenoxy}-acetic acid;
[00265] [4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid;
[00266] {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-
phenoxy}-acetic acid;
[00267] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-
phenylsulfanyl]-2-methyl-phenoxy }-acetic acid;
[00268] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-
phenylsulfanyl]-2-methyl-phenoxy}-aceticacid;
[00269] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-pyridin 2
yloxy)-phenylsulfanyl]-phenoxy}-aceticacid;
[00270] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(5-trifluoromethyl-pyridin-2-
yloxy)-phenylsulfanyl]-phenoxy}-aceticacid;
[00271] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-phenoxy)-
phenylsulfanyl]-phenoxy}-aceticacid;
[00272] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenyl-
sulfanyl]-2-methyl-phenoxy}-acetic acid; and
[00273] {2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl-
sulfanyl]-phenoxy}-acetic acid,
[00274] or a pharmaceutically acceptable salt thereof.
[00275] In another embodiment, the present invention provides a novel compound of formula III:
[00276] or a pharmaceutically acceptable salt thereof, wherein: [00277] R1 is CM alkyl substituted with 1-2 Rla;
[00278] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3-10 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb;
[00279] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3.6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 R1';
[00280] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; [00281] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, N02, CM alkyl, and C2.4 alkenyl;
[00282] R23 is selected from aryl substituted with 0-2 R2b and heteroaryl substituted with 0-2 R2b;
[00283] R2b, at each occurrence, is selected from OH substituted with 0-1 R20, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R2", -CN, NO2, C,.4 alkyl substituted with 0-2
R20, C2.4 alkenyl substituted with 0-2 R2c, aryl substituted with 0-2 R2c, heteroaryl substituted with 0-2 R2c, C3.6 cycloalkyl substituted with 0-2 R2c, and a heterocycle substituted with 0-2 R*;
[00284] R20, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 alkenyl, aryl substituted with 0-2 R2d, and heteroaryl substituted with 0-2 R2d; [00285] R2d, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl;
[00286] R3 is selected from Cl, F, CH3, and CH2CH3;
[00287] alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; [00288] R4a, at each occurrence, is selected from H, Cl, F, and CH3; [00289] R4b, at each occurrence, is selected from H, Cl, F, and CH3; [00290] R40, at each occurrence, is selected from H, Cl, F, and CH3; [00291] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00292] R5b, at each occurrence, is selected from H, Cl, F, and CH3; [00293] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00294] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00295] R5e, at each occurrence, is selected from H, Cl, F, and CH3.
[00296] In another embodiment, the present invention provides a novel compound of formula HI or a pharmaceutically acceptable salt thereof, wherein: [00297] R1 is CM alkyl substituted with 1-2 Rla;
[00298] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00299] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2l CM alkyl substituted with 0-2
Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered hev-eroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3-6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered hetero-cycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2;
[00300] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, €3-6 cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 RId and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2; [00301] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2> CM alkyl, and C2-4 alkenyl;
[00302] R2a is selected from aryl substituted with 0-2 R2b and 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and 8(0)0.2;
[00303] R2b, at each occurrence, is selected from OH substituted with 0-1 R2c, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R2*, -CN, NO2, C1-4alkyl substituted with 0-2 R20, C2.4 alkenyl substituted with 0-2 R2c, aryl substituted with 0-2 R2c, 5-10 membered heteroaryl substituted with 0-2 R26 and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, Cs-6 cycloalkyl substituted with 0-2 R20, and a 3-6 membered heterocycle substituted with 0-2 R20 and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2;
[00304] R20, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, CM alkenyl, aryl substituted with 0-2 R2d, and 5-10 membered heteroaryl substituted with 0-2 R24 and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0.2; [00305] RM, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and £2^ alkenyl; [00306] R3 is selected from Cl, F, CH3, and CH2CH3;
[00307] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)0-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; [00308] R4a, at each occurrence, is selected from H, Cl, F, and CH3; [00309] R4b, at each occurrence, is selected from H, Cl, F, and CH3; [00310] R40, at each occurrence, is selected from H, Cl, F, and CH3; [00311] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00312] R5b, at each occurrence, is selected from H, Cl, F, arid CH3; [00313] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00314] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00315] R5e, at each occurrence, is selected from H, Cl, F, and CH3.
[00316] In another embodiment, the present invention provides a novel compound of formula Ilia

(Formula Removed)
[00317] or a pharmaceutically acceptable salt thereof, wherein:
[00318] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C5_6 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb;
[00319] Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4alkyl substituted with 0-2 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C5-6cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc;
[00320] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld;
[00321] R2a is selected from aryl substituted with 0-2 R2b and heteroaryl substituted with 0-2 R2b and; and,
[00322] R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4alkyl, C2-4 alkenyl, aryl, heteroaryl, C5-6 cycloalkyl, and a heterocycle.
[00323] In another embodiment, the present invention provides a novel compound of formula Ilia or a pharmaceutically acceptable salt thereof, wherein:
[00324] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-6 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00325] Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alky! substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, Cs-6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00326] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2_4 alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2, C$.6 cycloalkyl substituted with 0-2 Rrd, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00327] R2a is selected from aryl substituted with 0-2 R2b and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2l and,
[00328] R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2_4 alkenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from 0, N, and S(O)o-2, C5.6 cycloalkyl, and a 5-6 membered heterocycle and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2.
[00329] In another embodiment, the present invention provides a novel compound of formula la, wherein:
[00330] R1 is CM alkyl substituted with 1-2 Rla;
[00331] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3-10cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb;
[00332] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, N02, C1-4 alkyl substituted with 0-2 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3.6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc;
[00333] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld; [00334] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and €2-4 alkenyl;
[00335] R2 is aryl substituted with 0-3 R2a or heteroaryl substituted with 0-2 R2a; [00336] R2a, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, Cl, F, NH2 substituted with 0-2 R2b, -CN, NO2, CM alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, heteroaryl substituted with 0-2 R2b, C3.6 cycloalkyl substituted with 0-2 R2b, and a heterocycle substituted with 0-2 R2b;
[00337] R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and, C2_4 alkenyl;
[00338] R3 is selected from Cl, F, CH3, and CH2CH3;
[00339] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; [00340] R4a, at each occurrence, is selected from H, Cl, F, and CH3;
[00341] R4b, at each occurrence, is selected from H, Cl, F, and CH3; [00342] R4*, at each occurrence, is selected from H, Cl, F, and CH3; [00343] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00344] R5b, at each occurrence, is selected from H, Cl, F, and CH3; [00345] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00346] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00347] R5c, at each occurrence, is selected from H, Cl, F, and CH3.
[00348] In another embodiment, the present invention provides a novel compound of formula la, wherein:
[00349] R1 is CM alkyl substituted with 1-2 Rla;
[00350] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-10 mem-bered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3-10cycloalkyl substituted with 0-2 Rlb, and a 3-8 mem-bered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00351] Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, CM alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3.6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2;
[00352] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2-4 alkenyl, aryl substituted with 0-2 RId, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from 0, N, and S(O)o-2, C3.6 cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2; [00353] Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, N02, CM alkyl, and C2-4 alkenyl;
[00354] R2 is aryl substituted with 0-3 R2a or 5-10 membered heteroaryl substituted with 0-2 R2a and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(0)o-2; [00355] R23, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, Cl, F, NH2 substituted with 0-2 R2b, -CN, NO2, C1-4alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1 -4 heteroatoms selected from O, N, and S(O)0-2, C3.6 cycloalkyl substituted with 0-2 R2b, and a 3-6 membered hctero-cycle substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2;
[00356] R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4alkyl, and, C2-4 alkenyl;
[00357] R3 is selected from Cl, F, CH3, and CH2CH3;
[00358] alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e; [00359] R4a, at each occurrence, is selected from H, Cl, F, and CH3; [00360] R4b, at each occurrence, is selected from H, Cl, F, and CH3; [00361] R4', at each occurrence, is selected from H, Cl, F, and CH3; [00362] R5a, at each occurrence, is selected from H, Cl, F, and CH3; [00363] R5b, at each occurrence, is selected from H, Cl, F, and CH3; [00364] R5c, at each occurrence, is selected from H, Cl, F, and CH3; [00365] R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, [00366] R5c, at each occurrence, is selected from H, Cl, F, and CH3.
[00367] In another embodiment, the present invention provides a novel compound of formula Ib:
j I\.
(Formula Removed)

[00368] or a pharmaceutically acceptable salt thereof, wherein: [00369] R1 is C1-4 alkyl substituted with 1 Rla;
[00370] Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-6 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2, C5.6 cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00371] Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o_2, C$-6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
[00372] Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and €2^ alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, Cj.e cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from 0, N, and S(O)0.2; [00373] R2 is aryl substituted with 0-2 R2a or 5-6 membered heteroaryl substituted with 0-2 R2a and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2; and, [00374] R2a, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, Cl, F, NH2 substituted with 0-2 R2b, -CN, NO2, C1-4 alkyl substituted with 0-2
R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-6 membered het-
eroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, Cs-6 cycloalkyl substituted with 0-2 R2b, and a 5-6 membered hetero-cycle substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2.
[00375] In another embodiment, the present invention provides a novel compound pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of the present invention or a pharmaceutically acceptable salt thereof.
[00376] In another embodiment, the present invention provides a novel method of treating type 2 diabetes, comprising: administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.
[00377] In another embodiment, the present invention provides a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the disease is selected from dyslipidemia, syndrome X (including the metabolic syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity), cardiovascular diseases (e.g., atherosclerosis and related diseases, including mortality reduction, coronary artery diseases, coronary heart diseases, heart attack, myocarc'ial ischemia, myocardial infarct, coronary infarct, transient ischemic attack (TIA), and stroke), hyperglycemia, hyperlipidemia, hypercholesterolemia, and hyperinsulinemia.
[00378] In another embodiment, the present invention provides a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the disease is selcted from non-insulin requiring Type 2 diabetes to insulin requiring Type 2 diabetes, decreasing apoptosis in mammalian cells (e.g., beta cells of Islets of Langerhans), renal diseases (e.g., glomerulonephritis, glomerulosclerosis, nephrotic syndrome, and hypertensive nephrosclerosis), improving cognitive functions in dementia,
treating diabetic complications, psoriasis, polycystic ovarian syndrome (PCOS), prevention and treatment of bone loss (e.g. osteoporosis), and lowering the bio-markers of atherosclerosis (e.g., c-reactive protein (CRP), TNF-ct, and IL-6).
[00379] In another embodiment, the present invention provides a novel process for the preparation of the compounds of the present invention or stereoisomers or pharmaceutically acceptable salts thereof.
[00380] In another embodiment, the present compounds are administered in combination with one or more further pharmacologically active substances selected from antiobesity agents, appetite regulating agents, antidiabetics, antihypertensive agents, agents for the treatment of complications resulting from or associated with diabetes, and agents for the treatment of complications and disorders resulting from or associated with obesity.
[00381] Suitable additional substances may be selected from CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, uro-cortin agonists, P3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR (retinoid X receptor) modulators or TR P agonists.
[00382] Suitable antiobesity agents include leptin, dexamphetamine, amphetamine, fenflura-mine, dexfenfluramine, sibutramine, orlistat, mazindol, and phentermine. [00383] Suitable antidiabetics include insulin, orally active hypoglycaemic agents, and GLP-1 (glucagon like peptide-1) derivatives (see WO 98/08871).
[00384] Orally active hypoglycaemic agents preferably include sulphonylureas, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists (see WO99/01423), GLP-1 agonists, potassium channel openers (see WO 97/26265 and WO 99/03861), DPP-IV (dipeptidyl peptidase-IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeo-genesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism (e.g., antihyperlipidemic agents and antilipidemic agents), compounds lowering food intake, RXR agonists, agents acting on the ATP-dependent potassium channel of the P-cells, and thiazolidinediones (e.g., troglitazone, ciglitazone, pioglitazone and rosiglitazone). [00385] Agents to be administered in combination with compounds of the present invention also include sulphonylureas (e.g., tolbutamide, glibenclamide, glipizide, and glicazide), biguanides (e.g., metformin), meglitinides (e.g., repaglinide and senaglinide), a-glucosidase inhibitors (e.g., miglitol and acarbose), an agent acting on the ATP-dependent potassium channel of the p-cells (e.g., the above sulphonylureas and repaglinide), and nateglinide. [00386] Antihyperlipidemic or antilipidemic agents include apolipoprotein A-I Milano, cho-lestyramine, colestipol, clofibrate, gemfibrozil, fenoflbrate, bezafibrate, tesaglitazar, muragli-tazar, EML-4156, LY-518674, LY-519818, MK-767, torcetrapib, atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, cerivastin, rosuvastatin, pitavastatin, acipimox, ezetimibe, probucol, dextrothyroxine and nicotinic acid.
[00387] In another embodiment the present compounds are administered in combination with more than one of the above-mentioned compounds (e.g, in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, or insulin and lovastatin).
[00388] Examples of ntihypertensive agents include p-blockers (e.g, alprenolol, atenolol, ti-molol, pindolol, propranolol, and metoprolol), ACE (angiotensin converting enzyme) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril), calcium channel blockers (e.g., nifedipine, felodipine, nicardipine, isradipine, nimodipine, dilti-azem and verapamil), and a-blockers (e.g., doxazosin, urapidil, prazosin and terazosln). [00389] It should be understood that any suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and optionally one or
more further pharmacologically active substances are considered to be within the scope of the present invention.
[00390] It is preferred that the compounds of the present invention have a solubility in water of at least 0.1 mg/L as determined at 25°C and pH 7.0. More preferably the solubility is at least 0.5 mg/L. Even more preferably the solubility is at least 1 mg/L. Still more preferably, the solubility is at least 2 mg/L. Further preferably the solubility is at least 10 mg/L. Even further preferably the solubility is at least 50 mg/L. Still further preferably the solubility is at least 200 mg/L.
[00391] It is preferred that compounds of the present invention have an ICso value of less than 5 Jim as determined by the PPAR transient transactivation assay. More preferably the ICso value is less than 1 /im. Even more preferably the ICso value is less than 500 nM. Still more preferably the ICso value is less than 100 nM. Further preferably the ICso value is less than 50 nM. Even further preferably the ICso value is less than 25 nM. Still further preferably the IC50 value is less than 10 nM. Even still further preferably the IC5o value is less than 5 nM. [00392] It is preferred that the compounds of the present invention have a molecular weight of less than 10CO g/mol. More preferably the molecular weight is less than 750 g/mol. Even more preferably the molecular weight is less than 600 g/mol. Still more preferably, the molecular weight is less than 550 g/mol. Further preferably the molecular weight is less than 500 g/mol. Even further preferably the molecular weight is less than 400 g/mol. [00393] It is preferred that compounds of the present invention are ionized at pH 7.4. [00394] It is preferred that the compounds of the present invention have only one ionized carboxylic acid group at a pH of from 5.5-9. More preferably the compounds have only one ionized carboxylic acid group at a pH of from 6-8. Even more preferably the compounds have only one ionized carboxylic acid group at a pH of from 6.5-7.5. Still more preferably, the compounds have only one ionized carboxylic acid group at pH 7.4.
[00395] It is preferred that the compounds of the present invention are zwitter-ionic with one ionized amine group and one ionized carboxylic acid group at a pH of from 5.5-9. More preferably the compounds are zwitter-ionic with one ionized amine group and one ionized carboxylic acid group at a pH of from 6-8. Even more preferably the compounds are zwitter-ionic with one ionized amine group and one ionized carboxylic acid group at a pH of from
6.5-7.5. Still more preferably, the compounds are zwitter-ionic with one ionized amine group and one ionized carboxylic acid group at pH 7.4.
PHARMACEUTICAL COMPOSITIONS
[00396] The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses. The pharmaceutical compositions of the present invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. The compositions may appear in conventional forms, which include capsules, tablets, aerosols, solutions, suspensions, andtopical applications.
[00397] Typical compositions include a compound of the present invention a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient, which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier, which can be in the form of a capsule, sachet, paper, or other container. In making the compositions, conventional techniques for the preparation of pharmaceutical compositions may be used. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container for example in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, ac?.cia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting
agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents. The formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
[00398] The pharmaceutical compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds. [00399] The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, trans-dermal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred. [00400] If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
[00401] For nasal administration, the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
[00402] For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxyiated castor oil.
[00403] Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
[00404] If desired, the pharmaceutical composition of the invention may comprise a compound of the present invention in combination with further pharmacologically active substances such as those described in the foregoing.
[00405] The compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of diseases related to the regulation of blood sugar. Mammals also include animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife. [00406] The compounds of the present invention are expected to be effective over a wide dosage range. A typical oral dosage is hi the range of from about 0.001 to about 100 ifig/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
[00407] The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain of from 0.05 to about 1000 mg, preferably from about 0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200 mg.
DEFINITIONS
[00408] All references described herein are incorporated in there entirety by reference. [00409] "Substituted" signifies that one or more hydrogen atoms are replaced by the designated substituent. Only pharmaceutically stable compounds are intended to be covered. [00410] When examples of definitions are provided, the definition is not meant to be limited to the specific examples.
[00411] The present invention includes all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass
numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
[00412] When O or S is listed as a substituent, oxo and sulfo, respectively, it is intended that a carbon atom be replaced by either the O or S. For example if alkyl were substituted by O, then an ether would be formed. Preferably heteroatom-heteroatom bonds such as O-O, O-S, O-N, S-S, and S-N are not formed.
[00413] "Alkyl" includes both straight chain and branched alkyl groups having the designated number of carbon atoms (e.g., 1, 2, 3,4,5, 6, 7, or 8). Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, 2-methyl-butyl, and 2-ethyl-butyl.
[00414] "Alkenyl" includes both straight chain and branched alkenyll groups having the designated number of carbon atoms (e.g., 2, 3,4,5, 6,7, or 8). Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, and 2-methyl-butenyl. [00415] "Alkynyl" includes both straight chain and branched alkynyl groups having the designated number of carbon atoms (e.g., 2, 3,4,5, 6, 7, or 8). Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 2-methyl-butynyl. [00416] "Aryl" includes phenyl, naphthyl, fluorene, anthracene, phenanthrenyl, azulenyl, and a partially saturated bicyclic carbocyclic ring. The partially saturated bicyclic carbocyclic ring consists of 8,9,10,11, or 12 carbon atoms, preferably 8,9, or 10 carbon atoms. Examples of partially saturated bicyclic carbocyclic rings include 1,2,3,4-tetrahydronaphthyl, in-danyl, indenyl, l,2,4a,5,8,8ot-hexahydronaphtyl, and l,3a-dihydropentalene. A preferred aryl group is phenyl.
[00417] "Cycloalkyl" means a ring having the number of designated carbon atoms and having only single bonds between the carbon atoms. Examples of cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Preferred cycloalkyl groups are cyclopentyl and cyclohexyl.
[00418] "Heteroaryl" signifies a mono-, bi-, or tricyclic ring consisting of carbon atoms and from one heteroatom to 5, wherein the heteroatom is selected from oxygen, nitrogen, and sulphur. If sulphur is present, then it can be mono- or di-oxidized. If a nitrogen is present, then it can be N, NH, or substituted N. The heterocycle can be attached via a carbon or nitrogen
atom, unless linking the nitrogen atom would lead to a quaternary nitrogen. If the heteroaryl is bicyclic, then one or both of the rings may have a heteroatom(s) present. If the heteroaryl is tricyclic, then one, two, or all three of the rings may have a heteroatom(s) present. If the net-erocycle is monocyclic, then this ring is aromatic (e.g., fully unsaturated). If the heteroaryl is bicyclic or tricyclic, then at least one ring is aromatic.
[00419] Examples of "heteroaryl" are pyrrolyl (e.g. pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl), fu-ranyl (e.g. furan-2-yl, furan-3-yl), thienyl (e.g. thien-2-yl, thien-3-yl), oxazolyl (e.g. oxazol-2-yl, oxazol-4-yl, oxazol-5-yl), thiazolyl (e.g. thiazol-2-yl, thiazol-4-yl, thiazol-5-yl), imidazolyl (e.g. imidazol-2-yl, imidazol-4-yl, imidazol-5-yl), pyrazolyl (e.g. pyrazol-1-yl, pyrazol-3-yl, pyrazol-5-yl), isoxazolyl (e.g. isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl), isothiazolyl (e.g. isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl), 1,2,3-triazolyl (e.g. 1,2,3-triazol-l-yl, 1,2,3-triazol-4-yl, l,2,3-triazol-5-yl), 1,2,4-triazolyl (e.g. 1,2,4-triazol-l-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl), 1,2,3-oxadiazolyl (e.g. 1,2,3-oxadiazol-4-yl, l,2,3-oxadiazol-5-yl), 1,2,4-oxa-diazolyl (e.g. l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl), 1,2,5-oxadiazolyl (e.g. 1,2,5-oxa-diazol-3-yl, l,2,5-oxadiazol-4-yl), 1,3,4-oxadiazolyl (e.g. l,3,4-oxadiazol-2-yl, 1,3,4-oxadia-zol-5-yl), l,2,3-thiadiazolyl(e.g. l,2,3-thiadiazol-4-yl, l,2,3-thiadiazol-5-yl), 1,2,4-thiadia-zolyl(e.g. l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl), 1,2,5-thiadiazolyl (e.g. 1,2,5-thiadia-zol-3-yl, l,2,5-thiadiazol-4-yl), 1,3,4-thiadiazolyl (e.g. l,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl), tetrazolyl (e.g. tetrazol-1-yl, tetrazol-5-yl), pyranyl (e.g. pyran-2-yl), pyridinyl (e.g. pyridine-2-yl, pyridine-3-yl, pyridine-4-yl), pyridazinyl (e.g. pyridazin-2-yl, pyridazin-3-yl), pyrimidinyl (e.g. pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl), pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, thiadiazinyl, azepinyl, azecinyl, indolyl (e.g. indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), isoindolyl, benzofuranyl (e.g. benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo[b]furan-5-yl, benzo[c]furan-2-yl, benzo[c]furan-3-yl, benzo[c]furan-5-yl), benzo-thienyl (e.g. benzotb]thien-2-yl, benzo[b]thien-3-yl, benzo[b]thien-5-yl, benzo[c]thien-2-yl, benzo[c]thien-3-yl, benzo[c]thien-5-yl), indazolyl (e.g. indazol-1-yl, indazol-3-yl, indazol-5-yl), indolizinyl (e.g. indolizin-1-yl, indolizin-3-yl), benzopyranyl (e.g. benzo[b]pyran-3-yl, benzo[b]pyran-6-yl, benzo[c]pyran-l-yl, benzo[c]pyran-7-yl), benzimidazolyl (e.g. benzimi-dazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzothiazolyl (e.g. benzothiazol-?-yl, benzothiazol-5-yl), benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotria-
zolyl, naphthyridinyl (e.g. l,8-naphthyridin-2-yl, 1,7-naphthyridin-2-yl, 1,6-naphthyridin-2-yl), phthalazinyl (e.g. phthalazin-1-yl, phthalazin-5-yl), pteridinyl, purinyl (e.g. purin-2-yl, purin-6-yl, purin-7-yl, purin-8-yl, purin-9-yl), quinazolinyl (e.g. quinazolin-2-yl, quinazolin-4-yl, quinazolin-6-yl), cinnolinyl, quinoliny (e.g. quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl), isoquinolinyl (e.g. isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl), qui-noxalinyl (e.g. quinoxalin-2-yl, quinoxalin-5-yl), pyrrolopyridinyl (e.g. pyrrolo[2,3-b]pyridi-nyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl), furopyridinyl (e.g. furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-c]pyridinyl), thienopyridinyl (e.g. thieno[2,3-b]pyridinyl, thi-eno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl), imidazopyridinyl (e.g. imidazot4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, imidazo[l,5-a]pyridinyl, imidazo[l,2-a]pyridinyl), imidazopyrimidi-nyl (e.g. imidazo[l,2-a]pyrimidinyl, imidazo[3,4-a]pyrimidinyl), pyrazolopyridinyl (e.g. pyra-zolot3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[l,5-a]pyridinyl), pyrazolopyrimidi-nyl (e.g. pyrazolo[l,5-a]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl), thiazolopyridinyl (e.g. thi-azolo[3,2-d]pyridinyl), thiazolopyrimidinyl (e.g. thiazolo[5,4-d]pyrimidinyl), imdazojhiazoly) (e.g. imidazo[2,l-b]thiazolyl), triazolopyridinyl (e.g. triazolo[4,5-b]pyridinyl), triazolopyrimi-dinyl (e.g. 8-azapurinyl), carbazolyl (e.g. carbazol-2-yl, carbazol-3-yl, carbazol-9-yl), phen-oxazinyl (e.g. phenoxazin-10-yl), phenazinyl (e.g. phenazin-5-yl), acridinyl (e.g. acridin-9-y1, acridin-10-yl), phenothiazinyl (e.g. phenothiazin-10-yl), carbolinyl (e.g. pyrido[3,4-b]indol-l-yl, pyrido[3,4-b]indol-3-yl), phenanthrolinyl (e.g. phenanthrolin-5-yl), pyrrolinyl, pyrazolinyl, imidazolinyl (e.g. 4,5-dihydroimidazol-2-yl, 4,5-dihydroimidazol-l-yl), indolinyl (e.g. 2,3-dihydroindol-1-yl, 2,3-dihydroindol-5-yl), dihydrobenzofuranyl (e.g. 2,3-dihydrobenzo-[b]furan-2-yl, 2,3-dihydrobenzo[b]furan-4-yl), dihydrobenzothienyl (e.g. 2,3-dihydrobenzo-[b]thien-2-yl, 2,3-dihydrobenzo[b]thien-5-yl), 4,5,6,7-tetrahydrobenzo[b]furan-5-yl), dihy-drobenzopyranyl (e.g. 3,4-dihydrobenzo[b]pyran-3-yl, 3,4-dihydrobenzo[b]pyran-6-yl, 3,4-dihydrobenzo[c]pyran-l-yl, dihydrobenzo[c]pyran-7-yl), oxazolinyl (e.g. 4,5-dihydrooxazol-2-yl, 4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl), isoxazolinyl, oxazepinyl, tetralwdro-indazolyl (e.g. 4,5,6,7-tetrahydroindazol-l-yl, 4,5,6,7-tetrahydrouidazol-3-yl, 4,5,6,7-teirahy-droindazol-4-yl, 4,5,6,7-tetrahydroindazol-6-yl), tetrahydrobenzimidazolyl (e.g. 4,5,6,7-tetrahydrobenzimidazol-1-yl, 4,5,6,7-tetrahydrobenzimidazol-5-yl), tetrahydroimidazo[4,5-c]pyridyl (e.g. 4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-l-yl, 4,5,6,7-tetrahydroimidazo[4,5-
]pyrid-5-yl, 4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-6-yl), tetrahydroquinolinyl (e.g. 1,2,3,4-tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinolinyl), tetrahydroisoquinolinyl (e.g. 1,2,3,4-tetre hydroisoquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinoxalinyl (e.g. 1,2,3,4-te-trahydroquinoxalinyl, 5,6,7,8-tetrahydroquinoxaliriyl), spiro[isoquinoline-3,l'-cyclohexan]-l-yl, spiro[piperidine-4,1' -benzo[c]thiophen]-1 -yl, spiro[piperidine-4,1' -benzo[c]furan]- 1-yl, spiro[piperidine-4,3'-benzo[b]furan]-l-yl, spiro[piperidine-4,3'-coumarin]-l-yl. A preferred heteroaryl is pyridinyl.
[00420] Other examples of "heteroaryl" are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, tri-azolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazolyl, oxazolyl, oxa-diazolyl, thiadiazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinnyl, indolyl, benzimida-zolyl, benzofuranyl, benzothienyl, pteridinyl and purinyl.
[00421] "Heterocyclyl" or "heterocycle" (heterocycle) signifies a mono-, bi-, or tricydic ring consisting of carbon atoms and from one heteroatom to 4, wherein the heteroatom is selected from oxygen, nitrogen, and sulphur. If sulphur is present, then it can be S, S(O), or S(O)2. If nitrogen is present, then it can be N, NH, substituted N, or N-oxide. The heterocycle is a saturated or partially saturated ring. From 0-2 CH2 groups of the heterocycle can be replaced by C(O). The heterocycle can be attached via a carbon or nitrogen atom, unless linking the nitrogen atom would lead to a quaternary nitrogen. If the heterocycle is bicyclic, then one or both of the rings may have a heteroatom(s) present. If the heterocycle is tricyclic, then one, two, or all three of the rings may have a heteroatom(s) present.
[00422] Examples of "heterocycle" are aziridinyl (e.g. aziridin-1-yl), azetidinyl (e.g. azetidin-1-yl, azetidin-3-yl), oxetanyl, pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), imidazolidinyl (e.g. imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl), oxazolidinyl (e.g. oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl), thiazolidinyl (e.g. thiazolidin 2-yl, thiazolidin-3-yl, thiazolidin-4-yl), isothiazolidinyl, piperidinyl (e.g. piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), homopiperidinyl (e.g. homopiperidin-1-yl, homopiperi-din-2-yl, homopiperidin-3-yl, homopiperidin-4-yl), piperazinyl (e.g. piperazin-1-yl, piperazin-2-yl), morpholinyl (e.g. morpholin-2-yl, morpholin-3-yl, morpholin-4-yl), thiomorpholinyl (e.g. thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl), 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, tetrahydrofuranyl (e.g. tetrahydrofuran-2-yl, tetrahydrofuran-3-
yl), tetrahydrothienyl, tetrahydro-l,l-dioxothienyl, tetrahydropyranyl (e.g. 2-tetrahydropyra-nyl), tetrahydrothiopyranyl (e.g. 2-tetrahydrothiopyranyl), 1,4-dioxanyl, 1,3-dioxanyl, octa-hydroindolyl (e.g. octahydroindol-1-yl, octahydroindol-2-yl, octahydroindol-3-yl, octahydro-indol-5-yl), decahydroquinolinyl (e.g. decahydroquinolin-1-yl, decahydroquinolin-2-yl, deca-hydroquinolin-3-yl, decahydroquinolin-4-yl, decahydroquinolin-6-yl), decahydroquinoxalinyl (e.g. decahydroquinoxalin-1-yl, decahydroquinoxalin-2-yl, decahydroquinoxalin-6-yl), 3-aza-bicyclo[3.2.2]nonyl, 2-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.0]hexyl, 2,5-diazabicyclo-[2.2.1]heptyl, atropinyl, tropinyl, quinuclidinyl, l,4-diazabicyclo[2.2.2]octanyl, 1,4-dioxa-spiro[4.5]decanyl (e.g. l,4-dioxaspiro[4.5]decan-2-yl, l,4-dioxaspiro[4.5]decan-7-yl), 1,4-dioxa-8-azaspiro[4.5]decanyl (e.g. l,4-dioxa-8-azaspiro[4.5]decan-2-yl, l,4-dioxa-8-aza-spiro[4.5]decan-8-yl), 8-azaspiro[4.5]decanyl (e.g. 8-azaspiro[4.5]decan-l-yl, 8-azaspiio-[4.5]decan-8-yl), 2-azaspiro[5.5]undecanyl (e.g. 2-azaspiro[5.5]undecan-2-yl), 2,8-diaza-spiro[4.5]decanyl (e.g. 2,8-diazaspiro[4.5]decan-2-yl, 2,8-diazaspiro[4.5]decan-8-yl), 2,8-diazaspiro[5.5]undecanyl (e.g. 2,8-diazaspiro[5.5]undecan-2-yl), l,3,8-triazaspiro[4.5]decanyl (e.g. l,3,8-triazaspiro[4.5]decan-l-yl, l,3,8-triazaspiro[4.5]decan-3-yl, and 1,3,8-triazaspi-ro[4.5]decan-8-yl).
[00423] Preferred examples of "heterocycle" are pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, imidzolidinyl, imidazolinyl, pyra-zolidinyl, pyrazolinyl, oxazolidinyl, oxazoline, isoxazolidinyl, isoxazoline, thioxazolidinyl, thioxazoline, isothioxazolidinyl, isothioxazoline, triazolidinyl, triazolinyl, tetrazolidinyl, tetrazolinyl, tetrahydropyranyl, dihydropyranyl, pyran, piperidinyl, piperazinyl, homcniperaz-inyl, morpholinyl. Preferred heterocycle groups are piperidinyl and morpholinyl. [00424] "Therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to activate glucokinase.
[00425] 'Treating" or "treatment" cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, e.g., arresting or slowing its develop-
ment; and/or (c) relieving the disease-state, e.g., causing regression of the disease state itself or some symptom of the disease state.
[00426] Pharmaceutically acceptable include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts, and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include, hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, and nitric acids. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, man-delic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluene-sulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hy-droxynaphthoates, glycerophosphates, and ketoglutarates. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium, zinc, and calcium salts. Examples of amines and organic amines include ammonium, methylamine, dimethylarnine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine, tetramethylamii;e, etha-nolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N-methyl-D-glucamine, and guanidine. Examples of cationic amino acids include lysine, arginine, and histidine. [00427] The pharmaceutically acceptable salts are prepared by reacting the compound of formula I with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, and magnesium hydroxide, in solvents such as ether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases such as lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic
acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, and tartaric acid in solvents such as ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
[00428] The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, enzymatic resolution, resolving the diastereo-meric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, and lactic acid wherever applicable or chiral bases such as brucine, (R$)- or (S)-phenyl-ethylamine, cinchona alkaloids and their derivatives. Commonly used methods are compiled by Jaques et al in "Enantiomers, Racemates and Resolution" (Wiley Interscience, 1981). More specifically a compound of the present invention may be converted to a 1:1 mixture of diastereomeric amides by treating with chiral amines, aminoacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatog-raphy and the stereoisomers of compound of formula I may be prepared by hydrolysincr the pure diastereomeric amide.
[00429] The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into a compound of the present invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
[00430] This invention will be better understood from the following examples, which are for purposes of illustration and are not intended to limit the invention defined in the claims which follow thereafter.EXAMPLES
[00431] All reactions involving air-sensitive reagents were performed under nitrogen using syringe-septum cap techniques. The glassware was dried by heating with a heat-gun. MgSO4 was used to dry solutions. Solvents were removed in vacua by rotary evaporation. Melting points were recorded on a Biichi 535. Bruker AMX 400 and Bruker DRX 300 instruments were used to record *H NMR spectra at 400 and 300 MHz, respectively, with tetramethylsi-lane (TMS) as internal standard. Coupling constants (J) are given in Hz.
[00432] Materials
[00433] Test compounds were synthesized or when commercially available they were purchased from Aldrich, Specs, Maybridge, or Bionet. For the synthesized compounds, the procedure for synthesis and measured characteristics of the compound are stated in the example. All compounds for which no synthesis procedure is stated in the examples are commercially available and have been purchased or were prepared by standard methods described in the literature. [00434] A general procedure may be as follows:
(scheme Removed)
[00435] The synthetic intermediate of formula I with Rl = H, R2 =Br and a carboxylic ester group e.g. [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acetate can be converted via a classical Mitsunobu reaction or a reaction can be performed between the phenol and an alkyl halides (or an alkyle mesylate, triflate, tosylate or alike) to a new intermediate of formula I where X1-R1 forms a ether or thioether group and R = Br. The new intermediate can be converted via a classical Sonogashira, Heck or Suzuki coupling protocol to a new intermediate where R2 is -OC-R2", -CH=CH-R2a or a substituted or non substituted aryl or heteroaryl. It is also possible to perform the reaction in the opposite way by first performing the Sonogashira, Heck or Suzuki coupling followed by the ether forming reaction as described above. The claimed compounds can also be performed as described for [4-(3-Bromo-5-cyclopropylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester by condensing e.g. l,3-dibromo-5-cyclopropylmethoxy-benzene or another substituted dibromo • phenyle ether with (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester or another substituted mercaptobezene. The intermediates formed can be converted to the claimed compounds by a classical ester hydrolyses reaction from the respective esters of I (scheme 1-3).
[00436] General procedure (A) [00437] HPLC systems
[00438] HPLC method A
[00439] The RP-purification was performed on a Gilson system (4 Gilson 306 pumps, Gilson 155 detector, Gilson reodyne manual injection, Gilson 811C mixer and a Gilson 202 fraction collector) using a Phenomenex RP synergi-MAX column (3µm, 30 mm x 250 mm) with gradient elution, 5 % to 100 % solvent B (acetonitrile) in solvent A (water) within 40 min, 60 mL/min, detection at 210 nm, room temperature. The pooled fractions were either evaporated to dryness in vacua, or evaporated in vacua until the MeCN is removed, and then frozen and freeze dried.
[00440] HPLC method B
[00441] The RP-purification was performed on a Gilson system (3 Gilson 306 pumps, Gilson 170 DAD detector and a Gilson 215 liquid-handler) using a Waters X-terra RP (10 /mi, .30 mm x 150 mm) with gradient elution, 5% to 95% solvent B (0.05% TFA in acetonitrile) in solvent A (0.05% TFA in water) within 15 min, 40 mL/min, detection at 210 nm, room temperature. The pooled fractions were either evaporated to dryness in vacua or evaporated in vacua until the MeCN is removed and then frozen and freeze dried.
[00442] HPLC-MS (System 1)
[00443] The RP-analysis was performed on an Agilent HPLC system (1100 degasser, 1100 pump, 1100 injector and a 1100 DAD) fitted with an Agilent MS detector system Model VL (MW 0-1000) and a S.E.D.E.R.E Model Sedex 55 ELS detector system using a Waters X-terra MS CIS column (5 /im, 3.0 mm x 50 mm) with gradient elution, 5% to 95% solvent B (0.05% TFA in acetonitrile) in solvent A (0.05% TFA in water) within 3 min, 2.7 mL/min.
[00444] Thin layer chromatography was performed on Merck DC-Alufolien, silica gel 60 F254 and components were visualized by UV254. Flash chromatography was performed using silica gel Merck 60 size 0.04-0-063 mm and a Quad 12/25 flash system.
3,5-dibromophenol was prepared as described by Yang, et al., Synth Commun; 2003,33,19, 3317-3326.
[00445] Intermediates
[00446] [4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester

(Formula Removed)

[00447] Step A: tert-Butyl-(3,5-dibromo-phenoxy)-dimethyl-silane
(Formula Removed)
[00448] 3,5-Dibromophenol (59.6 mmol; 15 g) and imidazole (65.5 mmol; 4.5 g) were dissolved in dichloromethane (150 mL) and terf-butyl-dimethylsilylchloride (65,5 mmol; 9,9 g) was added. The reaction mixture was stirred at room temperature for 16 hours, diluted with diethyl ether, and filtered. The organic solution was washed with saturated ammonium chloride, saturated sodium hydrogen carbonate, and water and dried and evaporated to dryness. Yield: 22 g. HPLC-MS: m/z: 366.9 (M+); Rt: 3.09 min.
[00449] Step B: 3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde(Formula Removed)
H [00450] tert-Butyl-(3,5-dibromo-phenoxy)-dimethyl-silane (22 g; 60.08 mmol) was dissolved
in THF (200 mL) in a dried reaction flask under an atmosphere of nitrogen. The mixture was
cooled to -78°C and n-BuLi (1.6 N in hexane; 41.25 mL; 66.09 mmol) was added while the temperature was kept between -60 and -78°C. The mixture was stirred for 15 min. and DMF (4.83 g; 66.08 mmol) was added. The reaction mixture was stirred for 1 h and methanol (5 mL) followed by saturated ammonium chloride was added. Etyl acetate (200 mL) was added and the organic phase was separated from the aqueous phase. The organic phase was washed with water, dried, and evaporated to dryness. The crude product was purified by flash chro-matography (heptane: dichloromethane (1:1). Yield 7 g. HPLC-MS: m/z: 317.0 (M+l); Rt: 2.7 min.
[00451] Step C: [3-Bromo-5-(tret-butyl-dimethyl-silanyloxy)-phenyl]-methanol
(Formula Removed)
[00452] 3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde (7 g, 22.2 mmol) was dissolved in THF and sodium borohydride (0.92 g; 24.4 mmol) waas added. The reaction mixture was stirred at room temperature for 2 h and water was added, and the reaction mixture was partly avaporated to strip off THF. Ethyl acetate was added and the phases separated. The organic phase was washed with water, dried, and evaporated to dryness. Yield: 6.4 ^, HPLC-MS: m/z: 317.0 (M+); Rt: 2.37 min.
[00453] Step D: {4-[3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
(Formula Removed)

[00454] [3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-phenyl]-methanol (6.4 g; 20.17 mmol) and (4-mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (5.02 g; 22.19 mmol) were dissolved inTHF (200 mL). Tributylphosphine (8.15 g; 40.34 mmol) and l,l'-(azodicarbonyl)-dipiperidine (10.17 g; 40.34 mmol) were added, and the reaction mixture was stirred for 14 h at room temperature. Water and ethyl acetate were added to the reaction mixture. The phases were separated. The organic phase was washed with water, dried, and evaporated. The crude product was purified by flash chromatography (heptane: dichloromethane (1:1)). Yield: 8 g; 80%. HPLC-MS: m/z: 527.0 (M+l); Rt: 3.10 min.
[00455] Step E: [4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester
(Formula Removed)

[00456] {4-[3-Bromo-5-(ferf-butyl-dimethyl-silanyloxy)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester 7 g, 13.3 mmol) was dissolved in THF under an atmosphere of nitrogen. Tetrabutylammonium fluoride 1 N in THF (15 mL) was added, and the reaction mixture was stirred at 60°C for 2h. Saturated sodium carbonate and water were added t.o-
gether with ethyl acetate, and the organic phase was separated. The organic phase was washed with water, dried, and evaporated to dryness. Yield: 3.2 g. HPLC-MS: m/z: 435.4 (M+Na); Rt: 2.22 min.
[00457] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-chloro-phenoxy]-acetic acid ethyl acetate
(Formula Removed)

[00458] (2-Chloro-4-mercapto-phenoxy)-acetic acid ethyl ester (3 g; 12,16 mmol), dibromo-phenol (3,67 g; 14,59 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.45 g; 0.49 mmol), and l,r-bis-(diphenylphosphineo)ferrocenE (0.40 g; 0.73 mmol) were added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (6,74 mL, 48,64 mmol) and NMP (10 mL) were added, and the reaction mixture was stirred in a microwave oven for 1 h at 100°C. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate phase was washed twice with a 5% aqueous citric acid solution. The organic phase was dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (dichloromethane → dichlormethane: ethyl acetate (1:1)). Yield 1.8 g. HPLC-MS: m/z: 441.2 (M+Na); Rt: 2.34 min.
[00459] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acetate
(Formula Removed)

[00460] (2-Methyl-4-mercapto-phenoxy)-acetic acid ethyl ester (6 g; 26,51 mmol), dibromo-phenol (8,68 g; 34,47 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.97 g; 1,06 mmol), and l,l'-bis-(diphenylphosphineo)ferrocene (0.88 g; 1,59 mmol) were added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (10.73 mL, 106 mmol) and NMP (20 mL) were added, and the reaction mixture was stirred in a microwave oven for 1 h at 105 °C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4 X 100 mL). The pooled organic phases were washed twice with water (30 mL), dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (heptane: ethyl acetate (10:1→ 7:3). Yield 6,5 g. HPLC-MS: m/z: 397.3 (M+); Rt: 2,33 min.
[00461] {4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-acetic acid ethyl ester
(Formula Removed)

[00462] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-chloro-phenoxy]-acetic acid ethy! acetate (1.7 g; 4.07 mmol), N-(3-hydroxypropyl)morpholine (0.59 g; 4.07 mmol) and tributyl-phosphine (1.8 g; 7.33 mmol) were dissolved in THF (100 mL) in a dried reaction flask under an atmosphere of nitrogen. l,l'-(Azodicarbonyl)dipiperidine (1.85 g; 7,33 mmol) dissolved
in THF (50 mL) was added to the reaction mixture, which was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and purified by flash chromatography (ethyl acetate: heptane). Yield: 1.1 g. HPLC-MS: m/z: 544.0 (M+); Rt: 1.78 min.
[00463] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester
(Formula Removed)

[00464] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-chloro-phenoxy]-acetic acid ethyl acetate (1.1 g; 2.63 mmol), 4-chlorophenylacetylene (1.08 g; 7.9 mmol), bis(triphenylphosphine)-palladium (II) chloride (0.15 g; 0.21 mmol) and copper iodide (0.03 g; 0.16 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (5 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100°C for Ih. The reaction mixture was evaporated to dryness and portioned between 5% aqueous citric acid and ethyl acetate. The organic phase was dried and evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate: heptane 1:3). Yield: 1.1 g. HPLC-MS: m/z: 473.3 (M+); Rt: 2.76 min.
[00465] [4-(3-hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester
(Formula Removed)

[00466] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acetate (3 g; 7.55 mmol), 3-phenyl-l-propyn (2.63 g; 22.65 mmol), bis(triphenylphosphine)palladium (II) chloride (0.42 g; 0.60 mmol) and copper iodide (0.086 g; 0.45 mmol) were dissolved in a mixture of triethylamine (3 mL) and DMF (6 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100 °C for 1 Ih. The reaction mixture was evaporated to dryness, and portioned between 5% aqueous citric acid and ethyl acetate. The organic phase was dried and evaporated to dryness. The crude product was purified by preparative HPLC method A. Yield: 1.4 g. HPLC-MS: m/z: 433.3 (M+); Rt: min.
[00467] [4-(3-Hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester
(Formula Removed)

[00468] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acetate (2.3 g; 5.79 mmol), phenylacetylene (1.9 mL; 17.4 mmol), bis(triphenylphosphine)palladivun (II) chloride (0.33 g; 0.46 mmol) and copper iodide (0.07 g; 0.35 mmol) were dissolved in a mixture of triethylamine (7 mL) and DMF (8 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100 °C for Ih. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid and ethyl acetate was added. The organic
phase was separated, dried and evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate: heptane 1:10→ 1:3). Yield: 1.2 g. HPLC-MS: ni/z: 419 (M+); Rt: 2.52 min.
[00469] {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
(Formula Removed)

[00470] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acsiate (3 g; 7.55 mmol), 4-prop-2-ynyl-morpholine (2.8 g; 22.65 mmol), bis(triphenylphosphine)-
palladium (II) chloride (0.42 g; 0.60 mmol) and copper iodide (0.09 g; 0.45 mmol) were dissolved in a mixture of triethylamine (7 mL) and DMF (8 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100 °C for 1.5 h. The reaction mixture was purified by preparative HPLC (method A). Yield: 1.4 g. HPLC-MS: m/z: 442.4 (M+);Rt: 1.54 min.
[00471] {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester(Formula Removed)

[00472] [4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester 20 (2.3 g; 5.6 mmol), 4-prop-2-ynyl-morpholine (2.1 g; 16.8 mmol), bis(triphenylphosphine)-
palladium (II) chloride (0.31 g; 0.45 mmol) and copper iodide (0.06 g; 0.34 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (10 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100 °C for Ih. The reaction mixture was purified by preparative HPLC (method A). Yield: 0.9 g. HPLC-MS: m/z: 456.1 (M+);Rt: 1.53min.
[00473] (4-[3-Hydroxy-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
(Formula Removed)

[00474] [4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (2 g; 4.9 mmol), 3-phenyl-l-propyn (1.7 g; 14.6 mmol), bis(triphenylphosphine)palladium (II) chloride (0.27 g; 0.39 mmol) and copper iodide (0.056 g; 0.29 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (10 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100°C for Ih. Further 3-phenyl-l-propyn (1.7 g; 14.6 mmol) was added and the reaction mixture was reacted in a microwave oven at 100°C for further Ih. The reaction mixture was purified by preparative HPLC (method A). Yield: 0.8 g. HPLC-MS: m/z: 434.6 (M+l); Rt: 2.43 min.
[00475] {4-[3-Bromo-5-cyclohexylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester
(Formula Removed)

[00476] [4-(3-Bromo-5-hydroxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl acetate ester (0.23 g; 0.58 mmol), cyclohexyl-methanol (80 /il; 0.64 mmol) and tributylphosphine (0.21 mL; 0.87 mmol) were dissolved in THF (10 mL) in a dried reaction flask under an atmosphere of nitrogen. l,r-(Azodicarbonyl)dipiperidine (0.22 g; 0,87 mmol) dissolved in THF (10 mL) was added to the reaction mixture, which was stirred at room temperature for 2 days. The reaction mixture was filtered, evaporated to dryness and purified by flash chroma-tography (ethyl acetate: heptane 1:1). Yield: 100 mg. HPLC-MS: m/z: 493.4 (M)+; Rt: 3.17 min.
[00477] {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester
(Formula Removed)
[00478] 1,3-Dibromo-5-cyclopentylmethoxy-benzene.
[00479] 3,5-Dibromophenol (5.0 g; 19.8 mmol), cyclopentane-methanol (2.0 g; 19.9 mmol) and tributylphosphine (8.8 mL; 35.7 mmol) were dissolved in dry THF (250 mL) in a dried reaction flask under an atmosphere of nitrogen. l,l'-(Azodicarbonyl)dipiperidine (9.01 g; 35.7 mmol) dissolved in dry THF (150 mL) was added to the reaction mixture, which was
stirred at room temperature for 16 hours. The reaction mixture was filtered, evaporated to dryness and purified by flash chromatography (heptane -> ethyl acetate: heptane 2:3). Yield: 5.68 g; 86 %.
[00480] [4-(3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester.
[00481] l,3-Dibromo-5-cyclopentylmethoxy-benzene (2.9 g; 8.6 rnmol), (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (1.5 g; 6.6 rnmol), tris(dibenzylideneacetone)-dipalladium(O) (0.18g, 0.20 rnmol) and l,l'-bis(diphenylphosphino)-ferrocen (0.22 g; 0.40 mmol) was added to a dried microwave flask under an atmosphere of nitrogene. The reaction flask was sealed and dry NMP (10 mL) and TEA (3,7 mL; 26.5 mmol) was added through the septum. The reaction flask was reacted in a microwave oven at 140°C for Ih. Ethyl acetate (30 mL) and aqueous 5% citric acid (30 mL) was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with ethyl acetate (30 mL X 2) and the pooled organic phases were dried (MgSO4) and evaporated to dryness. The reaction mixture was purified by flash chromatography (heptane→ heptane: ethyl acetate (Q.-l1/2i). Yield: 1.45 g (46%). HPLC-MS: m/z: 479.8 (M)+; Rt: 3.18 min.
[00482] {4-[3-Bromo-5-isobutoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester
(Formula Removed)

[00483] {4-[3-Bromo-5-isobutoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester was prepared as described for {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. Yield: 45%. HPLC-MS: m/z:. 454.8 (M+H)+; Rt: 3.07 min.
[00484] (4- {3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-acetic acid ethyl ester
(Formula Removed)

[00485] (4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-acetic acid ethyl ester was prepared as described for {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. Yield: 25%. HPLC-MS: m/z:.537.1 (M+2); Rt: 3.11 min.
[00486] {4-[3-Bromo-5-(2-ethyl-butoxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester
(Formula Removed)

[00487] {4-[3-Bromo-5-(2-ethyl-butoxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester was prepared as described for {4-[3-Bromo-5-cyclopentylmethoxy-phenyi sulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. Yield: 63%. HPLC-MS: m/z:. 481.0 (M)*; Rt: 3.20 min.
[00488] [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester
(Formula Removed)

[00489] [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl
ester was prepared as described for {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-
methyl-phenoxyj-acetic acid ethyl ester. Yield: 51%. HPLC-MS: m/z:.565.0 (M)+; Rt: 3.04
min.
[00490] {4-[3-Bromo-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid ethyl ester
(Formula Removed)

[00491] {4-[3-Bromo-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester was prepared as described for {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. Yield: 9%. HPLC-MS: m/z: 565.2 (M)+; Rt: 2.58 min.
[00492] {4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenylsulfanyl]-2-methyl-phenoxy}-aciuc acid ethyl ester
(Formula Removed)[00493] {4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester was prepared as described for {4-[3-Bromo-5-cyclopentylmethoxy-pheny!-sulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. Yield: 51%. HPLC-MS: m/z:. 508.R (M+H)+; Rt: 3.33 min.
[00494] {4-[3-Bromo-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester
(Formula Removed)

[00495] 2-(3,5-Dibromo-phenoxy)-3-trifluoromethyl-pyridine. [00496] 3,5-Dibromophenol (2.0 g; 7.9 mmol), 2-chloro-3-triflouropyridine (1.4 g; 7.9 mmol), potassium hydroxide (0.45 g; 7.9 mmol) and DMSO (40 mL) was added to a reaction flask under an atmosphere of nitrogen. The reaction mixture was reacted at 110 °C for 6 h. The reaction mixture was cooled to room temperature and ethyl acetate (30 ml) and water (120 mL) was added. The organic phase was separated form the aqueous phase and the aqueous phase was extracted with ethyl acetate (30 mL X 4). The combined organic phases were dried, evaporated to dryness and purified by flash chromatography (heptane -» ethyl acetate: heptane 1:8). Yield: 2.23 g; 71 %. HPLC-MS: m/z: 397.9 (M)+; Rt: 2.58 min.
[00497] {4-[3-Bromo-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester
[00498] 2-(3,5-Dibromo-phenoxy)-3-trifluoromethyl-pyridine (2.05 g; 5.17 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.9 g; 4.0 mmol) was condensed to give the title product applying the procedure described for {4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. The crude product was purified by flash chromatography (heptane → ethyl acetate: heptane 2:9). Yield 1.26 g (58%). HPLC-MS: m/z: 544.3 (M+2); Rt: 2.77 min.
[00499] {4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
(Formula Removed)

[00500] 2-(3,5-Dibromo-phenoxy)-5-trifluoromethyl-pyridine.
[00501] The title product was prepared as described for 2-(3,5-Dibromo-phenoxy)-3-tri-
fluoromethyl-pyridine Yield: 70%; HPLC-MS: m/z: 397.7 (M)+; Rt 2.60 min.
[00502] {4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00503] 2-(3,5-Dibromo-phenoxy)-5-trifluoromethyl-pyridine (2.5 g; 6.3 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (1.1 g; 4.9 mmol) was condensed to give the title product applying the procedure described for (4-[3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. The crude product was purified by
flash chromatography (heptane → ethyl acetate: heptane 2:9). Yield 1.4 g (53%). HPLC-MS: m/z: 544.3 (M+2); Rt: 2.80 min.
[00504] {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester(Formula Removed)[00505] 1,3-Dibromo-5-(3-trifluorornethyl-phenoxy)-benzene.
[00506] 3,5-Dibroraophenol (4.1 g; 16.2 mmol), 3-(triflouromethyl)-phenylboronic acid (6.2 g; 32.4 mmol), Cu(II) acetate (2.9 g; 16.2 mmol), TEA (5.6 mL; 40.5 mmol) and dichloro-methane (150 mL) and molecular sieves (2 ml) was added to a reaction flask the reaction mixture was stirred for 7 days. Further 3-(triflouromethyl)-phenylboronic acid (6.2 g; 32.4 mmol) was added and the reaction mixture stirred for 1 day. Further 3-(triflouromethyl)-phenyl-boronic acid (6.2 g; 32.4 mmol) and TEA (5.6 mL; 40.5 mmol) was added and the reaction mixture stirred for 1 day. 5% Aqueous citric acid (150 mL) was added and the two phases were separated. The aqueous phase was extracted with dichloromethane (50 mL X 2) and the organic phases were pooled, dried and evaporated to dryness. The crude product purified by flash chromatography (heptane → ethyl acetate: heptane 1:9). Yield: 1.86 g; HPLC-MS: m/z: 397. (M+H)+; Rt: 2.78 min.
[00507] {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00508] l,3-Dibromo-5-(3-trifluoromethyl-phenoxy)-benzene (1.35 g; 3.4 mmol) and (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.7 g; 3.1 mmol) was condensed to give the title product applying the procedure described for {4-[3-Bromo-5-cyclopentylmethoxy-
phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester. The crude product was purified by preparative HPLC (Method A) followed by flash chromatography (dichloromethane: heptane 3:7). Yield 0.5 g. HPLC-MS: m/z: 541.3 (M)+; Rt: 3.03 min.
[00509] [4-(3-Bromo-5-cyclopropylmethoxy-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester
(Formula Removed)

[00510] [4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (1.0 g; 2.43 mmol), cyclopropylcarbinol (175 mg; 2.43 mmol) and tributylphosphine (1.07 mL; 4.38 mmol) was dissolved in THF (100 mL) in a dried reaction flask under an atmosphere of nitrogen. l,l'-(Azodicarbonyl)dipiperidine (1.1 g; 4,38 mmol) dissolved in THF (20 mL) was added to the reaction mixture, which was stirred at room temperature for 16 hours. The reaction mixture was filtered, evaporated to dryness and purified by flash chromatography (ethyl acetate: heptane 1:9→ 2:3). Yield: 980 mg; 86%; HPLC-MS: m/z: 465.0(M)+; Rt: 2.74 min.
[00511] [4-(3-Bromo-5-cyclopropylmethoxy-phenylsulfanyl)-2-tnethyl-phenoxy]-acetic acid ethyl ester
[00512] Step A: l,3-Dibromo-5-cyclopropylmethoxy-benzene
[00513] 3,5-Dibromo-phenol (5g; 19.9 mmol), cyclopropylcarbinol (1.4 g; 19.9 mmol) and tributylphosphine (8.8 mL; 35.7 mmol) were dissolved in THF (500 mL) in a dried reaction flask under an atmosphere of nitrogen. l,l'-(Azodicarbonyl)dipiperidine (9.0 g; 35,7 mmol) dissolved in THF (100 mL) was added to the reaction mixture, which was stirred at room temperature for 16 hours. The reaction mixture was partly evaporated, filtered, evaporated to dryness and purified by flash chromatography (ethyl acetate: heptane 0:1→ 1:10). Yield: 545 g; 90%.
[00514] Step B: [4-(3-Bromo-5-cyclopropylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester
[00515] l,3-Dibromo-5-cyclopropylmethoxy-benzene (5.27 g; 17,23 mmol), (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (3g; 13.26 mmol), tris(dibenzylideneacetone)dipal-ladium (0) (0.36 g; 0,40 mmol), and l,r-bis-(diphenylphosphineo)ferrocene (0.44 g; 0,80 mmol) was added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (7.45 mL) and NMP (8 mL) was added, and the reaction mixture was stirred in a microwave oven for 1 h at 140 °C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4 X 100 mL). The pooled organic phases were dried and evaporated hi vacuo. The crude reaction product was purified by flash chromatography (heptane: ethyl acetate (20:1 -» 7:3). Yield 2.8 g; 47%). HPLC-MS: m/z: 451.0 (M+); Rt: 2.85 min
[00516] [4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-acetic acid ethyl ester
(Formula Removed)
[00517] StepAl: l,3-Dibromo-5-isobutoxy-benzene
[00518] Potassium hydroxide (15.9g; 284 mmol) was dissolved in water (300 ml) and 3,5-dibromo-phenol (47g; 188.5 mmol) was added. Benzyl tributylammoniumchloride (17.7g; 56.8 mmol) and toluene (200 ml) was added and the reaction mixture was heated to 85 °C. Bromoethylpropan (32.3 g; 325.7 mmol) was added over 5 hours and the reaction mixture was stirred at 85 °C for additional 16 h. The reaction mixture was cooled to room temperature and the phases were separated. Toluene (100 ml) was added to the organic phase which waa washed with 0.2 N aqueous HC1 (200 ml X 2) and water (200 ml X 2). The organic phase was evaporated to give the crude product which was purified by distillation (0.7.mm Hg; Bp: 98 °C); Yield: 43 g (colourless oil).
[00519] Step A2: (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester [00520] (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester was prepared as described for 2,6-difluoro-4-mercapto-phenoxy)acetic acid methyl ester (compound 21) in Eur. J. Med. Chem, 1995, 30, 403 (Kawashima, M. S.) except that (4-chlorosulfonyl-2,5-dimethyl-phenoxy)-acetic acid ethyl ester was reduced with 4 eq. of zn (dust) in a mixture of konc. sul-furic acid and ethanol at 80 °C.
[00521] Step B: [4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-acttic acid ethyl ester
[00522] 1,3-Dibromo-5-isobutoxy-benzene (1.66 g; 5.4 mmol), (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester (1.0 g; 4.1 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.11 g; 0,12 mmol), and l,l'-bis-(diphenylphosphineo)ferrocene (0.14 g; 0,25 mmol) were added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (2.3 mL) and NMP (10 mL) was added, and the reaction mixture was stirred in a microwave oven for 1 h at 140 °C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4 X 100 mL). The pooled organic phases were dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (hep-
tane: ethyl acetate (10:1 → 1:1). Yield: 1.3 g; 67%. HPLC-MS: m/z: 467.0 (M+); Rt: 3.10 min
[00523] [4-(3-Bromo-5-isobutoxy-phenoxy)-2-methyl-phenoxy]-acetic acid methyl ester
(Formula Removed)

[00524] Step A: 3-Bromo-5-isobutoxy-phenylboronic acid
[00525] l,3-Dibromo-5-isobutoxy-benzene (1. g; 3.3 mmol) was dissolved in dry THF (30 ml) in a dry reaction under stirring. The reaction mixture was cooled to -70 °C and n-BuLi (2M; 2.44 ml) was added. The reaction mixture was stirred for 15 min. and triisobutylborate (1.50 ml; 6.5 mmol) was added at -70 °C. The temperature was raised to -30 °C and stirred for l'/2 hour followed by a temperature increase to room temperature. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate (about 3 ml) and evaporated to dryness. The crude product was purified by prep HPLC (method B). Yield: 430 mg; 49 %. HPLC-MS: m/z: 272.9 (M+); Rt: 2.08 min
[00526] Step B: [4-(3-Bromo-5-isobutoxy-phenoxy)-2-methyl-phenoxy]-acetic acid methyl
ester
[00527] (4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (215 mg; 1.1 mmol), 3-
Bromo-5-isobutoxy-phenylboronic acid (523.4; 1.9 mmol), copper(II) acetate (199 mg; 1.1
mmol), crushed molsieves (about Ig) and triethylamine (0.46 ml; 3.3 mmol) was dissolved in
dichloromethane (40 ml) and stirred over night. The reaction mixture was filtered through
celite and evaporated to dryness. The crude product was purified by preperative HPLC
(method B). Yield: 300 mg; 65%. HPLC-MS: m/z: 423.5 (M+); Rt: 2.71 min
[00528] Example 1
[00529] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-l-yl-propoxy)-phenyl-
sulfanyl]-phenoxy} -acetic acid
(Formula Removed)
[00530] Step A: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-l-yl-propoxy)-phenylsulfanyl]-phenoxy} -acetic acid ethyl ester
[00531] [{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (0.4 g; 0.85 mmol), 3-piperidin-l-yl-propan-l-ol (0.12 g; 0.85 mmol) and tributylphosphine (0.37 mL; 1.5 mmol) were dissolved in THF (50 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1' -(Azodicarbonyl)dipiperidine (0.38 g; 1,5 mmol) dissolved in THF (25 mL) was added to the reaction mixture, which was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness and 5% aqueous citric acid and ethyl acetate was added. The organic phase was separated, dried, evaporated to dryness, and purified by prep HPLC (method A). Yield: 275 mg. HPLC-MS: m/z: 598.0 (M+); Rt: 2.3 min.
[00532] Step B: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-l-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic acid
[00533] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-piperidin-l-yl-propoxy)-phenyl-sulfanyl]-phenoxy}-acetic acid ethyl ester (275 mg; 0.46 mmol) was dissolved in ethanol (15 mL) and aqueous IN sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with 5% aqueous citric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 200 mg. HPLC-MS: m/z: 570.0 (M+); Rt: 2.07 min.
[00534] Example 2
[00535] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]-
phenoxy)-acetic acid
(Formula Removed)

[00536] Step A: {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenyl-sulfanyl]-phenoxy }-acetic acid ethyl ester
[00537] [4-(3-Hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl ester (0.25 g; 0.60 mmol), 3-morpholin-4-yl-propan-l-ol (0.12 g; 0.84 mmol) arrl oibu-tylphosphine (0.27 mL; 1.08 mmol) were dissolved in THF (20 mL) in a dried reaction flask under an atmosphere of nitrogen. l,l'-(Azodicarbonyl)dipiperidine (0.27 g; 1,08 mmol) dissolved in THF (10 mL) was added to the reaction mixture, which was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness, acetonitrile added, and the mixture filtered. The solution was purified by prep HPLC (method A). Yield: 150mg. HPLC-MS: m/z: 546.6 (M+H); Rt: 2.08 min.
[00538] Step B: {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenyl-sulfanyl]-phenoxy}-acetic acid
[00539] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy} -acetic acid ethyl ester (150 mg; 0.28 mmol) was dissolved in ethanol (15 mL), and aqueous IN sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with IN aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 110 mg. HPLC-MS: m/z: 518.1 (M+H); Rt: 1.86 min.
[00540] Example 3(Formula Removed)

[00541] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-sulfanyl]-phenoxy} -acetic acid
[00542] Step A: {2-Chloro-4-[3-(4-chloro-phenylemynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester
[00543] [{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (293 mg; 0.62 mmol) was dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 3-morpholin-4-yl-propan-l-ol (75 mg; 0.52 nanoi) and tributylphosphine (0.23 mL; 0.93 mmol) was added followed by l,l'-(Azodicarboayl)-dipiperidine (0.38 g; 1,5 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 16 h, filtered and evaporated in vacuo. The crude product was purified by prep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 600.4 (M+); Rt: 2.2 min. [00544] Step B: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-phenoxy }-acetic acid
[00545] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-sulfanylj-phenoxy) -acetic acid ethyl ester (200 mg; 0.33 mmol) was dissolved in ethanol (10 mL), and aqueous 1N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness, and purified by prep. HPLC (method A). Yield: 46 mg. HPLC-MS: m/z: 572.3 (M+); Rt: 2.03 min.
[00546] Example 4
[00547] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)-
phenylsulfanyl] -phenoxy} -acetic acid
(Formula Removed)

[00548] Step A: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-
benzyloxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester
[00549] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-
acetic acid ethyl ester (274 mg; 0.58 mmol) was dissolved in THF (15 mL) in a dried reaction
flask under an atmosphere of nitrogen. (4-Morpholin-4-ylmethyl-phenyl)-methanol (IOC mg;
0.48 mmol) and tributylphosphine (0.21 mL; 0.87 mmol) was added followed by l,l'-(Azodi-
carbonyl)dipiperidine (0.22 g; 0.87 mmol) dissolved in THF (10 mL). The reaction mixture
was stirred at room temperature for 5 h, filtered and evaporated in vacuo. The crude product
was purified by prep. HPLC (method A). Yield: 250 mg. HPLC-MS: m/z: 663.0 (M+H); Rt:
2.47 min.
[00550] Step B: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-
ben7yloxy)-phenylsulfanyl]-phenoxy}-acetic acid
[00551] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)-
phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (250 mg; 0.38 mmol) was dissolved in etha-
nol (10 mL), and aqueous IN sodium hydroxide (5 mL) was added. The reaction mixture was
stirred for 16 h, acidified with IN aqueous hydrochloric acid, and extracted with ethyl acetate.
The organic phase was dried, evaporated to dryness and purified by prep. HPLC (method A).
Yield: 32 mg. HPLC-MS: m/z: 634.5 (M+); Rt: 2.21 min.
[00552] Example 5
[00553] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(l-methyl-piperidin-4-ylmethoxy)-
phenylsulfanyl] -phenoxy} -acetic acid
(Formula Removed)

[00554] Step A: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(l-methyl-piperidin-4-yl-methoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester
[00555] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxyl-phenylsullfanyl]-phenoxy}•• acetic acid ethyl ester (274 mg; 0.58 mmol) was dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. l-(Methyl-piperidin-4-yl)-methanol (100 mg; 0.48 mmol) and tributylphosphine (0.21 mL; 0.87 mmol) were added followed by l,l'-(Azodi-carbonyl)dipiperidine (0.22 g; 0.87 mmol) dissolved in THF (10 mL). The reaction mixture was stirred at room temperature for 5 h, filtered, and evaporated in vacuo. The crude product was purified by prep. HPLC (method B). Yield: 250 mg. HPLC-MS: m/z: 663.0 (M+H); Rt: 2.47 min.
[00556] Step B: {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(l-methyl-piperidin-4-ylmethoxy)-phenylsulfanyl]-phenoxy }-acetic acid
[00557] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(l-methyl-piperidin-4-ylmethoxy)-phenylsulfanyl]-phenoxy)-acetic acid ethyl ester (60 mg; 0.10 mmol) was dissolved in etha-nol (7 mL), and aqueous 1N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep. HPLC (method B). Yield: 20 mg. HPLC-MS: m/z: 556.5 (M+); Rt: 2.10 min.
[00558] Example 6
[00559] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1 -ynyl)-phenyl-
sulfanylj-phenoxy} -acetic acid
(Formula Removed)
[00560] Step A: {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-phenylsulfanylj-phenoxy)-acetic acid ethyl ester
[00561] {4-[3-Hydroxy-5-(3-phenyl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.46 mmol), 3-morpholin-4-yl-propan-l-ol (101 mg; 0.69 mmol), tributylphosphine (0.28 mL; 1.39 mmol) and l,l'-(azodicarbonyl)dipiperidine (0.35 g; 1.39 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 1 h the reaction mixture was purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 560.5 (M+H); Rt: 2.07 min.
[00562] Step B: {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-phenylsulfanyl]-phenoxy}-acetic acid
[00563] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-phenyl-sulfanylj-phenoxy }-acetic acid ethyl ester (200 mg; 0.36 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 150 mg. HPLC-MS: m/z: 532.1 (M+);Rt: 1.87 min.
[00564] Example 7
[00565] {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-
methyl-phenoxy}-acetic acid
(Formula Removed)

[00566] Step A: {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00567] {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.45 mmol), 4-flourobenzylalcohol (85.7 mg; 0.68 mmol), tributylphosphine (0.27 mL; 1.36 mmol) and l,l'-(azodicarbonyl)dipiperidine (0.34 g; 1.36 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 1 h the reaction mixture was purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 550.3 (M+H); Rt: 2.00 min. [00568] Step B: {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid
[00569] {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy)-acetic acid ethyl ester (200 mg; 0.36 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 170 mg. HPLC-MS: m/z: 522.1 (M+);Rt: 1.77 min.
[00570] Example 8
[00571] {4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-
methyl-phenoxyj-acetic acid
(Formula Removed)

[00572] Step A: {4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-
sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00573] {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl
phenoxy}-acetic acid ethyl ester (200 mg; 0.45 mmol), cyclohexylmethanol (77.6 mg; 0.68
mmol), tributylphosphine (0.27 mL; 1.36 mmol) and l,l'-(azodicarbonyl)dipiperidine (0.34 g;
1.36 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of
nitrogen. After stirring for 1 h the reaction mixture was purified by prep. HPLC (method A).
Yield: 200 mg. HPLC-MS: m/z: 538.1 (M+H); Rt: 2.24 min.
[00574] Step B: {4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-
sulfanyl] -2-methyl-phenoxy} -acetic acid
[00575] {4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-
methyl-phenoxy }-acetic acid ethyl ester (200 mg; 0.37 mmol) was dissolved in ethanol (20
mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred
for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The
organic phase was dried and evaporated to dryness. Yield: 180 mg. HPLC-MS: m/z: 510.1
(M+);Rt: 1.98 min.
[00576] Example 9
[00577] {4-[3-Isobutoxy-5-(3-moipholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid
(Formula Removed)

[00578] Step A: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester
[00579] {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.57 mmol), 2-methyl-propan-l-ol (0.078 mL; 0.85 mmol) and tributylphosphine (0.31 mL; 1.25 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1' -(Azodicarbonyl)dipiperidine (0.31 g; 1.25 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After stirring for 16 h the reaction mixture was evaporated to dryness and purified by prep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 498.1 (M+); Rt: 2.03 min [00580] Step B: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid
[00581] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy)-acetic acid ethyl ester (140 mg; 0.28 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 130 mg. HPLC-MS: m/z: 470.0 (M+); Rt: 1.76 min. 8H(400 MHz; CDC13) 1.00 (d, 6H), 1.98-2.09 (m, 1H), 2.27 (s, 3H), 3.13-3.29 (m, 2H), 3.43-3.57 (m, 2H), 3.66 (d, 2H), 3.92-4.09 (m, 4H), 4.12 (s, 2H), 4.71 (s, 2H), 6.55 (m, 1H), 6.71-6.75 (m, 2H), 6.79 (m, 1H), 7.25-7.29 (m, 1H), 7.30 (m, 1H).
[00582] Example 10
[00583] {4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid
(Formula Removed)

[00584] Step A: {4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester
[00585] 4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.57 mmol), 4-(chloro-phenyl)-methanol (0.12 mg; 0.85 mmol) and tributylphosphine (0.31 mL; 1.25 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1' -(Azodicarbonyl)dipiperidine (0.31 g; 1.25 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After storing for 16 h the reaction mixture was evaporated to dryness and purified by prep. HPLC (method B). Yield: 200 mg. HPLC-MS: m/z: 566.1 (M+); Rt: 2.13 min. [00586] Step B: {4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy} -acetic acid
{4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (140 mg; 0.28 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 180 mg. HPLC-MS: m/z: 538.0 (M+); Rt: 1.84 min. δH(400 MHz; CDC13) 2.27 (s, 3H), 3.15-3.30 (m, 2H), 3.45 (d, 2H), 3.99-4.06 (m, 2H), 4.13-4.22 (m, 4H), 4.73 (s, 2H), 4.96 (s, 2H), 6.57-6.60 (m, 1H), 6.74 (d, 1H), 6.76-6.81 (m, 2H), 7.25-7.31 (m, 4H), 7.32-7.36 (m, 2H).
[00587] Example 11
[00588] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-
acetic acid
(Formula Removed)

[00589] {2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (50 mg; 0.11 mmol) was dissolved in ethanol (6 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep. HPLC (method B). Yield: 36 mg. HPLC-MS: m/z: 445.1 (M+); Rt: 2.44 min.
[00590] Example 12
[00591] {4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid

(Formula Removed)
[00592] Step A: {4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2 methyl-phenoxy}-acetic acid ethyl ester
[00593] 4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.57 mmol), 2-butyn-l-ol (0.064 mL; 0.85 mmol) and tributylphosphine (0.31 mL; 1.25 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. 1,1' -(Azodicarbonyl)dipiperidine (0.31 g; 1.25 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After stirring for 16 h the reaction mixture was evaporated to dryness and purified by prep. HPLC (method B). Yield: 150 mg. HPLC-MS: m/z: 494.0 (M+); Rt: 1.87 min.
[00594] Step B: {4-[3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid
[00595] {4- [3-But-2-ynyloxy-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2-methyl-phenoxy)-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 140 mg. HPLC-MS: m/z: 466.0 (M-i-); Rt: 1.60 min.
[00596] Example 13
[00597] {2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-
phenoxy}-acetic acid
(Formula Removed)

[00598] Step A: {2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenyl-sulfanyl]-phenoxy} -acetic acid ethyl ester
[00599] [4-(3-Hydroxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.48 mmol), 2-morpholin-4-yl-ethanol (0.22 g; 0.67 mmol) and tributylphosphine (0.24 mL; 0.96 mmol) were dissolved in THF (15 mL) in a dried reaction flask un-
der an atmosphere of nitrogen. l,1-(Azodicarbonyl)dipiperidine (0.24 g; 0.96 mmol) was dissolved in THF (10 mL) and added to the reaction mixture. After stirring for 16 h the reac tion mixture was evaporated to dryness and purified by flash chromatography (ethyl acetate: heptane (1:3 -» 1:9). Yield: 150 mg. HPLC-MS: m/z: 532.6 (M+H); Rt: 2.07 min.
[00600] Step B: {2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-acetic acid
[00601] {2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 140 mg. HPLC-MS: m/z: 504.1 (M+); Rt: 1.80 min.
[00602] Example 14
[00603] {2-Chloro-4-[3-(3-methoxy-prop-l-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-
sulfanyl]-phenoxy}-acetic acid
(Formula Removed)[00604] Step A: {2-Chloro-4-[3-(3-methoxy-prop-l-ynyl)-5-(3-morpholin-4-yl-propcxy)-phenylsulfanylj-phenoxy} -acetic acid ethyl ester
[00605] {4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-acetic acid ethyl ester (0.2 g; 0.37 mmol), 3-methoxy-propyne (0.10 g; 1.47 mmol), bis(triphenylphosphine) palladium (II) chloride (21 mg; 0.029 mmol) and copper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 150°C
for Ih. The reaction mixture was evaporated to dryness and extracted with ethyl acetate from
a aqueous 5% citric acid solution. The crude product was dried, evaporated to dryness and
purified by preparative HPLC (method B). Yield: 160 mg. HPLC-MS: m/z: 534.1 (M+); Rt:
1.79min.
[00606] Step B: {2-Chloro-4-[3-(3-methoxy-prop-l-ynyl)-5-(3-morpholin-4-yl-propoxy)-
phenylsulfanyl]-phenoxy} -acetic acid
[00607] {2-Chloro-4-[3-(3-methoxy-prop-l-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-sulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethaaol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture wa;. stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, and evaporated to dryness and purified by preparative HPLC (method B). Yield: 50 mg. HPLC-MS: m/z: 506.0 (M+); Rt: 1.56 min. δH(400 MHz; CDC13) 2.06-2.15 (m, 2H), 2.82-2.92 (m, 2H), 3.15-3.23 (m, 2H), 3.45 (s, 3H), 3.56 (d, 2H), 3.78(t, 2H), 3.95-4.03 (m, 4H), 4.30 (s, 2H), 4.89 (s, 2H), 5.91-5.94(m, 1H), 6.63-6.66 (m, 1H), 6.93 (d, 1H), 7.01-7.03 (m, 1H), 7.40 (dd,1H), 7.58 (d, 1H).
[00608] Example 15
[00609] {2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-l-ynyl-phenylsulfanyl]-
phenoxy}-acetic acid
(Formula Removed)

[00610] Step A: {2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-l-ynyl-phenylsulfanyl]-
phenoxy}-acetic acid ethyl ester
[00611] {4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyI]-2-chloro-phenoxy}-
acetic acid ethyl ester (0.2 g; 0.37 mmol), 1-pentyne (0.10 g; 1.47 mmol), bis(triphenyl-
phosphine)palladium (II) chloride (21 mg; 0.029 mmol) and copper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 150 °C for Ih. The reaction mixture was evaporated to dryness and extracted with ethyl acetate from a aqueous 5% citric acid solution. The crude product was dried, evaporated to dryness and purified by preparative HPLC (method B). Yield: 120 mg. HPLC-MS: m/z: 532.0 (M+); Rt: 2.02 min.
[00612] Step B: {2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent-l-ynyl-phenylsulfany!]-phenoxy)-acetic acid
[00613] {2-Chloro-4-[3-(3-morpholin-4-yl-propoxy)-5-pent- 1-ynyl-phenylsulfanyl]-phenoxy)-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, and evaporated to dryness and purified by preparative HPLC (method B). Yield: 70 mg. HPLC-MS: m/z: 504.1 (M+); Rt: 1.81 min.
[00614] Example 16
[00615] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-1 -ynyl)-benzyl-
sulfanyl]-phenoxy} -acetic acid
(Formula Removed)

[00616] Step A: {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-phenoxy}-acetic acid ethyl ester
[00617] {4-[3-Hydroxy-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.45 mmol), 3-morpholin-4-yl-propan-l-ol (97.6 mg; 0.67 mmol), tributylphosphine (0.27 mg; 1.34 mmol) and l,r-(Azodicarbonyl)dipiperidine (0.34 g; 1.34
mmol) were dissolved in THF (20 mL) in a dried reaction flask under an atmosphere of nitrogen. The reaction mixture was stirred for Ih and purified by prep. HPLC (method A). Yield: 200 mg. HPLC-MS: m/z: 574.3 (M+H); Rt: 2.07 min.
[00618] Step B: (2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-phenoxy}-acetic acid
[00619] {2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-benzyl-sulfanyl]-phenoxy} -acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 190 mg. HPLC-MS: m/z: 546. • (M+);Rt: 1.85 min.
[00620] Example 17
[00621] {4-[3-(4-Ruoro-benzyloxy)-5-(3-morpholin-4-yl-prop-lynyl)-benzylsulfanyl]-2-
methyl-phenoxy} -acetic acid
(Formula Removed)

[00622] Step A: {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-lynyl)-benzyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00623] {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1 -ynyl)-benzylsulfanyl]-2-methyl-phenoxy)-acetic acid ethyl ester (250 mg; 0.55 mmol), l-fluoro-4-methoxymethyl-benzene (103.8 mg; 0.82 mmol), tributylphosphine (0.33 mg; 1.65 mmol) and l,l'-(azodicarbonyl)-dipiperidine (0.414 g; 1.65 mmol) were dissolved in THF (15 mL) in a dried reaction flask
under an atmosphere of nitrogen. The reaction mixture was stirred for 16h and purified by prep. HPLC (method A). Yield: 160 mg. HPLC-MS: m/z: 564.1 (M+H); Rt: 1.99 min. [00624] Step B: (4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-lynyl)-benzyl-sulfanyl]-2-methyl-phenoxy} -acetic acid
[00625] {4-[3-(4-Fluoro-benzyloxy)-5-(3-morpholin-4-yl-prop-lynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (20 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 190 mg. HPLC-MS: m/z: 536.1 (M+);Rt: 1.76 min.
[00626] Example 18
[00627] {2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-l-ynyl)-benzyl-
sulfanyl]-phenoxy}-acetic acid
(Formula Removed)

[00628] Step A: {2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-phenoxy}-acetic acid ethyl ester
[00629] {4-[3-Hydroxy-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.56 mmol), 3-morpholin-4-yl-propan-l-ol (110.1 mg; 0.84 mmol), tributylphosphine (0.34 mL; 1.68 mmol) and l,r-(azodicarbonyl)dipiperidine (0.42 g; 1.68 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. After stirring for 2 h the reaction mixture was purified by prep. HPLC (method A). Yield: 50 mg. HPLC-MS: m/z: 560.2 (M+H); Rt: 2.03 min. [00630] Step B: {2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-l-ynyl)-benzyl-
sulfanyl]-phenoxy}-acetic acid
[00631] {2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-l-ynyl)-benzyl-sulfanyl]-phenoxy }-acetic acid ethyl ester (50 mg; 0.09 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (2 mL) was added. The reaction mixture was stirred for 16 h, acidified with 1 N aqueous hydrochloric acid and extracted with dichloromethane. The organic phase was dried and evaporated to dryness. Yield: 45 mg. HPLC-MS: m/z: 532.1 (M+);Rt: 1.79 min.
[00632] Example 19
[00633] {4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-
methyl-phenoxy}-acetic acid(Formula Removed)

[00634] Step A: {4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00635] [4-(3-Bromo-5-cyclohexylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl acetate (0.1 g; 0.203 mmol), 1-Ethynyl-4-methanesulfonyl-benzene (0.109 g; 0.6; mmol), bis(triphenylphosphine)palladium (II) chloride (11.4 mg; 0.016 mmol) and copper :o-dide (2.3 mg; 0.06 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 120°C for Ih. Water and dichloromethane was added to the reaction mixture and the phases were separated and washed with water. The organic phase was dried and evaporated to dryness. The crude product was purified by prep. HPLC (Metode A). Yield: 90 mg. HPLC-MS: m/z: 593.5 (M+H)+; Rt: 3.04 min.
[00636] Step B: {4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid
[00637] {4- [3-Cyclohexylmethoxy-5 -(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester (120 mg; 0.202 mmol) was dissolved in ethanol (50 mL), and aqueous 1 N sodium hydroxide (2 mL) was added. The reaction mixture was stirred for 30 min, acidified with 1 N aqueous hydrochloric acid and extracted with dichloromethane. The organic phase was dried and evaporated to dryness. Yield: 90 mg. HPLC-MS: m/z: 565.3 (M+H)+;Rt:2.81 min.
[00638] Example 20
[00639] {4-[3-Cyclopentylmethoxy-5-(4-methanesuhconyl-phenylethynyl)-phenylsulfanyl]-2-
methyl-phenoxy}-acetic acid
(Formula Removed)

[00640] Step A: {4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00641] [4-(3-Bromo-5-cyclopentylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-aceticacid ethyl acetate (0.24 g; 0.50 mmol), 1-Ethynyl-4-methanesulfonyl-benzene (0.271 g; 1.5 mmol), bis(triphenylphosphine)palladium (II) chloride (28.11 mg; 0.04 mmol) and copper iodide (5.7 mg; 0.03 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (5 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 120°C for Ih. Water and dichloromethane was added to the reaction mixture and the phases were separated and washed with water. The organic phase was dried and evaporated to dryness. The crude product was purified by prep. HPLC (Metode A). Yield: 180 mg. HPLC-MS: m/z: 579.4 (M+H)+; Rt: 3.00 min.
[00642] Step B: {4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid
[00643] {4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanylJ-2-methyl-phenoxy}-acetic acid ethyl ester (120 mg; 0.202 mmol) was dissolved in ethanol (50 mL), and aqueous 1 N sodium hydroxide (2 mL) was added. The reaction mixture was stirred for 30 min, acidified with 1 N aqueous hydrochloric acid and extracted with dichloromethane. The organic phase was dried and evaporated to dryness. Yield: 100 mg. HPLC-MS: m/z: 551.5(M+H)+;Rt:2.69min.
[00644] Example 21
[00645] {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-
phenoxy} -acetic acid
(Formula Removed)

[00646] Step A: {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-
methyl-phenoxy} -acetic acid ethyl ester
[00647] The title product was prepared as described for {4-[3-Cyclopentylmethoxy-5-(4-
methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester.
The crude product was purified by prep. HPLC (method B). Yield: 52%. HPLC-MS: m/z:
552.7 (M)+; Rt: 2.88 min.
[00648] Step B: {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-
methyl-phenoxy}-acetic acid
[00649] {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid ethyl ester (190 mg; 0.34 mmol) was dissolved in ethanol (10 mL), ai?.d
aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h.
acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 110 mg (61%). HPLC-MS: m/z: 525.1 (M+H)+; Rt: 2.55 min.
[00650] Example 22
[00651] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-
phenylsulfanyl]-2-methyl-phenoxy} -acetic acid
(Formula Removed)

[00652] Step A: {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00653] The title product was prepared as described for {4-[3-Cyclopentylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl estei. The crude product was purified by prep. HPLC (method B). Yield: 64 %. HPLC-MS: m/z: 635.4 (M+H)+; Rt: 2.92 min.
[00654] Step B: {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid
[00655] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (190 mg; 0.30 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 160 mg (89%). HPLC-MS: m/z: 607.1 (M+H)+; Rt: 2.82 mm.
[00656] Example 23
[00657] {4-[3-[2-(4-Chloro-phenyl)-emoxy]-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyi-
sulfanyl]-2-methyl-phenoxy} -acetic acid
(Formula Removed)

[00658] Step A: {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00659] (4- {3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl }-2-methyl-phenoxy)-acetic acid ethyl ester (300 mg; 0.56 mmol), 4-prop-2-ynyl-morpholine (280,4 mg; 2.2 mnol), bis(triphenylphosphine) palladium (II) chloride (31.4 mg; 0.045 mmol) and copper iodide (6.4 mg; 0.034 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 110 °C for 1.5 h. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid (30 mL) and ethyl acetate (30 mL) was added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were dried and evaporated to dryness and purified by preparative HPLC (method B). Yield: 300 mg; 92%. HPLC-MS: m/z: 580.7 (M+H)+; Rt: 2.16 min.
[00660] Step B: {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid
{4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (190 mg; 0.30 mmol) was dissolved in ethano! (25 mL), and aqueous 1 N sodium hydroxide (5 mL) was added. The reaction mixture wf s stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. Tne organic phase was dried and evaporated to dryness, redissolved in dichloromethane and evaporated to dryness. Yield: 250 mg (87%). HPLC-MS: m/z: 552.8 (M+H)+; Rt: 1.90 min.
[00661] Example 24
[00662] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenyl-
sulfanyl]-2-methyl-phenoxy}-acetic acid
(Formula Removed)
[00663] Step A: {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00664] (4-{3-Bromo-5-[2-(4-chloro-phenyl)-ethoxy]-phenylsulfanyl}-2-methyl-phenoxy)-acetic acid ethyl ester (270 mg; 0.46 mmol), (4-ethynyl-phenyl)-methanol (296 mg; 2.2 mmol), bis(triphenylphosphine) palladium (II) chloride (31.4 mg; 0.045 mmol) and copper iodide (6.4 mg; 0.034 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 niL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 110 °C for 1.5 h. The reaction mixture was evaporated to dryness, and 5% aqueous citric acid (30 mL) and ethyl acetate (30 mL) was added. The two phases were separated and the aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were dried and evaporated to dryness and purified by preparative HPLC (method B). Yield: 270 mg (83%). HPLC-MS: m/z: 587.1 (M+H)+; Rt: 2.96 min.
[00665] Step B: {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynv!) phenylsulfanyl]-2-methyl-phenoxy }-acetic acid
[00666] {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with
ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep HPLC (method B). Yield: 218 mg (85%). HPLC-MS: m/z: 559.1 (M+H)+; Rt: 2.61 min.
[00667] Example 25
[00668] {4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic
acid(Formula Removed) [00669] Step A: {4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy)-acetic acid ethyl ester
[00670] The title product was prepared from {4-[3-Bromo-5-(2-ethyl-butoxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (200 mg; 0.42 mmol), (phenyl acetylene (170 mg; 1.66 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 170 mg (82%). HPLC-MS: m/z: 502.9 (M)+; Rt: 3.32 min.
[00671] Step B: {4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phen-oxy}-acetic acid
[00672] {4-[3-(2-Ethyl-butoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N so dium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep HPLC (method B). Yield: 128 mg (80%). HPLC-MS: m/z: 475.1 (M+H)+; Rt: 3.06 min.
[00673] Example 26
[00674] [4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic
acid
(Formula Removed)

[00675] Step A: [4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester
[00676] The title product was prepared from [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (250 mg; 0.54 mmol), (phenyl acetylene (110 mg; 1.07 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 186 mg (70%). HPLC-MS: m/z: 487.1 (M+H)+; Rt: 3.17 min.
[00677] Step B: [4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid
[00678] {[4-(3-Cyclopentyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep HPLC (method B). Yield: 120 mg (69%). HPLC-MS: m/z: 459.1 (M+H)+; Rt: 2.86 min.
[00679] Example 27
[00680] {4- [3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-
2-methyl-phenoxy}-acetic acid
(Formula Removed)

[00681] Step A: {4-[3-(4-Huoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00682] The title product was prepared from {4-[3-Bromo-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (335 mg; 0.59 mmol), l-ethynyl-4-fluorobenzene (142.3 mg; 1.19 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 140 mg (39%). HPLC-MS: m/z: 605.5 (M+H)+; Rt: 2.80 min. [00683] Step B: {4-[3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid
[00684] {4- [3-(4-Fluoro-phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (270 mg; 0.46 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep HPLC (method B). Yield: 113 mg (85%). HPLC-MS: m/z: 599.4 (M+Na); Rt: 2.50 min.
[00685] Example 28
[00686] [4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-
acetic acid
(Formula Removed)

[00687] Step A: [4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester
[00688] The title product was prepared from [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.63 mmol), phenylacetylen (191.7 mg; 1.88 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 200 mg (64%). HPLC-MS: m/z: 500.8 (M)+; Rt: 3.30 min.
[00689] Step B: [4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid
[00690] {[4-(3-Cyclopentylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.40 mmol) was dissolved in THF (2 mL), ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 146 mg (78%). HPLC-MS: m/z: 472.9 (M)+; Rt: 3.03 min.
[00691] Example 29
[00692] {4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-
acetic acid
(Formula Removed)

[00693] Step A: {4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00694] The title product was prepared from {4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester (300 mg; 0.58 mmol), phenylace-tylen (181.1 mg; 1.8 mmol) applying the procedure described for {4-[3-[2-(4-ChIoro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 110 mg (33%). HPLC-MS: m/z: 529.6 (M+H)+; Rt: 3.38 min.
[00695] Step B: {4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid
[00696] {4-[3-(2-Cyclohexyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (110 mg; 0.208 mmol) was dissolved in THF (2 mL), ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 105 mg. HPLC-MS: m/z: 500.1 (M)+; Rt: 3.20 min.
[00697] Example 30
[00698] {4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2 methyl-
phenoxy}-acetic acid(Formula Removed)

[00699] Step A: {4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00700] The title product was prepared from 4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.42 mmol) and 4-prop-2-ynyl-morpho-line (156,0 mg; 1,26 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 210 mg (95%). HPLC-MS: m/z: 526.2 (M+H)+; Rt: 2.23 min
[00701] Step B: {4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}- acetic acid
[00702] {4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (210 mg; 0.40 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yie'.d. 144 mg (73%). HPLC-MS: m/z: 498.2 (M+H)+; Rt: 1.97 min.
[00703] Example 31
[00704] {4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid
(Formula Removed)

[00705] Step A: {4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-
methyl-phenoxyj-acetic acid ethyl ester
[00706] The title product was prepared from [4-(3-Bromo-5-cyclopentyloxy-phenylsuifanyl)-
2-methyl-phenoxy]-acetic acid ethyl ester (250 mg; 0.54 mmol) and 4-prop-2-ynyl-moipho-
line (134.48 mg; 1.07 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-
phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-
acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B).
Yield: 210 mg (95%). HPLC-MS: m/z: 510.2 (M+H)+; Rt: 2.03 min
[00707] Step B: (4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-
methyl-phenoxy} -acetic acid
[00708] {4-[3-Cyclopentyloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid ethyl ester (160 mg; 0.31 mmol) was dissolved in ethanol (10 mL), and
aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h.
acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic
phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield:
105 mg (70%). HPLC-MS: m/z: 482.2 (M+H)+; Rt: 1.77 min.
[00709] Example 32
[00710] {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-y 1-prop-1 -ynyl)-phenylsulfanyl]-2-
methyl-phenoxy} -acetic acid
(Formula Removed)
[00711] Step A: {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester
[00712] The title product was prepared from {4-[3-Bromo-5-(2-cyclohexyl-ethoxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (300 mg; 0.59 mmol) and 4-prop-2-ynyl-morpholine (222.0 mg; 1.77 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy] -5 - (4-hydroxymethy l-phenylethynyl)-phenylsulfanyl] -2-methyl-phenoxy} -acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 200 mg (30%). HPLC-MS: m/z: 551.8 (M)+; Rt: 2.35 min [00713] Step B: {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-aceticacid
[00714] {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester (200 mg; 0.36 mmol) was dissolved in THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 107 mg (57%). HPLC-MS: m/z: 523.9 (M)+; Rt: 2.06 min.
[00715] Example 33
[00716] {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-
methyl-phenoxy}-acetic acid

[00717] Step A: {4-[3-(2-Cyclohexyl-ethoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00718] The title product was prepared from {4-[3-Bromo-5-cyclopentylmethoxy-phenyl-sulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (260 mg; 0.54 mmol) and 4-prop-2-ynyl-morpholine (203.6 mg; 1.63 mmol) applying the procedure described for (4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 80 mg (28%). HPLC-MS: m/z: 523.9 (M)+; Rt: 2.19 min [00719] Step B: {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid
[00720] {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (80 mg; 0.15 mmol) was dissolved in THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 30 min. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 43 mg (57%). HPLC-MS: m/z: 495.8 (M)+; Rt: 1.92 min.
[00721] Example 34
[00722] {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-
methyl-phenoxy} -acetic
(Formula Removed)[00723] Step A: {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic ethyl ester
[00724] The title product was prepared from {4-[3-Hydroxy-5-(3-morpholin-4-yl-prop 1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (350 mg; 0.77 mmol), cyclohexylmethanol (131.6 mg; 1.15 mmol), tributylphosphine (0.465 mg; 2.31 mmol) and l,r-(azodicarbonyl)dipiperidine (0.581 g; 2.31 mmol) were dissolved in THF (50 mL) in a dried reaction flask under an atmosphere of nitrogen. The reaction mixture was stirred for 16h and purified by column chromatography; ethyl acetate: heptane (5:1). Yield: 120 mg. HPLC-MS: m/z: 552.1 (M+H)+; Rt: 2.19 min.
[00725] Step B: {4-[3-Cyclopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic
[00726] {4-[3-Cydopentylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic ethyl ester (120 mg; 0.22 mmol) was dissolved in THF (2 mL) and ethanol (8 mL), and aqueous 1 N sodium hydroxide (2 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 110 mg (90%). HPLC-MS: m/z: 524.2 (M+H)+; Rt: 1.97 min.
[00727] Example 35
[00728] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-
phenoxy}-acetic acid

[00729] Step A: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}- acetic acid ethyl ester
The title product was prepared from [4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.64 mmol) and 4-prop-2-ynyl-morpholine (221 mg; 2.6 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 140 mg (44%). HPLC-MS: m/z: 511.9 (M)+; Rt: 2.00 min.
[00730] Step B: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid
{{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (140 mg; 0.27 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acie;fiec! with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness, redissolved in dichloromethane and evaporated to dryness. Yield: 113 mg (86%). HPLC-MS: m/z: 484.9 (M+H)+; Rt: 1.70 min. δH(400 MHz; CDC13) 1.03 (d, 6H), 2.04-2.12 (m, 1H), 2.24 (s, 3H), 2.90-3.30 (m, 2H), 3.40-3.70 (m, 2H), 3.71 (d, 2H), 3.74 (s, 2H), 3.95-4.05 (m, 4H), 4.17 (s, 2H), 4.69 (s, 2H), 6.14 (m, 1H), 6.53 (d, 1H), 6.77(dd, 1H), 6.81 (m, 1H), 6.89 (m, 1H), 7.23 (d, 1H).
[00731] Example 36
[00732] [4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid
(Formula Removed)

[00733] Step A: [4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-acetic
acid ethyl ester
[00734] The title product was prepared from [4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-
methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.64 mmol) and phenylacetylen (262 mg;
2.6 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-
hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester.
The crude product was purified by preparative HPLC (method B). Yield: 130 mg (45%).
HPLC-MS: m/z: 489.1 (M+H)+; Rt: 3.01 min
[00735] Step B: [4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-acetic
acid
[00736] [4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-aceticacid
ethyl ester (130 mg; 0.27 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium
hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N
aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and
evaporated to dryness, redissolved in dichloromethane and evaporated to dryness. Yield: 120
mg (97%). HPLC-MS: m/z: 461.7 (M+H)+; Rt: 2.82 min.
[00737] Example 37
[00738] {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-
phenoxy}-acetic acid
(Formula Removed)

[00739] Step A: [{4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxy } -acetic acid ethyl ester
[00740] The title product was prepared from [4-(3-Bromo-5-isobutoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.64 mmol) and l-Ethynyl-4-methane-sulfonyl-benzene (347.0 mg; 1.93 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy } -acetic acid ethyl ester. The crude product was purified by preparative HPLC (method A). Yield: 260 mg (72%). HPLC-MS: m/z: 567.6 (M+H)+; Rt: 2.77 min [00741] Step B: {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxy} -acetic acid.
[00742] {4-[3-Isobutoxy-5-(4-methanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxy) -acetic acid ethyl ester (130 mg; 0.27 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness, redissolved in dichloromethane and evaporated to dryness. Yield: 230 mg (%). HPLC-MS: m/z: 539.5 (M+H)+; Rt: 2.49 min.
[00743] Example 38
[00744] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-
phenylsulfanyl]-2-methyl-phenoxy }-acetic acid

(Formula Removed)
[00745] Step A: {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester [00746] The title product was prepared from {4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester (250 mg; 0.46 mmol) and l-Ethynyl-4-methanesulfonyl-benzene (249.2 mg; 1.38 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 168 mg (57%). HPLC-MS: m/z: 642.1 (M+H)+; Rt: 2.75 min
[00747] Step B: {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid.
[00748] {{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester (168 mg; 0.26 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by prep* -rative HPLC (method B). Yield: 120 mg (75%). HPLC-MS: m/z: 614.1 (M+H)+; Rt: 2.45 min.
[00749] Example 39[00750] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-
phenylsulfanyl]-2-methyl-phenoxy }-acetic acid
(Formula Removed)

[00751] Step A: {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester [00752] The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-pvridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester (250 mg; 0.46 mmol) and l-Ethynyl-4-methanesulfonyl-benzene (249.2 mg; 1.38 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 197 mg (67%). HPLC-MS: m/z: 642.4 (M+H)+; Rt: 2.73 min
[00753] Step B: {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid.
[00754] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester (197 mg; 0.31 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 150 mg (80%). HPLC-MS: m/z: 614.4 (M+H)+; Rt: 2.42 min.
[00755] Example 40
[00756] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-1 -ynyl)-5-(3-trifluoromethyl-pyridin-2-
yloxy)-phenylsulfanyl]-phenoxy} -acetic acid
(Formula Removed)

[00757] Step A: {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy} -acetic acid ethyl ester [00758] The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy} -acetic acid ethyl ester (250 mg; 0.46 mmol) and 4-prop-2-ynyl-morpholine (173.09 mg; 1.38 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 262 mg (97%). HPLC-MS: m/z: 587.5 (M+H)+; Rt: 2.03 min [00759] Step B: {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy} -acetic acid.
[00760] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-pyridm-2-yloxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (262 mg; 0.45 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 178 mg (72%). HPLC-MS: m/z: 559.5 (M+H)+; Rt: 1.78 min.
[00761] Example 41
[00762] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(5-trifluoromethyl-pyridin-2-
yloxy)-phenylsulfanyl]-phenoxy}-acetic acid
(Formula Removed)

[00763] Step A: {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy} -acetic acid ethyl ester [00764] The title product was prepared from {4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.46 mmol) and 4-prop-2-ynyl-morpholine (173.09 mg; 1.38 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 270 mg (100%). HPLC-MS: m/z: 587.5 (M+H)+; Rt: 2.03 min [00765] Step B: {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy} -acetic acid.
[00766] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy} -acetic acid ethyl ester (262 mg; 0.45 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 174 mg (68%). HPLC-MS: m/z: 559.5 (M+H)+; Rt: 1.81 min.
[00767] Example 42
[00768] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-phenoxy)-
phenylsulfanyl] -phenoxy} -acetic acid
(Formula Removed)

[00769] Step A: {2-Memyl-4-[3-(3-morpholm-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-
phenoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester
[00770] The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-
phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (230 mg; 0.43 mmol) and 4-prop-
2-ynyl-morpholine (159.5 mg; 1.28 mmol) applying the procedure described for {4-[3-[2-(4-
Chloro-phenyl)-etlioxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-
phenoxy} -acetic acid ethyl ester. The crude product was purified by preparative HPLC
(method A). Yield: 160 mg. HPLC-MS: m/z: 586.5 (M+H)+; Rt: 2.18 min
[00771] Step B: {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-
phenoxy)-phenylsulfanyl]-phenoxy} -acetic acid.
[00772] {2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (160 mg; 0.27 mmol) was dissolved in etha nol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 128 mg (84%). HPLC-MS: m/z: 558.4 (M+H)+; Rt: 1.91 min.δH(400 MHz; CDC13) 2.26 (s, 3H), 3.05-3.55 (m, 4H), 3.91-4.04 (m, 4H), 4.11 (s, 2H), 4.70 (s, 2H), 6.71-6.78 (m, 3H), 6.81-6.84 (m, 1H), 7.11-7.16 (m, 1H), 7.19-7.23 (m, 1H), 7.27-7.33 (m, 2H), 7.37-7.41 (m, 1H), 7.43-7.49 (m, 1H).
[00773] Example 43
(Formula Removed)
[00774] (4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid
[00775] Step A: {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester
[00776] The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy }-acetic acid ethyl ester (230 mg; 0.43 mmol) and 1-Ethynyl-4-methanesulfonyl-benzene (229.7 mg; 1.28 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method A). Yield: 140 mg. HPLC-MS: m/z: 641.5 (M+H)+; Rt: 2.89 min [00777] Step B: {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid.
[00778] {4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (140 mg; 0.22 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate, dried and evaporated to dryness. The organic phase was purified by preparative HPLC (method B). Yield: 100 mg (75%). HPLC-MS: m/z: 635.1 (M+Na); Rt: 2.62 min.
[00779] Example 44
[00780] {2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl-
sulfanyl]-phenoxy} -acetic acid
(Formula Removed)

[00781] Step A: {2-Methyl-4-[3-phenylemynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-
phenylsulfanylj-phenoxy} -acetic acid ethyl ester
[00782] The title product was prepared from {4-[3-Bromo-5-(3-trifluoromethyl-phenoxy)-
phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (300 mg; 0.55 mmol) and
phenylacetylene (113 mg; 1.11 mmol) applying the procedure described for {4-[3-[2-(4-
Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-
phenoxy} -acetic acid ethyl ester. The crude product was purified by preparative HPLC
(method A). Yield: 150 mg. HPLC-MS: m/z: 564.5 (M+H)+; Rt: 3.00 min
[00783] Step B: {2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-
phenylsulfanyl]-phenoxy}-acetic acid.
[00784] {2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-
phenylsulfanyl]-phenoxy} -acetic acid ethyl ester (150 mg; 0.266 mmol) was dissolved in
THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The
reaction mixture was stirred for 1/2h. acidified with 5% aqueous citric acid and extracted with
ethyl acetate, dried and evaporated to dryness. Yield: 100 mg (75%). HPLC-MS: m/z: 535.7
(M)+; Rt: 2.78 min.
[00785] Example 45
[00786] {4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-
methyl-phenoxy)-acetic acid
(Formula Removed)

[00787] Step A: {4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzyl-sulfanyl]-2-methyl-phenoxy}-acetic acid acid ethyl ester
[00788] The title product was prepared from [4-(3-Bromo-5-cyclopropylmethoxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.43 mmol) and 4-prop-2-ynyl-morpholine (161 mg; 1.3 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 173 mg; 79%. HPLC-MS: m/z: 510.1 (M)+; Rt: 1.9 min.
[00789] Step B: {4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid
[00790] (4-[3-Cydopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy)-acetic acid acid ethyl ester (173 mg; 0.34 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 107 mg; 66%. HPLC-MS: m/z: 482.0 (M+H)+; Rt: 1.62 min.
[00791] Example 46
[00792] _{4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-
methyl-phenoxy)-acetic acid

[00793] Step A: {4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenyl-sulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester
[00794] The title product was prepared from [4-(3-Bromo-5-cyclopropylmethoxy-phenyl-sulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (250 mg; 0.55 mmol) and 4-prop-2-ynyl-morpholine (208 mg; 1.7 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 205 mg; 75%. HPLC-MS: m/z: 496.1 (M+H)+; Rt: 2.04 min.
[00795] Step B: {4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid
[00796] {4-[3-Cyclopropylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (205 mg; 0.41 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 160 mg; 83%. HPLC-MS: m/z: 468.1(M+H)+;Rt: 1.78 min.
[00797] Example 47
[00798] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2,5-dimethyl-
phenoxy}-acetic acid

(Formula Removed)

[00799] Step A: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2,5-dimethyl-phenoxy} -acetic acid ethyl ester
[00800] The title product was prepared from [4-(3-Bromo-5-isobutoxy-phenylsulfanyl)-2,5-dimethyl-phenoxy]-acetic acid ethyl ester (400 mg; 0.86 mmol) and 4-prop-2-ynyl-morpholine (321.3 mg; 2.6 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 350 mg; 80%. HPLC-MS: m/z: 512.2 (M+H)+; Rt: 2.09 min.
[00801] Step B: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2,5-dimethyl-phenoxy}-acetic acid
[00802] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2,5-dimethyl-phenoxy}-acetic acid ethyl ester (350 mg; 0.68 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 250 mg; 76%. HPLC-MS: m/z: 484.6 (M+H)+; Rt: 1.87 min.
[00803] Example 48 {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenoxy]-2-methyl-phenoxy}-acetic acid
(Formula Removed)

[00804] Step A: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenoxy]-2-methyl-phenoxy}-acetic acid ethyl ester
[00805] The title product was prepared from [4-(3-Bromo-5-isobutoxy-phenylsulfanyl> 2,5-dimethyl-phenoxy]-acetic acid ethyl ester (300 mg; 0.71 mmol) and 4-prop-2-ynyl-morpholine (266.1 mg; 2.1 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 260 mg; 79%. HPLC-MS: m/z: 468.7 (M+H)+; Rt: 1.94 min
[00806] Step B: {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenoxy]-2-methyl-phenoxy}-acetic acid
[00807] {4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenoxy]-2-methyl-phenoxy}-acetic acid ethyl ester (260 mg; 0.56 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 180 mg; 72%. HPLC-MS: m/z: 454.6 (M+H)+; Rt: 1.77 min. 6H(400 MHz; CDC13) 1.01 (d, 6H), 2.02-2.10 (m, 1H), 2.28 (s, 3H), 3.10-3.55 (m, 4H), 3.68 (d, 2H), 3.93-4.07 (m, 4H), 4.10 (s, 2H), 4.67 (s, 2H), 6.47 (m, 1H), 6.57-6.59 (m, 1H), 6.66-6.69 (m, 1H), 6.71 (d, 1H), 6.79 (dd, 1H), 6.86 (d, 1H).
PHARMACOLOGICAL METHODS IN VITRO PPAR-8 ACTIVATION ACTIVITY
[00808] The PPAR transient transactivation assay is based on transient transfection into human HEK293 cells of two plasmids encoding a chimeric test protein and a reporter protein respectively. The chimeric test protein is a fusion of the DNA binding domain (DBD) from the yeast GAL4 transcription factor to the ligand binding domain (LBD) of the human PPAR proteins. The PPAR-LBD moiety harbored in addition to the ligand binding pocket also the native activation domain (activating function 2 = AF2) allowing the fusion protein to function as a PPAR ligand dependent transcription factor. The GAL4 DBD will direct the chimeric protein to bind only to Gal4 enhancers (of which none existed in HEK293 cells). The reporter plasmid contained a Gal4 enhancer driving the expression of the firefly luciferase protein. After transfection, HEK293 cells expressed the GAL4-DBD-PPAR-LBD fusion protein. The fusion protein will in turn bind to the Gal4 enhancer controlling the luciferase expression, and do nothing in the absence of ligand. Upon addition to the cells of a PPAR ligand luciferase protein will be produced in amounts corresponding to the activation of the PPAR protein. The amount of luciferase protein is measured by light emission after addition of the appropriate substrate.
CELL CULTURE AND TRANSFECTION
[00809] HEK293 cells were grown in DMEM + 10% PCS. Cells were seeded in 96-well plates the day before transfection to give a confluency of 50-80 % at transfection. A total of 0,8 ng DNA containing 0,64 ug pMlo/LBD, 0,1 ug pCMVßGal, 0,08 ug pGL2(Ga!4)5 and 0,02 ug pADVANTAGE was transfected per well using FuGene transfection reagent according to the manufacturers instructions (Roche). Cells were allowed to express protein for 48 h followed by addition of compound.
[00810] Plasmids: Human PPAR-8 was obtained by PCR amplification using cDNA synthesized by reverse transcription of mRNA from human liver, adipose tissue and plancenta respectively. Amplified cDNAs were cloned into pCR2.1 and sequenced. The ligand binding domain (LBD) of each PPAR isoform was generated by PCR (PPAR6: aa 128 - C-terminus) and fused to the DNA binding domain (DBD) of the yeast transcription factor GAL4 by sub-
cloning fragments in frame into the vector pMl (Sadowski et al. (1992), Gene 118,137) generating the plasmids pMlaLBD, pMlyLBD and pM18. Ensuing fusions were verified by sequencing. The reporter was constructed by inserting an oligonucleotide encoding five repeats of the GAL4 recognition sequence (5 x CGGAGTACTGTCCTCCG(AG)) (Webster et al. (1988), Nucleic Acids Res. 16, 8192) into the vector pGL2 promoter (Promega) generating the plasmid pGL2(GAL4)5. pCMVßGal was purchased from Clontech and pADVANTAGE was purchased from Promega.
IN VITRO TRANSACTIVATION ASSAY
[00811] Compounds: All compounds were dissolved in DMSO and diluted 1:1000 upon addition to the cells. Compounds were tested in quadruple in concentrations ranging from O.OO1 to 300 uM. Cells were treated with compound for 24 h followed by luciferase assay. Each compound was tested in at least two separate experiments.
[00812] Luciferase assay: Medium including test compound was aspirated and 100 µl PBS incl.1mM Mg++ and Ca++ were added to each well. The luciferase assay was performed using the LucLite kit according to the manufacturer's instructions (Packard Instruments). Light emission was quantified by counting on a Packard LumiCounter. To measure 0-galactosidase activity 25µl supernatant from each transfection lysate was transferred to a new microplate. ß-Galactosidase assays were performed in the microwell plates using a kit from Promega and read in a Labsystems Ascent Multiscan reader. The p-galactosidase data were used to normalize (transfection efficiency, cell growth etc.) the luciferase data.
STATISTICAL METHODS
[00813] The activity of a compound is calculated as fold induction compared to an untreated sample. For each compound the efficacy (maximal activity) is given as a relative activity compared to Wy 14,643 for PPARa, Rosiglitazone for PPAR and Carbacyclin for PPAR8. The EC50 is the concentration giving 50% of maximal observed activity. EC50 values were calculated via non-linear regression using GraphPad PRISM 3.02 (GraphPad Software, San Diego, Ca).
[00814] While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications, and substitutions can be made therein without departing from the spirit and scope of the present invention. For example, effective dosages other than the preferred dosages as set forth herein may be applicable as a consequence of variations in the responsiveness of the mammal being treated for PPAR-5 mediated disease(s). Likewise, the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. Accordingly, the invention is not to be limited as by the appended claims. [00815] The features disclosed in the foregoing description and/or in the claims may both separately ans in any combination thereof be material for realising the invention in diverse forms thereof.
or a pharmaceutically acceptable salt thereof, wherein: X is selected from O, S, OCH2, and SCH2;
125
[00816] Preferred features of the invention: [00817] 1. A compound of formula I:
(Formula Removed)
X1 is O or S;
R1 is selected from H, C1-8 alkyl, C2.8 alkenyl, aryl, heteroaryl ,C3-10 cycloalkyl, and a hetero-cyclyl, wherein each R1 group is substituted with 0-4 Rla;
Rla, at each occurrence, is selected from S substituted with 0-1 Rlb, O substituted with G-l Rlb, halogen, NH2 substituted with 0-2 Rlb, -CN, NO2, C,.6 alkyl substituted with 0-3 Rlb, C2.6 alkenyl substituted with 0-2 Rlb, C2.6 alkynyl substituted with 0-2 Rlb, aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3-10cycloalkyl substituted with 0-2 Rlb, and het-erocycle substituted with 0-2 Rlb;
Rlb, at each occurrence, is selected from S substituted with 0-1 Rlc, O substituted with 0-1 Rlc, halogen, methanesulfonyl, NH2 substituted with 0-2 Rlc, -CN, NO2, d1-6 alkyl substituted with 0-3 Rlc, C2-6 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3-10 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc;
Rlc, at each occurrence, is selected from S substituted with 0-1 Rld, O substituted with 0-1 Rld, halogen, N42 substituted with 0-2 Rld, -CN, NO2, C1-6 alkyl substituted with 0-2 Rld, C2.6 alkenyl substitu'ed with 0-2 Rld, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3.io cycle; Ikyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld;
Rld, at each occ'irrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, C1-6 alkyl, C2.6 alkenyl, ary 1, CF3) and OCF3;
R2 is selected from -C=C-R2a, -CH=CH-R2a, aryl substituted with 0-3 R2a, and heteroaryl substituted with 0-3 R2a;
R2a, at each occurrence, is selected from S substituted with 0-1 R2b, O substituted with 0-1 R2b, halogen, NH2 substituted with 0-2 R2b, -CN, NO2, C1-6 alkyl substituted with 0-2 R2b, C2.6
alkenyl substitu'ed with 0-2 R2b, aryl substituted with 0-2 R2b, heteroaryl substituted with 0-2 R2b, C3-10 cyclo; Ikyl substituted with 0-2 R2b, and a heterocycle substituted with 0-2;
R2b, at each occ'irrence, is selected from S substituted with 0-1 R2c, O substituted with 0-1 R20, halogen, methanesulfonyl, NH2 substituted with 0-2 R2c, -CN, NO2, Ci.6alkyl substituted with 0-2 R20, C2-6 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R20, heteroaryl substituted with 0-2 R25, CMO cycloalkyl substituted with 0-2 R20, and a heterocycle substituted with 0-2 R20;
R2c, at each occurrence, is selected from S substituted with 0-1 R2d, O substituted with 0-1 R2d, halogen, NH2 substituted with 0-2 R2d, -CN, NO2, C,.6 alkyl substituted with 0-2 R2d, C2.6 alkenyl substitu'ed with 0-2 RM, aryl substituted with 0-2 R2d, heteroaryl substituted with 0-2 R2d, C3-10 cyckv.lkyl substituted with 0-2 R2d, and a heterocycle substituted with 0-2 R2d
R2d, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, Ci.6 alkyl, C2.6 alkenyl, aryl, CF3, and OCF3;
R3 is selected from halogen and C1-66 alkyl substituted with 0-2 R3a;
R3a, at each occurrence, is selected from OH, O, S, halogen, C(0)NH2, C(O)NH-CM alkyl, and C(O)N(CM alkyl)2;
alternatively, R3 and R5c combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)0.2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e;
R4a, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R4d;
R4d, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N'C1-4 al-kyl)2;
R4b, at each occurrence, is selected from H, halogen, and C1-6alkyl substituted with 0-2 R4";
R46, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 al-kyl)2;
R40, at each occurrence, is selected from H, halogen, and Ci-6 alkyl substituted with 0-2 R4f,
R4f, at each occurrence, is selected from OH, 0, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 al-kyl)2;
R5a, at each occurrence, is selected from H, halogen, CH3, and CH2CH3;
R5b, at each occurrence, is selected from H, halogen, CH3, and CH2CH3;
R5c, at each occurrence, is selected from H, halogen, CH3, and CH2CH3;
R5d, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; and,
R5c, at each occurrence, is selected from H, halogen, CH3, and CH2CH3.
[00818] 2. A compound of clause 1 wherein: X is selected from O, S, OCH2, and SCH2;
X'isOorS;
R1 is selected from H, C1-8g alkyl, C2.8 alkenyl, aryl, 5-10 membered heteroaryl consisting of carbon atoms ard 1-4 heteroatoms selected from O, N, and S(O)0.2> C3-10 cycloalkyl, and a 3-8
membered heterocycle consisting of carbon atoms and 1-3 heteroatoms selected from 0, N, and S(O)o-2, wherein each R1 group is substituted with 0-4 Rla;
Rla, at each occurrence, is selected from OH substituted with 0-1 Rlb, SH substituted with 0-1 Rlb, S, O, halogen, NH2 substituted with 0-2 Rlb, -CN, NO2, C1-6alkyl substituted with 0-3 Rlb, C2-6 alkenyl substituted with 0-2 Rlb, C2-6 alkynyl substituted with 0-2 Rlb, aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1 -3 heteroatoms selected from O, N, and S(0)0.2;
Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, S, O, halogen, methanesulfonyl, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-6alkyl substituted with 0-3 Rlc, C2.6 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 R!c, 5 10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 beteroa-toms selected from O, N, and S(O)0.2, C3.10 cycloalkyl substituted with 0-2 Rlc, and a 3-8 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0.2;
Rlc, at each occ>.irrence, is selected from OH substituted with 0-1 Rld, SH substituted with 0-1 Rld, S, O, halogen, NH2 substituted with 0-2 Rld, -CN, NO2, Ci.6alkyl substituted with 0-2 Rld, C2.6 alkenyl substituted with 0-2 Rld, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0.2, C3-10 cycloalkyl substituted with 0-2 Rld, and a 3-8 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0.2;
Rld, at each occ irrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, C1-6 a'kyi, C2.6 alkenyl, ary 1, CF3, and OCF3;
R2 is selected from -OC-R2a, -CH=CH-R2a substituted with 0-2 R2a, aryl substituted with 0-3 R2a, and 5-10 numbered heteroaryl substituted with 0-3 R2a and consisting of carbon atoms and 1-4 heteroa'oms selected from O, N, and S(0)o-2;
R2a, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, S, O, halogen, NH2 substituted with 0-2 R2b, -CN, NO2, C|.6alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3.10 cycloalkyl substituted with 0-2 R2b, and a 3-8 membered hetero-cycle substituted with 0-2 R2b and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0-2;
R2b, at each occurrence, is selected from OH substituted with 0-1 R2c, SH substituted with 0-1 R2*, S, O substituted with 0-1 R2c, halogen, methanesulfonyl, NH2 substituted with 0-2 R2c, -CN, NO2, C!.6a!kyl substituted with 0-2 R2c, C2.6 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R2c, 5-10 membered heteroaryl substituted with 0-2 R2c and consisting of carbon atoms and 1 -4 heteroatoms selected from O, N, and S(O)0-2, C3-10 cycloalkyl substituted with 0-2 R20, and a 3-8 membered heterocycle substituted with 0-2 R20 and consisting of carbon atoms and 1 -3 heteroatoms selected from O, N, and S(O)0-2;
P.20, at each occurrence, is selected from OH substituted with 0-1 R2d, SH substituted with 0-1 R2d, S, O, halogen, NH2 substituted with 0-2 R2d, -CN, NO2, C1-6alkyl substituted with 0-2 R2d, C2.6 alkenyl substituted with 0-2 R2d, aryl substituted with 0-2 R2d, 5-10 membered heteroaryl substituted with 0-2 R2d and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3-10 cycloalkyl substituted with 0-2 R2d, and a 3-8 membered hete>-o-cycle substituted with 0-2 R2d and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0.2;
RM, at each occ'irrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, C1-6alkyl, C2-6 alkenyl, an 1, CF3, and OCF3;
R3 is selected from halogen and C1-6 alkyl substituted with 0-2 R ";
R3a, at each occ irrence, is selected from OH, O, S, halogen, C(O)NH2, C(O)NH-C1-4 alkyl, and C(O)N(CM alkyl)2;
alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e;
R4a, at each occ'irrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R4d;
R4d, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4alkyl, and N(C1-4 al-kyl)2;
R4b, at each occ'irrence, is selected from H, halogen, and C1-8 alkyl substituted with 0-2 R4e;
R4", at each occurrence, is selected from OH, O, halogen, NH2, NH-Ci-4 alkyl, and N(C1-4 al-kyl)2;
R40, at each occurrence, is selected from H, halogen, and C1-4 alkyl substituted with 0-2 R4f;
R4f, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 al-kyl)2;
R5a, at each occurrence, is selected from H, halogen, CH3, and CH2CH3; R5b, at each occurrence, is selected from H, halogen, CH3, and CH2CH3;
R5c, at each occurrence, is selected from H, halogen, CH3, and CH2CH3;
R5d, at each occ>irrence, is selected from H, halogen, CH3, and CH2CH3; and, R5e, at each occurrence, is selected from H, halogen, CH3, and CH2CH3. [00819] 3. A compound of clause 1 or 2 wherein: X is selected from O, S, OCH2, and SCH2; X'isOorS;
R1 is selected from H, C1-8 alkyl, C2-8 alkenyl, aryl, 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.io cycloalkyl, and a 3-8 membered heteiocycle consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)o_2, wherein each R1 group is substituted with 0-4 Rla;
Rla, at each occurrence, is selected from OH substituted with 0-1 Rlb, SH substituted with 0-1 Rlb, S, O, halogen, NH2 substituted with 0-2 Rlb, -CN, NO2, C1-6alkyl substituted with 0-2 Rlb, C2.6 alkenyl substituted with 0-2 Rlb, C2.6 alkynyl substituted with 0-2 Rlb, aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting vl carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.io cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 Rlb and consisting of cat-bon atoms and 1 -3 heteroatoms selected from O, N, and S(O)o-2;
Rlb, at each occ'irrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, S, O, halogen, NH2 substituted with 0-2 Rlc, -CN, NO2, d-6 alkyl substituted with 0-2 Rlc, C2-6 alkeny! substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3-10 cycloalkyl substituted with 0-2 Rlc, and a 3-8 membered hetero-
cycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0-2;
Rlc, at each occurrence, is selected from OH substituted with 0-1 Rld, SH substituted with 0-1 Rld, S, O, halogen, NH2 substituted with 0-2 Rld, -CN, NO2, C1-6alkyl substituted with 0-2 Rld, C2_6 alkenyl substituted with 0-2 Rld, aryl substituted with 0-2 Rld, 5-10 membererf het-eroaryl substituied with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2,C3.10 cycloalkyl substituted with 0-2 Rld, and a 3-8 membered hetero-cycle substituted with 0-2 Rld and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0.2;
Rld, at each occurrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2) C1-6alkyl, C2.6 alkenyl, arty 1, CF3, and OCF3;
R2 is selected from -OC-R2", -CH=CH-R2a substituted with 0-2 R2a, aryl substituted with 0-3 R2a, and 5-10 numbered heteroaryl substituted with 0-3 R2aand consisting of carbon atoms and 1-4 heteroaioms selected from O, N, and S(O)o-2;
R2a, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, S, O, halogen, NH2 substituted with 0-2 R2b, -CN, NO2, C1-6alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-10 membered heteroaryl substituied with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.io cycloalkyl substituted with 0-2 R2b, and a 3-8 membered hetero-cycle substituted with 0-2 R2b and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0.2;
R2b, at each occ'irrence, is selected from OH substituted with 0-1 R2c, SH substituted with 0-1 R20, S, O, halogen, NH2 substituted with 0-2 R2c, -CN, NO2, C1-6 alkyl substituted with 0-2 R20, C2.6 alkenyl substituted with 0-2 R2c, aryl substituted with 0-2 R2c, 5-10 membered heteroaryl substituied with 0-2 R2c and consisting of carbon atoms and 1-4 heteroatoms relucted
from O, N, and S(O)0-2, C3-10cycloalkyl substituted with 0-2 R2c, and a 3-8 membered hetero-cycle substituted with 0-2 R2" and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0-2;
R20, at each occurrence, is selected from OH substituted with 0-1 R2d, SH substituted with 0-1 R2d, S, O, halog-n, NH2 substituted with 0-2 R2d, -CN, NO2, C1-6 alkyl substituted with 0-2 R2d, C2-6 alkenyl substituted with 0-2 R2d, aryl substituted with 0-2 R2d, 5-10 membered het-eroaryl substituted with 0-2 R2d and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, CB-IO cycloalkyl substituted with 0-2 R2d, and a 3-8 membered hetero-cycle substituted with 0-2 R2d and consisting of carbon atoms and 1-3 heteroatoms selected from O, N, and S(O)0-2;
R2d, at each occ'irrence, is selected from OH, SH, S, O, halogen, NH2, -CN, NO2, C1-6alkyl, C2.6 alkenyl, ary 1, CF3, and OCF3;
R3 is selected from halogen and Ci.6 alkyl substituted with 0-2 R3a;
R3a, at each occurrence, is selected from OH, O, S, halogen, C(O)NH2, C(O)NH-C1-4 alkyl, and C(O)N(C1-4alkyl)2;
alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heieroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e;
R4a, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R4d;
R4d, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4 alkyl, and N(CM alkyl).;
R4b, at each occurrence, is selected from H, halogen, and C1-6 alkyl substituted with 0-2 R46;
R46, at each occurrence, is selected from OH, O, halogen, NH2, NH-C1-4alkyl, and N(C1-4 al-kyl)2;
R40, at each occurrence, is selected from H, halogen, and C1-4 alkyl substituted with 0-2 R4f;
R4f, at each occurrence, is selected from OH, 0, halogen, NH2, NH-C1-4 alkyl, and N(C1-4 al-kyl)2;
R5a, at each occtirrence, is selected from H, halogen, CH3, and CH2CH3; R5b, at each occ'irrence, is selected from H, halogen, CH3, and CH2CH3; R5c, at each occ'irrence, is selected from H, halogen, CH3, and CH2CH3; R5d, at each occ'irrence, is selected from H, halogen, CH3, and CH2CH3; and, R5e, at each occurrence, is selected from H, halogen, CH3, and CH2CH3.
[00820] 4. A compound of any of the preceding clauses 1-3, wherein the compound is of formula la:
(Formula Removed)
pharmaceu! ically acceptable salt thereof.
[00821] 5. A compound of clause 1, wherein the compound is of formula II:
(Formula Removed)

II
or a pharmaceui ically acceptable salt thereof, wherein:
R1 is H, C1-8 alkyl, heteroaryl, and C3-10cycloalkyl, wherein each R1 group is substituted with 0-4 Rla;
Rla, at each occiirrence, is selected from C1-6 alkyl substituted with 0-3 Rlb; C2.6 alkynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3.i0 cycloalkyl subsiituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb;
Rlb, at each occiirrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, methanesulfonyl, C1-4 alkyl substituted with 0-3 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3-6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc;
alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld and, C3-6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld;
Rld, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl;
R2a is selected f om d.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and liet-eroaryl substituted with 0-2 R2b;
R2b, at each occ'.irrence, is selected from OH substituted with 0-1 R2c, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R2", -CN, NO2, methanesulfonyl, Ci.4 alkyl substituted with 0-2 R20, C2.4 alkenyl substituted with 0-2 R2", aryl substituted with 0-2 R2c, heteroaryl substituted with 0-2 R20, C3.e cycloalkyl substituted with 0-2 R20, and a heterocycle substituted with 0-2 R20;
R20, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 alkenyl, aryl substituted with 0-2 R2d, and heteroaryl substituted with 0-2 R2d;
R2d, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2-4 alkenyl;
R3 is selected from Cl, F, CH3, and CH2CH3;
alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5c;
R4a, at each occirrence, is selected from H, Cl, F, and CH3;
R4b, at each occ'irrence, is selected from H, Cl, F, and CH3; R4c, at each occ'irrence, is selected from H, Cl, F, and CH3; R5a, at each occurrence, is selected from H, Cl, F, and CH3; R5b, at each occurrence, is selected from H, Cl, F, and CH3; R5c, at each occurrence, is selected from H, Cl, F, and CH3;,
R5d, at each occurrence, is selected from H, Cl, F, and CH3; and,
R5e, at each occurrence, is selected from H, Cl, F, and CH3.
[00822] 6. A compound of clause 5 wherein:
R1 is H, C1-8alkyl, 5-10 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, and C3.10 cycloalkyl, wherein each R1 group is substituted with 0-4 Rla;
Rla, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 Rlb; C2-6 alkynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, 5-10 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from 0, N, and S(O)o-2;
Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, methanesulfonyl, CM alkyl substituted with 0-3 Rlc, C24 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 mem-
bered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3.6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2;
Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1.4 alkyl, and C2-44 alkenyl, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of ca1 bon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, Cs.g cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of ca'bon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
Rld, at each occ'.irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl;
R2" is selected f-om C1-6alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-10 membered heteioaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2;
R2b, at each occurrence, is selected from OH substituted with 0-1 R^, SH substituted -v'ith 0-1 R20, Cl, F, NH2 substituted with 0-2 R2c, -CN, NO2, methanesulfonyl, CM alkyl substituted with 0-2 R2*, C2-4 alkenyl substituted with 0-2 R2c, aryl substituted with 0-2 R2c, 5-10 membered heteroaryl substituted with 0-2 R2* and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3.e cycloalkyl substituted with 0-2 R2*, and a 3-6 membered heterocycle substituted with 0-2 R2c and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
R2*, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 alkenyl, aryl subs ituted with 0-2 R2d, and 5-10 membered heteroaryl substituted with 0-2 R2d and consisting c f carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0.2;
R2d, at each occ'.irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl;
R3 is selected from Cl, F, CH3, and CH2CH3;
alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)0.2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e;
R4a, at each occ'.irrence, is selected from H, Cl, F, and CH3; R4b, at each occ'irrence, is selected from H, Cl, F, and CH3; R40, at each occ'irrence, is selected from H, Cl, F, and CH3; R5a, at each occurrence, is selected from H, Cl, F, and CH3; R5b, at each occ'irrence, is selected from H, Cl, F, and CH3; R5c, at each occurrence, is selected from H, Cl, F, and CH3; R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, R5', at each occ'irrence, is selected from H, Cl, F, and [00823] 7. A compound of clause 5 or 6, wherein: R1 is H or CM alkyl substituted with 1-4 Rla;
u, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-10 membered het-eroaryl substituied with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3-10 cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered hetero-cycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2;
Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 P.lc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2-4 alkenyl substiUred with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2,C3.6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2;
R'c, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.., alkenyl, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of ca bon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C$.6 cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl;
R2a is selected f, om C1-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-10 membered heteioaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heterca-toms selected from O, N, and S(O)o-2;
R2b, at each occ'jrrence, is selected from OH substituted with 0-1 R2", SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R20, -CN, NO2,C1-4 alkyl substituted with 0-2 R2c, C2.4 alkenyl substitu'ed with 0-2 R20, aryl substituted with 0-2 R20,5-10 membered heteroaryl sub-
stituted with 0-2 R20 and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-6, cycloalkyl substituted with 0-2 R20, and a 3-6 membered heterocycle substituted with 0-2 R2c and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2;
R26, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2-4 al-kenyl, aryl substituted with 0-2 R2d, and 5-10 membered heteroaryl substituted with 0-2 R2d and consisting c f carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2;
R2*1, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, N02, C1-4 alkyl, and C2.4 alkenyl;
R3 is selected from Cl, F, CH3, and CH2CH3;
alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e;
R4a, at each occurrence, is selected from H, Cl, F, and CH3; R4b, at each occurrence, is selected from H, Cl, F, and CH3; R40, at each occ1 irrence, is selected from H, Cl, F, and CH3; R5a, at each occ'irrence, is selected from H, Cl, F, and CH3; R5b, at each occurrence, is selected from H, Cl, F, and CH3; R5c, at each occurrence, is selected from H, Cl, F, and CH3;
Ria, at each occurrence, is selected from H, Cl, F, and CHs; and,
R5e, at each occurrence, is selected from H, Cl, F, and CH3.
[00824] 8. A compound of clause 5, wherein the compound is of formula Ha:
(Formula Removed)

or a pharmaceutically acceptable salt thereof, wherein:
R1 is H, C1-6 alkyl, aryl, heteroaryl, and C3-10 cycloalkyl, wherein each R1 group is substituted withO-lRla;
Rla, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 Rlb; C2-6 alkynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb and, C5. 6 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb and;
Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, methanesulfonyl, d 4alkyl substituted with 0-3 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted w.th C-2 Rlc, heteroaryl substituted with 0-2 Rlc, C5.6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc;
Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, d.4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C5.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld;
Rld, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl;
R2a is selected from d.6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and heteroaryl substituted with 0-2 R2b;
R2b, at each occ irrence, is selected from OH substituted with 0-1 R20, SH, Cl, F, NH2, -CN, NO2, methanesi Ifonyl, CM alkyl, C2.4 alkenyl, aryl, heteroaryl, C5.6 cycloalkyl, and a hetero-cycle;
R20, at each occurrence, is CM alkyl;
R3 is selected from Cl, F, CH3, and CH2CH3; and,
alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e.
[00825] 9. A compound of clause 8 wherein:
R1 is H, Cj-e alkyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-4 heteroatoms selected fnm O, N, and S(O)o-2, and C3-10 cycloalkyl, wherein each R1 group is substituted with 0-1 Rla;
Rla, at each occurrence, is selected from C1-.6 alkyl substituted with 0-3 Rlb; C2-6 alkynyl substituted with 0-2 Rlb; aryl substituted with 0-2 Rlb, 5-6 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5.6 cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered heterocycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(0)o-2;
Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, methanesulfonyl, C,. 4 alkyl substituted with 0-3 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and .1 -2 heteroatoms sel ;cted from O, N, and S(O)o-2. C5-6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2;
Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5.6 cycloalkyl substituted with 0-2 Rld, and a 5-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
Rld, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2, alkenyl;
R2a is selected from Ci-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2;
R2b, at each occ'irrence, is selected from OH substituted with 0-1 R20, SH, Cl, F, NH2, -CN, NO2> methanesi Ifonyl, CM alkyl, C2-4 alkenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms ai d 1-2 heteroatoms selected from O, N, and S(O)o_2,, C5-6 cycloalkyl, and a 5-6 membered heterocycle and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(0)0.2;
R20, at each occurrence, is CM alkyl;
R3 is selected from Cl, F, CH3, and CH2CH3; and,
alternatively, R3 and R5c combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5c.
[00826] 10. A compound of clause 8 or 9 wherein: R1 is H or C1-4alky! substituted with 1 Rla;
Rla, at each occ'irrence, is selected from aryl substituted with 0-2 Rlb, 5-6 membered het-eroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered hetero-cycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2;
Rlb, at each occ*irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2, C5.6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle sub ;tituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, Ci-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of ca bon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5.5 cycloal-kyl substituted with 0-2 Rld, and a 5-6 membered heterocycle substituted with 0-2 Rld and consisting of ca:bon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2;
Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl;
R2a is selected f/om C1-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1 -2 heteroatoms selected from O, N, and S(O)o-2;
R2b, at each occ irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 al-kenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2,, C5-6 cycloalkyl, and a 5-6 membered heterocycle and consisting of carbon atoms ard 1-2 heteroatoms selected from O, N, and S(O)o-2;
R3 is selected from Cl, F, CH3, and CH2CH3; and,
alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbun atoms and 0-2 heieroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e.
100827] 11. A compound of clause 8 wherein:
R1 is H, Ci.6 alkyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from O and N; C3-10 cycloalkyl, wherein each R1 group is substituted with 0-1 Rla;
Rla, at each occ'irrence, is selected from C1-4 alkyl substituted with 0-3 Rlb; C2-6 alkyiiyl substituted with 0-1 Rlb aryl substituted with 0-1 Rlb, heteroaryl substituted with 0-1 Rlb, C5.6 cycloalkyl substituted with 0-1 Rlb, and a heterocycle substituted with 0-1 Rlb;
Rlb, at each occ;irrence, is selected from Cl, F, methanesulfonyl, and CM alkyl substituted with 0-3 Rlc, and;
Rlc, at each occurrence, is selected from Cl, F and a heterocycle ;

R2" is selected f/ora C1.6alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and het-
eroaryl substituted with 0-2 R2b;
R2b, at each occ irrence, is selected from OH optionally substituted with CM alkyl, Cl, F, methanesulfonyl, aryl, heteroaryl, C5_6 cycloalkyl, and a heterocycle ;
R3 is selected from Cl, F, CH3, and CH2CH3..
[00828] 12. A compound of clause 11 wherein:
R1 is H, C1-6 alkyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroa-toms selected from O and N; C3-10 cycloalkyl, wherein each R1 group is substituted with 0-1 R";
Rla, at each occurrence, is selected from CM alkyl substituted with 0-3 Rlb; C2-6 alkynyl substituted with 0-1 Rlb aryl substituted with 0-1 Rlb, 5-6 membered heteroaryl substituted with 0-1 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O and N, C5_6 cycloalkyl substituted with 0-1 Rlb, and a 5-6 membered heterocycle substituted with 0-1 Rlb;
Rlb, at each occ'irrence, is selected from Cl, F, methanesulfonyl, and CM alkyl substituted with 0-3 Rlc, and;
Rlc, at each occurrence, is selected from Cl, F and a 5-6 membered heterocycle consisting of carbon atoms ard 1-2 heteroatoms selected from O and N;
R2" is selected f-om C1-6 alkyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, and 5-6 membered heteioaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O and N;
R2b, at each occurrence, is selected from OH optionally substituted with C1-4 alkyl, Cl, F, methanesulfonyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroa-toms selected from O and N, C5.6 cycloalkyl, and a 5-6 membered heterocycle consisting of carbon atoms ai d 1-2 heteroatoms selected from O and N;
R3 is selected from Cl, F, CH3, and CH2CH3.
[00829] 13. A compound of clause 12 wherein R is CM alkyl substituted with 1 R11
[00830] 14. A compound of clause 5, wherein the compound is of of formula lib
(Formula Removed)

or a pharmaceutically acceptable salt thereof.
[00831] 15. A compound of clause 14 wherein R2a is selected from aryl substituted witn 0-2 R2t> and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2-
[00832] 16. A compound of clause 14, wherein R1 is C1-6 alkyl.
[00833] 17. A compound of clause 14, wherein R2a is C1-4 alkyl substituted with a heterocycle.
[00834] 18. A compound of clause 14, wherein the R2" is CM alkyl substituted with mor-pholinyl.
[00835] 19. A compound of clause 14, wherein R3 is selected from Cl and CH3.
[00836] 20. A compound of clause 14, wherein X is selected from S and SCH2 [00837] 21. A compound of clause 14, wherein X is S. [00838] 22. A compound of clause 14, wherein X is O. [00839] 23. A compound of clause 14, wherein X is SCH2. [00840] 24. A compound of clause 14, wherein X1 is O.
[00841] 25. A compound of clause 14, wherein R1 is aryl substituted with 0-1 Rla; wherein Rla, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2) CM alkyl.
[00842] 26. A compound of clause 14, wherein ein R1 is Ci.6 alkyl substituted with Pla, and wherein Rla is aryl substituted with 0-1 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2,-CN,NO2, C1-4 alkyl.
[00843] 27. A compound of clause 14, wherein R1 is C1-4 alkyl substituted with Rla, wherein Rla is heteroary! substituted with 0-1 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2,-CN, NO2. C1-4alkyl.
[00844] 28. A compound of clause 14, wherein R1 is C1-6 alkyl substituted with Rla, wherein Rla is heterocyclyl substituted with 0-1 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2,-CN, NO2> C1-4alkyl.
[00845] 29. A compound of clause 14, wherein R1 is C1-6 alkyl substituted with Rla, v.herein Rla is C5.6 cyclcalkyl substituted with 0-2 Rlb; and wherein Rlb is selected from OH, SH, Cl, F, NH2,-CN, N02, C1-4 alkyl.
[00846] 30. A compound of clause 14, wherein R2ais aryl substituted with R2b; whereir- R2'J is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl.
[00847] 31. A compound of clause 14, wherein R2ais Ci-6 alkyl substituted with R2b; wherein R2b is selected from aryl substituted with R2c; and wherein R2* is selected from OH, SH, Cl, F, NH2,-CN, NO2, C1-4 alkyl.
[00848] 32. A compound of clause 14, wherein R2a is C1-6 alkyl substituted with R2b; wherein R2b is selected from heteroaryl substituted with R20; and wherein R2c is selected from OH, SH,
Cl, F, NH2, -CN, N02, CM alkyl.
•
[00849] 33. A compound of clause 1, wherein the compound is selected from:.
{2-Chloro-4-[3-(4-chloro-phenylemynyl)-5-(3-piperidin-l-yl-propoxy)-phenylsulfanyl]-
phenoxy}-acetic acid;
{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-
acetic acid;
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-
phenoxy)-acetic acid;
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(4-morpholin-4-ylmethyl-benzyloxy)-phenyl-
sulfanyl]-phenoxy} -acetic acid;
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(l-methyl-piperidin-4-ylmethoxy)-phenyl-
sulfanyl]-phemxy} -acetic acid;
{2-Methyl-4-[3-(3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-phenylsulfanyl]-
phenoxy}-acetic acid;
{4-[3-(4-Fluoro benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-meihyl-
phenoxy}-acetic acid;
{4-[3-Cyclohexylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid;
{4-[3-Isobutoxy-5 -(3-morpholin-4-yl-prop-1 -ynyl)-phenylsulfanyl]-2-methyl-phenoxy} -
acetic acid;
{4-[3-(4-Chloro-benzyloxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid;
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-hydroxy-phenylsulfanyl]-phenoxy}-acetic acid;
{4-[3-But-2-yn\loxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-
acetic acid;
{2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-acetic
acid;
{2-Chloro-4-[3-(3-methoxy-prop-l-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-
phenoxy}-acetic acid;
{2-Chloro-4- [3- (3 -morpholin-4-y l-propoxy)-5-pent-1 -ynyl-phenylsulfanyl] -phenoxy} -acetic
acid;
{2-Methyl-4-[3 (3-morpholin-4-yl-propoxy)-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-
phenoxy}-acetic acid;
{4-[3-(4-Fluoro benzyloxy)-5-(3-morpholin-4-yl-prop-1 ynyl)-benzyIsulfanyl]-2-methyl-
phenoxy}-acetic acid; and,
{2-Methyl-4-[3-(3-morpholin-4-yl-ethoxy)-5-(3-phenyl-prop-l-ynyl)-benzylsulfanyl]-
phenoxy)-acetic acid;
or a pharmacem ically acceptable salt thereof.
[00850] 34. A compound of clause 1, wherein the compound is selected from:.
{4-[3-Cyclohexylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-metliyl-
phenoxy}-acetic acid;
{4-[3-Cyclopen!.ylmethoxy-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid;
{4-[3-Isobutoxj-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-
acetic acid;
{4-[3-[2-(4-Chl )ro-plienyl)-ethoxy]-5-(4-methanesulfonyl-phenylethynyl)-phenylsulfanyl]-2-
methyl-phenoxy}-acetic acid;
{4-[3-[2-(4-Chl )ro-phenyl)-ethoxy]-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-
methyl-phenox)} -acetic acid;
{4-[3-[2-(4-Chl )ro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-
methyl-phenoxy} -acetic acid;
{4-[3-(2-Ethyl-hutoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-aceticacid;
[4-(3-Cyclopeniyloxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid;
{4-[3-(4-Fluoro phenylethynyl)-5-(4-methanesulfonyl-benzyloxy)-phenylsulfanyl]-2-methyl-
phenoxy)-acetic acid;
[4-(3-Cyclopeniylmethoxy-5-phenylethynyl-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid;
{4-[3-(2-Cyclol exyl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-2-methyl-phenoxy}-acetir
acid;
{4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid;
{4-[3-Cyclopen'yloxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid;
{4-[3-(2-Cyclol exyl-ethoxy)-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid;
{4-[3-Cyclopen!ylmethoxy-5-(3-moq)holin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic acid;
{4-[3-Cyclopen'ylmethoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-
phenoxy}-acetic;
{4-[3-Isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic
acid;
[4-(3-Isobutoxy-5-phenylethynyl-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid;
{4-[3-Isobutoxy-5-(4-raethanesulfonyl-phenylethynyl)-benzylsulfanyl]-2-methyl-phenoxyj-
acetic acid;
{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-
phenylsulfanyl] 2-methyl-phenoxy{-acetic acid;
{4-[3-(4-Methanesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-
phenylsulfanyl] -2-methyl-phenoxy }-acetic acid;
{2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-pyridin-2-yloxy)-
phenylsulfanyl] phenoxy} -acetic acid;
{2-Methyl-4-[3-(3-morpholin-4-yl-prop-l-ynyl)-5-(5-trifluoromethyl-pyridin-2-yloxy)-
phenylsulfanyl] phenoxy}-acetic acid;
{2-Methyl-4-[3 (3-morpholin-4-yl-prop-l-ynyl)-5-(3-trifluoromethyl-phenoxy)-
phenylsulfanyl] phenoxy}-acetic acid;
{4-[3-(4-Methauesulfonyl-phenylethynyl)-5-(3-trifluoromethyl-phenoxy)-phenylsulfanyl]-
methyl-phenoxy} -acetic acid; and
{2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-
phenoxy}-acetic acid,
or a pharmaceuucally acceptable salt thereof.
[00851] 35. A compound of clause 1, wherein the compound is of formula formula III:

(Formula Removed)

or a pharmaceuiically acceptable salt thereof, wherein:
R1 is CM alkyl substituted with 1-2 Rla;

with 0-2 Rlb, C3-10 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2
Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, heteroaryl substituted vith Rlb;
Rlb, at each occ irrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2-4 alkenyl substitu'ed with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3.6 cycloa'kyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc;
Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3.6 cycloalkyl substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld;
Rld, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl;
R2a is selected f-om aryl substituted with 0-2 R2b and heteroaryl substituted with 0-2 P2b;
R2b, at each occ1 irrence, is selected from OH substituted with 0-1 R2c, SH substituted with 0-1 R20, Cl, F, NH2 substituted with 0-2 R20, -CN, NO2, C1-4 alkyl substituted with 0-2 R2c, C2.4 alkenyl substitu'ed with 0-2 R20, aryl substituted with 0-2 R20, heteroaryl substituted with 0-2 R20, C3.6 cycloa'kyl substituted with 0-2 R2*, and a heterocycle substituted with 0-2 R20;
R20, at each occ'irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, C2.4 alkenyl, aryl subs:ituted with 0-2 R2d, and heteroaryl substituted with 0-2 R2d;
RM, at each occ•irrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl;
R3 is selected fr 3m Cl, F, CH3, and CH2CH3;
alternatively, R3 and R5c combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heieroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e;
R4a, at each occ-irrence, is selected from H, Cl, F, and CH3;
R4b, at each occurrence, is selected from H, Cl, F,
R40, at each occurrence, is selected from H, Cl, F, and CH3; R5a, at each occurrence, is selected from H, Cl, F, and CH3; R5b, at each occurrence, is selected from H, Cl, F, and CH3; RSc, at each occurrence, is selected from H, Cl, F, and CH3;
R5d, at each occ1 irrence, is selected from H, Cl, F, and CH3; and,
R5e, at each occurrence, is selected from H, Cl, F, and [00852] 36. A compound of clause 35, wherein: R1 is C1-4 alkyl substituted with 1-2 Rla;
Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-10 membered het-eroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-10 cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered hetero-cycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0 1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2) Ci.4 alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-64 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and 8(0)0-2;
Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-10 membered heteroaryl substituted with 0-2 R'd and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-6cyyclor.l-kyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl;
R2a is selected from aryl substituted with 0-2 R2b and 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and 8(0)0.2;
R2b, at each occurrence, is selected from OH substituted with 0-1 R2", SH substituted with 0 1 R20, Cl, F, NH2 substituted with 0-2 R2c, -CN, NO2, CM alkyl substituted with 0-2 R2', C2.4 alkenyl substituted with 0-2 R20, aryl substituted with 0-2 R20, 5-10 membered heteroaryl substituted with 0-2 R20 and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-6 cycloalkyl substituted with 0-2 R20, and a 3-6 membered heterocycle substituted with 0-2 R2c and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2;
R20, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, C2-4 al-kenyl, aryl substituted with 0-2 R2d, and 5-10 membered heteroaryl substituted with 0-2 R2d and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2;
R2d, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2-4 alkenyl;
R3 is selected from Cl, F, CH3) and CH2CH3;
alternatively, R3 and R5c combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from 0, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e;
R4a, at each occurrence, is selected from H, Cl, F, and CH3; R4b, at each occurrence, is selected from H, Cl, F, and CH3; R40, at each occurrence, is selected from H, Cl, F, and CH3;
R5a, at each occurrence, is selected from H, Cl, F, and CH3;
R5b, at each occurrence, is selected from H, Cl, F, and CH3;
R5c, at each occurrence, is selected from H, Cl, F, and CH3;
R5 , at each occurrence, is selected from H, Cl, F, and CH3; and,
R5e, at each occurrence, is selected from H, Cl, F, and CH3.
[00853] 37. A compound of clause 35, wherein the compound is of formula formula Ilia
(Formula Removed)
Ilia or a pharmaceutically acceptable salt thereof, wherein:
Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C5.6 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2 Rlb;
Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C5.6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc;
Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, d1-4 alkyl, and C2-4 alkenyl, aryl substituted with 0-2 Rld, heteroaryl substituted with 0-2 Rld, C3.6 cycloa:ky! substituted with 0-2 Rld, and a heterocycle substituted with 0-2 Rld;
R2" is selected from aryl substituted with 0-2 R2b and heteroaryl substituted with 0-2 R2b and-and,
R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, C2.4 alkenyl, aryl, heteroaryl, C5-6 cycloalkyl, and a heterocycle.
[00854] 38. A compound of clause 37 wherein:
Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-6 membered heteroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected
from O, N, and S(O)o-2, C5.6 cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered hetero-cycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms seiscted from O, N, and S(O)o-2;
Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o_2;
Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rld, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C^ cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
R2" is selected from aryl substituted with 0-2 R2b and 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2; and,
R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2) C1-4 alkyl, C2.4 alkenyl, aryl, 5-6 membered heteroaryl consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2, C5_6 cycloalkyl, and a 5-6 membered heterocycle and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2.
[00855] 39. A compound of clause 4, wherein: R1 is Ci.4 alkyl substituted with 1-2 Rla;
Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, heteroaryl substituted with 0-2 Rlb, C3-10 cycloalkyl substituted with 0-2 Rlb, and a heterocycle substituted with 0-2
Rlb;
Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, heteroaryl substituted with 0-2 Rlc, C3.6 cycloalkyl substituted with 0-2 Rlc, and a heterocycle substituted with 0-2 Rlc;
Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and C2.4 alkenyl, aryl substituted with 0-2 Rl d, heteroaryl substituted with 0-2 Rl d, C3.6 cycloalkyl substituted with 0-2 Rl d, and a heterocycle substituted with 0-2 Rl d;
Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4alkyl, and C2.^ alkenyl;
R2 is aryl substituted with 0-3 R2a or heteroaryl substituted with 0-2 R2a;
R2", at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, Cl, F, NH2 substituted with 0-2 R2b, -CN, NO2, C1-4 alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, heteroaryl substituted with 0-2 R2b, C3-6 cycloalkyl substituted with 0-2 R2b, and a heterocycle substituted with 0-2 R2b;
R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl, and, C2.4 alkenyl;
R3 is selected from Cl, F, CH3, and CH2CH3;
alternatively, R3 and R5e combine to form a 5, 6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and RSe;
R4a, at each occurrence, is selected from H, Cl, F, and CH3; R4b, at each occurrence, is selected from H, Cl, F, and CH3; R40, at each occurrence, is selected from H, Cl, F, and CH3; R5a, at each occurrence, is selected from H, Cl, F, and CH3;
R5b, at each occurrence, is selected from H, Cl, F, and CH3;
R5c, at each occurrence, is selected from H, Cl, F, and CH3; R5d, at each occurrence, is selected from H, Cl, F, and CH3; and, R5c, at each occurrence, is selected from H, Cl, F, and CH3. [00856] 40. A compound of clause 39, wherein: R1 is CM alkyl substituted with 1-2 Rla;
Rla, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-10 membered het-eroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3_io cycloalkyl substituted with 0-2 Rlb, and a 3-8 membered hetero-cycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2;
Rlb, at each occurrence, is selected from OH substituted with 0-1 Rlc, SH substituted with 0-1 Rlc, Cl, F, NH2 substituted with 0-2 Rlc, -CN, NO2, CM alkyl substituted with 0-2 Rlc, C2.4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-10 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)0-2, C3.6 cycloalkyl substituted with 0-2 Rlc, and a 3-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2-4 alkenyl, aryl substituted with 0-2 R l d, 5-10 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-6 cycloalkyl substituted with 0-2 Rl d, and a 3-6 membered heterocycle substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2;
Rld, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, CM alkyl, and C2.4 alkenyl;
R2 is aryl substituted with 0-3 R2a or 5-10 membered heteroaryl substituted with 0-2 R2a anil consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2;
R , at each occurrence, is selected from OH substituted with 0-1 R , SH substituted with 0-1 R2b, Cl, F, NH2 substituted with 0-2 R2b, -CN, NO2, C1-4 alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-10 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-4 heteroatoms selected from O, N, and S(O)o-2, C3-6 cycloalkyl substituted with 0-2 R2b, and a 3-6 membered heterocycle substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o.2;
R2b, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, N02, C1-4 alkyl, ar-d, C2_4 alkenyl;
3 is selected from Cl, F, CH3, and CH2CH3;
alternatively, R3 and R5e combine to form a 5,6, or 7 membered ring consisting of carbon atoms and 0-2 heteroatoms selected from O, N, and S(O)o-2 and there are 0-2 ring double bonds in the bridging portion formed by R3 and R5e;
R4a, at each occurrence, is selected from H, Cl, F, and CH3; R4b, at each occurrence, is selected from H, Cl, F, and CHs; R4c, at each occurrence, is selected from H, Cl, F, and CH3; R5a, at each occurrence, is selected from H, Cl, F, and CH3;
R5b, at each occurrence, is selected from H, Cl, F, and CH3;
R5c, at each occurrence, is selected from H, Cl, F, and CH3;
R5d, at each occurrence, is selected from H, Cl, F, and CH3; and,
R5e, at each occurrence, is selected from H, Cl, F, and CH3.
[00857] 41. A compound of clause 40, wherein the compound is of formula Ib:
(Formula Removed)

or a pharmaceutically acceptable salt thereof, wherein:
la, at each occurrence, is selected from aryl substituted with 0-2 Rlb, 5-6 membered het-eroaryl substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2, C5-6cycloalkyl substituted with 0-2 Rlb, and a 5-6 membered hetero-cycle substituted with 0-2 Rlb and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2;
Rlb, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, C1-4 alkyl substituted with 0-2 Rlc, C2-4 alkenyl substituted with 0-2 Rlc, aryl substituted with 0-2 Rlc, 5-6 membered heteroaryl substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 Rlc, and a 5-6 membered heterocycle substituted with 0-2 Rlc and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0.2;
Rlc, at each occurrence, is selected from OH, SH, Cl, F, NH2, -CN, NO2, Ci.4 alkyl, and C2-4 alkenyl, aryl substituted with 0-2 Rl d, 5-6 membered heteroaryl substituted with 0-2 Rld and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)o-2, C3-6 cycloalkyl substituted with 0-2 Rld, and a 3-6 membered heterocycle substituted with 0-2 Rl d and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2;
R2 is aryl substituted with 0-2 R2a or 5-6 membered heteroaryl substituted with 0-2 R2a and consisting of carbon atoms and 1-2 heteroatoms selected from O, N, and S(O)0-2; and.
R2a, at each occurrence, is selected from OH substituted with 0-1 R2b, SH substituted with 0-1 R2b, Cl, F, NH2 substituted with 0-2 R2b, -CN, NO2, C1-4 alkyl substituted with 0-2 R2b, C2.6 alkenyl substituted with 0-2 R2b, aryl substituted with 0-2 R2b, 5-6 membered heteroaryl substituted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from 0, N, and S(O)o-2, C5-6 cycloalkyl substituted with 0-2 R2b, and a 5-6 membered heterocycle substi-
tuted with 0-2 R2b and consisting of carbon atoms and 1-2 heteroatoms selected from 0, N, and S(O)0-2.
[00858] 42. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of one of clauses 1 -41 or a pharmaceutically acceptable salt.
[00859] 43. A pharmaceutical composition for treating type 2 diabetes, comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically
acceptable carriers or excipients,
[00860] 44. A pharmaceutical composition for treating dyslipidemia, syndrome X (including the metabolic syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity), cardiovascular diseases (e.g., atherosclerosis and related diseases, including mortality reduction, coronary artery diseases, coronary heart diseases, heart attack, myocardial ischemia, myocardial infarct, coronary infarct, transient ischemic attack (TIA), and stroke), hyperglycemia, hyperlipidemia, hypercholesterolemia, and hyperinsulinemia, comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients.
[00861] 45. A pharmaceutical composition for treating dyslipidemia comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients.
[00862] 46. A pharmaceutical composition for treating syndrome X (including the p syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity), comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients.
[00863] 47. A pharmaceutical composition for treating cardiovascular diseases (e.g., atherosclerosis and related diseases, including mortality reduction, coronary artery diseases,
coronary heart diseases, heart attack, myocardial ischemia, myocardial infarct, coronary infarct, transient ischemic attack (TIA), and stroke), comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients
[00864] 48. A pharmaceutical composition for treating hyperglycemia comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients.
[00865] 49. A pharmaceutical composition for treating hyperlipidemia comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients.
[00866] 50. A pharmaceutical composition for treating hypercholesterolemia comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients
[00867] 51. A pharmaceutical composition for treating hyperinsulinemia comprising a compound according to any of the clauses 1-41 together with one or more pharmaceutically acceptable carriers or excipients
[00868] 52. A pharmaceutical composition according to any one of the clauses 42-51 for oral, nasal, transdermal, pulmonal or parenteral administration.
[00869] 53. Use of a compound according to any one of the clauses 1-41 as a pharmaceutical composition.
[00870] 54. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating type 2 diabetes.
[00871] 55. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating dyslipidernia, syndrome X (including the metabolic syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity), cardiovascular diseases (e.g., atherosclerosis and related diseases, including mortality reduction, coronary artery diseases, coronary heart diseases, heart attack, myocardial ischemia, myocardial infarct, coronary infarct, transient ischemic attack (TIA), and stroke), hyperglycemia, hyperlipidemia, hypercholesterolemia, and hyperinsulinemia.
[00872] 56. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating dyslipidernia.
[00873] 57. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating syndrome X (including the metabolic syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyce .iaemia, and obesity).
[00874] 58. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating cardiovascular diseases (e.g., atherosclerosis and related diseases, including mortality reduction, coronary artery diseases, coronary heart diseases, heart attack, myocardial ischemia, myocardial infarct, coronary infarct, transient ischemic attack (TIA), and stroke).
[00875] 59. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating hyperglycemia.
[00876] 60. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating hyperlipidemia.
[00877] 61. Use of a compound according to any one of the clauses 1-41 for the preparation
of a pharmaceutical composition for treating hypercholesterolemia.
[00878] 62. Use of a compound according to any one of the clauses 1-41 for the preparation of a pharmaceutical composition for treating hyperinsulinemia
[00879] 63. A method of treating type 2 diabetes, comprising: administering a therapeutically effective amount of a compound of one of clauses 1-41 or a pharmaceutically acceptable salt.
[00880] 64. A method of treating a disease, comprising: administering a therapeutically effective amount of a compound of one of clauses 1-41 or a pharmaceutically acceptable salt, wherein the disease is selected from dyslipidemia, syndrome X (including the metabolic syndrome, e.g., hypertension, impaired glucose tolerance (IGT), insulin resistance, hypertrigyceridaemia, and obesity), cardiovascular diseases (e.g., atherosclerosis and related diseases, including mortality reduction, coronary artery diseases, coronary heart diseases, heart attack, myocardial ischemia, myocardial infarct, coronary infarct, transient ischemic attack (TIA), and stroke), hyperglycemia, hyperlipidemia, hypercholesterolemia, and hyperinsulinemia.
[00881] 65. A compound of one of clauses 1-41 or a pharmaceutically acceptable salt thereof, wherein the compound has a solubility in water of at least 0.1 mg/L as determined at 25°C and pH7.0.
[00882] 66. The compound of clause 65, wherein the compound has a solubility in water of at least 0.5 mg/L.
[00883] 67. The compound of clause 66, wherein the compound has a solubility in water of at least 1 mg/L.
[00884] 68. The compound of clause 67, wherein the compound has a solubility in water of at least 2 mg/L.
[00885] 69. The compound of clause 68, wherein the compound has a solubility in water of at least 10 mg/L.
[00886] 70. The compound of clause 69, wherein the compound has a solubility in water of at least 50 mg/L.
[00887] 71. The compound of clause 70, wherein the compound has a solubility in water of at least 200 mg/L.
[00888] 72. A compound of one of clauses 1-41 or a pharmaceutically acceptable salt thereof, wherein the compound has an ICso value of less than 1/tm as determined by the PPAR transient transactivation assay.
[00889] 73. The compound of clause 72, wherein the compound has an IC50 value of less than 500 nm.
[00890] 74. The compound of clause 73, wherein the compound has an ICso value of less than 100 nm.
[00891] 75. The compound of clause 74, wherein the compound has an ICso value of less than 50 nm.
[00892] 76. The compound of clause 75, wherein the compound has an ICso value of less than 25 nm.
[00893] 77. The compound of clause 76, wherein the compound has an ICso value of less than 10 nm.
[00894] 78. The compound of clause 77, wherein the compound has an ICso value of less than 5 nm.
[00895] 79. A compound of one of clauses 1-41, wherein the compound has a molecular weight of less than 750 g/mol.
[00896] 80. The compound of clause 79, wherein the compound has a molecular weight of less than 600 g/mol.
[00897] 81. The compound of clause 80, wherein the compound has a molecular weight of less than 550 g/mol.
[00898] 82. The compound of clause 81, wherein the compound has a molecular weight of less than 500 g/mol.
[00899] 83. The compound of clause 82, wherein the compound has a molecular weight of less than 400 g/mol.
[00900] 84. A compound of one of clauses 1-41, wherein the compound is ionized at a pH of from 5.5-9.
[00901] 85. The compound of clause 84, wherein the compound has only one ionized car-boxylic acid group at a pH of from 6-8.
[00902] 86. The compound of clause 85, wherein the compound has only one ionized car-boxylic acid group at a pH of from 6.5-7.5.
[00903] 87. The compound of clause 86, wherein the compound has only one ionized car-boxylic acid group at pH 7.4.
[00904] 88. A compound of one of clauses 1-41, wherein the compound is a z witter-ion with one ionized amine group and one ionized carboxylic acid group at a pH of from 5.5-9.
[00905] 89. The compound of clause 88, wherein the compound is a zwitter-ion with one ionized amine group and one ionized carboxylic acid group at a pH of from 6-8.
[00906] 90. The compound of clause 89, wherein the compound is a zwitter-ion with one ionized amine group and one ionized carboxylic acid group at a pH of from 6.5-7.5
[00907] 91. The compound of clause 90, wherein the compound is a zwitter-ion with one ionized amine group and one ionized carboxylic acid group at pH 7.4.

We Claim:
1. A compound of formula IIb or a pharmaceutically acceptable salt thereof:
(Formula Removed)
wherein:
X is S or SCH2;
X1 is O;
R1 is C1-6 alkyl;
R2 is -OC-R2a;
R2a is C1-4 alkyl substituted with morpholinyl; and
R3 is chloro or methyl.
2. The compound as claimed in claim 1, wherein X is SCH2.
3. The compound as claimed in claim 1, wherein X is S.
4. The compound as claimed in claim 1 wherein the compound is {4-[3-isobutoxy-5-(3-morpholin-4-yl-prop-l-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid or a pharmaceutically acceptable salt thereof.
5. A compound as claimed in claim 1, wherein the compound is {4-[3-isobutoxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methyl-phenoxy}-acetic acid or a pharmaceutically acceptable salt thereof.

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Patent Number

277165

Indian Patent Application Number

9775/DELNP/2007

PG Journal Number

48/2016

Publication Date

18-Nov-2016

Grant Date

11-Nov-2016

Date of Filing

17-Dec-2007

Name of Patentee

VTVX HOLDINGS II LLC

Applicant Address

4170 MENDENHALL OAKS PKWY, HIGH POINT,NC-27265

Inventors:

#	Inventor's Name	Inventor's Address
1	EBDRUP SOREN	NYMARKSVEJ 11, DK-4000 ROSKILDE DENMARK.

PCT International Classification Number

C07D 213/64

PCT International Application Number

PCT/EP2006/063703

PCT International Filing date

2006-06-29

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	05105937.6	2005-06-30	EUROPEAN UNION
2	05112755.3	2005-12-22	EUROPEAN UNION