FIELD OF THE INVENTION Compounds, compositions and methods are provided for modulating the activity of the estrogen-related receptors and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder related to the activity of the estrogen-related receptor.

BACKGROUND OF THE INVENTION Nuclear receptors are a superfamily of transcription factors that regulate a wide variety of cellular processes. Nuclear receptors share extensive homology at the amino acid and nucleotide sequence levels, the most highly conserved region being the DNA binding domain (DBD) which contains two zinc finger motifs and the next most highly conserved region being the ligand binding domain (LBD) which is responsible for ligand recognition, dimerization, coactivator interaction and ligand- dependent transcriptional activation. In general, these receptor proteins interact with recognition motifs in the promoter region of their target genes called the response element and modulate gene expression in response to ligands. Additionally, some orphan nuclear receptors may regulate regulate target gene expression in the absence of a ligand.

Classic members of the nuclear receptor superfamily, such as the glucocorticoid receptor, mineralocorticoid receptor, estrogen receptor and the thyroid hormone receptor are receptors that were identified as a consequence of the initial discovery of their hormones. Orphan nuclear receptors, on the other hand, are those receptors that were identified by their structural similarities to the classic nuclear receptors, and which were not associated with a putative ligand at the time of their discovery. Examples of nuclear receptors that are referred to as"orphans"include the farnesoid X receptor (FXR (NR1 H4)), liver X receptor (LXRa (NR1 H2) and LXRß (NR1 H3)), estrogen related receptor (ERRa, ß and y or NR3B1, NR3B2 and NR3B3, respectively).

ERR The estrogen related receptor subfamily, currently comprised of three members, ERRa, ERRAI and ERRy are close relatives of the estrogen receptor (ER), all sharing a high degree of homology in their DNA binding domains and ligand binding domains. It is now known that the ER and ERR subfamilies share some common promoter binding sites, a subset of common target genes, as well as some common coregulator proteins and synthetic ligands.

ERRs bind to DNA as monomers or dimers to a variety of recognition motifs including the consensus ERR response element (ERRE) as well as to other elements including those recognized by ER (Sladek, R. et. al., Mol. Cell. Biol.

17,5400-5409, 1997; Johnston, S. D. et. al., Mol. Endocrinol. 11,342-352, 1997; Yang, N. et. al., J. Biol. Chem. 271,5975-5804, 1996). Transcriptional crosstalk between the ER and ERR subfamilies therefore occurs at the level of competition for binding sites as well as for coregulator proteins. Modulators of the ERR subfamily are therefore expected to act either by directly modulating the transcriptional effect of ERR or by indirect effects on ER signaling pathways, thereby having utility for both ERR and ER related diseases and disorders.

Transcriptional target genes common to both the ER and ERR subfamilies include those estrogen responsive genes such as the estrogen-inducible breast cancer marker gene, pS2 (Lu, D. , et al., 2001, Cancer Res. 61: 6755-6761), aromatase cytochrome p450, a key enzyme involved in estrogen biosynthesis that is up-regulated in many estrogen-responsive breast cancers (Yang, N. , et al. 1998, Cancer Research 58: 5695-5700), lactoferrin, an immune response modulator (Yang, N. , et al., 1996, J Biol Chem. 271: 5795-5804; Zhang, Z. and Teng, C. T. , 2000, J Biol Chem. 275: 20837-20846) and osteopontin, an extracellular bone matrix molecule secreted by osteoblasts which is believed to play an important role in bone formation and remodeling (Vanacker J. M. et al., 1998, Cell Growth Differ 9: 1007-1014).

Although it has been determined that 17-ß estradiol and other natural ligands for ER are not ERR ligands, two synthetic ER ligands used clinically for the treatment of breast cancer, the synthetic estrogen diethylstilbestrol (DES) and 4- hydroxy tamoxifen (OHT), which belongs to a class of drugs called selective estrogen receptor modulators (SERMs), have been discovered to the ERR subfamily with high affinity. DES acts as an inverse agonist to all three isoforms of ERR by interfering with coactivator interactions while OHT acts as an inverse agonist to ERR (3 and ERRy but

not ERRa (Tremblay, G. B. et al, 2001, Genes Dev. 15: 833-838; Trembla, G. B. et al, 2001, Endocrinology 142 (10): 4572-4575; Lu, D. et al., 2001, Cancer Res. 61: 6755- 6761; Coward, P. et. al., 2001, Proc. Natl. Acad. Sci. U. S. A. 98: 8880-8884). This suggests that the ERR subfamily presents a new target for the development of new classes of drugs that are capable of selectively modulating a subset of estrogen's actions, without creating the same side effect profile of classical estrogen receptor modulators. The fact that well-established ER ligands such as DES and OHT are ERR ligands also suggests that classic ER modulating drugs may be exerting their effects at least in part through an ERR regulated pathway and that the modulation of ERR activity presents an alternative pathway for the treatment of diseases that were previously considered to be estrogen mediated.

In one embodiment, ERR modulators, including ERRa modulators, are expected to have therapeutic use in the treatment, prevention and diagnosis cancer, including breast cancer (See U. S. Patent Application No. 2003/0152959). ERRa modulators may also have therapeutic value as a general anti-cancer agent by inhibiting cell growth or tumor angiogenesis. ERRa modulators are also expected to have therapeutic value in the prevention and treatment of diseases of the bone and cartilage such as rheumatoid arthritis and osteoporosis (See U. S. Patent Application No. 2002/0187953). The functional interaction between ER and the proinflammatory transcription factor NF-kB suggests that ERR modulators may also play a role in preventing inflammatory diseases caused by the release of proinflammatory cytokines, such as rheumatoid arthritis or atherosclerosis. Because ERRs are highly expressed in the tissues of the central nervous system which are also estrogen target tissues, ERRa modulators are also contemplated for the prevention and treatment of psychoses and neurodegenerative or stress-related disorders such as Parkinson's disease, Alzheimer's disease, depression and anxiety.

ERRa has more recently been discovered to act as a metabolic regulator. ERRa regulates the expression of medium-chain acyl CoA dehydrogenase (MCAD), a key enzyme in fatty acid P oxidation (Vega, R. B. et al., 1997, J Biol Chem 272: 31693-31699; Sladek, R. et. al., 1997, Mol. Cell. Biol. 17: 5400-5409). It has also been discovered that the transcriptional coactivator PPARy coactivator-1a (PGC-1a), which is believed to be a broad regulator of cellular energy metabolism, binds to ERRa and enhances the transactivation of the MCAD gene (Huss et al., 2002, J Biol. Chem 277: 40265-40274). Since PGC-1a plays a key role in the upregulation of oxidative respiration and because there appears to be a correlation between reduced oxidative

respiration and insulin resistance and/or type 2 diabetes mellitus (See Mootha et al., 2003, Nat Gen 34: 267-273; Patti et al., 2003, Proc. Natl. Acad. Sci. U. S. A. 100: 8466- 8471), ERR modulators are expected to have therapeutic use in the treatment and prevention of diseases related to insulin resistance such as type 2 diabetes mellitus and the metabolic syndrome.

A study of the ERRa knockout mice model also suggests that ERRa plays a role as a key regulator of fat metabolism, including fatty acid synthesis, fatty acid oxidation, intestinal fat transfer and fat deposition in hepatic and adipocytic tissues. The knockout mice were found to have a lean phenotype with decreased white adipose tissue deposits and showing resistance to high-fat induced obesity. (Luo J. et al., 2003, Mol. Cell. Biol., 23: 7947-7956; see also, US Patent Application No.

2003/0028910). Microarray analysis conducted on adipose tissues from the knockout mice showed altered regulation of several enzymes involved in lipid metabolism, including MCAD and fatty acid synthase. ERRa modulators are therefore contemplated for use in the treatment and prevention of diseases relating to fat metabolism, including hyperlipidemia, obesity and the metabolic syndrome.

Considering the wide range of activity of the nuclear hormone receptor ERRa, the compounds described herein which are capable of modulating ERRa activity, are useful for treating a range of disease states including cancer, diabetes, obesity, hyperlipidemia, arthritis, atherosclerosis, osteoporosis, anxiety, depression, Parkinson's disease and Alzheimer's disease.

SUMMARY OF THE INVENTION Compounds for use in compositions and methods for modulating the activity of nuclear receptors are provided. In particular, compounds for use in compositions and methods for modulating the estrogen related receptors (ERR) are provided. In one embodiment, the compounds provided herein are ERR modulators.

In another embodiment, the compounds provided herein are agonists, partial agonists, antagonists or inverse agonists of ERR or ERRa. It is to be understood that partial agonists that exhibit low efficacy are, in certain embodiments, antagonists.

In certain embodiments, the compounds of the invention are compounds of formula (I) :

or a pharmaceutical acceptable derivative thereof, wherein : bond a is a single bond or a double bond R'is selected from the group consisting of hydrogen, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl,-OR'0,-N (R") (R'2),-N=C (R4) (R5),-NR'9NR"R'2,-NR'9NR'9C (J) R'0, -NR19NR19C (J) oR'0,-NR'9NR'9C (J) NR"R'2,-NR'9NR'9C (J) SR10, -SR10, -C (J) R'°, -C(J)OR10, -C(J)N(R11)(R12), -C(J)SR10, -OC (J) R'°,-NR'9C (J) R, 0, -NR19C(J)N(R11)(R12), -Si(R13) 3, -S (O) tR'3 and-N (R'9) S (0) 2R13 ; R2 is selected from the group consisting of hydrogen, halo, cyano, nitro, azido, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl,-OR20,-N (Rz') (R22),-SR2°,-OC (J) R20 OC (J) OR20, -OC (J) N (R21)(R22), -OC (J) SR20, -NR19C (J) R20, -NR19C (J) OR20, -NR19C (J) N (R2') (R22),-NR'9C (J) SR20, <BR> <BR> <BR> and-S -C(J)OR20, -C(J)N(R21)(R22), -C(J)SR20, -Si(R23)3, -S(O)tR23, -N(R20)S(O)2R23<BR> -C(J)R20, -C(J)OR20, -C(J)N(R21)(R22), -C(J)SR20, -Si(R23)3, -S(O)tR23, -N(R20)S(O)2R and -S(O)2N(R21)(R22); R3 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally

substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl ; R4 and R5, together with the carbon atom to which they are attached, form an optionally substituted heterocyclyl ; each R9 is alkylene ; R'° is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl,-R9-OR'S,-R9-N (R'6) (R"),-R9-SR'5,-R9-C (J) R'5,-R9-C (J) OR'5, -R9-C(J)N(R16)(R17), -R9-C(J)SR15, -R9-OC(J)R15, -R9-OC(J)OR15, -R9-OC (J) N (R16)(R17), -R9-OC (J) SR'5,-R9-OC (J) R'5,-R9-NR'4C (J) OR'S,-R9-NR'4C (J) N (R16)(R17), -R9-NR14C(J)SR15, -R9-S(O)tR18, -R9-N(R15) S (O) 2R'8 and-R9-S (O) 2N (R'6) (R") ; R11 and R12 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl,-R9-OR'S,-R9-N (R'6) (R"),-R9-SR'5,-R9-C (J) R'5, -R9-C (J) OR'5,-R9-C (J) N (R16)(R17), -R9-C (J) SR'5,-R9-OC (J) R'5,-R9-oC (J) OR'5, -R9-OC (J) N (R'6) (R"),-R9-OC (J) SR'5,-R9-oC (J) R15, -R9-NR14C(J)OR15, -R9-NR14C(J) N (R'6) 6)(R17), -R9-NR14C(J)SR15, R9-S(O)tR18, -R9-N(R15)S(O)2R18 and -R9-S(O)2N(R16)(R17); or R"and R'2, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl, or optionally substituted heteroaryl ; each R'3, R'8 and R23 are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted

heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl ; each R'4, R'5, R'9 and R20 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl ; each R16 and R'7 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl ; or R16 and R'7 together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ; each R2'and R22 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl ; or R2'and R22 together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ; R30, R3', R32, R33 and R34 are each independently selected from the group consisting of hydrogen, halo, cyano, nitro, azido, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally

substituted heteroaryl, optionally substituted heteroaralkyl,-OR4°,-N (R4') (Raz),-SRao, -C(J)R40, -C(J)OR40, -C(J)N(R41)(R42), -C(J)SR40, -OC(J)R40, -OC (J) OR4°, -OC(J)N(R41)(R42), -OC(J)SR40, -NR49C (J) R40, -NR49C(J)OR40, -N R49C(J)N(R41)(R42), -NR49C(J)SR40, -Si(R43)3, -S(O)tR43,-N(R40)S(O)2R43, -S(O)2N(R41)(R42), -P(O)u(R44)2, - OP(O)u(R44)2, -R9-OR40, -R9-N(R41)(R42), -R9-SR40, -R9-C(J)R40, -R9-C(J)OR40, -R9-C(J)N(R41)(R42), -R9-C(J)SR40, -R9-OC(J)R40, -R9-OC (J) OR40,-R9-OC (J) N (R41)(R42), - R9-OC (J) SR40, -R9-NR49C(J)R40, -R9-NR49C(J)OR40, -R9-N R49C(J) N (R41)(R42), -R9-NR49C(J)SR40, -R9-S(O)tR43, -R9-N(R40)S(O)2R43 and -R9-S(O) 2N (R41)(R42); or a pair of adjacent substituents selected from the following : R30 and R3', R3'and R32, R32 and R33 and R33 and R34, together with the carbon atoms to which they are attached, form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl ; while the remaining unpaired substituents R30, R31, R32, R33 and R34 are as described above; each R40 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl,-R9-oR50,-R9-N (R5') (R52),-R9-SR50,-R9-C (J) R50, -R9-C (J) oR50-R9-C (J) N (R5') (R -R9-C(J)SR50, -R9-OC(J)R50, -R9-OC (J) OR50, -R9-OC(J)N(R51)(R52), -R9-OC(J)SR50, -R9-NR49C(J)R50, -R9-NR49C(J)OR50, -R9-NR49C(J) N (R51)(R52), -R9-NR49C(J)SR50, -R9-Si(R53)3, -R9-S(O)tR53, -R9-N (R45) S (O) 2R53 and-R9-S (O) 2N (R5') (R52) ; R4'and R42 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl,-R9-oR50,-R9-N (R5') (R52),-R9-SR50,-R9-C (J) R50, -R9-C (J) OR50,-R9-C N(R51)(R52), -R9-C(J)SR50, -R9-OC(J)R50, -R9-OC (J) OR50, -R9-OC (J) N (R5') (R -R9-OC(J)SR50, -R9-NR49C(J)R50, -R9-NR49C(J)OR50, -R9-NR49C(J)N(R51)(R52), -R9-NR49C(J)SR50, -R9-Si(R53)3 -R9-S(O)tR53, -R9-N(R45) S (0) 2R53 and-R9-S (O) 2N (R5') (R5z) ;

or R4'and R42, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ; R43 and R53 are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl ; each R44 is independently selected from the group consisting of substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl, hydroxy, optionally substituted alkoxy and optionally substituted amino; each R49 and R50 are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl ; R5'and R52 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl ; or R5'and R52, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl or optionally substituted heteroaryl ; each J is independently O, =NR60 or S;

each R50 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl and -OR61; each R6'is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted haloalkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaralkyl ; t is 1 to 2; and u is 0 to 1 ; as a single isomer or as a mixture of isomers, including steroisomers, regioisomers and tautomers; with the provisos that: when R'is methoxy, substituted or unsubstituted phenyl,-NHC (O) CH3, -NHC (J) NH2,-NHNHC6H5,-NHNHC (O) CH3 or-NR"R'2 ; R2 is cyano; R3 is hydrogen; R"is hydrogen, substituted or unsubstituted phenyl, unsubstituted naphthyl, hydroxy ethyl, acetic acid ethyl ester, dimethyl-substituted benzothiazole, methoxy-substituted benzothiazole, thiol substituted [1,3, 4] thiadiazole or [1,2, 4] thiadiazole optionally substituted with phenyl ; R12 is hydrogen; or R"and R12 together form quinolinyl ; J is O or S; one of R30 or R34 is H or Cl ; one of R 31 or R33 is H, Br, N02, Cl or CH3 ; and R32 is -N(R41)(R42) ; then R4'and R42 cannot be methyl, cyanoethyl, chloroethyl, unsubstituted benzyl, optionally substituted 4-ethoxy phenyl, ethanoic acid or propionic acid; and when R'is-OR'°,-OCH=CHR'°,-OR9CH=CHR'°,-OR90R'S or -oR9SR'5 ; R9is alkylene ; R10 and R'5 are aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl ; R2 is cyano; R 3 is hydrogen; and R32 is hydroxy, alkoxy,-OC (O) OR40 or -OC(O)NR41R42 ; and one of R 31 and R 33 is hydroxy, alkoxy, - OC (O) OR4° or-OC (O) NR4'R42 ; then the other of R3'and R33 cannot be hydrogen,

hydroxy, alkoxy,-OC (O) OR or-OC (O) NR'R, wherein R is hydrogen, alkyl, aryl or aralkyl, R4'is alkyl and R42 is hydrogen or alkyl ; and when R'is-OR'O,-OCH=CHR'O,-OR9CH=CHR'O,-OR90R 15 or -oR9SR15 ; R9 is alkylen ; Rlo and R'5 are aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl ; R2 is cyano and R3 is hydrogen; then the pair of adjacent substituents R3'and R32 or R32 and R33 cannot together form methylene dioxy.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

"Alkyl"refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1, 1-dimethylethyl (t-butyl), and the like.

"Alkenyl"refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a double bond, e. g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1, 4-dienyl, and the like.

"Alkynyl"refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms, and which is attached to the rest of the molecule by a single bond or a triple bond, e. g., ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-3-ynyl and the like.

"Alkylene"and"alkylene chain"refer to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having from one to eight carbon atoms, e. g., methylene, ethylene,

propylene, n-butylen and the like. The alkylen chain may be attached to the rest of the molecule through any two carbons within the chain.

"Alkenylene"or"alkenylene chain"refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to eight carbon atoms, wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule, e. g., ethenylene, prop-1-enylene, but-2-enylene and the like.

The alkenylene chain may be attached to the rest of the molecule through any two carbons within the chain.

"Alkoxy"refers to the radical having the formula-OR wherein R is alkyl or haloalkyl. An"optionally substituted alkoxy"refers to the radical having the formula- OR wherein R is an optionally substituted alkyl as defined herein.

"Alkynylene"or"alkynylene chain"refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to eight carbon atoms, wherein the unsaturation is present only as triple bonds and wherein a triple bond can exist between the first carbon of the chain and the rest of the molecule, e. g., ethynylene, prop-1-ynylene, but-2-ynylene, pent-1-ynylene, pent-3-ynylene and the like. The alkynylene chain may be attached to the rest of the molecule through any two carbons within the chain.

As used herein, "amidino"refers to a radical having the formula - C (=NR) N (R') R" where R, R'and R"are each independently hydrogen or alkyl.

"Amino"refers to a radical having the formula-NR'R"wherein R'and R" are each independently hydrogen, alkyl or haloalkyl. An"optionally substituted amino" refers to a radical having the formula-NR'R"wherein one or both of R'and R"are optionally substituted alkyl as defined herein.

"Aryl"refers to a radical of carbocylic ring system wherein at least one of the rings is aromatic. The aryl may be fully aromatic, examples of which are phenyl, naphthyl, anthracenyl, acenaphthylenyl, azulenyl, fluorenyl, indenyl and pyrenyl. The aryl may also contain an aromatic ring in combination with a non-aromatic ring, examples of which are acenaphene, indene, and fluoren.

"Aralkyl"refers to a radical of the formula-RaRb where Ra is an alkyl radical as defined above, substituted by Rb, an aryl radical, as defined above, e. g., benzyl. Both the alkyl and aryl radicals may be optionally substituted as defined herein.

"Aralkoxy"refers to a radical of the formula-ORaRb where-RaRb is an aralkyl radical as defined above. Both the alkyl and aryl radicals may be optionally substituted as defined herein.

"Atherosclerosis"refers to process whereby atherosclerotic plaques form within the inner lining of the artery wall leading to atherosclerotic cardiovascular diseases. Atherosclerotic cardiovascular diseases can be recognized and understood by physicians practicing in the relevant fields of medicine, and include without limitation, restenosis, coronary heart disease (also known as coronary artery heart disease or ischemic heart disease), cerebrovascular disease including ischemic stroke, multi-infarct dementia, and peripheral vessel disease, including intermittent claudication, and erectile dysfunction.

"Cycloalkyl"refers to a stable monovalent monocyclic or bicyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from three to ten carbon atoms, and which is saturated and attached to the rest of the molecule by a single bond, e. g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norbornane, norbornene, adamantyl, bicyclo [2.2. 2] octane and the like.

"Cycloalkylalkyl"refers to a radical of the formula-RaRd where Ra is an alkyl radical as defined above and Rd is a cycloalkyl radical as defined above. The alkyl radical and the cylcoalkyl radical may be optionally substituted as defined herein.

"Dyslipidemia"refers to abnormal levels of lipoproteins in blood plasma including both depressed and/or elevated levels of lipoproteins (e. g., elevated levels of Low Density Lipoprotein, (LDL), Very Low Density Lipoprotein (VLDL) and depressed levels of High Density Lipoprotein (HDL).

"EC50"refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.

"ERRa-related disease, condition or disorder"and the like refers to a condition in which ERRa activity is implicated in the disease, condition or disorder, or in which the modulation of ERRa activity is useful or effective in the treatment of the disease, condition or disorder. In some instances, inappropriate ERRa activity may be only one of multiple underlying causes of the disease, condition or disorder, for example, when ER activity is also implicated in the disease, condition or disorder.

ERR related diseases, conditions or disorders, or more particularly, ERRa related diseases, conditions or disorders include (a) metabolic disorders such as

hyperglycemia, insulin insensitivity, diabetes, obesity, hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, hypertension, hyperinsulinemia, hyperuricemia, or a combination thereof to make up the disease state known as the metabolic syndrome (also called"Syndrome X"), (b) diseases, conditions or disorders relating to proliferative cell activity such as cancer, including breast cancer, (c) diseases, conditions or disorders relating to the bone or cartilage, including osteoporosis, osteoarthritis and rheumatoid arthritis, (d) diseases, conditions or disorders relating to the inflammatory response, including rheumatoid arthritis and atherosclerosis, and (e) pyschoses and neurodegenerative or stress- related disorders including Parkinson's disease, Alzheimer's disease, depression, anxiety and chemical dependency.

"ERR modulator"or"a compound capable of modulating ERR activity" refer to those compounds which modulate the activity of nuclear receptors of the ERR subfamily, in the manner of an agonist, partial agonist, inverse agonist or antagonist.

As used herein, "ERR a"refers to all mammalian forms of such receptor including, for example, alternative splice isoforms and naturally occurring isoforms.

Representative ERRa species include, without limitation the rat (Genbank Accession XM215174), mouse (Genbank Accession NM007953), and human (GenBank Accession NM_004451, XM_048286) forms of the receptor.

As used herein,"ERR (3"refers to all mammalian forms of such receptor including, for example, alternative splice isoforms and naturally occurring isoforms.

Representative ERR (3 species include, without limitation the rat (GenBank Accession NM_011934), mouse (Genbank Accession NM_011934), and human (GenBank Accession NM_00452) forms of the receptor.

As used herein,"ERR y"refers to all mammalian forms of such receptor including, for example, alternative splice isoforms and naturally occurring isoforms.

Representative ERR y species include, without limitation the rat (GenBank Accession XM341170), mouse (Genbank Accession NM 011935), and human (GenBank Accession NM_001438) forms of the receptor.

As used herein"ERR", "ERRs"or"ERR subfamily"refers to all species of ERRa, ERR (3 and ERRy.

As used herein, "guanidino"refers to a radical having the formula - N (R) C (=NR') NR"R"'wherein R, R', R"and R"'are each independently hydrogen or alkyl.

"Halo","halogen"or"halide"refers to F, Cl, Br or 1.

"Haloalkyl"refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl and 1-chloro-2-fluoroethyl.

"Haloalkenyl"refers to an alkenyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, 1-chloro-2-fluoroethenyl.

"Heterocyclyl"refers to a stable 3-to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heterocyclic ring system radical may be a monocyclic, bicyclic or tricyclic ring or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen or sulfur atoms in the heterocyclic ring system radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated or aromatic. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic radicals include, but are not limited to: acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzisoxazinyl, benzo [4, 6] imidazo [1,2-a] pyridinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzofuranyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl, <BR> <BR> <BR> <BR> <BR> benzothiazolyl, ß-carbolinyl, carbazolyl, chromanyl, chromonyl, cinnolinyl, coumarinyl,<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> decahydroisoquinolinyl, dibenzofuranyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydropyranyl, dioxolanyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1, 4-dithianyl, furanonyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazopyridinyl, imidazothiazolyl, indazolyl, indolinyl, indolizinyl, indolyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isobenzothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroindolyl, octahydroisoindolyl, oxadiazolyl, oxazolidinonyl, oxazolidinyl, oxazolopyridinyl, oxazolyl, oxiranyl, perimidinyl, phenanthridinyl, phenathrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,

quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuryl, tetrahydrofuranyl, tetrahydroisoquinolinyt, tetrahydropyranyl, tetrahydrothienyl, tetrazolyl, thiadiazolopyrimidinyl, thiadiazolyl, thiamorpholinyl, thiazolidinyl, thiazolyl, thiophenyl, triazinyl, triazolyl and 1,3, 5-trithianyl.

"Heteroaralkyl"refers to a radical of the formula-RaRf where Ra is an alkyl radical as defined above and Rf is a heteroaryl radical as defined herein. The alkyl radical and the heteroaryl radical may be optionally substituted as defined herein.

"Heteroaralkoxy"refers to a radical of the formula-ORaRfwhere-RaRfis a heteroaralkyl radical as defined above. The alkyl radical and the heteroaryl radical may be optionally substituted as defined herein.

"Heteroaryl"refers to a heterocyclyl radical as defined above which is aromatic. The heteroaryl radical may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.

Examples of such heteroaryl radicals include, but are not limited to: acridinyl, benzimidazolyl, benzindolyl, benzisoxazinyl, benzo [4,6] imidazo [1, 2-a] pyridinyl, benzofuranyl, benzonaphthofuranyl, <BR> <BR> <BR> benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl,<BR> <BR> <BR> <BR> <BR> benzoxazinyl, benzoxazolyl, benzothiazolyl, ß-carbolinyl, carbazolyl, cinnolinyl, dibenzofuranyl, furanyl, imidazolyl, imidazopyridinyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isobenzothienyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, naphthyridinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxazolopyridinyl, oxazolyl, oxiranyl, perimidinyl, phenanthridinyl, phenathrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thiophenyl, triazinyl and triazolyl.

"Heterocyclylalkyl"refers to a radical of the formula-RaRe wherein Ra is an alkyl radical as defined above and Re is a heterocyclyl radical as defined herein.

The alkyl radical and the heterocyclyl radical may be optionally substituted as defined herein.

"Heterocyclylalkoxy"refers to a radical of the formula-ORaRewherein -RaRe is a heterocyclylalkyl radical as defined above. The alkyl radical and the heterocyclyl radical may be optionally substituted as defined herein.

"Hyperlipidemia"refers to the presence of an abnormally elevated level of lipids in the blood. Hyperlipidemia can appear in at least three forms: (1)

hypercholesterolemia, i. e. , an elevated LDL cholesterol level above normal (2) hypertriglyceridemia, i. e. , an elevated triglyceride level above normal and (3) combined hyperlipidemia, i. e. , a combination of hypercholesterolemia and hypertriglyceridemia.

"IC50" refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of nuclear receptor. In the case of the constitutively active receptors ERRa, ERR (3, or ERRy IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of constitutive receptor activity, in an assay that measures such response.

"Imine"refers to =NR, wherein R is hydrogen or alkyl.

"Optionally substituted alkyl","optionally substituted alkenyl"and "optionally substituted alkynyl"refer to alkyl radicals, alkenyl radicals and alkynyl radicals, respectively, that may be optionally substituted by one or more substituents independently selected from the group consisting of nitro, halo, azido, cyano, cycloalkyl, heteroaryl, heterocyclyl, -ORx, -N(Ry)(Rz), -SRx, -C (J) Rx, -C (J) OR, - C (J) N (Ry) (Rz), -C (J) SR',-S (O) Rx (where t is 1 or 2), -OC (J) RX,-OC (J) ORX, -OC (J) N (Ry) (Rz), -OC (J) SRX,-N (Rx) C (J) Rx,-N (Rx) C (J) ORx-N (Rx) C (J) N (Ry) (RZ), -N(Rx) C (J)SRx, -Si(Rw)3, -N(Rx)S(O)2Rw, -N(Rx)S(O)2N(Ry)(Rz), -S(O)2N(Ry)(Rz), - P(O)(Rv)2, -OP(O)(Rv)2, -C(J)N(Rx)S(O)2R5, -C(J)N(Rx)N(Rx)S(O)2Rx, -C(Rx)=N(ORx), and-C (Rx) =NN (Ry) (RZ), wherein : Rx is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl ; R''and RZ are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl ; or Ry and Rz, together with the nitrogen atom to which they are attached, form a heterocyclyl or heteroaryl ; Rw is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl ; Rv is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy,-ORxor-N (Ry) (RZ) ; and J is O, NRx or S.

Unless stated otherwise specifically in the specification, it is understood that the substitution can occur on any carbon of the alkyl, alkenyl or alkynyl group.

"Optionally substituted aryl","optionally substituted cycloalkyl", "optionally substituted heteroaryl"and"optionally substituted heterocyclyl"refers to aryl, cycloalkyl, heterocyclyl and heteroaryl radicals, respectively, that are optionally substituted by one or more substituents selected from the group consisting of nitro, halo, haloalkyl, haloalkenyl, azido, cyano, oxo, thioxo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, -Ru-ORx, - Ru-N(Ry)(Rz), -Ru -SRx, -Ru -C(J)Rx, -Ru -C(J)ORx, -Ru -C (J) N (Ry) (RZ),-Ru-C (J) SRx, -RU-S (O) tRx (where t is 1 or 2),-RU-OC (J) Rx,-RU-OC (J) OR",-R"-OC (J) N (Ry) (Rz), -Ru-OC (J) SRx,-R"-N (Rx) C (J) Rx, -Ru-N (RX) C (J) ORx, -Ru-N(Rx) C (J) N (R'') (RZ), - Ru-N(Rx)C(J)SRx, -Ru-Si(Rw)3, -Ru-N(Rx)S(O)2Rw, -Ru-N(Rx)S(O)2N(Ry)(Rz), - "-S 2NN(Ry)(RZ),-R"-P (O) (Rv) 2,-R"-OP (O) (R') 2,-R"-C (J) N (Rx) S (0) 2R5, - R"-C (J) N (Rx) N (Rx) S (O) 2Rx, -Ru-C (RX) =N (ORx) and-R"-C (RX) =NN (Ry) (RZ), wherein : each Ru is independently alkylene or a direct bond; each Rv is independently alkyl, alkenyl, alkynyl, cycloalkyl, <BR> <BR> <BR> <BR> cycloalkylalkyl, heteorcyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy,-OR'or-N (R (R') ; R'is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaratkyl ; each R'is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteorcyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl ; Ry and Rz are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl ; Ry and Rz, together with the nitrogen atom to which they are attached, form a heterocycle or heteroaryl ; and J is O, NRx or S.

"Oxo"refers to =O.

"Thioxo"refers to =S.

"Pharmaceutically acceptable derivatives"of a compound include salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization. The compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs. Pharmaceutical acceptable salts include, but are not limited to, amine salts, such as but not limited to

N, N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates ; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates and fumarates.

Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl and heterocyclyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of formula C=C (OR) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of formula C=C (OC (O) R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl.

Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2,3 or 4, solvent or water molecules.

"Polymorph"refers to the different crystal forms of a compound, resulting from the possibility of at least two different arrangements of the molecules of the compound in the solid state. Polymorphs of a given compound will be different in crystal structure but identical in liquid or vapor states. Different polymorphic forms of a given substance may differ from each other with respect to one or more physical properties, such as solubility and dissociation, true density, crystal shape, compaction behavior, flow properties, and/or solid state stability.

"Prodrug"is a compound that, upon in vivo administration, is metabolized by one or more steps or processes or otherwise converted to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes. The prodrug may be

designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e. g. , Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).

"Sulfide"refers to the radical having the formula-SR wherein R is an alkyl or haloalkyl group. An"optionally substituted sulfide"refers to the radical having the formula-SR wherein R is an optionally substituted alkyl as defined herein.

Unless specifically stated otherwise, where a compound may assume alternative tautomeric, regioisomeric and/or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the present invention.

For example, where a compound is described as having one of two tautomeric forms sketched below, it is intended that the both tautomers be encompassed within the scope of the present invention.

When the compounds described herein contain olefinic double bonds, it is intended that the compound descriptions include both E and Z geometric isomers.

For example, where a compound is described as having one of the E and Z configurations sketched below, it is intended that both configurations be included in the scope of the present invention.

In some instances, a crossed double bond as shown below is used to depict a compound as having either an E or Z configuration.

It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. In the case of amino acid residues, such residues may be of either the L-or D-form. The configuration for naturally occurring amino acid residues is generally L. When not specified the residue is the L form. As used herein, the term"amino acid"refers to a-amino acids which are racemic, or of either the D-or L-configuration. The designation"d"preceding an amino acid designation (e. g., dAla, dSer, dVal, etc. ) refers to the D-isomer of the amino acid.

The designation"dl"preceding an amino acid designation (e. g., dlPip) refers to a mixture of the L-and D-isomers of the amino acid. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.

Optical active (+) and (-), (R) -and (S) -, or (D) -and (L) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as reverse phase HPLC.

As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of

analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC) and mass spectrometry (MS), used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Methods for purification of the compounds to produce substantially chemically pure compounds are known to those of skill in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers. In such instances, further purification might increase the specific activity of the compound.

Where the number of any given substituent is not specified (e. g., haloalkyl), there may be one or more substituents present. For example,"haloalkyl" may include one or more of the same or different halogens.

As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (see, Biochem. 1972, 11 : 942-944).

AcOH acetic acid anhyd anhydrous CDI 1, 1'-carbonyidiimidazole CHCI3 chloroform conc concentrated DCM dichloromethane DOTAP N- [1- (2, 3-Dioleoyloxy)]-N, N, N-trimethylammonium propane methylsulfate DMF N, N-dimethylformamide DMSO dimethyl sulfoxide Et20 diethyl ether EtOAc ethyl acetate EtOH ethanol (100%) Hex hexanes MeOH methanol NH40Ac ammonium acetate Pd/C palladium on activated carbon Pd [PPH3] 4 Tetrakis (triphenylphosphine) palladium (0) satd saturated TBAF Tetrabutylammonium fluoride TBSCI Tert-butyldimethylsilyl chloride TEA triethylamine THF tetrahydrofuran

B. Preparation of the compounds Starting materials in the synthesis examples provided herein are either available from commercial sources or via literature procedures. All commercially available compounds and solvents were used without further purification unless otherwise indicated. Flash chromatography was performed using Merck Silica Gel 60 (230-400 mesh) following standard protocol (Still et al. (1978) J. Org. Chem. 43,2923).

Proton ('H) nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 400 MHz NMR spectrometer. CDCI3 (99.8% D, Cambridge Isotope Laboratories) or DMSO-d6 (99.9 % D, Cambridge Isotope Laboratories) was used in all experiments as indicated. Significant peaks are tabulated and typically include: number of protons, and multiplicity (s, singlet ; d, doublet; t, triplet ; q, quartet; m, multiplet ; br s, broad singlet). Chemical shifts are reported as parts per million (6) relative to the middle point of the solvent peak. Low-resolution mass spectra (MS) were obtained as electrospray ionization (ESI) mass spectra, which were recorded on a Perkin-Elmer SCIEX HPLC/MS instrument using reverse-phase conditions (acetonitrile/water, 0.05% trifluoroacetic acid). The infrared (IR) spectra were acquired on an Avatar 360 FT-IR instrument. The samples were prepared as KBr pellets, and the absorptions are reported as wavenumbers (v) in the unit of reciprocal centimeters (cm-').

It is understood that in the following description, combinations of substituents and/or variables of the depicted formulae are permissible only if such contributions result in stable compounds. It will also be appreciated by those skilled in the art that in the process described below the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Protecting groups may

be added or removed in accordance with standard techniques, which are well known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T. W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed., Wiley-Interscience.

The following illustrations depict general preparations of compounds claimed herein and consist of reactions typically known to one skilled in the art of chemical synthesis. The substituents R'-R3, R6-R8, R'2, R30-R34 are as defined above in the Summary of the Invention. The substituents X, Y, and Z are defined below in the text or in the synthesis Schemes. One of ordinary skill in the art could easily ascertain which choices for each substituent are possible for the reaction conditions of each Scheme. Moreover, the substituents are selected from components as indicated in the specification heretofore, and may be attached to starting materials, intermediates, and/or final products according to methods known to those of ordinary skill in the art.

Also it will be apparent to one skilled in the art that many of the products could exist as one or more geometrical isomers, that is E/Z isomers, enantiomers, diastereomers, or tautomers.

In general, compounds of formula (I), such as structures (3a, b), can be synthesized accordingly to Scheme 1 by the condensation of aldehyde (2a) (R3 = H) or ketone (2b) (R3 = alkyl, aryl) with a nucleophilic reactant of structure (1a) (reaction (I) in Scheme 1). Several specific condensation protocols, such as the Aldol Reaction, can be used to accomplish the transformation in reaction (I) (House, H. O. Modern Synthetic Reactions, 2nd Ed. W. A. Benjamin, Menlo Park, CA, 1972). Horner- Wadsworth-Emmons methodology can also be used to carry out the transformation (Wadsworth, W. S. Org. React. (1977) 25,73). For example, when R'= OEt and R = H or substituted alkyl, 2-diethyloxyphosphonyl-propionic acid ethyl ester (4) can be reacted, in the presence of alkoxide base, with benzaldehyde or ketone (2a, b) to provide acrylic acid ethyl ester (5a, b) (reaction (2) in Scheme 1) (see Petroski, R. J. et. al. Synth. Commun. (2001) 31,89).

Scheme 1 O 30 ) sR2 R XR-H20 R14R31 (1) I R Rsa Rs2 R3 I R 1a 2a R3 = H R R34 R32 2b R3= alkyl, aryl 3a, b R33 0 0 0 O . 0 z + 2a, b t-BuOK---o R2 R30 R34 R32 n R34-R32 5a, b R33

The R'group of compounds of formula (I) (3a, b) can be varied based on choice of starting reagent (1a-c) or by modifications to the carboxyl group after the condensation step. The R'group on starting reagent (1b) can be derived using common carboxylic acid derivatization methodology, such as the preparation of amide (1c) (reaction (I), Scheme 2). Reactions such as hydrolysis, transesterification, amidation, and the Weinreb amide synthesis, among others, can be employed to install the R'group. The direct product (5a, b) of the Horner-Wadsworth-Emmons reaction can also be transformed in an analogous manner. Therefore, the ethyl ester group on (5a, b) can easily be changed to various esters, amides, sulfonamides, hydrazides, ketones, etc. as described in the Summary of Invention to yield general Formula 1 (3a, b) (reaction (2), Scheme 2).

Scheme 2 0 RNH2 0 2 RNH2 0 R10 R2 RNH RHNR2 U) 1b 1b 1c R'=OH convert to R R2 R30 R2 Roi R3 W (2 : 3 3 R34 R32 R34 R32 R33 R33 5a, b 3a, b

When in compounds of formula (I) the substituent R2 is ester, cyano, nitro, or a similar group, such as structures (3c, d) in Scheme 3 (where R2 = CN), the compound can be prepared using the Knoevenagel Condensation (Tietz, L. F. et al Comp. Org. Syn. (1991) 2, 341 ; Watson, B. T. et al Tetrahedron Lett. (1998) 39,6087).

By example, the active methylene precursor (6) can be reacted with benzaldehyde (2a) or ketone (2b) in the presence of acid or base to afford compound (3c, d) (Scheme 3).

The condensation reaction between reactants (2a, b) and (6) may produce a single geometrical isomer or a mixture of E and Z isomers around the C=C bond.

Scheme 3 O R3 N R1) 9 R Jt acid o base Ra R3 y/31 R3a R32 heat R33 R34 R32 R33 2a R3 = H 3c, d 2b R3= alkyl, aryl In general, compounds of formula (II), (8a) (where X = (C-R6), Z = S), formula (III) (8b) (where X = N, Z= O), and formula (IV), (8c) (where X = N, Z = S), can be prepared using acetamide reagents (7a-c) and benzaldehyde (2a) via Knoevenagel Condensation in the presence of acid or base as depicted in Scheme 4 (reaction (1) in Scheme 4) when R2 is an activating group such as cyano, nitro, or carbonyl. Thus, for example, the aromatic aldehyde (2c) (R3 = H, R 31 = MeO, R32 = OCH2CH2OAr) can be condensed with cyanoacetamide compound (9) in a mixture of DMF and TEA to yield the product, thiadiazolo-cyanoacrylamide (10) (reaction (2), Scheme 4) (Santagati, M. et. al. Pharmazie (1994) 49,880). The Knoevenagel Condensation products (8a-c) can exist as two tautomers as shown in reaction (1) of Scheme 4.

Scheme 4 30 X-N 0 ? ?. X 9 tautomerizat ! on.,,,., (1) R2 R34 R32 \ ruz 34 I/32 fZ3 \ R34 R32 R3 R l, R31 7bX=N, Z=O R,3 Ri N neo 7c X = N, Z = S R33 N-N 0 N (2) N H I H DMF. TEA heat 10 10

The double bond in compounds of formula (I) (3a-c) can be converted to the single bond analogs (11a-c) upon treatment with various hydride reducing agents (eq 1, Scheme 5). Hydrogenation conditions can also convert the double bond on compounds (3a-c) to a single bond (March, J Advanced Organic Chemistry, 4th Ed. ; John Wiley : New York (1992); Carruthers, W. Some Modern Methods of Organic Synthesis, 3rd Ed.; Cambridge University Press: Cambridge, UK (1986) ). The reduction of the double bond using NaBH3CN produces a racemic mixture of compounds (11a-c). Stereoselective reduction methods that provide a high enatiomeric excess of one stereoisomer can be used to provide chiral compounds (11a-c). In general, these reduction methods can also be applied to compounds of formulae (II), (III) and (IV) (8a-c) of the claims for the conversion of the a- (3 unsaturated bonds into single bond analogs (11 d-f) (reaction (2), Scheme 5).

Scheme 5 0 0 R30 R 30 hydride reagent hydrogenation 3a R3 = H R R33 3a R 3 = hui R33 R33 3b R3 = alkyl, aryl 11a-c 3c R2 = CN

Cyanoacetamide precursor (9) can be synthesized from 5-ethyl-2- amino [1,3, 4] thiadiazole (12) by using ethyl cyanoacetate and sodium methoxide in MeOH at reflux as shown in reaction (2) of Scheme 6 (Santagati, M. et. al. Pharmazie (1994) 49,880.). Acylation of 5-ethyl-2-amino [1,3, 4] thiadiazole (12) with the appropriate acid chloride will also provide the cyanoacetamide precursor (9). The general precursor structures (7a-c) can be prepared in an analogous manner. The thiazole (14a), oxadiazole (14b), and thiadiazole (14c) heterocycles required for the preparation of intermediates (7a-c) can be synthesized using known methods (Katrintzky, A. R., Pozharskii, A. F. Handbook of Heterocyclic Chemistry, 2nd Ed. ; Pergamon Press: New York (1992) ). For example, 2-amino- [1, 3, 4] thiadiazole (14c) (where X = N, Z = S) can be prepared via a dehydration cyclization reaction in either sulfuric acid or polyphosphoric acid using acyl thiosemicarbazide (13c) (where X = NH, Z = S) as shown in reaction (2) of Scheme 6 (Padhy, A. K. et al Indian J. Chem. Sect.

B (1999) 38,998 ; Turner, S. et al J Med. Chem. (1988), 31, 902.). In addition to this synthetic methodology, an extensive list of commercial heterocycles (14a-c) is available.

Scheme 6 0 H acid X-N X-N 0 , N NH2 acid/X/-N\\ X-N O T dehydration R8'ZNH2 z H

13aX=CR6 Z=S 14aX=CR6 Z=S 13bX=NH Z=O 14bX=N Z=O 7a-c 13cX= NH Z= S 14cX= N Z= S The substituted aromatic aldehydes, such as compound (2a), can be purchased or synthesized using methodology known to those of ordinary skill in the art (Carey, F. A. , Sundberg, R. J. Advanced Organic Chemistry, 3rd Ed.; Plenum : New York (1993)). The groups R30-34 on benzaldeyde (2a) can be widely varied in order to prepare the type of analogs described in the Examples. Several selected examples of the synthesis of substituted aromatic aldehydes (2d-f), relevant to the Invention, are shown in Scheme 7. When the aromatic aldehyde precursor (15) contains a hydroxyl group, alkylation with a wide range of alkyl halides (RY) can provide a facile method for installing substituent groups on the aromatic ring to yield (2d) (reaction (1) in Scheme 7). For the purpose of attaching an alkyl ether linkage to the aromatic aldehyde, such as with compound (2e), the synthetic processes shown in reactions (2)- (3) of Scheme 7 can be used. By example, aromatic aldehyde precursor (15) can be alkylated using 2-bromoethanol to prepare ethylene ether compound (16). Compound (16) can be reacted under Mitsunobu coupling conditions with phenol (17) to synthesize aromatic aldehyde (2e) (reaction (2)). Alternatively, compound (16) can be converted to the alkyl halide compound (18) by using precedented procedures, such as reaction with PPh3CI2 (eq 3). Alkyl halide (18) can be converted to aromatic aldehyde (2e) by reaction with phenol (17) and an appropriate base such as n-butyl lithium. Additionally, transition metal mediated coupling reactions, such as that shown in reaction (4) of Scheme 7, can be employed for the installation of ring substituents to prepare aldehyde (2f). Moreover, installation of the aromatic ring substituents can proceed via various aromatic substitution reactions and metal mediated coupling reactions using aldehyde intermediates that do not contain a hydroxyl group.

Scheme 7

0 0 Ray H base 2d OH 15 2d OH O BrOH 17 - OH H OH H I I) /base _ Mitsunobu 16 2e O O PPh3Cl2 17 ) ! " ! T- rt-BuL) (3) 16 18 0 0 PhB (OH) 2 OH Cu (onc) 2"70_0 (4) H W 4) 15 2f The compounds of formulae (II), (III) and (IV) (8a-c) can be alkylated with simple alkyl halides (R'Y) in the presence of base to yield compounds (19a-c) (reaction (1), Scheme 8). Three sites of alkylation are possible including the exocyclic nitrogen, the endocyclic nitrogen, and the oxygen. In systems similar to (8a-c) the alkylation has been reported as regioselective, with the endo-nitrogen alkylated product isolated. (Cho, N. S. et al Heterocycles (2001) 55 (3) 579). By example, the thiadiazolo-acrylamide compound (8c) has been reacted with iodomethane in the presence of K2CO3 (eq 2). Spectral analysis is consistent with literature, indicating the methyl group was added to the thiadiazole 3-position nitrogen yielding the compound (19d). However, other alkylation products may be obtained by using different reaction conditions.

Scheme 8 X-N 0 R7y. P 2 z N R30 base p2 RZ-X-N O R8tzXN 31 R8tZAN tR31 (1) Ra z H I Rao base R2 (1) R3 R R3 R31 rus, R34 R32 33 8bX=N Z=O R R33 8cX=N Z=S

C. Evaluation of the activity of the compounds Those of skill in the art recognize that various methods may be used to characterize and profile the activity of the claimed compounds and compositions.

Suitable cell based assays for assaying the activity of the claimed compounds include, but are not limited to, the co-transfection assay, the use of GAL4 chimeras and protein- protein interaction assays (see, for example, Lehmann. et a/., J. Biol Chem. 1997, 272 (6): 3137-3140).

In addition many biochemical screening formats exist for screening compound activities to identify high affinity ligands which include, but are not limited to, direct binding assays, ELISAs, fluorescence polarization assays, fluorescence resonance energy transfer assays (FRET) and Time resolved FRET based coactivator recruitment assays (see, generally, Glickman et al., J. Biomolecular Screening, 2002, 7 (1) : 3-10).

Binding assays employing fluorescent materials that are well known in the art are described in, e. g. , Lakowicz, J. R., Principles of Fluorescence Spectroscopy, New York: Plenum Press (1983); Herman, B. , Resonance energy transfer microscopy, in: Fluorescence Microscopy of Living Cells in Culture, Part B, Methods in Cell Biology, vol. 30, ed. Taylor, D. L. & Wang, Y. L. , San Diego: Academic Press (1989), pp. 219-243; Turro, N. J., Modern Molecular Photochemistry, Menlo Park: Benjamin/Cummings Publishing Col, Inc. (1978), pp. 296-361.

For example, fluorescence polarization assays are based on the principle that a fluorescent-labeled compound that is excited by plane polarized light will emit fluorescent light displaying a degree of polarization that is related to the bulk and rotational mobility of the fluorescent-labeled compound. A fluorescent compound that is bound to a protein or receptor will be relatively immobile and have a slow rate of rotation. When the immobilized fluorescent compound is excited by planepolarized light, it will emit polarized fluorescent light in the same plane since the molecule will have rotated very little during its brief period of fluorescence. An unbound fluorescent compound, on the other hand, will exhibit greater rotational mobility and hence emit less polarized or depolarized light during its period of fluorescence when excited by planepolarized light. A high fluorescence polarization value therefore indicates that a fluorescent labeled compound has high affinity for a receptor molecule.

If a fluorescent labeled ligand is available, fluorescence polarization assays provide a way of detecting binding of compounds to the nuclear receptor of interest by measuring changes in fluorescence polarization from competitive displacement or binding inhibition of a trace amount of the label ligand by the compound. Alternatively, a fluorescent labeled coactivator peptide to the nuclear receptor of interest having the receptor binding motif LXXLL can be used to detect ligand binding to the nuclear receptor of interest.

FRET-based assays rely upon the fact that energy transfer from a labeled donor molecule to a labeled acceptor molecule only occurs when donor and acceptor are in close proximity. Typically, FRET is exploited to measure the ligand dependent interaction of a co-activator peptide with a nuclear receptor in order to characterize the agonist or antagonist activity of the compounds disclosed herein. The assay in such a case involves the use of a recombinant epitope, or affinity tagged nuclear receptor ligand binding domain (LBD) fusion protein and a synthetic biotinylated peptide derived from the receptor interacting domain (-LXXLL motif) of a co-activator peptide such as the steroid receptor coactivator 1 (SRC-1), TIF2, DRIP1 or AiB1. Typically the tagged-LBD is labeled with a lanthanide chelate such as europium (Eu), via the use of antibody specific for the tag, and the co-activatorpeptide is labeled with allophycocyanin via a streptavidin-biotin linkage.

In the presence of an agonist for the nuclear receptor, the peptide is recruited to the tagged-LBD bringing europium and allophycocyanin into close proximity to enable energy transfer from the europium chelate to the allophycocyanin.

Upon excitation of the complex with light at 340 nm excitation energy absorbed by the

europium chelate is transmitted to the allophycocyanin moiety resulting in emission at 665 nm. If the europium chelate is not brought in to close proximity to the allophycocyanin moiety there is little or no energy transfer and excitation of the europium chelate results in emission at 615 nm. Thus the intensity of light emitted at 665 nm gives an indication of the strength of the protein-protein interaction. The activity of a nuclear receptor antagonist can be measured by determining the ability of a compound to competitively inhibit the activity of an agonist for the nuclear receptor. In the case of a constitutively active receptor, compound activity may be measured in terms of its ability to disrupt interaction between the receptor and the co-activator peptide.

Fluorescence in a sample can be measured using a fluorimeter, a fluorescent microscope or a fluorescent plate reader. Suitable instrumentation for fluorescence microplate readers include without limitation the CytoFluor 4000 available from PerSeptive Biosystems. For 96-well based assays, black walled plates with clear bottoms, such as those manufactured by Costar may be used. In general, all of these systems have an excitation light source which can be manipulated to create a light source with a defined wavelength maxima and band width which passes through excitation optics to excite the sample.

Typically the excitation wavelength is designed to selectively excite the fluorescent sample within its excitation or absorption spectrum. For most FRET based assays the excitation wavelength is usually selected to enable efficient excitation of the donor while minimizing direct excitation of the acceptor. In response the sample (if fluorescent) emits radiation that has a wavelength that is different from the excitation wavelength. Collection optics then collect the emission from the sample, and direct it to one or more detectors, such as photomultiplier tubes or CCD cameras. Preferably the detector will include a filter to select specific wavelengths of light to monitor. For time resolved applications, for example time resolved FRET, the excitation and or emission optical paths include control mechanisms to precisely terminate illumination and then to wait for a precise period of time before collecting emitted light. By using compounds such as lanthanides that exhibit relatively long-lived light emission it is possible to gain significant enhancements in detection sensitivity and accuracy.

The detection devices can include a temperature controller to maintain the sample at a specific temperature while it is being scanned. According to one embodiment, a multi-axis translation stage moves a microtiter plate holding a plurality of samples in order to position different wells to be exposed. The multi-axis translation

stage, temperature controller, auto-focusing feature, and electronics associated with imaging and data collection can be managed by an appropriately programmed digital computer. The computer also can transform the data collected during the assay into another format for presentation.

Suitable instrumentation for luminescence measurements include standard liquid scintillation plate readers, including without limitation the Wallac Microbeta, or PE Biosystems Northstar, or equivalents commercially available from Packard, Perkin Elmer and a number of other manufacturers.

In addition to the binding assays mentioned above, a variety of cell based assay methodologies may be successfully used in screening assays to identify and profile the affinity of compounds of the present invention for ERR. These approaches include the co-transfection assay, translocation assays, complementation assays and the use of gene activation technologies to over express endogenous nuclear receptors.

Three basic variants of the co-transfection assay strategy exist, co- transfection assays using full-length nuclear receptor, co transfection assays using chimeric nuclear receptors comprising the ligand binding domain of the nuclear receptor of interest fused to a heterologous DNA binding domain, and assays based around the use of the mammalian two hybrid assay system.

The basic co-transfection assay is based on the co-transfection into the cell of an expression plasmid to express the nuclear receptor of interest in the cell with a reporter plasmid comprising a reporter gene whose expression is under the control of a promoter sequence that is capable of interacting with that nuclear receptor. (See for example U. S. Patents Nos. 5,071, 773,5, 298,429 and 6,416, 957). Treatment of the transfected cells with an agonist for the nuclear receptor increases the transcriptional activity of that receptor which is reflected by an increase in expression of the reporter gene which may be measured by a variety of standard procedures. Alternatively, the host cell may be a primary cell or a cell line derived directly from a primary cell type, which endogenously expresses the nuclear receptor and appropriate co-factors. An assay system may comprise of transfecting into such a host cell a suitable reporter gene (s) and monitoring the transcriptional activity of the nuclear receptor in response to the addition of a test compound.

Typically, the expression plasmid comprises: (1) a promoter, such as an SV40 early region promoter, HSV tk promoter or phosphoglycerate kinase (pgk) promoter, CMV promoter, Sra promoter or other suitable control elements known in the

art, (2) a cloned polynucleotide sequence, such as a cDNA encoding a receptor, co- factor, or a fragment thereof, ligated to the promoter in sense orientation so that transcription from the promoter will produce a RNA that encodes a functional protein, and (3) a polyadenylation sequence. As an example not to be construed as a limitation, an expression cassette of the invention may comprise the cDNA expression cloning vectors, or other preferred expression vectors known and commercially available from vendors such as Invitrogen, (CA), Stratagene, (CA) or Clontech, (CA). Alternatively expression vectors developed by academic groups such as the pCMX vectors originally developed in the Evans lab may also be used (Umesono et al., 1991, Cell 65: 1255-1266).

The transcriptional regulator sequences in an expression cassette are selected by the practitioner based on the intended application ; depending upon the specific use, transcription regulation can employ inducible, repressible, constitutive, cell-type specific, developmental stage-specific, sex-specific, or other desired type of promoter or control sequence.

Alternatively, the expression plasmid may comprise an activation sequence to activate or increase the expression of an endogenous chromosomal sequence. Such activation sequences include for example, a synthetic zinc finger motif (for example see US Patents 6,534, 261 and 6,503, 7171) or a strong promoter or enhancer sequence together with a targeting sequence to enable homologous or non- homologous recombination of the activating sequence upstream of the gene of interest.

In another embodiment of these methods chimeras may be used in place of the full-length nuclear receptor. Such chimeras typically comprise the ligand binding domain of the ERR coupled to a heterologous DNA binding domain (DBD).

Typically for such chimeric constructs, DNA binding domains from yeast or bacterially derived transcriptional regulators such as members of the GAL 4 and Lex A (GenBank accession number ILEC)/Umud super families may be used. GAL4 (GenBank Accession Number P04386, ) is a positive regulator for the expression of the galactose-induced genes. (see, for example, Keegan et al., 1986, Science 231: 699- 704). Reporter plasmids may be constructed using standard molecular biological techniques by placing cDNA encoding for the reporter gene downstream from a suitable minimal promoter. For example luciferase reporter plasmids may be constructed by placing cDNA encoding firefly luciferase (typically with SV40 small t intron and poly-A tail, (de Wet et al., 1987, Mol. Cell. Biol. 7: 725-735) down stream

from the herpes virus thymidine kinase promoter (located at nucleotides residues-105 to +51 of the thymidine kinase nucleotide sequence, pBLCAT2 (Luckow & Schutz, 1987, Nucl. Acid. Res. 15: 5490-5494) ) which is linked in turn to the appropriate response elements.

Alternatively, heterologous DNA binding domains from distinct, well- defined nuclear receptors are used, for example including without limitation, the DBDs of the glucocorticoid receptor, GR (accession no. NM000176) (amino acids 421-486), mineralocorticoid receptor, MR (accession no. NM_055775) (amino acids 603-668), androgen receptor, AR (accession no XM_010429NM_055775) (amino acids 929- 1004), progesterone receptor, PR (amino acids 622-695), and estrogen receptor alpha, ERa (accession no. XM_045967) (amino acids 185-250).

The choice of hormone response element is dependent upon the type of assay to be used. In the case of the use of the full length ERR a known ER or ERRE would typically be used. In the case of an ERR-LBD-GAL4 fusion, a GAL4 UAS would be used. An example of a GAL4 UAS binding site typically used is the MH100 binding site (Kang et al., 1993, J Biol. Chem. 268 (13): 9629-9363).

Numerous reporter gene systems are known in the art and include, for example, alkaline phosphatase (see, Berger, J., et al., 1988, Gene, 66: 1-10; and Kain, S. R. , 1997, Methods. Mol. Biol. 63: 49-60), ß-galactosidase (See, U. S. Patent No.

5,070, 012 and Bronstein, I., et al., 1989, J. Chemilum. Biolum. 4: 99-111), chloramphenicol acetyltransferase (See, Gorman et al., 1982, Mol. Cell Biol. 2: 1044-5), p-gtucuronidase, peroxidase, p-tactamase (U. S. Patent Nos. 5,741, 657 and 5,955, 604), catalytic antibodies, luciferases (U. S. Patents 5,221, 623; 5,683, 888; 5,674, 713; 5,650, 289; and 5,843, 746) and naturally fluorescent proteins (Tsien, R. Y., 1998, Annu. Rev. Biochem. 67: 509-544, ).

Numerous methods of co-transfecting the expression and reporter plasmids are known to those of skill in the art and may be used for the co-transfection assay to introduce the plasmids into a suitable cell type.

One method for identifying compounds that promote co-factor recruitment or nuclear receptor heterodimerization is the mammalian two-hybrid assay (see, for example, US Patent Nos. US 5,667, 973,5, 283,173 and 5,468, 614). A typical two-hybrid assay involves the expression of two fusion proteins, one of which is can be the GAL4 DNA binding domain fused to a"bait"protein such as a coactivator peptide, and the other of which is a strong transactivation domain of a transcriptional activator such as VP16 fused to a"prey"protein such as a nuclear receptor. The interaction of

the"bait"and"prey"protein brings the transcriptional activator to the promoter which leads to transcriptional activity which can be detected by the activation of a reporter gene (Fields, S. and Song, O., 1989, Nature 340: 245,; Willy et al., 1995, Gene & Development 9: 1033-1045). In one example of a two-hybrid assay, functional interaction between a GAL4-SRC-1 fusion protein and VP16-ERR fusion protein leads to constitutive activation of a suitable reporter plasmid, such as luciferase reporter construct comprising GAL4 upstream Activating Sequences (UAS).

Any compound which is a candidate for modulation of ERR may be tested by any of the above methods. Generally, compounds are tested at several different concentrations to optimize the chances that regulation of the receptor will be detected and recognized if present. Typically assays are performed in triplicate and vary within experimental error by less than 15%. Each experiment is typically repeated three or more times with similar results.

Agonist activity may be measured by the activity of the reporter gene normalized to the internal control and the data plotted as fold activation relative to untreated cells. Antagonist activity can be measured by determining the ability of a compound to competitively inhibit the activity of an agonist or the receptor's constitutive activity. A control compound (agonist or antagonist) may be included along with DMSO for normalization of the assay data.

Additionally the compounds and compositions can be evaluated for their ability to increase or decrease the expression of genes known to be modulated by ERR and other nuclear receptors in vivo, using Northern-blot, RT PCR or oligonucleotide microarray analysis to analyze RNA levels. Western-blot analysis can be used to measure expression of proteins encoded by ERR target genes. Genes that are known to be regulated by the ERR include without limitation, osteopontin, medium-chain acyl CoA dehydrogenase (MCAD), aromatase, lactoferrin and pS2.

All methods discussed thus far may be adapted for use in high throughput screening. High throughput screening systems are commercially available (see, e. g. , Zymark Corp. , Hopkinton, MA; Air Technical Industries, Mentor, OH; Beckman Instruments Inc., Fullerton, CA; Precision Systems, Inc., Natick, MA) that enable these assays to be run in a high throughput mode. These systems typically automate entire procedures, including all sample and reagent pipetting, liquid dispensing timed incubations, and final readings of the microplate in detector (s) appropriate for the assay. These configurable systems provide high throughput and rapid start up as well as a high degree of flexibility and customization. The

manufacturers of such systems provide detailed protocols for various high throughput systems. Thus, for example, Zymark Corp. provides technical bulletins describing screening systems for detecting the modulation of gene transcription, ligand binding, and the like.

Assays that do not require washing or liquid separation steps are preferred for such high throughput screening systems and include biochemical assays such as fluorescence polarization assays (see, for example, Owicki, J. , 2000, Biomol.

Screen 5 (5): 297), scintillation proximity assays (SPA) (see, for example, Carpenter et al., 2002, Methods MoL Biol. 190: 31-49) and fluorescence resonance energy transfer energy transfer (FRET) or time resolved FRET based coactivator recruitment assays (Mukherjee et al., 2002, J. SteroidBiochem. Mol. Biol. 81 (3): 217-25; Zhou et al., 1998, Mol. Endocrinol. 12 (10): 1594-604).

Established animal models exist for a number of diseases of direct relevance to the claimed compounds and these can be used to further profile and characterize the claimed compounds. These model systems include Zucker (fa/fa) rats or (db/db) mice for studying diabetic dyslipidemia, nude mice transplanted with tumor cells for tumor growth studies, non-obese diabetic mouse (NOD) for type-1 diabetes studies and ovariectimized rats (OVX) for osteoporosis studies.

Additionally ERR animal models (e. g. , knockout mice) can be used to further evaluate the present compounds and compositions in vivo (Luo J. et al., 2003, Mol. Cell. Biol., 23: 7947-7956).

D. Administration of the Compounds of the Invention Also provided herein are methods of using the disclosed compounds and composition for the local or systemic treatment or prophylaxis of human and veterinary diseases, disorders and conditions mediated by ERRa, including without limitation : (a) diseases or disorder relating to the metabolic syndrome including hyperglycemia, insulin insensitivity, diabetes, obesity, hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, hypertension, hyperinsulinemia, hyperuricemia, or a combination thereof; (b) diseases or disorders relating to cancer; (c) diseases or disorder relating to the bone or cartilage, including arthritis, osteoarthritis and rheumatoid arthritis,

(d) inflammatory diseases, conditions or disorders due to the release of proinflammatory cytokines including rheumatoid arthritis and atherosclerosis, and (e) pyschoses and neurodegenerative or stress-related disorders including Parkinson's disease, Alzheimer's disease, depression, anxiety and chemical dependency.

In one embodiment, the dislosed compounds and compositions are ERRa modulators. In another embodiment, the disclosed compounds and compositions are ERRa antagonists. In yet another embodiment, the disclosed compounds and compositions are ERRa partial agonists. In yet another embodiment, the disclosed compounds and compositions are ERRa inverse agonists.

Administration of the disclosed compounds and compositions, or their pharmaceutical acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration of agents for serving similar utilities. The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutical acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. Pharmaceutical compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of a compound of the invention in aerosol form may hold a plurality of dosage units. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed. , (Mack Publishing Company, Easton, Pennsylvania, 1990). The composition to be administered will, in any event, contain a therapeutical effective amount of a compound of the invention, or a pharmaceutical acceptable salt thereof, for treatment of a disease-state

associated with the activity of a nuclear receptor in accordance with the teachings of this invention.

In one embodiment, the pharmaceutical composition may be in the form of a solid or liquid. In one aspect, the carrier (s) are particulate, so that the compositions are, for example, in tablet or powder form. The carrier (s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid or an aerosol, which is useful in, e. g., inhalator administration.

When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin ; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like ; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring ; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, e. g. , a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, e. g. , an elixir, syrup, solution, emulsion or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred composition contain, in addition to the present compounds, one or more of a sweetening agent, preservatives, dyelcolorant and flavor enhancer.

In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent may be included.

In one embodiment, the liquid pharmaceutical compositions, whether they are solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution,

preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite ; cheating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile.

In one embodiment, the liquid pharmaceutical composition intended for either parenteral or oral administration should contain an amount of a compound of the invention such that a suitable dosage will be obtained. Typically, this amount is at least 0. 01 % of a compound of the invention in the composition. When intended for oral administration, this amount may be varied to be between 0.1 and about 70% of the weight of the composition. Preferred oral pharmaceutical compositions contain between about 4% and about 50% of the compound of the invention. Preferred pharmaceutical compositions and preparations according to the present invention are prepared so that a parenteral dosage unit contains between 0.01 to 1 % by weight of the compound of the invention.

In another embodiment, the pharmaceutical composition may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following : petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. Topical formulations may contain a concentration of the compound of the invention from about 0.1 to about 10% w/v (weight per unit volume).

In another embodiment, the pharmaceutical composition may be intended for rectal administration, in the form, e. g. , of a suppository, which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.

In another embodiment, the pharmaceutical composition may include various materials, which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents.

Alternatively, the active ingredients may be encased in a gelatin capsule.

In another embodiment, the pharmaceutical composition in solid or liquid form may include an agent that binds to the compound of the invention and thereby assists in the delivery of the compound. Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, a protein or a liposome.

In another embodiment, the pharmaceutical composition may consist of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient (s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit. One skilled in the art, without undue experimentation may determine preferred aerosols.

In another embodiment, the pharmaceutical composition may be prepared by methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining a compound of the invention with sterile, distilled water so as to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compound of the invention so as to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system.

In one embodiment, the disclosed compounds, or their pharmaceutical acceptable salts, are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed ; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy. Generally, a therapeutical

effective daily dose is from about 0.1 mg to about 20 mg/kg of body weight per day of a compound of the invention, or a pharmaceutical acceptable salt thereof; preferably, from about 0.1 mg to about 10 mg/kg of body weight per day; and most preferably, from about 0.1 mg to about 7.5 mg/kg of body weight per day.

Compounds of the invention, or pharmaceutical acceptable derivatives thereof, may also be administered simultaneously with, prior to, or after administration of one or more of the therapeutic agents described above in the Summary of the Invention. Such combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of the invention and one or more additional active agents, as well as administration of the compound of the invention and each active agent in its own separate pharmaceutical dosage formulation.

Suitable agents for combination therapy include those that are commercially available and those currently in development or that will be developed.

Exemplary agents useful for treatment of metabolic disorders in combination with the compounds and composition disclosed herein include, but are not limited to: (a) anti- diabetic agents including sulfonylureas (such as chlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase, glimepiride, and glipizide), biguanides (such as metformin), thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, and rosiglitazone), and related insulin sensitizers, such as selective and non-selective activators of PPARa, PPARß and PPARy ; dehydroepiandrosterone (also referred to as DHEA or its conjugated sulphate ester, DHEA-S04) ; antiglucocorticoids ; TNFa inhibitors; a-glucosidase inhibitors (such as acarbose, miglitol, and voglibose), pramlintide (a synthetic analog of the human hormone amylin), other insulin secretogogues (such as repaglinide, gliquidone, and nateglinide), insulin ; agonists, partial agonists, antagonists, or inverse agonists of LXRa and/or LXRß ; FXR agonists, partial agonists, antagonists, or inverse agonists; (b) agents for the treatment of obesity including phenylpropanolamine, phentermine, diethylpropion, mazindol, fenfluramine, dexfenfluramine, phentiramine, ß3 adrenoceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors (such as orlistat), and leptins. Other agents used in treating obesity or obesity-related disorders include neuropeptide Y, enterostatin, cholecytokinin, bombesin, amylin, histamine H3 receptors, dopamine Dz receptors, melanocyte stimulating hormone, corticotrophin releasing factor, galanin and gamma amino butyric acid (GABA); (c) anti-atherosclerotic agents including

antihyperlipidemic agents, plasma HDL-raising agents, antihypercholesterolemic agents, cholesterol biosynthesis inhibitors including HMG-CoA reductase inhibitor, such as lovastatin (MEVACORO ; see, U. S. Patent No. 4,231, 938); simvastatin (ZOCORO ; see, U. S. Patent No. 4,444, 784); pravastatin sodium (PRAVACHOLO ; see, U. S. Patent No. 4,346, 227); fluvastatin sodium (LESCOLO ; see, U. S. Patent No.

5,354, 772); atorvastatin calcium (LIPITORO ; see, U. S. Patent No. 5,273, 995) and rivastatin (also known as cerivastatin; see, U. S. Patent No. 5,177, 080), acyl-coenzyme A: cholesterol acytransferase (ACAT) inhibitors, probucol, raloxifene, nicotinic acid, niacinamide, cholesterol absorption inhibitors, bile acid sequestrants (such as anion exchange resins, or quaternary amines (e. g., cholestyramine or colestipol)), low density lipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B6, vitamin B, 2, anti-oxidant vitamins, p-blockers, angiotensin 11 antagonists, angiotensin converting enzyme inhibitors, platelet aggregation inhibitors, fibrinogen receptor antagonists, aspirin or fibric acid derivatives; (d) anti-cancer agents including anti-metabolites (e. g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e. g. , vinca alkaloid such as vincristine, vinblastine ; taxanes such as paclitaxel, docetaxel), an alkylating agent (e. g., cyclophosphamide, melphalan, carmustine, nitrosoureas such as bischloroethyinitrosurea and hydroxyurea), platinum agents (e. g. cisplatin, carboplatin, oxaliplatin, JM-216, CI-973), anthracyclines (e. g., doxrubicin, daunorubicin), antitumor antibiotics (e. g. , mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase inhibitiors (e. g. , etoposide, camptothecins) or any other cytotoxic agents, (estramustine phosphate, prednimustine), hormones or agents acting on nuclear hormone receptors (steroids and anti-steroids, estrogens, anti-estrogens, androgens, anti-androgens, glucocorticoids, dexamethasone), (e) agents for the treatment of osteoporosis including parathyroid hormone (PTH) or physiologically active fragment thereof, (hPTHF 1-34) or dietary calcium supplement ; and (f) anti-arthritic agents including matrix metalloproteinase inhibitor, an inhibitor of pro-inflammatory cytokines (e. g. , anti-TNF molecules, TNF soluble receptors, and IL1 beta, non-steroidal anti-inflammatory drugs (NSAIDs) such as prostaglandin synthase inhibitors (e. g., choline magnesium salicylate, salicylsalicyclic acid), or corticosteroids, such as methylprednisone, prednisone, or cortisone.

Combination therapy can also include co-administration of the compound or composition disclosed herein with a treatment method such as radiation therapy for the treatment of cancer. Another combination therapy comprises administration to a human afflicted with a neurological disorder, a combination of a

monoamine oxidase inhibitor such as phenelzine, tranylcypromine, pargyline, deprenyl, moclobemide, brofaromine, moclobemide or selegiline with any of the claimed compounds or compositions.

The foregoing examples are provided only to illustrate the present invention and are in no way intended to limit to the scope thereof. The skilled practitioner will understand that considerable variations in the practice of this invention are possible within the spirit and scope as claimed below.

Although only one of two possible geometric isomers around the double bond (i. e. , the E and Z isomers) is exemplified, alternative geometric isomers are also meant to be included in the compound descriptions. For those compounds with alternative tautomeric forms, although only one of two possible tautomers is exemplified, the alternative isomers are also meant to be included in the compound descriptions. The'H NMR data indicate that the compounds are one isomer, but it is not known which isomer is the actual compound prepared. The NMR spectra were acquired on a Bruker 400 MHz instrument. The chemical shifts are reported in ppm (6) and are relative to the central peak of the solvent. The following abbreviations are used: br s = broad singlet, s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, m = multiplet.

Low-resolution mass spectra (MS) were obtained as electrospray ionization (ESI) mass spectra, which were recorded on a Perkin-Elmer SCIEX HPLC/MS instrument using reverse-phase conditions (acetonitrile/water, 0.05% trifluoroacetic acid). The infrared (IR) spectra were acquired on an Avatar 360 FT-IR instrument. The samples were prepared as KBr pellets, and the absorptions are reported as wavenumbers (v) in the unit of reciprocal centimeters (cm~'). Flash chromatography was performed using Merck Silica Gel 60 (230-400 mesh) following standard protocol (Still et al. (1978) J. Org. Chem. 43,2923).

The syntheses of compounds of this invention are illustrated by, but not limited to the following examples.

EXAMPLE 1 PREPARATION OF 2-CYANO-N- (5-ETHYL- [1, 3, 4] THIADIAZOL-2-YL)-ACETAMIDE :

A. To a N2 purged 250 mL flask, attached with cooling condenser and stir bar, was added 5-ethyl-2-amino- [1, 3, 4]-thiadiazole (6.05 g, 46.8 mmol), anhydrous MeOH (110 mL), ethyl cyanoacetate (5.0 mL, 47.0 mmol), and a 25 wt% solution of sodium methoxide in MeOH (12.8 mL, 56.3 mmol). The mixture was stirred at reflux for 8 h. The reaction solution was cooled to ambient temperature and poured into 600 mL of ice water. The pH was lowered to pH = 5 by the dropwise addition of acetic acid. The resulting white precipitates were filtered under reduced pressure. The crude product was dissolved in hot MeOH (450 mL), and a fine white precipitate was allowed to form as the mixture was cooled to ambient ambient temperature. The product was isolated by filtration under reduced pressure to provide 4.90 g (55 % yield) of title compound.'H NMR (DMSOd6) 6 12.8 (1H, br s), 4.07 (2H, s), 3.00 (2H, q, J = 7.5 Hz), 1.30 (3H, t, J = 7. 5 Hz) ; IR (KBr) vmax 3195,2916, 2749,2260, 1698,1582 cm-' ; MS (ESI) : 197 (MH+).

B. Preparation of 2-(2-chloroethoxy)-1, 3-dimethyl benzene: To a 250 mL flask attached with cooling condenser was added 2, 6-dimethyl phenol (6.12g, 50.1 mmol), anhydrous MeCN (45 mL), 1-bromo-2-chloroethane (12.5 mL, 150 mmol), and-325 mesh K2CO3 (35 g, 251 mmol). The reaction slurry was vigorously stirred at reflux for 1 d. The reaction mixture was allowed to cool to ambient temperature, and the mixture was diluted with EtOAc (100 mL). The remaining K2CO3 was removed by filtration under reduced pressure. The reaction solution was concentrated under reduced pressure. The crude product was chromatographed (Si02, hex/EtOAc100 : 0 to 95: 5) to provide the above compound (5.3 g, 57 %).'H NMR (CDCI3) 8 7. 01- 7. 04 (2H, m), 6.93-6. 96 (1 H, m), 4.05 (2H, t, J= 5.7 Hz), 3.83 (2H, t, J= 5.7 Hz), 2.31 (6H, s).

C. Preparation of 4- (2- (2, 6-dimethylphenoxy) ethoxy) -3- methoxybenzaldehyde :

To a 250 mL flask was added 2- (2-chloroethoxy) 1, 3-dimethylbenzene (4.23 g, 22.9 mmol), vanillin (3.45 g, 22.7 mmol), and anhydrous DMF (34 mL). To the flask was added-325 mesh K2CO3 (16 g, 120 mmol). The reaction mixture was allowed to vigorously stir at 70 °C for 1 d. The reaction mixture was diluted with EtOAc (150 mL) prior to filtration under reduced pressure. The filtrate solution was washed with sat.

NH4CI (70 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was chromatographed (Si02, hexane/EtOAc 100: 0 to 70: 30) to provide the title compound (3. 81g, 56 %).'H NMR (CDCI3) 8 9.87 (1H, s), 7.43-7. 47 (2H, m), 7.08 (1H, d, J= 8.1 Hz), 7.02 (2H, d, J= 7.5 Hz), 6.92-6. 96 (1H, m), 4.45-4. 47 (2H, m), 4.20-4. 23 (2H, m), 3.93 (3H, s), 2.32 (6H, s); MS (ESI) 301 (MH+).

D. Preparation of 2-Cyano-3- {4- [2- (2, 6-dimethyl-phenoxy)-ethoxy]- 3-methoxy-phenyl}-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-acrylamide : To a 25 mL flask was added 4- (2- (2, 6-dimethylphenoxy) ethoxy) -3- methoxybenzaldehyde (182 mg, 606 µmol), 2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acetamide (118 mg, 601 ilmol), anhydrous DMF (6 mL), absolute EtOH (2 mL) and TEA (150 µL, 1.08 mmol). The reaction solution was allowed to stir at 50 °C for 17 h.

The reaction solution was diluted with EtOAc (100 mL), washed with sat. NH4CI (50 mL x 3), dried over Na2SO4, filtered, and concentrated to approximately 1/3 the original volume. The yellow precipitates were collected by filtration under reduced pressure.

The crude precipitate was dissolved in a warm mixture of EtOAc and DCM. The product solution was allowed to cool to ambient ambient temperature, and the resulting yellow precipitate was filtered under reduced pressure to afford the title compound (125 mg, 43 %). The crude precipitate was alternatively chromatographed (Si02, DCM: MeOH 100: 0 to 95: 5) to provide the title compound.'H NMR (CDCI3) 6 10.1-10. 3 (1H, brs), 8.37 (1H, s), 7.81 (1H, d, J = 2. 1 Hz), 7.51 (1H, dd, J = 2. 1 Hz, 8.5 Hz), 7.01-7. 07 (3H, m), 6.93-6. 96 (1H, m), 4.47 (2H, m), 4.22 (2H, m), 3.95 (3H, s), 3.08 (2H, q, J = 7.6 Hz), 2.32 (6H, s), 1.43 (3H, t, J = 7.6 Hz); IR (KBr) vm,,, 2926, 2860, 2211,1594, 1509 cm-1; MS (ESI) 479 (MH+).

EXAMPLE 2 PREPARATION OF 4-(2-HYDROXYETHOXY)-3-METHOXYBENZALDEHYDE :

A. To a 250 mL flask was added vanillin (4.80 g, 31.3 mmol), anhydrous DMF (90 mL), and 2-bromoethanol (9.0 mL, 126 mmol). To the solution was added K2CO3 (21 g, 152 mmol), and the reaction slurry was stirred at 65 °C for 4 h. The reaction mixture was diluted with EtOAc (200 mL) and filtered under reduced pressure. The reaction solution was concentrated under reduced pressure, and the crude material was chromatographed (Si02, hexane/EtOAc 100: 0 to 80: 20) to afford the title compound (5.0 g, 81 % yield).'H NMR (CDCI3) 6 9.85 (1H, s), 7.41-7. 46 (2H, m), 7.01 (1H, d, J = 8. 1 Hz), 4.21 (2H, t, J = 4. 5 Hz), 4.03 (2H, t, J = 4.5 Hz), 3.92 (3H, s); MS (ESI) 197 (MH+).

B. Preparation of 4- (2- (3, 5-dimethylphenoxy) ethoxy) -3- methoxybenzaldehyde :

To a 50 mL flask, purged with dry N2, was added 4- (2-hydroxyethoxy)-3- methoxybenzaldehyde (302 mg, 1.54 mmol), triphenylphosphine (408 mg, 1.55 mmol),

and anhydrous THF (20 mL). The reaction solution was cooled to 0 °C prior to the addition of diisopropylazodicarboxylate (300 IlL, 1.54 mmol). The reaction solution was stirred at 0 °C for 10 min prior to the addition of a THF (5 mL) solution containing 3, 5-dimethylphenol (207 mg, 1.69 mmol) and TEA (240 L, 1.69 mmol). The reaction solution was stirred 7 h at ambient ambient temperature. The solution was concentrated under reduced pressure and the crude material was chromatographed (Si02, hexane/EtOAc 100: 0 to 80: 20) to provide the title compound (42 mg, 10 %).'H NMR (CDCI3) 8 9.86 (1 H, s), 7.42-7. 47 (2H, m), 7.07 (1H, d, J = 8.2 Hz), 6.63 (1 H, s), 6.58 (2H, s), 4.44-4. 47 (2H, m), 4.36-4. 38 (2H, m), 3.92 (3H, s), 2.29 (6H, s) ; MS (ESI) 301 (MH+) C. Preparation of 2-Cyano-3- {4- [2- (3, 5-dimethyl-phenoxy)-ethoxy]- 3-methoxy-phenyl}-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide : The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (2- (3, 5-dimethylphenoxy) ethoxy)-3-methoxybenzaldehyde and 2-cyano- N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) 6 8.36 (1H, s), 7.79 (1H, d, J = 2. 1 Hz), 7.50 (1 H, dd, J = 2. 1 Hz, 8. 6 Hz), 7.05 (1H, d, J = 8.5 Hz), 6.63 (1 H, s), 6.57 (2H, s), 4.47 (2H, m), 4.37 (2H, m), 3.96 (3H, s), 3.08 (2H, q, J = 7.6 Hz), 2.29 (6H, s), 1.44 (3H, t, J = 7.6 Hz) ; MS (ESI) 479 (MH+).

EXAMPLE 3 PREPARATION OF 4- (2- (M-TOLYLOXY) ETHOXY)-3-METHOXYBENZALDEHYDE :

A. The title compound was prepared in a manner similar to that described in Example 2B by using 3-methylphenol in place of 3, 5-dimethylphenol.'H NMR (CDCl3) 6 d 9.85 (1 H, s), 7.42-7. 47 (2H, m), 7.07 (1 H, d, J = 8.2 Hz), 6.57-6. 68 (4H, m), 4.42-4. 46 (2H, m), 4.34-4. 36 (2H, m), 3.95 (3H, s), 2.33 (3H, s); MS (ESI) 287 (MH+).

B. Preparation of 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3- methoxy-4- (2-m-tolyloxy-ethoxy)-phenyl]-acrylamide : The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (2- (m-tolyloxy) ethoxy)-3-methoxybenzaldehyde and 2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) 6 9.92 (1H, br s), 8.37 (1H, s), 7.79 (1H, d, J = 2. 1 Hz), 7.51 (1H, dd, J = 2. 1 Hz, 8. 5 Hz), 7.18 (1H, t, J= 7. 8 Hz), 7.06 (1H, d, J = 8.5 Hz), 6.74-6. 81 (3H, m), 4.48-4. 50 (2H, m), 4.38-4. 41 (2H, m), 3.94 (3H, s), 3.09 (2H, q, J = 7.6 Hz), 2.34 (3H, s), 1.44 (3H, t, J = 7.6 Hz); MS (ESI) 465 (MH+).

EXAMPLE 4 PREPARATION OF 4-(2-(2, 6-DIMETHYLPHENOXY) ETHOXY)-3-ETHOXYBENZALDEHYDE : A. The title compound was prepared in a manner similar to that described in Example 1C by using 3-ethoxy-4-hydroxyl-benzaldehyde and 2- (2- chloroethoxy) 1, 3-dimethylbenzene. 1H NMR (CDCl3) # 9. 86 (1H, s), 7.40-7. 46 (2H, m), 7.01-7. 05 (3H, m), 6.93-6. 97 (1 H, m), 4.43 (2H, m), 4. 21 (2H, m), 4.14 (2H, q, J = 7.0 Hz), 2.35 (6H, s), 1.48 (3H, t, J = 7.0 Hz).

B. Preparation of 2-Cyano-3- {4- [2- (2, 6-dimethyl-phenoxy)-ethoxy]- 3-ethoxy-phenyl}-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-acrylamide :

The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (2- (2, 6-dimethylphenoxy) ethoxy)-3-ethoxybenzaldehyde and 2-cyano-N- (5-ethyl- [1, 3, 41thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) 6 8.40 (1H, s), 7.80 (1H, d, J = 2.1 Hz), 7.51 (1 H, dd, J = 2.1 Hz, 8.5 Hz), 7.00-7. 05 (3H, m), 6.92-6. 97 (1 H, m), 4.44 (2H, m), 4.21 (2H, m), 4.15 (2H, q, J = 7.0 Hz), 3.09 (2H, q, J = 7.6 Hz), 2.35 (3H, s), 1.50 (3H, t, J = 7.0 Hz), 1.43 (3H, t, J = 7.6 Hz); MS (ESI) 493 (MH+).

EXAMPLE 5 PREPARATION OF 2-CYANO-N-THIAZOL-2-YL-ACETAMIDE :

A. The title compound was prepared in a manner similar to that described in Example 1A by using 2-aminothiazole in place of 5-ethyl-2-amino- [1,3, 4] thiadiazole.'H NMR (DMSO-d6) 6 12.4-12. 5 (1H, br s), 7.46 (1H, d, J = 3.6 Hz), 7.28 (1 H, d, J = 3.6 Hz), 4.03 (2H, s).

B. Preparation of 2-Cyano-3- (4-hydroxy-3-methoxy-phenyl)-N- thiazol-2-yl-acrylamide : The above compound was prepared in a manner similar to that described in Example 1D by using vanillin and 2-cyano-N-thiazol-2-yl-acetamide.'H NMR (DMSO-d6) 5 8.32

(1 H, s), 7.76 (1 H, d, J = 1.5 Hz), 7.54 (1 H, d, J = 4.4 Hz), 7.22 (1 H, d, J = 3.8 Hz), 6.97 (1H, d, J = 8.3 Hz), 3.85 (3H, s) ; MS (ESI) 330 (MH+).

EXAMPLE 6 PREPARATION OF 2-CYANO-N- (5-ETHYL- [1, 3, 4] THIADIAZOL-2-YL)-3-(4-HYDROXY-3- METHOXY-PHENYL)-ACRYLAMIDE :

The title compound was prepared in a manner similar to that described in Example 1 D by using vanillin and 2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acetamide. 1H NMR (DMSO-d6) # 10. 4 (1H, br s), 8.34 (1H, s), 7.76 (1H, s), 7.54 (1H, dd, J = 2.0 Hz, 8.4 Hz), 6.96 (1H, d, J = 8.3 Hz), 4.02 (1 H, s), 3.83 (3H, s), 2.94 (2H, q, J = 7.6 Hz), 1.29 (3H, t, J = 7.6 Hz); MS (ESI) 331 (MH+).

EXAMPLE 7 PREPARATION OF 2-CYANO-N-[5-ETHYL-3-(2-METHOXY-ETHYL)-3H-[1, 3, 4] THIADIAZOL-2- YLIDENE]-3-[3-METHOXY-4-(2-METHOXY-ETHOXY)-PHENYL]-ACRYLAMID E : To a flask was added 2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yi)-3- (4- hydroxy-3-methoxy-phenyl)-acrylamide (101 mg, 306 µmol), anhydrous DMF (4 mL), and 2-bromoethyl methylether (58 µL, 615 limon). To the reaction solution was added K2CO3 (130 mg, 941 fol). The reaction was stirred at 50 °C for 3 h. The excess K2CO3 was removed by filtration under reduced pressure. The filtrate was concentrated under reduced pressure, and the residue was chromatographed (SiO2, hex/DCM 100: 0 to 50: 50) to provide the title product (20 mg, 15 % yield).'H NMR (CDCI3) 8 8.27 (1 H, s), 7.86 (1 H, d, J = 2.0 Hz), 7.46 (1 H, dd, J = 2.0 Hz, 8.5 Hz), 6.97 (1 H, d, J = 8.4 H), 4.62 (2H, t, J = 5.4 Hz), 4.26 (2H, t, J = 4.8 Hz), 3.95 (3H, s), 3.92 (2H, m), 3. 82 (2H, m), 3. 46 (3H, s), 3.42 (3H, s), 2.92 (2H, q, J = 7.6 Hz), 1.38 (3H, t, J = 7.6 Hz) ; MS (ESI) 447 (MH+).

EXAMPLE 8 PREPARATION OF 3-METHOXY-4- (METHOXYMETHOXY) BENZALDEHYDE :

A. The title compound was prepared in a manner similar to that described in Example 2A by using methoxy methylchloride in place of 2-bromoethanol.

'H NMR (CDCI3) S 9.86 (1 H, s), 7.42-7. 44 (2H, m), 7.27-7. 29 (1 H, m), 5.33 (2H, s), 3.95 (2H, s), 3.52 (3H, s).

B. Preparation of 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (3- methoxy-4-methoxymethoxy-phenyl)-acrylamide :

The above compound was prepared in a manner similar to that described in Example 1 D by using 3-methoxy-4- (methoxymethoxy) benzaldehyde and 2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acetamide.'H NMR (CDC13) 8 8. 40 (1H, s), 7.87 (1H, d, J = 2. 1 Hz), 7.49 (1H, dd, J = 2.1 Hz, 8.5 Hz), 7.29 (1H, d, J = 5.2 Hz), 5.37 (2H, s), 3.99 (3H, s), 3.56 (3H, s), 3.08 (2H, q, J = 7.6 Hz), 1.45 (3H, t, J = 7.6 Hz); MS (ESI) 375 (MH+).

EXAMPLE 9 PREPARATION OF 2-CYANO-N- [5-ETHYL-3-METHYL-3H- [1, 3, 4] THIADIAZOL-2-YLIDENE]-3- (3- METHOXY-4-METHOXYMETHOXY-PHENYL)-ACRYLAMIDE :

To a flask was added 2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- (3- methoxy-4-methoxymethoxy-phenyl)-acrylamide (405 mg, 1.08 mmol), K2CO3 (300 mg, 2.17 mmol), and anhydrous DMF (7 mL). To the reaction slurry was added iodomethane (70 pL, 1.12 mmol). The reaction mixture was stirred at 45 °C for 20 min.

To the mixture was added EtOAc (75 mL), and the mixture was filtered under reduced pressure. The filtrate was washed with sat NH4CI (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to approximately 1/2 the volume.

The yellow precipitates were filtered under reduced pressure and reprecipitated in warm EtOAc to afford the title product (250 mg, 60 %).'H NMR (CDC13) 8 8.30 (1H, s), 7. 91 (1 H, d, J = 2. 1 Hz), 7.43 (1 H, dd, J = 2. 1 Hz, 8. 5 Hz), 7.23 (1 H, d, J = 8. 4 Hz), 5.32 (2H, s), 4.03 (3H, s), 3.98 (3H, s), 3.53 (3H, s), 2.91 (2H, q, J = 7.6 Hz), 1.38 (3H, t, J = 7.6 Hz) ; MS (ESI) 389 (MH+).

EXAMPLE 10 PREPARATION OF 2-CYANO-N- [5-ETHYL-3- (2-METHOXY-ETHYL)-3H- [1, 3, 4] THIADIAZOL-2- YLIDENE]-3-(4-HYDROXY-3-METHOXY-PHENYL)-ACRYLAMIDE :

To a flask was added 2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4- hydroxy-3-methoxy-phenyl)-acrylamide (113 mg, 342 limon), anhydrous DMF (5 mL) and 2-bromomethyl methylether (33 L, 346 mmol). The reaction solution was cooled to 0 °C prior to the addition of a 1.0 M THF solution of LiN (TMS) 2 (340 Pal). The reaction solution was allowed to stir, warming to ambient temperature and then at 50 °C for 12 h. The reaction solution was diluted with EtOAc (100 mL), washed with NH4CI (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was chromatographed (SiO2 hex/EtOAc 100: 0 to 75: 25) to afford the title compound (57 mg, 43 %). 'H NMR (CDCl3) # 8.27 (1H, s), 7.92 (1H, d, J=2. 1 Hz), 7.40 (1 H, dd, J = 2. 1 Hz, 8. 5 Hz), 6.99 (1H, d, J=8. 2Hz), 6.31 (1H, br s), 4.62 (2H, t, J = 5.4 Hz), 3.99 (3H, s), 3.93 (2H, t, J = 5.4 Hz), 3.42 (3H, s), 2.92 (2H, q, J = 7.6 Hz), 1.38 (3H, t, J = 7.6 Hz); MS (ESI) 389 (MH+).

EXAMPLE 11 PREPARATION OF 2-CYANO-N- [5-ETHYL-3-METHYL-3H- [1, 3, 4] THIADIAZOL-2-YLIDENE]-3- (4- HYDROXY-3-METHOXY-PHENYL)-ACRYLAMIDE :

The title compound was prepared in a manner similar to that described in Example 10 by using iodomethane in place of 2-bromomethyl methylether.'H NMR (CDCl3) 6 8. 30 (1H, s), 7.93 (1H, d, J = 2. 1 Hz), 7.41 (1H, dd, J = 2. 1 Hz, 8.5 Hz), 6.99 (1 H, d, J = 8.3 Hz), 6.16 (1 H, s), 4.03 (3H, s), 3.97 (3H, s), 2.90 (2H, q, J = 7.6 Hz), 1.38 (3H, t, J = 7.6 Hz); MS (ESI) 345 (MH+).

EXAMPLE 12 PREPARATION OF 2-CYANO-N-(5-ETHYL-[1, 3, 4]THIADIAZOL-2-YL)-3-[4-(2-HYDROXY- ETHOXY)-3-METHOXY-PHENYL]-ACRYLAMIDE

The title compound was prepared in a manner similar to that described in Example 1 D by using 4-(2-hydroxyethoxy)-3-methoxybenzaldehyde and 2-cyano-N- (5-ethyl-[1, 3,4] thiadiazol-2-yl)-acetamide. H NMR (CDCI3) 8 8.31 (1H, s), 7.73 (1H, d, J = 2. 1 Hz), 7.46 (1 H, dd, J= 2. 1 Hz, 8.1 Hz), 6.97 (1 H, d, J = 8. 4 Hz), 4.24 (2H, m), 4.06 (2H, m), 3.90 (3H, s), 3.08 (2H, q, J = 7.6 Hz), 1.43 (3H, t, J = 7.6 Hz); MS (ESI) 375 (MH+) EXAMPLE 13 PREPARATION OF N- [3-BENZYL-5-ETHYL-3H- [1, 3, 4]THIADIAZOL-2-YLIDENE]-2-CYANO-3-(4- HYDROXY-3-METHOXY-PHENYL)-ACRYLAMIDE

The title compound was prepared in a manner similar to that described in Example 10 by using benzyl bromide in place of 2-bromomethyl methylether.

1H NMR (CDCl3) # 8. 27 (1H, s), 7.96 (1H, d, J = 2. 1 Hz), 7.58-7. 60 (2H, m), 7.32-7. 39 (4H, m). 6.99 (1 H, d, J = 8.2 Hz), 6. 15 (1H, s), 5.56 (2H, s), 4.01 (3H, s), 2.89 (2H, q, J =7. 6 Hz), 1.36 (3H, t, J = 7.6 Hz); MS (ESI) 421 (MH+).

EXAMPLE 14 PREPARATION OF 4-(2-CHLOROETHOXY)-3-METHOXYBENZALDEHYDE A. The title compound was prepared in a manner similar to that described in Example 2A by using 2-bromo-chloroethane in place of 2-bromoethanol.

'H NMR (CDCI3) 6 9.86 (1H, s), 7.41-7. 45 (2H, m), 6.98 (1H, d, J = 8Hz), 4.35 (2H, t, J = 6.1 Hz), 3.91 (3H, s), 3.87 (2H, t, J = 6.1 Hz); MS (ESI) 215 (MH)+.

B. Preparation of 3- [4- (2-Chloro-ethoxy)-3-methoxy-phenyl]-2- cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide : The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (2-chloroethoxy)-3-methoxybenzaldehyde and 2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acetamide. 1H NMR (CDC ! 3) S 10.2 (1H, br s), 8.37 (1H, s), 7.81 (1H, d, J = 2.1 Hz), 7.50 (1H, dd, J= 2.1 Hz, 8.5 Hz), 6.97 (1H, d, J = 8.5 Hz), 4.38

(2H, t, J = 6. 1 Hz), 3.96 (3H, s), 3.90 (2H, t, J =6. 1 Hz), 3. 09 (2H, q, J = 7.6 Hz), 1.44 (3H, t, J = 7.6 Hz) ; MS (ESI) 393 (MH+).

EXAMPLE 15 PREPARATION OF 3-[4-(2-CHLORO-ETHOXY)-3-METHOXY-PHENYL]-2-CYANO-N-[5-ETHYL- 3- METHYL-3H- [1, 3, 4] THIADIAZOL-2-YLIDENE]-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 9 by using 3- [4- (2-chloro-ethoxy)-3-methoxy-phenyl]-2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide in place of 2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- 3-(3-methoxy-4-methoxymethoxy-phenyl)-acrylamide. 1H NMR (CDCI3) â 8.35 (1H, s), 7.81 (1 H, d, J = 2. 1 Hz), 7.49 (1 H, dd, J = 2. 1 Hz, 8. 5 Hz), 6.98 (1 H, d, J = 8. 5 Hz), 4.38 (2H, t, J = 6.1 Hz), 4.02 (3H, s), 3.96 (3H, s), 3.90 (2H, t, J = 6. 1 Hz), 3.09 (2H, q, J = 7.6 Hz), 1.44 (3H, t, J = 7.6 Hz); MS (ESI) 407 (MH+).

EXAMPLE 16 PREPARATION OF 2-CYANO-N-(5-METHYLSULFANYL-[1, 3, 4] THIADIAZOL-2-YL)-ACETAMIDE A. The title compound was prepared in a manner similar to that described in Example 1A by using 5-methythio-2-amino [1,3, 4] thiadiazole in place of 5- ethyl-2-amino [1,3, 4] thiadiazole.'H NMR (DMSO-d6) 8 12.7-12. 9 (1H, br s), 3.72 (2H , s), 2.66 (3H, s); MS (ESI) 217 (MH+).

B. Preparation of 2-Cyano-3- {4- [2- (2, 6-dimethyl-phenoxy)-ethoxy]- 3-methoxy-phenyl}-N- (5-methylsulfanyl- [1, 3,4] thiadiazol-2-yl)-acrylamide :

The above compound was prepared in a manner similar to that described in Example 1D by using 2-cyano-N- (5-methylsulfanyl- [1, 3,4] thiadiazol-2-yl)-acetamide in place of 2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acetamide. 1H NMR (CDC) s) 5 10.0-10. 2 (1H, br s), 8.37 (1 H, s), 7.80 (1 H, d, J = 2.1 Hz), 7.52 (1 H, dd, J = 2.1 Hz, 8.5 Hz), 7.07 (1 H, d, J= 8.5 Hz), 7.02 (1H, d, J= 7.4 Hz), 6.93-6. 96 (1H, m), 4.47 (2H, m), 4.22 (2H, m), 3.96 (3H, s), 2.77 (3H, s), 2.32 (6H, s) ; MS (ESI) 497 (MH+).

EXAMPLE 17 PREPARATION OF 2-CYANO-3-{4-[2-(2, 6-DIMETHYL-PHENOXY)-ETHOXY]-3-METHOXY- PHENYL}-N-[5-ETHYL-3-METHYL-3H-[1, 3, 4] THIADIAZOL-2-YLIDENE]-ACRYLAMIDE

The title compound was prepared in a manner similar to that described in Example 9 by using 2-cyano-3- {4- [2- (2, 6-dimethyl-phenoxy)-ethoxy]-3-methoxy- phenyl}-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide in place of 2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-3- (3-methoxy-4-methoxymethoxy-phenyl)-acrylamide.'H NMR (CDCl3) # 8. 31 (1 H, s), 7.88 (1 H, d, J = 2. 1 Hz), 7.51 (1 H, dd, J = 2. 1 Hz, 8.5 Hz), 7.01- 7.05 (3H, m), 6.92-6. 96 (1H, m), 4.45 (2H, m), 4.21 (2H, m), 4.03 (3H, s), 3.96 (3H, s), 2.92 (2H, q, J = 7.5 Hz), 2.31 (6H, s), 1.38 (3H, t, J = 7.5 Hz); MS (ESI) 493 (MH').

EXAMPLE 18 PREPARATION OF 2-CYANO-3- {4- [2- (2, 6-DIMETHYL-PHENOXY)-ETHOXY]-3-METHOXY- PHENYL}-N-THIAZOL-2-YL-ACRYLAMIDE

The title compound was prepared in a manner similar to that described in Example 1 D by using 2-cyano-N-thiazol-2-yl-acetamide in place of 2-cyano-N- (5- ethyl- [1, 3,4] thiadiazol-2-yl)-acetamide. 1H NMR (CDCI3) 8 9.66 (1H, br s), 8.38 (1H, s), 7.79 (1 H, d, J = 2.1 Hz), 7.48-7. 73 (2H, m), 7.01-7. 08 (4H, m), 6.93-6. 96 (1 H, m), 4.46- 4.48 (2H, m), 4.21-4. 23 (2H, m), 3.96 (3H, s), 2.32 (6H, s) ; IR (KBr) Vmax 3005,2925, 2860,2205, 1666,1515 cm-1 ; MS (ESI) 450 (MH+).

EXAMPLE 19 PREPARATION OF N- (5-TERT-BUTYL- [1, 3, 4] THIADIAZOL-2-YL)-2-CYANO-ACETAMIDE A. The title compound was prepared in a manner similar to that described in Example 1A by using 5-tert-butyl-2-amino [1,3, 4] thiadiazole in place of 5- ethyl-2-amino [1,3, 4] thiadiazole.'H NMR (CDCI3) 5 3.98 (2H, s), 1.49 (9H, s), IR (KBr) vmax 3187, 2968,2749, 2260,1700, 1580 cm-1 ; MS (ESI) 225 (MH+).

B. Preparation of 2-Cyano-3- {4- [2- (2, 6-dimethyl-phenoxy)-ethoxy]- 3-methoxy-phenyl}-N-(5-tert-butyl-[1, 3,4] thiadiazol-2-yl)-acrylamide The above compound was prepared in a manner similar to that described in Example 1D by using N- (5-tert-butyl- [1, 3,4] thiadiazol-2-yl)-2-cyano-acetamide in place of 2-

cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDC13) 8 10. 03 (1H, br s), 8.36 (1H, s), 7.81 (1H, d, J = 2.1 Hz), 7.50 (1H, dd, J = 2.1 Hz, 8.5 Hz), 7.01-7. 07 (3H, m), 6.93-6. 96 (1 H, m), 4.48 (2H, t, J = 4.9 Hz), 4.22 (2H, t, J = 4.9 Hz), 3.96 (3H, s), 2.32 (6H, s), 1.49 (9H, s) ; IR (KBr) vax 3161,2960, 2226,1621 cm~1 ; MS (ESI) 507 (MH+).

EXAMPLE 20 PREPARATION OF 2-CYANO-N-(5-TRIFLUOROMETHYL-[1,3,4]THIADIAZOL-2-YL)-ACETAMI DE A. The title compound was prepared in a manner similar to that described in Example 1A by using 5-trifluoromethyl-2-amino [1,3, 4] thiadiazole in place of 5-ethyl-2-amino [1,3, 4] thiadiazole. MS (ESI) 238 (MH+).

B. Preparation of 1-(2-chloroethoxy)-2-allylbenzene : The above compound was prepared in a manner similar to that described in Example 1B by using 2-allylphenol in place of 2, 6-dimethylphenol. 1H NMR (CDCI3) 8 7.17-7. 21 (2H, m), 6.95 (1H, t, J = 7.4 Hz), 6. 83 91H, d, J = 8 Hz), 6.02 (1H, m), 5.04-5. 10 (2H, m), 4.25 (2H, t, J = 5.8 Hz), 3.83 (2H, t, J = 5.8 Hz), 3.43 (2H, d, J = 6.7 Hz).

C. Preparation of 4- (2- (2-allylphenoxy) ethoxy) -3- methoxybenzaldehyde : The above compound was prepared in a manner similar to that described in Example 1 C by using 1- (2-chloroethoxy)-2-allylbenzene in place of 2- (2-chloroethoxy) 1,3- dimethylbenzene.'H NMR (CDCl3) 8 9.86 (1H, s), 7.42-7. 46 (2H, m), 7.14-7. 20 (2H,

m), 7.07-7. 09 (1H, d, J = 8.1 Hz), 6.89-6. 95 (2H, m), 5.97 (1 H, m), 4.98-5. 05 (2H, m), 4.47-4. 49 (2H, m), 4.38-4. 04 (2H, m), 3.91 (3H, s), 3.36 (2H, d, J = 6.6 Hz); MS (ESI) 313 (MH+).

D. Preparation of 3- {4- [2- (2-Allyl-phenoxy)-ethoxy]-3-methoxy- phenyl}-2-cyano-N- (5-trifluoromethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide : The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (2- (2-allylphenoxy) ethoxy)-3-methoxybenzaldehyde and 2-cyano-N- (5- ethyl- (1, 3,4] thiadiazol-2-yl)-acetamide. 1H NMR (CDCl3) # 8. 42 (1H, s), 7.82 (1H, d, J= 2.1 Hz), 7.55 (1H, dd, J=2. 1 Hz, 8. 5 Hz), 7.15-7. 22 (2H, m), 7.10 (1H, d, J=8. 5Hz), 6.90-6. 96 (2H, m), 5.96 (1 H, m), 4.99-5. 05 (2H, m), 4.50-4. 52 (2H, m), 4.41-4. 43 (2H, m), 3.96 (3H, s), 3.36 (2H, d, J = 6.5 Hz); MS (ESI) 531 (MH+).

EXAMPLE 21 PREPARATION OF 3- {4- [2- (2-ALLYL-PHENOXY)-ETHOXY]-3-METHOXY-PHENYL}-2-CYANO-N- (5-METHYLSULFANYL- [1, 3, 4] THIADIAZOL-2-YL)-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1 D by using 4- (2- (2-allylphenoxy) ethoxy)-3-methoxybenzaldehyde and 2- cyano-N- (5-methylsulfanyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) # 8.36 (1 H, s), 7.79 (1 H, d, J = 2.1 Hz), 7.51 (1 H, dd, J = 2. 1 Hz, 8.5 Hz), 7.14-7. 22 (2H, m), 7.08 (1 H, d, J = 8.5 Hz), 6.90-6. 96 (2H, m), 5.96 (1 H, m), 4.98-5. 05 (2H, m), 4.51-4. 53 (2H, m), 4.40-4. 42 (2H, m), 3.95 (3H, s), 3.36 (2H, d, J = 6.5 Hz), 2.75 (3H, s) ; MS (ESI) 509 (MH+).

EXAMPLE 22 <BR> <BR> PREPARATION OF 2-CYANO-3-{4-[2-(2, 6-DIMETHYL-PHENOXY)-ETHOXY]-3-METHOXY-<BR> <BR> PHENYL}-N- (5-TRIFLUOROMETHYL- 1, 3, 4] THIADIAZOL-2-YL)-ACRYLAMIDE

The title compound was prepared in a manner similar to that described in Example 1 D by using 2-cyano-N- (5-trifluoromethyl- [1, 3,4] thiadiazol-2-yl)-acetamide in place of 2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) 8 10.1 (1H, br s), 8.42 (1H, s), 7.82 (1H, d, J = 2.1 Hz), 7.55 (1 H, dd, J = 2. 1 Hz, 8.5 Hz), 7.09 (1 H, d, J = 8.5 Hz), 7.02 (2H, d, J = 7.2 Hz), 6.93-6. 97 (1 H, m), 4.48-4. 50 (2H, m), 4.22-4. 24 (2H, m), 3.97 (3H, s), 2.32 (6H, s); MS (ESI) 519 (MH+).

EXAMPLE 23 <BR> <BR> <BR> <BR> PREPARATION OF 3- (4- [2- (2-ALLYL-PHENOXY)-ETHOXY]-3-METHOXY-PHENYL}-N- (5-TERT- BUTYL- 1, 3, 4]THIADIAZOL-2-YL)-2-CYANO-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1 D by using 4- (2- (2-allylphenoxy) ethoxy)-3-methoxybenzaldehyde and N- (5-tert-butyl- [1, 3,4] thiadiazol-2-yl)-2-cyano-acetamide.'H NMR (CDCl3) 8 10.04 (1H, br s), 8.36 (1H, s), 7.81 (1H, d, J = 2 Hz), 7.50 (1H, dd, J = 2.0 Hz, 8.6 Hz), 7.15-7. 22 (2H, m), 7.07 (1 H, d, J = 8.5 Hz), 6.90-6. 96 (2H, m), 5.93-6. 00 (1 H, m), 4.99-5. 05 (2H, m), 4.50-4. 52 (2H, m), 4.40-4. 42 (2H, m), 3.94 (3H, s), 3.36 (2H, d, J = 6.6 Hz), 1.49 (9H, s); MS (ESI) 519 (MH+).

EXAMPLE 24 PREPARATION OF 2-CYANO-N- (1, 3, 4] THIADIAZOL-2-YL)-ACETAMIDE

A. The title compound was prepared in a manner similar to that described in Example 1A by using 2-amino [1,3, 4] thiadiazole in place of 5-ethyl-2- amino [1,3, 4] thiadiazole.'H NMR (DMSO-d6) 8 12.6-13. 0 (1H, br s), 8.95 (1H, s), 3.88 (2H, s) ; IR (KBr) via 3195, 3085,2929, 2261,1699, 1574 cm-1 ; MS (ESI) 168 (MH+).

B. Preparation of 2-Cyano-3- {4- [2- (2, 6-dimethyl-phenoxy)-ethoxy]- 3-methoxy-phenyl}-N- [1, 3,4] thiadiazol-2-yl-acrylamide : The above compound was prepared in a manner similar to that described in Example 1 D by using 2-cyano-N- [1, 3,4] thiadiazol-2-yl-acetamide in place of 2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acetamide.'H NMR (CDOs) # 10.04 (1H, br s), 8.91 (1H, s), 8.41 (1 H, s), 7.82 (1 H, d, J = 2 Hz), 7.53 (1 H, dd, J = 2.0 Hz, 8.5 Hz), 7.08 (1 H, d, J = 8.5 Hz), 7.01-7. 05 (2H, m), 6.92-6. 96 (1H, m), 4.47-4. 49 (2H, m), 4.21-4. 23 (2H, m), 3.96 (3H, s), 2.32 (6H, s) ; MS (ESI) 451 (MH+).

EXAMPLE 25 <BR> <BR> <BR> <BR> <BR> PREPARAT ! ONOF3- {4- [2- (2-ALLYL-PHENOXY)-ETHOXY]-3-METHOXY-PHENYL}-2-CYANO-N- [1, 3, 4] THIADIAZOL-2-YL-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1 D by using 4- (2- (2-allylphenoxy) ethoxy)-3-methoxybenzaldehyde and 2-

cyano-N- [1, 3,4] thiadiazol-2-yl-acetamide.'H NMR (CDC13) b 10. 01 (1H, brs), 8.91 (1H, s), 8.41 (1H, s), 7.81 (1H, d, J = 2.0 Hz), 7.53 (1H, dd, J = 2 Hz, 8 Hz), 7.13-7. 22 (2H, m), 7.09 (1 H, d, J = 8.6 Hz), 6. 89- 6. 96 (2H, m), 5.90-6. 02 (2H, m), 5.95 (1 H, m), 4.97- 5.05 (2H, m), 4.53 (2H, t, J = 5.3 Hz), 4.41 (2H, t, J = 5.3 Hz), 3.95 (3H, s), 3.36 (2H, d, J = 7 Hz); MS (ESI) 463 (MH+).

EXAMPLE 26 PREPARATION OF 2- (3-CHLOROPROPOXY)-1, 3-DIMETHYLBENZENE A. The title compound was prepared in a manner similar to that described in Example 1 B by using 1-bromo-3chloropropane in place of 1-bromo- 2chloroethane.'H NMR (CDCI3) 6 7.03 (2H, d, J = 7.6 Hz), 6.93-6. 96 (1 H, m), 3.92 (2H, t, J = 6.3 Hz), 3.86 (2H, t, J = 6.3 Hz), 2.36 (6H, s), 2.26 (2H, m); MS (ESI) 199 (MH+).

B. Preparation of 4- (3- (2, 6-dimethylphenoxy) propoxy) -3- methoxybenzaldehyde : The above compound was prepared in a manner similar to that described in Example 1C by using 2- (3-chloropropoxy)-1, 3-dimethylbenzene in place of 2- (2- chloroethoxy) 1, 3-dimethylbenzene. 1H NMR (CDCI3) # 9.86 (1H, s), 7.42-7. 47 (2H, m), 7.05 (1 H, d, J = 8. 2 Hz), 6.99 (2H, d, J = 7. 3 Hz), 6.90-6. 92 (1 H, m), 4.41 (2H, t, J = 6. 3 Hz), 3.99 (2H, t, J = 6.3 Hz), 3.94 (3H, s), 2.36 (2H, m), 2.24 (6H, s); MS (ESI) 315 (MH+).

C. Preparation of 2-Cyano-3- {4- [3- (2, 6-dimethyl-phenoxy)-propoxy]- 3-methoxy-phenyl}-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide :

The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (3- (2, 6-dimethylphenoxy) propoxy)-3-methoxybenzaldehyde and in place of 4- (2- (2, 6-dimethylphenoxy) ethoxy)-3-methoxybenzaldehyde.'H NMR (CDCI3) 8 10.8-10. 9 (1H, bs), 8.37 (1H, s), 7.81 (1H, d, J = 2 Hz), 6.93-7. 05 (3H, m), 6.91 (1H, m), 4.43 (2H, t, J = 6.5 Hz), 3.99 (2H, t, J = 6.1 Hz), 3.95 (3H, s), 3.09 (2H, q, J = 7.6 Hz), 2.37 (2H, m), 2.24 (6H, s), 1.44 (3H, t, J = 7.6 Hz); MS (ESI) 493 (MH+).

EXAMPLE 27 PREPARAT ! ONOF2-CYANO-3- {4- [3- (2, 6-DtMETHYL-PHENOXY)-PROPOXY]-3-METHOXY- PH (5-METHYLSULFANYL-[1,3,4]THIADIAZOL-2-YL)-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1 D by using 4- (3- (2, 6-dimethylphenoxy) propoxy)-3-methoxybenzaldehyde and 2-cyano-N- (5-methylsulfanyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) 8 9.6-9. 8 (1H, br s), 8.37 (1 H, s), 7.80 (1H, d, J = 2.1 Hz), 7.52 (1H, dd, J = 2. 1 Hz, 8.5 Hz), 6.93-7. 04 (3H, m), 6.92 (1 H, m), 4.44 (2H, t, J = 6 Hz), 3.99 (2H, t, J = 6 Hz), 3.95 (3H, s), 2.77 (3H, s), 2.38 (2H, m), 2.24 (6H, s); MS (ESI) 511 (MH+).

EXAMPLE 28 PREPARATION OF N- (5-TERT-BUTYL- 1, 3, 4] THIADIAZOL-2-YL)-2-CYANO-3- 4- 3- (2, 6- DIMETHYL-PHENOXY)-PROPOXY]-3-METHOXY-PHENYL}-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1 D by using 4- (3- (2, 6-dimethylphenoxy) propoxy)-3-methoxybenzaldehyde

and N- (5-tert-butyl- [1, 3,4] thiadiazol-2-yl)-2-cyano-acetamide.'H NMR (CDCI3) 8 9.94 (1H, br s), 8.36 (1H, s), 7.81 (1H, d, J =2.1 Hz), 7.51 (1H, dd, J = 2.1 Hz, 8.5 Hz), 6.99- 7.05 (3H, m), 6.92 (1H, m), 4.43 (2H, t, J = 6 Hz), 3.99 (2H, t, 6 Hz), 3.95 (3H, s), 2.38 (2H, m), 2.24 (6H, s), 1.49 (9H, s); MS (ESI) 521 (MH').

EXAMPLE 29 PREPARATION OF 5-PHENYL-2-AMINO[1, 3, 4] THIADIAZOLE

A. To a 250 mL flask was added thiosemicarbazide (5.21 g, 57.2 mmol) and anhydrous pyridine (40 mL). To the reaction solution at 0 °C was added, dropwise, benzoyl chloride (6.64 mL, 57.2 mmol). The reaction solution was allowed to stir at ambient ambient temperature for 16 h. The reaction solution was poured into 250 mL ice water. The resulting precipitates were isolated by filtration under reduced pressure. The white precipitates were added portion wise to conc. H2SO4 (100 mL) at ambient temperature. The solution was allowed to heat at 40 °C for 30 min. The solution was poured into 800 mL of ice water. The resulting precipitates were isolated by filtration under reduced pressure to afford the title compound (1.8 g, 20 %).'H NMR (DMSO-d6) 8 7.89-7. 92 (2H, m), 7.33-7. 45 (3H, m); MS (ESI) 178 (MH+).

B. Preparation of 2-cyano-N- (5-phenyl- [1, 3,4] thiadiazol-2-yl)- acetamide:

The above compound was prepared in a manner similar to that described in Example 1A by using 5-phenyl-2-amino [1,3, 4] thiadiazole in place of 5-ethyl-2- amino [1,3, 4] thiadiazole.'H NMR (DMSO-d6) 8 7.92 (1H, m), 7.87 (1H, m), 7.34-7. 49 (3H, m), 3.74 (2H, br s) ; MS (ESI) 245 (MH+).

C. Preparation of 3- {4- [2- (2-Allyl-phenoxy)-ethoxy]-3-methoxy- phenyl}-2-cyano-N- (5-phenyl- [1, 3,4] thiadiazol-2-yl)-acrylamide

The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (2- (2-allylphenoxy) ethoxy) -3- methoxybenzaldehyde and 2-cyano-N- (5-pheyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) â 10.21 (1H, br s), 8. 41 (1H, s), 7.92-7. 95 (2H, m), 7.83 (1H, d, J = 2.1 Hz), 7.47-7. 55 (4H, m), 7.15-7. 21 (2H, m), 7.07 (1H, d, J= 8.5 Hz), 6.90-6. 96 (2H, m), 5.97 (1 H, m), 4.99-5. 05 (2H, m), 4.52 (2H, m), 4.41 (2H, m), 3.94 (3H, s), 3.36 (2H, d, J = 6.6 Hz); MS (ESI) 539 (MH+).

EXAMPLE 30 PREPARATION OF 2-CYANO-N- (5-METHYL- [1, 3, 4] THIADIAZOL-2-YL)-ACETAMIDE A. The title compound was prepared in a manner similar to that described in Example 1A by using 5-methyl-2-amino [1,3, 4] thiadiazole in place of 5- ethyl-2-amino [1,3, 4] thiadiazole. MS (ESI) 183 (MH+).

B. Preparation of 3- {4- [2- (2-Allyl-phenoxy)-ethoxy]-3-methoxy- phenyl}-2-cyano-N- (5-methyl- [1, 3, 4] thiadiazol-2-yl)-acrylamide : The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (2- (2-allylphenoxy) ethoxy)-3-methoxybenzaldehyde and 2-cyano-N- (5- methyl-[1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) 8 8.38 (1H, s), 7.80 (1H, d, J =2. 1 Hz), 7.51 (1H, dd, J=2. 1 Hz, 8. 5 Hz), 7.14-7. 19 (2H, m), 7.08 (1H, d, J = 8. 5 Hz), 6.90-6. 96 (2H, m), 5.96 (1H, m), 4.98-5. 04 (2H, m), 4.51-4. 53 (2H, m), 4.40-4. 42 (2H, m), 3.94 (3H, s), 3.36 (2H, d, J = 6.6 Hz), 2.74 (3H, s); MS (ESI) 465 (MH+).

EXAMPLE 31 PREPARATION OF 5- (4'-DIMETHYLAMINOPHENYL)-2-AMINO [1, 3, 4] THIADIAZOLE

A. The title compound was prepared in a manner similar to that described in Example 29A by using 4-dimethylaminobenzoyl chloride in place of benzoyl chloride. MS (ESI) 222 (MH).

B. Preparation of 2-Cyano-N- [5- (4-dimethylamino-phenyl)- [1,3, 4] thiadiazol-2-yl]-acetamide : The above compound was prepared in a manner similar to that described in Example 1A by using 5- (4'-dimethylaminophenyl)-2-amino [1,3, 4] thiadiazole in place of 5-ethyl-2- amino [1,3, 4] thiadiazole. MS (ESI) 288 (MH+).

C. Preparation of 2-Cyano-N- [5- (4-dimethylamino-phenyl)- [1,3, 4] thiadiazol-2-yl]-3-{4-[2-(2,6-dimethyl-phenoxy)-ethoxy]-3-me thoxy-phenyl}- acrylamide : The above compound was prepared in a manner similar to that described in Example 1D by using 2-cyano-N-[5-(4-dimethylamino-phenyl)-[1, 3,4] thiadiazol-2-yl]-acetamide in place of 2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) 8 8.40 (1H, s), 7.76 (1H, d, J= 2.1 Hz), 7.71 (2H, d, J= 8. 9 Hz), 7.46 (1H, dd, J = 2. 1 Hz, 8.5 Hz), 6.98 (1 H, s), 6.95 (2H, d, J = 6.6 Hz), 6.89 (1H, m), 6.75 (2H, d, J = 8.9 Hz), 4.39 (2H, m), 4.15 (2H, m), 3.86 (3H, s), 2.98 (6H, s), 2.22 (6H, s); MS (ESI) 570 (MH+).

EXAMPLE 32 PREPARATION OF 3- {4- [2- (2-ALLYL-PHENOXY)-ETHOXY]-3-METHOXY-PHENYL}-2-CYANO-N- [5-(4-DIMETHYLAMINO-PHENYL)-[1,3,4]THIADIAZOL-2-YL]-ACRYLAMI DE

The title compound was prepared in a manner similar to that described in Example 1 D by using 4- (2- (2-allylphenoxy) ethoxy)-3-methoxybenzaldehyde and 2- cyano-N- [5- (4-dimethylamino-phenyl)- [1, 3,4] thiadiazol-2-yl]-acetamide.'H NMR (CDCI3) # 8. 41 (1 H, s), 7.80-7. 85 (3H, m), 7.53 (1H, dd, J = 2.0 Hz, 8.3 Hz), 7.13-7. 22 (2H, m), 7.07 (1 H, d, J = 8.3 Hz), 6.85-6. 96 (4H, m), 5.96 (1 H, m), 4.96-5. 06 (2H, m), 4.51 (2H, m), 4.41 (2H, m), 3.94 (3H, s), 3.36 (2H, d, J = 6.6 Hz), 3.07 (6H, s); MS (ESI) 583 (MH+) EXAMPLE 33 PREPARATION OF 4-(2, 4-BIS (TRIFLUOROMETHYL) BENZYLOXY)-3-METHOXY BENZALDEHYDE A. The title compound was prepared in a manner similar to that described in Example 1C by using 2, 4-bis-trifluoromethylbenzyl bromide in place of 2- (2-chloroethoxy) 1, 3-dimethylbenzene. 1H NMR (CDCI3) 5 9.85 (1H, s), 7.96-7. 98 (2H, m), 7.86 (1H, d, J = 8.3 Hz), 7.48 (1 H, d, J = 1.9 Hz), 7.42 (1H, dd, J = 1.9 Hz, 8.1 Hz), 6.93 (1 H, d, J = 8.1 Hz), 5.48 (2H, s), 3.99 (3H, s); MS (ESI) 379 (MH+).

B. Preparation of 3- [4- (2, 4-Bis-trifluoromethyl-benzyloxy)-3- methoxy-phenyl]-2-cyano-N- (5-trifluoromethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide

The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (2, 4-bis (trifluoromethyl) benzyloxy)-3-methoxybenzaldehyde and 2- cyano-N- (5-trifluoromethyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (DMSO-d6) 8 8.37 (1 H, s), 7.92 (1 H, d, J = 8.2 Hz), 7.87 (1 H, s), 7.80-7. 85 (2H, m), 7.41 (1 H, dd, J = 2.0 Hz, 8.6 Hz), 6.90 (1H, d, J = 8.3 Hz), 5.39 (2H, s), 3.91 (3H, s); IR (KBr) vma, 3220, 2945,2224, 1597,1513 cm'' ; MS (ESI) 597 (MH+).

EXAMPLE 34 <BR> <BR> <BR> <BR> PREPARATION OF 3-[4-(2, 4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-PHENYL]-2- CYANO-N-[1, 3, 4] THIADIAZOL-2-YL-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1 D by using 4- (2, 4-bis (trifluoromethyl) benzyloxy)-3-methoxybenzaldehyde and 2-cyano-N- [1, 3,4] thiadiazol-2-yl-acetamide. 1H NMR (DMSO-d6) 8 8.71 (1H, s), 8.30 (1 H, s), 7.79-7. 91 (4H, m), 7.36 (1 H, dd, J = 2.1 Hz, 8.5 Hz), 6.85 (1 H, J = 8.4 Hz), 5.38 (2H, s), 3.90 (3H, s); MS (ESI) 529 (MH+).

EXAMPLE 35 PREPARATION OF 5- (4'-METHOXYBENZYLTHIOL)-2-AMINO [1, 3, 4] THIADIAZOLE A. To a 100 mL flask was added 5-thiol-2-amino [1,3, 4] thiadiazole (1. 57g, 11.8 mmol) and H2O (6.0 mL). To the suspension was added a 6 N KOH (2.0

mL). The reaction suspension was allowed to stir at 0 °C for 10 min prior to the addition of 4-methoxylbenzyl chloride (1.60 mL, 11.8 mmol). The mixture was stirred at ambient temperature for 2 h. The the mixture was added H2O (25 mL), and the white precipitates were isolated by filtration under reduced pressure. The precipitates were washed with H20 (40 mL) then Et20 (50 mL) and dried under reduced pressure to afford the title compound (2.12 g, 71 %).'H NMR (DMSO-d6) 8 7.12-7. 18 (2H, m), 6.73-6. 77 (2H, m), 4.28 (2H, s), 3.66 (3H, s), 3.19 (2H, s); MS (ESI) 254 (MH+).

B. Preparation of 2-Cyano-N- [5- (4-methoxy-benzylsulfanyl)- [1,3, 4] thiadiazol-2-yl]-acetamide : The above compound was prepared in a manner similar to that described in Example 1A by using 5- (4'-methoxybenzylthio)-2-amino [1,3, 4] thiadiazole in place of 5-ethyl-2- amino [1,3, 4] thiadiazole. MS (ESI) 323 (MH+).

C. Preparation of 2-Cyano-3- {4- [2- (2, 6-dimethyl-phenoxy)-ethoxy]- 3-methoxy-phenyl}-N- [5- (4-methoxy-benzylsulfanyl)- [1, 3, 4] thiadiazol-2-yll-acrylamide : The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (2- (2, 6-dimethylphenoxy) ethoxy)-3-methoxybenzaldehyde and 2-cyano- N- [5- (4-methoxy-benzylsulfanyl)- [1, 3,4] thiadiazol-2-yl]-acetamide.'H NMR (CDCI3) 8 8.36 (1 H, s), 7.78 (1 H, d, J = 2.1 Hz), 7.60 (1 H, dd, J = 2. 1 Hz, 8. 5 Hz), 7.28 (2H, d, J = 7.5 Hz), 6.97-7. 03 (3H, m), 6.90 (1H, m), 6.81 (2H, d, J = 7.5 Hz), 4.40 (2H, m), 4.39 (2H, s), 4.17 (2H, m), 3.91 (3H, s), 3.75 (3H, s), 2.27 (6H, s); MS (ESI) 603 (MH+).

EXAMPLE 36 PREPARATION OF 4- (2-METHOXYETHOXY)-3-METHOXYBENZALDEHYDE

A. The title compound was prepared in a manner similar to that described in Example 1 C by using 2-bromoethyl methylether in place of 2- (2- chloroethoxy) 1, 3-dimethylbenzene.'H NMR (CDCl3) # 9.85 (1H, s), 7.40-7. 44 (2H, m), 7. 01 (1H, d, J = 8.1 Hz), 4.26 (2H, m), 3.92 (3H, s), 3.82 (2H, m), 3.46 (3H, s); MS (ESI) 211 (MH+).

B. Preparation of 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3- methoxy-4-(2-methoxy-ethoxy)-phenyl]-acrylamide The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (2-methoxyethoxy)-3-methoxybenzaldehyde and 2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) b 8.43 (1H, s), 7.80 (1H, s), 7.51 (1H, d, J = 8.4 Hz), 6.99 (1H, d, J = 8.4 Hz), 4.28 (2H, m), 3.93 (3H, s), 3.83 (2H, s), 3.45 (3H, s), 3.09 (2H, q, J = 7.6 Hz), 1.42 (3H, t, J = 7.6 Hz) ; MS (ESI) 389 (MH').

EXAMPLE 37 PREPARATION OF 4- (2-ETHOXYETHOXY)-3-METHOXYBENZALDEHYDE A. The title compound was prepared in a manner similar to that described in Example 1 C by using 2-bromoethyl ethylether in place of 2- (2- chloroethoxy) 1, 3-dimethylbenzene.'H NMR (CDCI3) 8 9.85 (1H, s), 7.36-7. 41 (2H, m), 6.98 (1H, d, J= 8.1 Hz), 4.22 (2H, m), 3.88 (3H, s), 3.83 (2H, m), 3.56 (2H, q, J = 6.5 Hz), 1.20 (3H, t, J = 6.5 Hz); MS (ESI) 225 (MH+).

B. Preparation of 2-Cyano-3- [4- (2-ethoxy-ethoxy)-3-methoxy- phenyl]-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-acrylamide :

The above compound was prepared in a manner similar to that described in Example 1 D by using 4-(2-ethoxyethoxy)-3-methoxybenzaldehyde and 2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) 5 8.44 (1H, s), 7.81 (1H, s), 7.52 (1 H, d, J = 8.5 Hz), 7.00 (1 H, d, J =8.5 Hz), 4.29 (2H, m), 3.94 (3H, s), 3.87 (2H, m), 3.61 (2H, q, J = 7. 0 Hz), 3.10 (2H, q, J = 7. 6 Hz), 1.44 (3H, t, J = 7. 6 Hz), 1.25 (3H, t, J = 7.0 Hz) ; MS (ESI) 403 (MH+).

EXAMPLE 38 PREPARATION OF 4-((2-METHOXYETHOXY)METHOXY)-E-METHOXYBENZALDEHYDE A. The title compound was prepared in a manner similar to that described in Example 1C by using 1- (chloromethoxy)-2-methoxyethane in place of 2- (2-chloroethoxy) 1, 3-dimethylbenzene. 1H NMR (CDCI3) 8 9.86 (1H, s), 7.39-7. 42 (2H, m), 7.29 (1H, d, J = 8.1 Hz), 5.39 (2H, s), 3.93 (3H, s), 3.68 (2H, m), 3.53 (2H, m), 3.34 (3H, s); MS (ESI) 241 (MH+).

B. Preparation of 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3- methoxy-4-(2-methoxy-ethoxymethoxy)-phenyl]-acrylamide : The above compound was prepared in a manner similar to that described in Example 1D by using 4-((2-methoxyethoxy) methoxy>3-methoxybenzaldehyde and 2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acetamide. 1H NMR (CDCl3) # 8.41 (1H, s), 7.84 (1H, d, J = 2.0 Hz), 7.47 (1 H, dd, J = 2.0 Hz, 8.5 Hz), 7.29 (1 H, d, J = 8.5 Hz), 5.43 (2H, s),

3.96 (3H, s), 3.87 (2H, m), 3.56 (2H, m), 3.37 (3H, s), 3.08 (2H, q, J = 7.6 Hz), 1.43 (3H, t, J = 7.6 Hz) ; MS (ESI) 418 (MH+).

EXAMPLE 39 <BR> <BR> <BR> <BR> PREPARATION OF 3-[4-(2, 4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-PHENYL]-2- CYANO-N-(5-PHENYL-[1, 3, 4] THIADIAZOL-2-YL)-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1 D by using 4- (2, 4-bis (trifluoromethyl) benzyloxy)-3-methoxybenzaldehyde and 2-cyano-N- (5-pheyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) b 10.3-10. 4 (1 H, br s), 8.41 (1 H, s), 7.88-7. 97 (6H, m), 7.47-7. 50 (4H, m), 6.91 (1 H, d, J = 8.5 Hz), 5.48 (2H, s), 4.01 (3H, s); MS (ESI) 605 (MH+).

EXAMPLE 40 PREPARATION OF 2-CYANO-3-{4-[2-(2, 6-DIMETHYL-PHENOXY)-ETHOXY]-3-METHOXY- PHENYL}-N-(5-MERCAPTO-[1, 3, 4]THIADIAZOL-2-YL)-ACRYLAMIDE To a flask was added 2-cyano-3- {4- [2- (2, 6-dimethyl-phenoxy)-ethoxy]-3- methoxy-phenyl}-N-[5-(4-methoxy-benzylsulfanyl)-[1, 3,4] thiadiazol-2-yl]-acrylamide (61 mg, 101 µmol), DCM (5.0 mL), and trifluoroacetic acid (6.0 mL). The solution was allowed to reflux for 8 h. The reaction solution was diluted with DCM (50 mL), neutralized by washing with sat NaHCO3 (40 mL x 3), dried over MgS04, filtered, and concentrated under reduced pressure. The crude residue was chromatographed (Si02, DCM/MeOH 100: 0 to 90: 10) to afford the title compound (11mg, 22 %).

MS (ESI) 483 (MH+).

EXAMPLE 41 PREPARATION OF 5- (2-MORPHOLINOETHYLTHIO)-1, 3, 4-THIADIAZOL-2-AMINE

A. The title compound was prepared in a manner similar to that described in Example 35A by using 4- (2-chloroethyl) morpholine in place of 4- methoxybenzyl bromide.'H NMR (DMSO-d6) 6 3.55 (4H, m), 3.20 (2H, t, J = 6.9 Hz), 2.59 (2H, t, J = 6.9 Hz), 2.39 (4H, m); MS (ESI) 247 (MH+).

B. Preparation 2-Cyano-N- [5- (2-morpholin-4-yl-ethylsulfanyl)- [1,3, 4] thiadiazol-2-yl]-acetamide : The above compound was prepared in a manner similar to that described in Example 1A by using 5- (2-morpholinoethylthio)-1, 3, 4-thiadiazol-2-amine in place of 5-ethyl-2- amino [1,3, 4] thiadiazole. 1 H NMR (CDCI3) 8 3.93 (2H, s), 3.76 (4H, m), 3.47 (2H, t, J = 6.5 Hz), 2.87 (2H, m), 2.62 (4H, m) ; MS (ESI) 314 (MH+).

C. Preparation of 2-Cyano-3- {4- [2- (2, 6-dimethyl-phenoxy)-ethoxy]- 3-methoxy-phenyl}-N- [5- (2-morpholin-4-yl-ethylsulfanyl)- [1, 3,4] thiadiazol-2-yl]- acrylamide : The above compound was prepared in a manner similar to that described in Example 1 D by using 2-cyano-N- [5- (2-morpholin-4-yl-ethylsulfanyl)- [1, 3,4] thiadiazol-2-yl]- acetamide in place of 2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCl3) 8 8.38 (1 H, s), 7.80 (1 H, d, J = 2.0 Hz), 7.52 (1 H, dd, J = 2.0 Hz, 8.5 Hz), 7.06 (1 H, d, J = 8.5 Hz), 7.02 (2H, d, J = 7.4 Hz), 6.94 (1 H, m), 4.47 (2H, m), 4.21 (2H, m),

3.95 (3H, s), 3.77 (4H, br s), 3.50 (2H, m), 2.88 (2H, br s), 2.62 (4H, br s), 2.31 (6H, s) ; MS (ESI) 596 (MH+).

EXAMPLE 42 <BR> <BR> <BR> <BR> <BR> PREPARATION OF 3-{4-[2-(2-ALLYL-PHENOXY)-ETHOXY]-3-METHOXY-PHENYL}-2-CYANO- N- [5-(2-MORPHOLIN-4-YL-ETHYLSULFANYL)-[1,3,4]THIADIAZOL-2-YL]- ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1 D by using 2-cyano-N- [5- (2-morpholin-4-yl-ethylsulfanyl)- [1, 3,4] thiadiazol- 2-yl]-acetamide and 4- (2- (2-allylphenoxy) ethoxy)-3-methoxybenzaldehyde.'H NMR (CDCI3) 8 8.39 (1H, s), 7.79 (1 H, d, J = 2.0 Hz), 7.52 (1H, dd, J = 2.0 Hz, 8.4 Hz), 7.14- 7.21 (2H, m), 7.08 (1H, d, J = 8.5 Hz), 6.88-6. 96 (2H, m), 5.96 (1H, m), 4.99-5. 04 (2H, m), 4.52 (2H, m), 4.41 (2H, m), 3.94 (3H, s), 3. 79 (4H, br s), 3.53 (2H, br s), 3.36 (2H, d, J = 6.6 Hz), 2.94 (2H, br s), 2.66 (4H, br s); MS (ESI) 608 (MH+).

EXAMPLE 43 <BR> <BR> PREPARATION OF 4-(2-(2, 6-DIMETHYLPHENOXY) ETHOXY)-3, 5-DIMETHOXYBENZALDEHYDE A. The title compound was prepared in a manner similar to that described in Example 1C by using syringaldehyde in place of vanillin.'H NMR (CDCI3) # 9. 87 (1H, s), 7.14 (2H, s), 7.00 (2H, d, J = 7. 0 Hz), 6.92 (1H, m), 4.47 (2H, t, J = 5 Hz), 4.11 (2H, t, J = 5 Hz), 3.92 (6H, s), 2.30 (6H, s); MS (ESI) 331 (MH+).

B. Preparation of 2-Cyano-3-{4-[2-(2,6-dimethyl-phenoxy)-ethoxy]- 3, 5-dimethoxy-phenyl}-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-acrylamide :

The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (2- (2, 6-dimethylphenoxy) ethoxy) -3, 5-dimethoxybenzaldehyde in place of 4-(2-(2,6-dimethylphenoxy)ethoxy)-3-methoxybenzaldehyde. 1H NMR (CDCI3) 8 8.34 (1H, s), 7.19 (2H, s), 6.94 (2H, d, J = 7.5 Hz), 6.87 (1H, m), 4.45 (2H, t, J = 5Hz), 4.04 (2H, t, J = 5 Hz), 3.85 (6H, s), 3.02 (2H, q, J = 7.6 Hz), 2.24 (6H, s), 1.37 (3H, t, J = 7.6 Hz); MS (ESI) 509 (MH+).

EXAMPLE 44 PREPARATION OF 2-CYANO-3-{4-[2-(2, 6-DIMETHYL-PHENOXY)-ETHOXY]-3, 5-DIMETHOXY- PHENYL}-N- (5-TRI FLUOROMETHYL- 1, 3, 4] THIADIAZOL-2-YL)-ACRYLAMI DE The title compound was prepared in a manner similar to that described in Example 1 D by using 2-cyano-N- (5-trifluoromethyl- [1, 3,4] thiadiazol-2-yl)-acetamide and 4-(2-(2,6-dimethylphenoxy)ethoxy)-3,5-dimethoxybenzaldehyde. 1H NMR (CDCI3) 8 8.41 (1 H, s), 7.35 (2H, s), 7.01 (2H, d, J = 7.5 Hz), 6.92 (1 H, m), 4.55 (2H, t, J = 5 Hz), 4.11 (2H, t, J = 5 Hz), 3.93 (6H, s), 2.31 (6H, s); MS (ESI) 549 (MH+).

EXAMPLE 45 PREPARATION OF 4-(2-(2, 6-DIMETHYLPHENOXY) ETHOXY)-3-CHLORO-5- METHOXYBENZALDEHYDE A. The title compound was prepared in a manner similar to that described in Example 1C by using 5-chlorovanillin in place of vanillin.'H NMR (CDCI3)

8 9. 85 (1H, s), 7.52 (1H, d, J = 1.8 Hz), 7.37 (1H, d, J = 1.8 Hz), 7.02 (2H, d, J = 7. 4 Hz), 6.93 (1H, m), 4.50 (2H, m), 4.16 (2H, m), 3.94 (3H, s), 2.32 (6H, s); MS (ESI) 335 (MH+) B. Preparation of 3- {3-Chloro-4- [2- (2, 6-dimethyl-phenoxy)-ethoxy]- 5-methoxy-phenyl}-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide The above compound was prepared in a manner similar to that described in Example 1 D by using 4-(2-(2, 6-dimethylphenoxy) ethoxy)-3-chloro-5-methoxybenzaldehyde in place of 4-(2-(2, 6-dimethylphenoxy) ethoxy)-3-methoxybenzaldehyde'H NMR (CDCI3) # 8. 40 (1 H, s), 7.80 (1 H, d, J = 1. 8 Hz), 7.56 (1 H, d, J = 1. 8 Hz), 7.02 (2H, m), 6.94 (1 H, m), 4.55 (2H, m), 4.42 (2H, m), 4.01 (3H, s), 3.09 (2H, q, J = 7.6 Hz), 2.32 (6H, s), 1.44 (3H, t, J = 7.6 Hz); MS (ESI) 513 (MH+).

EXAMPLE 46 <BR> <BR> <BR> PREPARATION OF 3- {3-CHLORO-4- [2- (2, 6-DIMETHYL-PHENOXY)-ETHOXY]-5-METHOXY-<BR> <BR> <BR> <BR> PHENYL}-2-CYANO-N- (5-TRIFLUOROMETHYL- 1, 3, 4] THIADIAZOL-2-YL)-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1D by using 2-cyano-N- (5-trifluromethyl- [1, 3,4] thiadiazol-2-yl)-acetamide and 4- (2- (2, 6-dimethylphenoxy) ethoxy)-3-chloro-5-methoxybenzaldehyde.'H NMR (CDCI3) 8 10.1-10. 3 (1H, br s), 8.37 (1H, s), 7.75 (1H, d, J = 2.1 Hz), 7.57, (1H, d, J = 2.1 Hz), 7.01 (2H, d, J= 7.4 Hz), 6.92-6. 95 (1H, m), 4.58 (2H, m), 4.15 (2H, m), 3.97 (3H, s), 2.32 (6H, s); MS (ESI) 553 (MH+).

EXAMPLE 47 PREPARATION OF 3-METHOXY-4-PHENOXYBENZALDEHYDE

A. To a flask was added vanillin (1.03 g, 6.77 mmol), phenyl boronic acid (1.65 g, 13.5 mmol), copper (lI) acetate (1.22g, 6.77 mmol), 4A molecular sieves (1g), DCM (73 mL), and TEA (4.7 mL, 34 mmol). The reaction solution was allowed to stir at ambient ambient temperature under N2 for 11 h. The reaction mixture was diluted with DCM (100 mL), and the suspension was filtered under reduced pressure. The filtrate was washed with sat NH4CI (50 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was chromatographed (SiO2, hex/EtOAc 100: 0 to 85: 15) to provide the title compound (232 mg, 15 %).'H NMR (CDCI3) ã 9. 89 (1H, s), 7.43 (1H, d, J = 1. 8 Hz), 7.28 (1 H, m), 7.08-7. 16 (2H, m), 6.96 (2H, m), 6.82 (1H, d, J= 8.1 Hz), 6.75 (1H, dd, J= 1.0 Hz, 8.6 Hz), 3.85 (3H, s); MS (ESI) 229 (MH+).

B. Preparation of 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(3- methoxy-4-phenoxy-phenyl)-acrylamide The above compound was prepared in a manner similar to that described in Example 1 D by using 3-methoxy-4-phenoxybenzaldehyde in place of 4- (2- (2, 6- dimethylphenoxy) ethoxy)-3-methoxybenzaldehyde.'H NMR (CDCI3) 8 8.44 (1H, s), 7.90 (1 H, d, J = 2.0 Hz), 7.38-7. 43 (2H, m), 7.21 (1 H, m), 7.08 (2H, m), 6.86 (2H, d, J = 8.4 Hz), 3.99 (3H, s), 3.09 (2H, q, J = 7.6 Hz), 1.44 (3H, t, J = 7.6 Hz) ; MS (ESI) 407 (MH+).

EXAMPLE 48 PREPARATION OF 4- (O-TOLYLOXY)-3-METHOXYBENZALDEHYDE

A. The title compound was prepared in a manner similar to that described in Example 47A by using 2-methylphenyl boronic acid in place of phenyl boronic acid. MS (ESI) 243 (MH+).

B. Preparation of 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- (3- methoxy-4-o-tolyloxy-phenyl)-acrylamide : The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (o-tolyloxy)-3-methoxybenzaldehyde in place of 4-(2-(2, 6- dimethylphenoxy) ethoxy)-3-methoxybenzaldehyde.'H NMR (CDCI3) å 8.48 (1H, s), 7.92 (1H, d, J = 2.1 Hz), 7.43 (1H, dd, J = 2.1 Hz, 8.5 Hz) 7.16-7. 28 (3H, s). 6.99 (1H, d, J = 8.4 Hz), 6.62 (1H, d, J = 8.4 Hz), 4.02 (3H, s), 3.10 (2H, q, J = 7.6 Hz), 2.20 (3H, s), 1.45 (3H, t, J = 7.6 Hz); MS (ESI) 421 (MH+).

EXAMPLE 49 PREPARATION OF 2-CYANO-3- (3-METHOXY-4-0-TOLYLOXY-PHENYL)-N- (5- TRIFLUOROMETHYL-[1, 3, 4]THIADIAZOL-2-YL)-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1D by using 2-cyano-N-(5-trifluoromethyl-[1, 3,4] thiadiazol-2-yl)-acetamide and 4-(o-tolyloxy)-3-methoxybenzaldehyde. 1H NMR (CDCl3) # 8. 40 (1H, s), 7.90 (1H, d, J = 2. 0 Hz), 7.41 (1H, dd, J = 2.0 Hz, 8.5 Hz), 7.30 (1H, d, J = 7.2 Hz), 7.18-7. 27 (2H, m), 7.01 (1 H, d, J = 8.0 Hz), 6.64 (1 H, d, J =8.5 Hz), 4.05 (3H, s), 2.20 (3H, s) ; MS (ESI) 462 (MH+).

EXAMPLE 50 PREPARATION OF [2-(2-CYANO-ACETAMIDE)-THIAZOL-4-YL]-ACETIC ACID

A. The title compound was prepared in a manner similar to that described in Example 1A by using 2-amino-4-thiazole-acetic acid in place of 5-ethyl-2- amino [1,3, 4] thiadiazole. 1H NMR (DMSO-d6) # 7. 10 (1H, s), 4.75 (2H, s), 3.32 (2H, s); MS (ESI) 248 (MH+).

B. Preparation of [2- (2-Cyano-3- {4- [2- (2, 6-dimethyl-phenoxy)- ethoxy]-3-methoxy-phenyl}-acryloylamino)-thiazol-4-yl]-aceti c acid : The above compound was prepared in a manner similar to that described in Example 1 D by using [2-(2-Cyano-acetamide)-thiazol-4-yl]-acetic acid in place of 2-cyano-N- (5- ethyl- [1, 3,4] thiadiazol-2-yl)-acetamide. MS (ESI) 508 (MH+).

EXAMPLE 51 PREPARATION OF [2- (3- {4- [2- (2-ALLYL-PHENOXY)-ETHOXY]-3-METHOXY-PHENYL}-2-CYANO- ACRYLOYLAMINO)-THIAZOL-4-YL]-ACETIC ACID The title compound was prepared in a manner similar to that described in Example 1D by using 2- (6, 7-dihydro-5-imino-7-oxo-5H-thiazolo [3, 2-a] pyrimidin-3- yl) acetic acid and 4- (2- (2-allylphenoxy) ethoxy)-3-methoxybenzaidehyde. MS (ESI) 520 (MH+).

EXAMPLE 52 PREPARATION OF 2-CYANO-N-(4-METHYL-THIAZOL-2-YL)-ACRYLAMIDE

A. The title compound was prepared in a manner similar to that described in Example 1A by using 2-amino-4-methylthiazole in place of 5-ethyl-2- amino [1,3, 4] thiadiazole.'H NMR (DMSO-d6) S 7.09 (1H, s), 4.75 (2H, s), 2.32 (3H, s); MS (ESI) 182 (MH+).

B. Preparation of 2-Cyano-3- {4- [2- (2, 6-dimethyl-phenoxy)-ethoxy]- 3-methoxy-phenyl}-N- (4-methyl-thiazol-2-yl)-acrylamide :

The above compound was prepared in a manner similar to that described in Example 1 D by using 2-cyano-N- (4-methyl-thiazol-2-yl)-acrylamide in place of 2-cyano-N- (5- ethyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) â 8. 38 (1H, s), 7.80 (1H, d, J = 2.1 Hz), 7.49 (1H, dd, J= 2.1 Hz, 8.5 Hz), 7.01-7. 06 (3H, s), 6.94-6. 96 (1H, m), 6.62 (1 H, s), 4.47 (2H, t, J = 4.9Hz), 4.21 (2H, m), 3.95 (3H, s), 2.40 (3H, s), 2.31 (6H, s); MS (ESI) 482 (MH+).

EXAMPLE 53 PREPARATION OF 3-{4- [2- (2-ALLYL-PHENOXY)-ETHOXY]-3-METHOXY-PHENYL}-2-CYANO-N- (4-METHYL-TH IAZOL-2-YL)-ACRYLAM I DE

The title compound was prepared in a manner similar to that described in Example 1 D by using 2-cyano-N- (4-methyl-thiazol-2-yl)-acrylamide and 4- (2- (2- allylphenoxy) ethoxy)-3-methoxybenzaldehyde'H NMR (CDCI3) 8 8.43 (1H, s), 7.83 (1 H, d, J = 2.0 Hz), 7.52 (1 H, dd, J = 2.0 Hz, 8.5 Hz), 7.13-7. 22 (2H, m), 7.07 (1 H, d, J =8.5 Hz), 6.89-6. 96 (2H, m), 6.97 (1H, m), 4.96-5. 06 (2H, m), 4.51 (2H, m), 4.41 (2H, m), 3.94 (3H, s), 3.36 (2H, d, J = 6.8 Hz), 2.43 (3H, s); MS (ESI) 494 (MH+).

EXAMPLE 54 PREPARATION OF 4-(2-(2, 6-DIMETHYLPHENOXY) ETHOXY)-3-METHOXY-5- NITROBENZALDEHYDE A. The title compound was prepared in a manner similar to that described in Example 1C by using 5-nitrovanillin in place of vanillin.'H NMR (CDCI3) 5 9.92 (1H, s), 7.85 (1H, d, J = 1.8 Hz), 7.64 (1H, d, J = 1.8 Hz), 7.01 (2H, m), 6.93 (1H, m), 4.63 (2H, t, J = 5.0 Hz), 4.16 (2H, t, J = 5.0 Hz), 4.01 (3H, s), 2.30 (6H, s); MS (ESI) 346 (MH+).

B. Preparation of 2-Cyano-3- {4- [2- (2, 6-dimethyl-phenoxy)-ethoxy]- 3-methoxy-5-nitro-phenyl}-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide :

The above compound was prepared in a manner similar to that described in Example 1 D by using 4-(2-(2, 6-dimethylphenoxy) ethoxy)-3-methoxy-5-nitrobenzaldehyde in place of 4- (2- (2, 6-dimethylphenoxy) ethoxy)-3-methoxybenzaldehyde. MS (ESI) 524 (MH+).

EXAMPLE 55 PREPARATION OF 3- 4- (2, 4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-PHENYL-N- (5-TERT-suTYL-[1, 3, 4] THIADIAZOL-2-YL)-2-CYANO-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1 D by using 4- (2, 4-bis (trifluoromethyl) benzyloxy)-3-methoxybenzaldehyde and N- (5-tert-butyl- [1, 3,4] thiadiazol-2-yl)-2-cyano-acetamide.'H NMR (CDC13) 8 8.36 (1 H, s), 7. 94-7. 96 (2H, m), 7.87-7. 90 (2H, m), 7.42 (1 H, dd, J = 2.1 Hz, 8.5 Hz), 6.89 (1 H, d, J = 8.5 Hz), 5.47 (2H, s), 3.99 (3H, s), 1.45 (9H, s); MS (ESI) 585 (MH+).

EXAMPLE 56 <BR> <BR> <BR> <BR> <BR> PREPARATtONOF3- [4- (2, 4-B ! S-TR ! FLUOROMETHYL-BENZYLOXY)-3-METHOXY-PHENYL]-2- CYANO-N- (5-METHYLSULFANYL- [1, 3, 4] THIADIAZOL-2-YL)-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1D by using 4- (2, 4-bis (trifluoromethyl) benzyloxy)-3-methoxybenzaldehyde and 2-cyano-N- (5-methylsulfanyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCl3) 8 8.45 (1 H, s), 7.93-7. 98 (2H, m), 7.84-7. 89 (2H, m), 7.50 (1 H, dd, J = 2.1 Hz, 8.6 Hz), 6.93 (1 H, d, J = 8.6 Hz), 5.49 (2H, s), 4.01 (3H, s), 2.78 (3H, s); MS (ESI) 575 (MH+).

EXAMPLE 57 <BR> <BR> PREPARAT ! ONOF2-CYANO-2- {4- [2- (2, 6-DtMETHYL-PHENOXY)-ETHOXY]-3-METHOXY-<BR> <BR> BENZYL}-N- (5-ETHYL- [1, 3, 4] THIADIAZOL-2-YL)-ACETAMIDE

To a N2 purged flask was added 2-cyano-3- {4- [2- (2, 6-dimethyl- phenoxy)-ethoxy]-3-methoxy-phenyl}-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-acrylamide (100 mg, 209 limon), anhydrous DME (9 mL), NaBH3CN (40 mg, 627 µmol), and acetic acid (4 mL). The reaction solution was stirred at ambient temperature for 2 h. The solution was diluted with EtOAc (100 mL), washed with sat. NaHCO3 (100 x 3), washed with sat NaCl (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure.

The crude material was chromatographed (SiO2, DCM/MeOH 100: 0 to 98: 2) to afford the title product (20 mg, 20 %). 'H NMR (CDCl3) # 7.00 (2H, d, J = 7.5 Hz), 6.84-6. 94 (4H, m), 4.43 (1H, m), 4.31 (2H, m), 4.14 (2H, m), 3.78 (3H, s), 3.33-3. 41 (2H, m), 3.10 (2H, q, J = 7.6 Hz), 2.29 (6H, s), 1.44 (3H, t, J = 7.6 Hz); MS (ESI) 481 (MH+).

EXAMPLE 58 PREPARATION OF 2-[4-(2,4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-BENZYL]-2 - CYANO-N- (5-TRIFLUOROMETHYL- 1, 3, 4] THIADIAZOL-2-YL)-ACETAMIDE The title compound was prepared in a manner similar to that described in Example 57 by using 3- [4- (2, 4-bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2- cyano-N- (5-trifluoromethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide in place of 2-cyano-3- {4- [2- (2, 6-dimethyl-phenoxy)-ethoxy)-3-methoxy-phenyt}-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide.'H NMR (CDCI3) 6 7. 98 (1 H, d, J = 8. 0 Hz), 7.93 (1 H, s), 7.82 (1 H, d, J = 8.0 Hz), 6.88 (1 H, d, J = 2.0 Hz), 6.83 (1 H, dd, J = 2.0 Hz, 8.2 Hz), 6.72 (1 H, d, J = 8.2 Hz), 5.34 (2H, s), 4.23 (1 H, t, J = 7.3 Hz), 3.86 (3H, s), 3.33-3. 41 (2H, m) ; MS (ESI) 500 (MH+) EXAMPLE 59 PREPARATION OF 3, 4-BIS (BENZYLOXY) BENZALDEHYDE

A. The title compound was prepared in a manner similar to that described in Example 1C by using 3, 4-dihydroxy-benzaldehdye and benzyl chloride.

'H NMR (CDCI3) 8 9. 91 (1H, s), 7.37-7. 50 (12H, m), 7.06 (1H, d, J= 8.2 Hz), 5.26 (2H, s), 5.22 (2H, s); MS (ESI) 319 (MH+).

B. Preparation of 3- (3, 4-Bis-benzyloxy-phenyl)-2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide :

The above compound was prepared in a manner similar to that described in Example 1 D by using 3,4-bis (benzyloxy) benzaldehyde in place of 4- (2- (2, 6- dimethylphenoxy) ethoxy)-3-methoxybenzaldehyde.'H NMR (CDCI3) 8 8.31 (1H, s), 7.80 (1H, d, J= 2.1 Hz), 7.28-7. 52 (11H, m), 6.98 (1H, d, J = 8. 6 Hz), 5.27 (2H, s), 5.23 (2H, s), 3.07 (2H, q, J = 7.6 Hz), 1.41 (3H, t, J = 7.6 Hz); MS (ESI) 497 (MH+).

EXAMPLE 60 PREPARATION OF 3- (3, 4-BtS-BENZYLOXY-PHENYL)-2-CYANO-N- [1, 3, 4] THIADIAZOL-2-YL- ACRYLAMIDE

The title compound was prepared in a manner similar to that described in Example 1 D by using 3,4-bis (benzyloxy) benzaldehyde and 2-cyano-N- [1,3, 4] thiadiazol-2-yl-acetamide'H NMR (CDCI3) 8 8.42 (1H, s), 7.92 (1H, s), 7.46 (1H, d, J = 2. 1 Hz), 6.90-7. 10 (11 H, m), 6.64 (1 H, d, J = 8.0 Hz), 4.84 (2H, s), 4.79 (2H, s); MS (ESI) 468 (MH+).

EXAMPLE 61 PREPARATION OF 3-(3, 4-BIS-BENZYLOXY-PHENYL)-2-CYANO-N-(5-METHYLSULFANYL- [1, 3, 4] THIADIAZOL-2-YL)-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1 D by using 3,4-bis (benzyloxy) benzaldehyde and 2-cyano-N- (5- methylsulfanyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCI3) 6 8.30 (1H, s), 7.79 (1H, d, J = 2. 0 Hz), 7.31-7. 51 (11H, m), 6.99 (1H, d, J = 8. 6 Hz), 5. 28 (2H, s), 5.24 (2H, s), 2.72 (3H, s); MS (ESI) 468 (MH+).

EXAMPLE 62 PREPARATION OF 2-CYANO-N-(5-ETHYL-[1, 3, 4] OXADIAZOL-2-YL)-ACETAMIDE

A. The title compound was prepared in a manner similar to that described in Example 1A by using 5-ethyl-2-amino[1. 3.4] oxadiazole in place of 5-ethyl- 2-amino [1,3, 4] thiadiazole. MS (ESI) 181 (MH+).

B. Preparation of 3- [4- (2, 4-Bis-trifluoromethyl-benzyloxy)-3- methoxy-phenyl]-2-cyano-N- (5-ethyl- [1, 3,4] oxadiazol-2-yl)-acrylamide : The above compound was prepared in a manner similar to that described in Example 1 D by using 4- (2, 4-bis (trifluoromethyl) benzyloxy)-3-methoxybenzaldehyde and 2- cyano-N- (5-ethyl- [1, 3,4] oxadiazol-2-yl)-acetamide. 1H NMR (DMSO-d6) 8 8.22 (1H, s), 8.18 (1H, d, J = 8.6 Hz), 8.11 (1H, s), 8.03 (1H, d, J = 8.3 Hz), 7.77 (1H, s), 7.59 (1H, d, J = 8.6 Hz), 7.21 (1 H, d, J = 8.6 Hz), 5.44 (2H, s), 3.84 (3H, s), 2.74 (2H, q, J = 7.6 Hz), 1.23 (3H, t, J = 7.6 Hz); MS (ESI) 541 (MH+).

EXAMPLE 63 PREPARATION OF 2-CYANO-3- {4- [2- (2, 6-DIMETHYL-PHENOXY)-ETHOXY]-3-METHOXY- PHENYL}-N-(5-ETHYL-[1, 3, 4] OXADIAZOL-2-YL)-ACRYLAM I DE The title compound was prepared in a manner similar to that described in Example 1D by using 2-cyano-N- (5-ethyl- [1, 3, 4] oxadiazol-2-yl)-acetamide in place of 2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acetamide.'H NMR (CDCl3) 8 8.33 (1H, s), 7.86 (1H, s), 7.51 (1H, dd, J = 2.1 Hz, 8.4 Hz), 7.01-7. 05 (3H, m), 6.95 (1H, m), 4.46 (2H, t, J = 4.8 Hz), 4.21 (2H, m), 3.95 (3H, s), 2.83 (2H, q, J = 7.6 Hz), 2.31 (6H, s), 1.39 (3H, t, J = 7.6 Hz); MS (ESI) 463 (MH+).

EXAMPLE 64 PREPARATION OF 3-[4-(2, 4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-PHENYL]-2- METHYL-ACRYLIC ACID ETHYL ESTER

To a 50 mL flask was added triethyl-2-phosphonopropionate (0.50 mL, 2.33 mmol), anhydrous hexane (7.0 mL), and potassium-t-butoxide (314 mg, 2.57 mmol). The solution was stirred at ambient temperature for 30 min prior to the addition of 4- (2, 4-bis (trifluoromethyl) benzyloxy)-3-methoxybenzaldehyde (300 mg, 0.93 mmol) in a solution of DCM (10 mL). The reaction solution was stirred at ambient temperature for 3 h. The solution was diluted with EtOAc (50 mL) and H20 was added to quench. The organic phase was washed with sat. NH4CI (100 mL x 3), partitioned, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was chromatographed (Si02, hex/EtOAc 100: 0 to 90: 10) to afford the title compound (267 mg, 65 % yield).'H NMR (CDCI3) # 7.99 (1 H, d, J = 8.3 Hz), 7.94 (1 H, s), 7.84 (1 H, d, J = 8.3 Hz), 7.62 (1 H, s), 6.94-7. 01 (2H, m), 6.83 (1 H, d, J = 8.3 Hz), 5.42 (2H, s), 4.27 (2H, q, J = 7.1 Hz), 3.93 (3H, s), 2.13 (3H, d, J = 1.3 Hz), 1.35 (3H, t, J = 7. 1 Hz).

EXAMPLE 65 PREPARATION OF 3-[4-(2, 4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-PHENYL]-2- METHYL-ACRYLIC ACID To a 20 mL glass vial was added 3- [4- (2, 4-Bis-trifluoromethyl- benzyloxy)-3-methoxy-phenyl]-2-methyl-acrylic acid ethyl ester (200 mg, 433 mol), EtOH (5 mL), and 2N NaOH (10 mL, 20 mmol). The reaction solution was allowed to

stir at 45 °C for 16 h. The reaction solution was diluted with EtOAc (100 mL) and 1 N HCI was added to make the aqueous phase slightly acidic. The organic phase was partitioned, washed with H20 (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was chromatographed (SiO2, DCM/MeOH 100: 0 to 92: 8) to provide pure title compound (169 mg, 90 % yield).

'H NMR (CDCI3) 5 8.00 (1 H, d, J = 8.2 Hz), 7.95 (1 H, s), 7.85 (1 H, d, J = 8.2 Hz), 7.76 (1H, s), 7.01-7. 03 (2H, m), 6.85 (1H, d, J = 8.1 Hz), 5.44 (2H, s), 3.95 (3H, s), 2.16 (3H, s) ; MS (ESI) 435 (MH), 452 (M+H20).

EXAMPLE 66 <BR> <BR> <BR> <BR> <BR> PREPARATION OF 3- [4- (2, 4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-PHENYL]-2- METHYL-ACRYLIC ACID N'-PHENYL-HYDRAZIDE

To a 25 mL flask attached with condenser was added 3- [4- (2, 4-Bis- trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2-methyl-acryli c acid (160 mg, 370 pmol), DCM (5 mL), and a, a-dicloromethyl methylether (260 L, 2.96 mmol). The solution was allowed to reflux under N2 for 3h prior to removal of excess a, a- dicloromethyl methylether under reduced pressure. To the flask containing the crude acid chloride was added CHCI3 (5 mL), phenyl hydrazine (75 tiL, 0.74 mmol), and TEA (155 pLL, 1.11 mmol). The reaction solution was stirred at 65 °C for 9 h. The solution was diluted with DCM (100 mL), washed with sat. NH4CI (50 mLx 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the crude material which was chromatographed (Si02, DCM : MeOH 100: 0 to 92: 8) to afford the title compound (18 mg, 10 % yield). 1 H NMR (CDCI3) â 8. 00 (1 H, d, J = 8. 3 Hz), 7.94 (1 H, s), 7.84 (1 H, d, J = 8. 3 Hz), 7.82 (1 H, br s), 7.40 (1 H, s), 6.90-6. 98 (6H, m), 6.84 (1H, d, J = 8.3 Hz), 5.42 (2H, s), 3.93 (3H, s), 2.18 (3H, s); MS (ESI) 525 (MH'), 547 (M+NH3).

EXAMPLE 67 <BR> <BR> PREPARATION OF N-BENZYL-3- [4- (2, 4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-<BR> <BR> PHENYL]-2-METHYL-ACRYLAMIDE

The title compound was prepared in a manner similar to that described in Example 66 by using benzyl amine in place of phenyl hydrazine.'H NMR (CDC) s) 8 7.99 (1 H, d, J = 8.3 Hz), 7.94 (1 H, s), 7.83 (1 H, d, J = 8.3 Hz), 7.28-7. 39 (6H, m), 6.92 (1H, d, J = 2. 0 Hz), 6.88 (1H, dd, J = 2.0 Hz, 8. 3 Hz), 6. 78-6. 83 (1H, m), 6.12 (1H, t, J = 5. 3 Hz), 5.41 (2H, s), 4.57 (2H, d, J = 5. 6 Hz), 3.92 (3H, s), 2.13 (3H, d, J = 1. 3 Hz) ; MS (ESI) 524 (MH+).

EXAMPLE 68 PREPARATION OF 3-[4-(2,4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-PHENYL]-2 - METHYL-ACRYLIC ACID N-PENTAFLUOROPHENYL-HYDRAZIDE The title compound was prepared in a manner similar to that described in Example 66 by using pentafluorophenyl hydrazine in place of phenyl hydrazine.'H NMR (CDC13) å 8.31-8. 37 (1H, m), 8.13-8. 30 (1H, m), 7.99 (1H, d, J= 8. 3 Hz), 7.94 (1 H, s), 7.84 (1 H, d, J = 8.3 Hz), 7.37 (1 H, d, J = 4.8 Hz), 6.90-6. 95 (2H, m), 6.82-6. 87 (1H, m), 5.42 (2H, s), 3.93 (3H, s), 2.16 (3H, dd, J = 1.3 Hz, 3.8 Hz); MS (ESI) 615 (MH+).

EXAMPLE 69 <BR> <BR> PREPARATION OF N- {3- [4- (2, 4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-PHENYL]-<BR> ; <BR> 2-METHYL-ACRYLOYL}-METHANESULFONAMIDE

The title compound was prepared in a manner similar to that described in Example 66 by using methanesulfonamide in place of phenyl hydrazine.'H NMR (CDCI3) # 8.16 (1 H, br s), 7.98 (1 H, d, J = 8.4 Hz), 7.95 (1 H, s), 7.85 (1 H, d, J = 8.4 Hz), 7.38 (1H, s), 6.94-6. 98 (2H, m), 6.84-6. 87 (1H, m), 5. 45 (2H, s), 3.94 (3H, s), 3.40 (3H, s), 2.16 (3H, d, J = 1.6 Hz) ; MS (ESI) 512 (MH), 529 (M+H20).

EXAMPLE 70 PREPARATION OF 3- [4- (2, 4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-PHENYL]-2- M ETHYL-N- [1, 3, 4] TH IADIAZOL-2-YL-AC RYLAM I DE

The title compound was prepared in a manner similar to that described in Example 66 by using 2-amino- [1, 3, 4]-thiadiazole in place of phenyl hydrazine.'H NMR (CDCI3) 8 8.81 (1H, s), 8.00 (1H, d, J = 8.3 Hz), 7.95 (1H, s), 7.85 (1 H, d, J = 8.3 Hz), 7.72 (1H, s), 6.98-7. 10 (2H, m), 6.86 (1H, d, J = 8.3 Hz), 5.44 (2H, s), 3.95 (3H, s), 2.33 (3H, s); MS (ESI) 518 (MH+).

EXAMPLE 71 PREPARATION OF 3- 4- (2, 4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-PHENYL]-N- (5-ETHYL- [1, 3, 4] TH IAD IAZOL-2-YL)-2-METHYL-ACRYLAM I DE

The title compound was prepared in a manner similar to that described in Example 66 by using 5-ethyl-2-amino-[1, 3, 4]-thiadiazole in place of phenyl hydrazine.'H NMR (CDCI3) å 8. 00 (1 H, d, J = 8. 3 Hz), 7.95 (1 H, s), 7.85 (1 H, d, J = 8.3 Hz), 7.66 (1 H, s), 6.99-7. 06 (2H, m), 6.85 (1 H, d, J = 8.3 Hz), 5.43 (2H, s), 3.94 (3H, s), 2.97 (2H, q, J = 7.6 Hz), 2.30 (3H, d, J = 1.3 Hz), 1.32 (3H, t, J = 7.6 Hz); MS (ESI) 546 (MH+).

EXAMPLE 72 PREPARATION OF 3- [4- (2, 4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-PHENYL]-2- CYANO-N-(5-(4-METHOXY-BENZYLSULFANYL)-[1,3,4]THIADIAZOL-2-YL )-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1D by using 4- (2, 4-bis (trifluoromethyl) benzyloxy)-3-methoxybenzaldehyde and 2-cyano-N- [5- (4-methoxy-benzylsulfanyl)- [1, 3,4] thiadiazol-2-yl]-acetamide.'H NMR (CDC13) 8 7.78 (1H, s), 7.41-7. 48 (1H, m), 7.35-7. 37 (2H, m), 7.28 (1H, s), 6.91 (1 H, dd, J = 2.0 Hz, 8.6 Hz), 6.72 (2H, d, J = 8.7 Hz), 6.44 (1 H, d, J = 8.5 Hz), 6.25 (2H, d, J = 8.7 Hz), 4.87 (2H, s), 3.81 (2H, s), 3.37 (3H, s), 3.19 (3H, s); MS (ESI) 681 (MH+).

EXAMPLE 73 <BR> <BR> PREPARATION OF 3-[4-(2, 4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-PHENYL]-2-<BR& gt; <BR> CYANO-N- (5- (2-MORPHOLIN-4-YL-ETHYLSULFANYL)- 1, 3, 4] THIADIAZOL-2-YL)-ACRYLAMIDE

The title compound was prepared in a manner similar to that described in Example 1 D by using 4- (2, 4-bis (trifluoromethyl) benzyloxy)-3-methoxybenzaldehyde and 2-cyano-N- [5- (2-morpholin-4-yl-ethylsulfanyl)- [1, 3,4] thiadiazol-2-yl]-acetamide.'H NMR (CDCI3) 8 8.36 (1H, s), 7.95-7. 97 (2H, m), 7.84-7. 89 (2H, m), 7.46 (1H, dd, J = 2.1 Hz, 8.5 Hz), 6.92 (1 H, d, J = 8.5 Hz), 5.48 (2H, s), 4.01 (3H, s), 3.71 (4H, t, J = 4.5 Hz), 3.47 (2H, t, J = 7.0 Hz), 2.79 (2H, t, J = 7.0 Hz), 2.53 (4H, t, J = 4.5 Hz); MS (ESI) 674 (MH+).

EXAMPLE 74 PREPARATION OF 3- 4- (2, 4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3- METHOXY-PHENYL]-2- CYANO-N-(5-METHYL-[1, 3, 4] THIADIAZOL-2-YL)-ACRYLAMIDE The title compound was prepared in a manner similar to that described in Example 1 D by using 4- (2, 4-bis (trifluoromethyl) benzyloxy)-3-methoxybenzaldehyde and 2-cyano-N- (5-methyl- [1, 3, 4] thiadiazol-2-yl)-acetamide.'H NMR (DMSO-d6) 8 8.39 (1H, s), 8.05 (1H, d, J = 7.9 Hz), 7.97-8. 00 (2H, m), 7.88 (1H, s), 7.54 (1H, d, J = 8.4 Hz), 7.07 (1H, d, J = 8.5 Hz), 5.47 (2H, s), 3.96 (3H, s), 2.64 (3H, s); MS (ESI) 543 (MH+).

EXAMPLE 75 PREPARATION OF 2-CYANO-3-PHENYL-N- (5-ETHYL- [1, 3, 4] THIADIAZOL-2-YL)-ACRYLAMIDE AND VARIATIONS A. A 0.25 M stock solution of 2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2- yl)-acetamide was prepared in 1.0 M diisopropylethylamine in DMF. Benzaldehyde and other heterocyclic aldehydes were individually weighed and were dissolved to 0.25 M using a Tecan Genesis workstation. The Tecan was used to dispense 200 µL of template 1 to each reaction vessel then was used to dispense 400 L of aldehyde stock solutions to individual reaction vessels. The reaction vessels were sealed and were heated at 45-50 °C, with agitation, for 18 hours. The reaction vessels were then cooled, unsealed, and 50 L of aminopropyl-functionalized silica gel (Aldrich) was dispensed to each reaction vessel. Activated 4 angstrom molecular sieves (powdered, 50 L) were then dispensed to each reaction. Reaction vessels were then sealed and were heated at 45-50 °C with agitation for 3 h. Reactions were then unsealed and were filtered to remove solids.

B. Sample solutions were dried in vacuo using a Genevac.

Samples were dissolved in 500 pL of DMSO and 500 pL of methanol and purity was determined by LC-MS with using a combination of UV254, UV220, and ELSD detection [purity = (UV254+UV220/2)]. The HPLC conditions were: 4.6 mm x 50 mm C18 column, 10-90% acetonitrile gradient over 5 minutes (mobile phases were H20 with 0.05 % TFA and acetonitrile with 0.035 % TFA), with a flow rate of 3.5 ml/min. Samples which were <80% pure were purified using a mass directed LC-MS purification. Purified samples were concentrated in vacuo then were dissolved in DMSO and were reformatted into 96 well microtiter plates. Samples were tested for purity using LC-MS and quantity was estimated by correlating ELSD response to a standard concentration-ELSD response curve. Samples were then concentrated to dryness and were dissolved in DMSO to a final concentration of 10 uM based on ELSD quantitation.

C. The following compounds were prepared in the manner described above in Steps A and B using the appropriate aldehyde in place of benzaldehyde : 2-Cyano-3- (3, 4-dimethoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 345 (MH+) ; 3- (4-Benzyloxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES) : 391 (MH+) ;

2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-phenyl)- acrylamide ; MS (ES): 301 (MH+) ; Acetic acid 4- [2-cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]- phenyl ester; MS (ES): 343 (MH+); 2-Cyano-3- (2, 4-dichloro-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 353 (MH+) ; 3- (2-Bromo-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 363 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (2-fluoro-phenyl)- acrylamide ; MS (ES): 303 (MH+) ; 3- (4-tert-Butyl-phenyl)-2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 341 (MH+) ; 3- (2-Chloro-4-fluoro-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 337 (MH+) ; 2-Cyano-3- (2, 5-dimethyl-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 313 (MH+) ; 2-Cyano-5- (4-methoxy-phenyl)-penta-2, 4-dienoic acid (5-ethyl- [1,3, 4] thiadiazol-2-yl)-amide ; MS (ES): 341 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(4-hydroxy-3, 5-dimethoxy- phenyl)-acrylamide ; MS (ES): 361 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-3-iodo-5- methoxy-phenyl)-acrylamide ; MS (ES): 457 (MH+) ; 2-Cyano-3- (3, 4-dihydroxy-phenyl)-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 317 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-3-methoxy-5- nitro-phenyl)-acrylamide ; MS (ES): 376 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yi)-3- (4-hydroxy-3-methoxy-5- nitro-phenyl)-acrylamide ; MS (ES): 376 (MH+) ; 3-(4-Benzyloxy-3,5-dimethyl-phenyl)-2-cyano-N-(5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 419 (MH+) ; 2-Cyano-3- (3, 5-dibromo-2-methoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES) : 471 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- (4-hexyloxy-phenyl)- acrylamide ; MS (ES): 385 (MH+) ;

Acetic acid 4- [2-cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]- 2, 6-dimethoxy-phenyl ester; MS (ES): 403 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yi)-3- (4-imidazol-1-yi-phenyl)- acrylamide ; MS (ES): 351 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(2-trifluoromethyl-phenyl)- acrylamide ; MS (ES): 353 (MH+) ; 3- (2-Chloro-3, 4-dimethoxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 379 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- ( 1-methyl-1 H-indol-3-yl)- acrylamide ; MS (ES): 338 (MH+) ; 2-Cyano-3- (2, 6-dichloro-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 353 (MH+) ; 2-Cyano-3-(4-dimethylamino-2-nitro-phenyl)-N-(5-ethyl-[1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 373 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- (2-iodo-phenyl)-acrylamide ; MS (ES): 411 (MH+) ; {2- [2-Cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]-phenoxy}- acetic acid ; MS (ES): 359 (MH+) ; 2-Cyano-3- (3-ethoxy-2-hydroxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2- yl)-acrylamide ; MS (ES): 345 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (2-fluoro-3-trifluoromethyl- phenyl)-acrylamide ; MS (ES): 371 (MH+) ; 3- [3- (4-Chloro-phenoxy)-phenyl]-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2- yl)-acrylamide ; MS (ES): 411 (MH+) ; 8- [2-Cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]- naphthalene-1-carboxylic acid ; MS (ES): 379 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3- (4-methoxy-phenoxy)- phenyl]-acrylamide ; MS (ES): 407 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (2-hydroxy-4, 6-dimethoxy- phenyl)-acrylamide ; MS (ES): 361 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (2-nitro-phenyl)-acrylamide ; MS (ES): 330 (MH+) ; 2-Cyano-3- (3, 4-dihydroxy-5-methoxy-phenyl)-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 347 (MH+) ;

2-Cyano-3-(3,5-dihydroxy-phenyl)-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 317 (MH+) ; 2-Cyano-3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-N-(5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 413 (MH+) ; 3- (3-Benzyloxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 391 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-3-nitro-phenyl)- acrylamide ; MS (ES): 346 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- (2-fluoro-4-iodo-phenyl)- acrylamide ; MS (ES): 429 (MH+) ; 3-(2,5-Bis-trifluoromethyl-phenyl)-2-cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2- yl)-acrylamide ; MS (ES): 421 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-iodo-phenyl)-acrylamide ; MS (ES): 411 (MH+) ; 2-Cyano-3- [4- (3-dimethylamino-propoxy)-phenyl]-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 386 (MH+) ; 3-(2-Chloro-5-trifluoromethyl-phenyl)-2-cyano-N-(5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 387 (MH+) ; 2-Cyano-3-(2-difluoromethoxy-phenyl)-N-(5-ethyl-[1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 351 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- (4-fluoro-3-methyl-phenyl)- acrylamide ; MS (ES): 317 (MH+) ; 2-Cyano-3-(3,5-dimethyl-phenyl)-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 313 (MH+) ; 3- (3-Bromo-4-hydroxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 379 (MH+) ; 3-(2-Chloro-6-fluoro-3-methyl-phenyl)-2-cyano-N-(5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 351 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (3-p-tolyloxy-phenyl)- acrylamide ; MS (ES): 391 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (3-methoxy-2-nitro-phenyl)- acrylamide ; MS (ES): 360 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3-(2, 3, 6-trichloro-phenyl)- acrylamide ; MS (ES): 387 (MH+) ;

2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3-(2-fluoro-6-trifluoromethyl- phenyl)-acrylamide ; MS (ES): 371 (MH+) ; 3-(2,4-Bis-trifluoromethyl-phenyl)-2-cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2- yl)-acrylamide ; MS (ES): 421 (MH+) ; 3- (3-Chloro-2-fluoro-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 337 (MH+) ; 3- (5-Bromo-2-fluoro-phenyl)-2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 381 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4]thiadiazol-2-yl)-3-(3-vinyl-phenyl)-acrylamide ; MS (ES): 311 (MH+) ; 3- (4-Butyl-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 341 (MH+) ; 3-Biphenyl-2-yl-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 361 (MH+) ; 2-Cyano-3- (2, 5-dihydroxy-phenyl)-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 317 (MH+) ; 2-Cyano-3- (4-ethyl-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 313 (MH+) ; 3-(2-Chloro-phenyl)-2-cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 319 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (3-hydroxy-phenyl)- acrylamide ; MS (ES): 301 (MH+) ; 3- (6-Chloro-2-fluoro-3-methyl-phenyl)-2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 351 (MH+) ; 2-Cyano-3-(3,4-dimethyl-phenyl)-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 313 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (3-hydroxy-4-methoxy- phenyl)-acrylamide ; MS (ES): 331 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(4-hydroxy-3, 5-dimethyl- phenyl)-acrylamide ; MS (ES): 329 (MH+) ; 3- (4-Allyloxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 341 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3-(2, 4, 5-trimethyl-phenyl)- acrylamide ; MS (ES): 327 (MH+) ;

2-Cyano-3- (2, 3-dimethoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 345 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (2, 3, 4-trimethoxy-phenyl)- acrylamide ; MS (ES): 375 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(2, 4, 6-trimethyl-phenyl)- acrylamide ; MS (ES): 327 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (3-fluoro-2-methyl-phenyl)- acrylamide ; MS (ES): 317 (MH+) ; 2-Cyano-3- (2-ethyl-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 313 (MH+) ; 2-Cyano-3- (3-ethoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 329 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-propoxy-phenyl)- acrylamide ; MS (ES): 343 (MH+) ; 2-Cyano-3- (2, 3-dimethyl-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 313 (MH+) ; 3-Biphenyl-4-yl-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 361 (MH') ; 2-Cyano-3- (2, 6-dimethyl-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 313 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (3-phenoxy-phenyl)- acrylamide ; MS (ES): 377 (MH+) ; 2-Cyano-3- (2, 3-difluoro-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 321 (MH+); 2-Cyano-3- (4-difluoromethoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 351 (MH+) ; 3- (2-Bromo-5-fluoro-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 381 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- (5-hydroxy-2-nitro-phenyl)- acrylamide ; MS (ES): 346 (MH+) ; 3- (3-Bromo-4-methoxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2- yl)-acrylamide ; MS (ES): 393 (MH+) ; Carbonic acid ter-butyl ester 4- [2-cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2- ylcarbamoyl)-vinyl]-2-methoxy-phenyl ester; MS (ES): 431 (MH+) ;

2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(2-fluoro-5-methyl-phenyl)- acrylamide ; MS (ES): 317 (MH+) ; 2-Cyano-5-phenyl-penta-2, 4-dienoic acid (5-ethyl- [1, 3,4] thiadiazol-2-yl)- amide; MS (ES): 311 (MH+) ; 2-Cyano-5-(2-methoxy-phenyl)-penta-2, 4-dienoic acid (5-ethyl- [1,3, 4] thiadiazol-2-yl)-amide ; MS (ES): 341 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3-pentamethylphenyl- acrylamide ; MS (ES): 355 (MH+) ; 3- (3-Chloro-4-methoxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2- yl)-acrylamide ; MS (ES): 349 (MH+) ; 3- [3- (4-tert-Butyl-phenoxy)-phenyl]-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 433 (MH+) ; 3- (6-Bromo-2-hydroxy-3-methoxy-phenyl)-2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 409 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- [3- (1, 1,2, 2-tetrafluoro- ethoxy)-phenyl]-acrylamide ; MS (ES): 401 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3-[4-(1, 1,2, 2-tetrafluoro- ethoxy)-phenyl]-acrylamide ; MS (ES): 401 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (3-fluoro-4-methoxy- phenyl)-acrylamide ; MS (ES): 333 (MH+) ; 2-Cyano-3- (3-difluoromethoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 351 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (5-fluoro-2-methoxy- phenyl)-acrylamide ; MS (ES): 333 (MH+) ; 3-(5-Bromo-2,4-dimethoxy-phenyl)-2-cyano-N-(5-ethyl-[1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 423 (MH+) ; 2-Cyano-3- (4-dimethylamino-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 328 (MH+) ; 2-Cyano-3- (2, 5-diethoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 373 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yi)-3- (4-methoxy-2, 3-dimethyl- phenyl)-acrylamide ; MS (ES): 343 (MH+) ; 2-Cyano-3- (3-ethoxy-4-methoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2- yl)-acrylamide ; MS (ES): 359 (MH+) ;

2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(1H-indol-3-yl)-acrylamide; MS (ES): 324 (MH+) ; 3- (1-Acetyl-1 H-indol-3-yl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 366 (MH+) ; 3- (2-Chloro-4-hydroxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)- acrylamide ; MS (ES): 335 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] iadiazol-2-yl)-3-{4-[(2-hydroxy-ethyl)-methyl- amino]-phenyl}-acrylamide ; MS (ES): 358 (MH+) ; 3- (5-Bromo-2-ethoxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 407 (MH+) ; 3- (2-Benzyloxy-3-methoxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 421 (MH+) ; 2-Cyano-3- (4-diethylamino-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 356 (MH+) ; 2-Cyano-3- (2, 4-diethoxy-phenyl)-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 373 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- (6-nitro-benzo [1,3] dioxol-5- yl)-acrylamide ; MS (ES): 374 (MH+) ; 8- [2-Cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]- naphthalene-1-carboxylic acid ; MS (ES): 379 (MH+); 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (4-hydroxy-naphthalen-1-yl)- acrylamide ; MS (ES): 351 (MH+); 2-Cyano-3- (4-dimethylamino-naphthalen-1-yl)-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 378 (MH+); 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(2-methyl-naphthalen-1-yl)- acrylamide ; MS (ES): 349 (MH+); 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(4-methyl-naphthalen-1-yl)- acrylamide ; MS (ES): 349 (MH+); 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-naphthalen-2-yl-acrylamide ; MS (ES): 335 (MH+); 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-(4-methoxy-naphthalen-1- yl)-acrylamide ; MS (ES): 365 (MH+); 3-Benzo [1,3] dioxol-4-yl-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)- acrylamide ; MS (ES): 329 (MH+); and

3- (6-Bromo-benzo [1,3] dioxol-5-yl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 407 (MH+).

EXAMPLE 76 <BR> <BR> <BR> <BR> <BR> <BR> PREPARATION OF 3-[4-(4-TERT-BUTYL-BENZYLoXY)-3-METHoXY-PHENYL]-2-CYANo-N-(5 ETHYL- 1, 3, 4] THIADIAZOL-2-YL)-ACRYLAMIDE AND VARIATIONS A. A stock solution of vanillin was prepared 0. 5 M in DMF.

Individual alkyl or benzyl halides (for example, 4-tert-butyl-benzyl chloride) were weighed and diluted to 0.25 M using a Tecan Genesis workstation. To individual reaction vessels was dispensed 5 L of powdered potassium carbonate. The Tecan was used to dispense 200 L of vanillin stock (100 µmol to each reaction vessel then 600 L of alkyl halides (150 pmol) were dispensed to individual reaction vessels.

Reaction vessels were sealed and heated at 45-50 °C, with agitation, for 15 h. Vessels were then cooled, unsealed, and 50 pL of thiopropyl-functionalized silica gel (Aldrich) was dispensed. The vessels were then sealed, heated, and agitated, for 8 h. The reactions were then cooled and a stock solution of 2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acetamide was prepared in 1.0 M diisopropylethylamine in DMF. To each reaction was dispensed 200 pL (50, umol) of template 2. Reactions were sealed, heated at 45-50 °C, and agitated for 18 h. Reaction vessels were then unsealed and 50 pL of aminopropyl-functionalized silica gel (Aldrich) was dispensed followed by 50 L of activated and powdered 4 angstrom molecular sieves (Aldrich). The reaction vessels were sealed and were heated at 45-50 °C, with agitation, for 5 h. Reactions were then unsealed and were filtered to remove solids. The filtrate was concentrated to dryness in vacuo then was dissolved in 500 pL of dichloroethane. The Tecan workstation was used to dispense 2500 L of hexanes to individual filter-tubes and samples were aspirated and dispensed into the hexanes. The solids were collected, washed with 500 pL of hexanes, and were treated with 500 uL of DMSO. Samples were agitated to effect dissolution then were filtered and concentrated in vacuo.

Library samples were then purified as needed and were processed as described for Example 75B.

B. The following compounds were prepared in the manner described above in Step A using the appropriate alkyl halide and benzyl halides :

2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (2-phenoxy- ethoxy)-phenyl]-acrylamide ; MS (ES): 451 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4]thiadiazol-2-yl)-3-[4-(2-fluoro-benzyloxy)-3- methoxy-phenyl]-acrylamide ; MS (ES): 439 (MH) ; 3- [4- (2-Chloro-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5-ethyl- [1,3, 4]thiadiazol-2-yl)-acrylamide ; MS (ES): 455 (MH+) ; 3- [4- (2-Chloro-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 455 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (3-methyl- benzyloxy)-phenyl]-acrylamide ; MS (ES): 435 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (naphthalen- 2-ylmethoxy)-phenyl]-acrylamide ; MS (ES): 471 (MH+) ; 3- [4- (2-Chloro-6-fluoro-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5- ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 473 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (2-methyl- benzyloxy)-phenyl]-acrylamide ; MS (ES): 435 (MH+) ; 2-Cyano-3- [4- (3, 4-dichloro-benzyloxy)-3-methoxy-phenyl]-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 489 (MH+) ; 3- [4- (Biphenyl-2-ylmethoxy)-3-methoxy-phenyl]-2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 497 (MH+); 3- [4- (2-Benzenesulfonylmethyl-benzyloxy)-3-methoxy-phenyl]-2-cyan o- N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 575 (MH+) ; 2-Cyano-3- [4- (3, 4-dimethyl-benzyloxy)-3-methoxy-phenyl]-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 449 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-[3-methoxy-4-(2-nitro- benzyloxy)-phenyl]-acrylamide ; MS (ES): 466 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (2-nitro- benzyloxy)-phenyl]-acrylamide ; MS (ES): 466 (MH+) ; 2-Cyano-3- [4- (2-cyano-benzyloxy)-3-methoxy-phenyl]-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 446 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (3-nitro- benzyloxy)-phenyl]-acrylamide ; MS (ES): 466 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yt)-3- [3-methoxy-4- (4-methoxy- 3, 5-dimethyl-pyridin-2-ylmethoxy)-phenyl]-acrylamide ; MS (ES): 480 (MH+) ;

2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- ( [1, 2,4] oxadiazol-3-ylmethoxy)-phenyl]-acrylamide ; MS (ES): 413 (MH+) ; 2-Cyano-3- [4- (2, 5-difluoro-benzyloxy)-3-methoxy-phenyl]-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 457 (MH+) ; 2-Cyano-3- [4- (2, 3-difluoro-benzyloxy)-3-methoxy-phenyl]-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 457 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (3- trifluoromethoxy-benzyloxy)-phenyl]-acrylamide ; MS (ES): 505 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [4- (4-isopropyl-benzyloxy)- 3-methoxy-phenyl]-acrylamide ; MS (ES): 463 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- [4- (2-fluoro-4, 5-dimethoxy- benzyloxy)-3-methoxy-phenyl]-acrylamide ; MS (ES): 499 (MH+) ; 3-[4-(2,4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2 -cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 557 (MH+) ; 3- [4- (2, 4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2-cyano-N - (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 557 (MH+) ; 3- [4- (2, 4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2-cyano-N - (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 557 (MH+) ; 3-[4-(2,4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2 -cyano-N- (5-ethyl-[1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 557 (MH+) ; 3- [4- (2-Chloro-5-fluoro-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5- ethyl-[1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 473 (MH+) ; 2-Cyano-3- [4- (2, 5-dimethyl-benzyloxy)-3-methoxy-phenyl]-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES) : 449 (MX) ; 3- [4- (3-Bromo-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5-ethyl- [1, 3, 4]thiadiazol-2-yl)-acrylamide ; MS (ES): 499 (MH+) ; 2-Cyano-3- [4- (3, 5-dimethoxy-benzyloxy)-3-methoxy-phenyl]-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 481 (MH+) ; 3- [4- (4-Bromo-2-fluoro-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5- ethyl-[1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 517 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (2- trifluoromethoxy-benzyloxy)-phenyl]-acrylamide ; MS (ES): 505 (MH+) ; 2-Cyano-3-[4-(2,6-dichloro-benzyloxy)-3-methoxy-phenyl]-N-(5 -ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 489 (MH+) ;

2-Cyano-3- [4- (2, 6-dichloro-benzyloxy)-3-methoxy-phenyl]-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 489 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (4-methyl- benzyloxy)-phenyl]-acrylamide ; MS (ES): 435 (MH+) ; 2-Cyano-3-[4-(3,4-difluoro-benzyloxy)-3-methoxy-phenyl]-N-(5 -ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 457 (MH+) ; 2-Cyano-3-[4-(2,4-dichloro-benzyloxy)-3-methoxy-phenyl]-N-(5 -ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 489 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (2, 3,4- trifluoro-benzyloxy)-phenyl]-acrylamide ; MS (ES): 475 (MH+) ; 3-[4-(3-Chloro-2,6-difluoro-benzyloxy)-3-methoxy-phenyl]-2-c yano-N-(5- ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 491 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (5-methyl-2- nitro-benzyloxy)-phenyl]-acrylamide ; MS (ES): 480 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (2-methoxy- benzyloxy)-phenyl]-acrylamide ; MS (ES): 451 (MH+) ; 2-Cyano-3-[4-(3,5-dimethyl-benzyloxy)-3-methoxy-phenyl]-N-(5 -ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 449 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [4- (3-iodo-benzyloxy)-3- methoxy-phenyl]-acrylamide ; MS (ES): 547 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3-[3-methoxy-4-(2, 3,5, 6- tetrafluoro-4-methyl-benzyloxy)-phenyl]-acrylamide ; MS (ES): 507 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3-[4-(4-iodo-benzyloxy)-3- methoxy-phenyl]-acrylamide ; MS (ES): 547 (MH+) ; 2-Cyano-3- [4- (2-difluoromethoxy-benzyloxy)-3-methoxy-phenyl]-N- (5- ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 487 (MH+) ; 3- (4-Benzyloxy-3-methoxy-phenyl)-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol- 2-yl)-acrylamide ; MS (ES): 421 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (4- trifluoromethoxy-benzyloxy)-phenyl]-acrylamide ; MS (ES): 505 (MH+) ; 3-[4-(4-Chloro-benzyloxy)-3-methoxy-phenyl]-2-cyano-N-(5-eth yl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 455 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (2-methyl- naphthalen-1-ylmethoxy)-phenyl]-acrylamide ; MS (ES): 485 (MH+) ;

3- [4- (2-Bromo-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 499 (MH+) ; 2-Cyano-3- [4- (4, 5-dimethoxy-2-nitro-benzyloxy)-3-methoxy-phenyl]-N- (5-ethyl-[1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 526 (MH+) ; 3- [4- (3, 4-Bis-benzyloxy-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5- ethyl-[1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 633 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-[3-methoxy-4-(2, 3,5, 6- tetrafluoro-4-trifluoromethyl-benzyloxy)-phenyl]-acrylamide ; MS (ES): 561 (MH+) ; 3- [4- (4-Chloro-2-nitro-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5- ethyl-[1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 500 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (4-nitro- benzyloxy)-phenyl]-acrylamide ; MS (ES): 466 (MH+) ; 4- {4- [2-Cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]-2- methoxy-phenoxymethyl}-benzoic acid methyl ester; MS (ES): 479 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (4- methylsulfanyl-benzyloxy)-phenyl]-acrylamide ; MS (ES): 467 (MH+) ; 4- {4- [2-Cyano-2- (5-ethyl- [1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]-2- methoxy-phenoxymethyl}-benzoic acid; MS (ES): 465 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- [4- (2-fluoro-5- trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-acrylamide ; MS (ES): 507 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- ( 1-methyl-2- oxo-2-phenyl-ethoxy)-phenyl]-acrylamide ; MS (ES): 463 (MH+) ; 2-Cyano-3- [4- (2, 4-dimethyl-benzyloxy)-3-methoxy-phenyl]-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 449 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (2- trifluoromethyl-benzyloxy)-phenyl]-acrylamide ; MS (ES): 489 (MH+) ; {4-[2-Cyano-2-(5-ethyl-[1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]-2- methoxy-phenoxy}-acetic acid tert-butyl ester; MS (ES): 445 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- (3-methoxy-4-phenethyloxy- phenyl)-acrylamide ; MS (ES): 435 (MH+) ; {4-[2-Cyano-2-(5-ethyl-[1, 3,4] thiadiazol-2-ylcarbamoyl)-vinyl]-2- methoxy-phenoxy}-acetic acid ethyl ester; MS (ES): 417 (MH+) ; 2-Cyano-3-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methoxy-phenyl]-N -(5- ethyl- [1, 3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 429 (MH+) ;

2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- {4- [2- (4-fluoro-phenyl)- ethoxy]-3-methoxy-phenyl}-acrylamide ; MS (ES): 453 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- {4- [2- (1 H-indol-3-yl)-ethoxy]- 3-methoxy-phenyl}-acrylamide ; MS (ES): 474 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- {3-methoxy-4- [2- (4-nitro- phenyl)-ethoxy]-phenyl}-acrylamide ; MS (ES): 480 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- [4- (2-fluoro-3- trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-acrylamide ; MS (ES): 507 (MH+) ; 2-Cyano-3- [4- (2, 3-dihydro-benzo [1,4] dioxin-2-ylmethoxy)-3-methoxy- phenyl]-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 479 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (2, 4,5- trifluoro-benzyloxy)-phenyl]-acrylamide ; MS (ES): 475 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [4- (4-fluoro-2- trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-acrylamide ; MS (ES): 507 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [4- (4-fluoro-2- trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-acrylamide ; MS (ES): 507 (MH+) ; 3-{4-[2-(4-tert-Butyl-phenyl)-2-oxo-ethoxy]-3-methoxy-phenyl }-2-cyano- N-(5-ethyl-[1, 3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 505 (MH+) ; 3-[4-(2-Chloro-5-trifluoromethyl-benzyloxy)-3-methoxy-phenyl ]-2-cyano- N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 523 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [4- (2-fluoro-6- trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-acrylamide ; MS (ES): 507 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- [4- (2-fluoro-6- trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-acrylamide ; MS (ES): 507 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- [4- (3-fluoro-5- trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-acrylamide ; MS (ES): 507 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (2, 4,6- trifluoro-benzyloxy)-phenyl]-acrylamide ; MS (ES): 475 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- [4- (5-fluoro-2- trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-acrylamide ; MS (ES): 507 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- [4- (5-fluoro-2- trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-acrylamide ; MS (ES): 507 (MH+) ; 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (2-methyl- thiazol-4-ylmethoxy)-phenyl]-acrylamide ; MS (ES): 442 (MH+) ;

2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (4-methyl-3- nitro-benzyloxy)-phenyl]-acrylamide ; MS (ES): 480 (MH+) ; 3-[4-(6-Chloro-pyridin-3-ylmethoxy)-3-methoxy-phenyl]-2-cyan o-N-(5- ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 456 (MH+) ; 3- [4- (4-tert-Butyl-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 477 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3, 4]thiadiazol-2-yl)-3-[3-methoxy-4-(pyridin-3- ylmethoxy)-phenyl]-acrylamide ; MS (ES): 422 (MH+) ; 3- [4- (4-Benzyloxy-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 527 (MH+); 2-Cyano-N-(5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (naphthalen- 1-ylmethoxy)-phenyl]-acrylamide ; MS (ES): 471 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (2-methoxy-5- nitro-benzyloxy)-phenyl]-acrylamide ; MS (ES): 496 (MH+) ; 3- [4- (2-Bromo-5-methoxy-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5- ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 529 (MH+) ; 2-Cyano-3- [4- (2'-cyano-biphenyl-4-ylmethoxy)-3-methoxy-phenyl]-N- (5- ethyl- [1, 3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 522 (MH+) ; 3- [4- (2, 5-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2-cyano-N - (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 557 (MH+) ; 3- [4- (2, 5-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2-cyano-N - (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 557 (MH+) ; 3-[4-(Biphenyl-4-ylmethoxy)-3-methoxy-phenyl]-2-cyano-N-(5-e thyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 497 (MH+) ; 2-Cyano-3- [4- (3, 5-di-tert-butyl-benzyloxy)-3-methoxy-phenyl]-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 533 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [4- (2-fluoro-3-methyl- benzyloxy)-3-methoxy-phenyl]-acrylamide ; MS (ES): 453 (MH+) ; N-(3-Cyano-5-ethyl-[1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (5-methyl- isoxazol-3-ylmethoxy)-phenyl]-acrylamide ; MS (ES): 428 (MH+) ; 3- [4- (2-Chloro-4-fluoro-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5- ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; MS (ES): 473 (MH+) ; 3- [4- (4-Chloro-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-acrylamide ; MS (ES): 455 (MH+) ;

2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [3-methoxy-4- (3-methoxy- benzyloxy)-phenyl]-acrylamide ; MS (ES): 451 (MH+) ; 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- [4- (4-fluoro-benzyloxy)-3- methoxy-phenyl]-acrylamide ; MS (ES): 439 (MH+) ; and 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3- {3-methoxy-4- [4- (styryl)- benzyloxy]-phenyl}-acrylamide ; MS (ES): 523 (MH+).

EXAMPLE 77 PREPARATION OF 4-(2,4-BIS-TRIFLUOROMETHYL-BENZYLOXY)-3-METHOXY-BENZALDEHYDE A. Into a 250 mL round-bottomed flask was weighed 518 mg (3.41 mmol) of vanillin, 1.0 g (3.26 mmol) of 2, 4-bis-trifluoromethyl benzyl bromide, 500 mg of K2CO3, 5 mL of acetonitrile, and 2 mL of DMF. The resulting suspension was stirred under nitrogen at 80 °C for 19 h. The reaction was then poured into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with brine, dried (MgS04), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Jones Flashmaster, 50 g Si02, gradient elution from 100% hexanes to 100% ethyl acetate over 30 minutes). Appropriate fractions were combined, concentrated, and dried under high vacuum to afford the product as a colorless solid, yield : 1.06 g (86%).'H NMR (400 MHz, CDCI3) 8 : 9.88 (s, 1H), 7.97 (d, J = 8 Hz, 1 H), 7.96 (s, 1 H), 7.85 (d, J = 8 Hz, 1 H), 7.48 (s, 1 H), 7.42 (d, J = 8 Hz, 1H), 6.93 (d, J = 8 Hz, 1 H), 5.48 (s, 2H), 3.99 (s, 3H) ; MS (ESI) 379 (MH+).

B. Preparation of 3- [4- (2, 4-Bis-trifluoromethyl-benzyloxy)-3- methoxy-phenyl]-2-cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide. Into a 25 mL round-bottomed flask was weighed 57.2 mg (291 mol) of 2-cyano-N- (5-ethyl- [1,3, 4] thiadiazol-2-yl)-acetamide and 104.4 mg of 4- (2, 4-Bis-trifluoromethyl-benzyloxy)- 3-methoxy-benzaldehyde from Step A. The solids were treated with 1.2 mL of 1. 0 M diisoproylethylamine in DMF and the resulting suspension was stirred at 60 °C for 20 h.

The suspension was concentrated in vacuo to remove DMF and the crude product was purified by silica gel flash chromatography (Jones Flashmaster, 20 g Si02, gradient

elution from 0% to 100% ethyl acetate-hexanes over 30 minutes). Product was recovered as a yellow-tan solid, yield : 10.1 mg (7%).'H NMR (400 MHz, CDCl3) 6 : 8.37 (s, 1H), 7.96 (m, 2H), 7.86 (m, 2H), 7.45 (d, J = 8 Hz, 1 H), 6.91 (d, J = 8 Hz, 1 H), 5.48 (s, 2H), 4.00 (s, 3H), 3.08 (q, J = 7.5 Hz, 2H), 1.43 (t, J = 7.5 Hz, 3H); MS (ESI) 557 (MH+).

C. In a manner similar to that described in Step B, but replacing 2, 4-bis-trifluoromethyl benzyl bromide with 4-fluoro-2- (trifluoromethyl) benzyl bromide, 2-fluoro-6- (trifluoromethyl) benzyl bromide, 3-fluoro-6-(trifluoromethyl)benzyl bromide, 2,5-bis (trifluoromethyl) benzyl bromide, 2-(trifluoromethyl)benzyl bromide, respectively, the following compounds were prepared: 3- [4- (4-fluoro-2-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2-c yano- N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; 'H NMR (400 MHz, DMSO-d6) 8 : 8.33 (s, 1 H), 7.8-7. 53 (m, 5H), 7.22 (d, J = 8 Hz, 1 H), 5.25 (s, 2H), 3.76 (s, 3H), 2.90 (q, J = 7 Hz, 2H), 1.23 (t, J = 7 Hz, 3H); MS (ESI) 507 (MH+) ; 3- [4- (2-fluoro-6-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2-c yano- N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ;'H NMR (400 MHz, DMSO-d6) 8 : 8.29 (s, 1H), 7.7-7. 54 (m, 5H), 7.31 (d, J= 8 Hz, 1H), 5.14 (s, 2H), 3.66 (s, 3H), 2.84 (q, J= 7.5 Hz, 2H), 1. 17 (t, J = 7.5 Hz, 3H); MS (ESI) 507 (MH+) ; 3- [4- (2-fluoro-6-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2-c yano- N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ;'H NMR (400 MHz, DMSO-d6) 8 : 8.33 (s, 1 H), 7.84 (dd, J = 5 Hz, 1 H), 7.47 (s, 1 H), 7.76 (m, 2H), 7.4 (m, 1 H), 7.22 (d, J = 9 Hz, 1 H), 5.29 (s, 2H), 3.79 (s, 3H), 2.90 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H); MS (ESI) 507 (MH+) ; 3- [4- (2, 4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2-cyano-N - (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ; 'H NMR (400 MHz, DMSO-d6) 8 : 8.39 (s, 1 H), 8.23 (s, 1 H), 8.08 (d, J = 8 Hz, 1 H), 8.02 (d, J = 8 Hz, 1 H), 7.80 (s, 1 H), 7.66 (d, J = 8 Hz, 1 H), 7.34 (d, J = 8 Hz, 1 H), 5.43 (s, 2H), 3.84 (s, 3H), 2.96 (q, J = 7.5 Hz, 2H), 1.29 (t, J = 7. 5 Hz, 3H); MS (ESI) 557 (MH+) ; and 3- [4- (2, 4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2-cyano-N - (5-ethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide ;'H NMR (400 MHz, DMSO-d6) 8 : 8.54 (s, 1H), 8.00-7. 87 (m, 3H), 7.83-7. 73 (m, 3H), 7.42 (d, J = 8.5 Hz, 1 H), 5.50 (s, 2H), 3.98 (s, 3H), 3.11 (q, J = 7.5 Hz, 2H), 1.44 (t, J = 7.5 Hz, 3H); MS (ESI) 489 (MH+).

EXAMPLE 78 FLUORESCENCE POLARIZATION (FP) ASSAY The human ERRa ligand binding domain consisting of amino acids 188- 423 (see GenBank sequence XM048286) was cloned into the pET15b expression vector (Novagen, Inc., Madison, WI) with the 6-Histidine tag in frame with the N- terminus of the ligand binding domain.

6-His-tagged ERRa ligand-binding domain fusion protein was expressed in E. Coli and purified on Ni-NTA resin (Qiagen Inc., Valencia, CA) following standard protocols. The purity of the protein was checked using SDS PAGE and Coomassie blue staining. The protein was judged to be approximately 90% pure by this method.

1X FP Buffer (20 mM KH2PO4 Ph 7.3, 150 mM NaCI, 2 mM CHAPS, 2 mM EDTA, 10 mM DTT) containing 10 nM of 5, 6-Carboxyflurescein-ILRKLLQE (SynPep Corp. , Dublin, CA), 5.5 zM His-ERRa protein and 50 M or 10 LM of test compound were added to each well of a 384-well black assay plate.

Plates were incubated at ambient temperature in the dark for at least 1 hour. FP (mP) was measured on an LJL Analyst (LJL Biosystems, Inc., Sunnyvale, CA) (excitation wavelength : 485 nm; emission wavelength : 530 nm).

The mP value of His-ERRa plus the peptide was used as a high control and set as 100% activity. The mP value of the peptide only was set as the low control.

Antagonist cut-off was set as >25% max inhibition (75% activity compared to high control).

EXAMPLE 79 GAL4-ERRa CO-TRANSFECTION ASSAY Compound activity was also determined in a cell based assay using a GAL4-ERRa chimera to identify active compounds.

CMX-GAL4-ERRa was constructed by cloning nucleotides encoding amino acids 174-423 of ERRa (see GenBank sequence XM048286) into the vector pCMX-GAL4 (Perlmann et al., 1993, Genes & Development 7: 1411-1422) comprising nucleotides encoding for amino acids 1-147 of the GAL4 DNA binding domain.

The TK-MH100x4-Luc (GAL4uAs-TK-Luciferase) reporter constructs were constructed by insertion of four copies of the Gal4 UAS (Kang et al. 1993, J. Biol.

Chem. 268: 9629-9635) into the Hind III site of TK-Luc. The parental plasmid TK-Luc was prepared by insertion of the Herpes simplex virus thymidine kinase gene promoter (-105 to +51) obtained from the plasmid pBLCAT2 by digestion with Hindlll and Xhol (described in Luckow et al., 1987, Nuc. Acid. Res. 15: 5490) into the plasmid MTV-LUC described by Hollenberg and Evans, 1988, Cell 55: 899-906) after removal of MTV-LTR promoter sequence from MTV-LUC via digestion with Hindill and Xhol. Correct cloning was confirmed by restriction digestion and or sequencing.

Assays were performed using CV-1 (African Green Monkey Kidney Cells) (ATCC) cells at 70 percent confluency in T175 flasks grown with media containing 10% charcoal/Dextran-treated fetal bovine serum. Cells were transiently transfected with a DNA mixture containing 12 g of CMX-GAL4-ERRa (comprising the ligand binding domain), 6 ig of TK-MH100x4-Luc, and 2 ug of CMX-pGal using the transfection reagent FuGENE6 (Roche Molecular Biochemicals, Indianapolis, IN) following recommended protocols and instructions provided by the manufacturer.

Following incubation with transfection reagents for 5 hours at 37°C, cells were washed, removed from the flasks with 1X Trypsin-EDTA solution (Sigma-Aldrich, Inc. St. Louis, MO, and then resusupended in media containing 5% charcoal/Dextran-treated fetal bovine serum to give a final concentration of 1.1 x 105 cells/ml.

Assay plates were prepared by dispensing approximately 5 gl of each compound into a well of a 384 well plate to achieve a final compound concentration of approximately 10 M after addition of cells. Cells were added to assay plates (45 zip via the use of a MultiDrop dispenser (MTX Labs, Inc., Vienna, VA). The assay plates containing both compounds and screening cells were incubated for approximately 20 hours at 37°C and 5% C02 in a tissue culture incubator.

After incubation of the transfected cells with compounds, Lysis buffer (1% Triton X-100, 10% Glycerol, 5 mM DTT, 1 mM EGTA, 25 mM Tricine) and Luciferin assay buffer (0.73 mM ATP, 22.3 mM Tricine, 0.11 mM EDTA, 33.3 mM DTT, 0.2M MgS04, 11 mM Luciferin, 6.1 mM Coenzyme A, 0.01 mM HEPES) were prepared. Media was removed from the plates and lysis buffer and luciferin assay buffer mixed in a 1: 1 ratio and then 30 pl was added to each well (384-well plate).

Plates were read on the Northstar (Northstar Technologies, Inc., Acton, MA) and data <BR> <BR> <BR> was analyzed using ActivityBase (ID Business Solutions, Ltd. , Guildford, Surrey, UK).

Luciferase values were normalized with ß-galactosidase values using the pCMX-ßGal

expression plasmid, to normalize for transfection efficiency as described previously (Willy et al., 1995, Gene & Development, 9: 1033-1045).

No reporter-driven luciferase activity was observed without ERR transfection, indicating the ERR-dependency of the compounds.

The following table provides in vitro ERRa activity data of representative compounds described in the Examples. Average IC, 50 values for inverse agonist activity in the GAL4-ERRa assay are provided as follows : V: less than 0.5 lM ; W: 0.5 µM-1 µM ; X: lu to 2 HM ; Y: 2 µM to 5 µM and Z: greater than 5 µM. Average percent inhibition with respect to ERRa activity relative to a control (3- [4- (2, 4-Bis- trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2-cyano-N- (5-triftuoromethyl- [1,3, 4] thiadiazol-2-yl)-acrylamide) is provided as follows. A: 100-120% of control activity, B: 80-100% of control activity, C: 60-80 % and D: represents 40-60%.

Table Example ERRa ICs0 % control 3-[4-(2,4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2 -cyano- V A N- (5-trifluoromethyl- [1, 3,4] thiadiazol-2-yf)-acrylam ide 3-[4-(2,4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2 -cyano- W A N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-acrylamide 3-[4-(2,4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2 -cyano- W A N- [1, 3,4] thiadiazol-2-yl-acrylamide 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3-[4-(4-fluoro-2-trifluoromethyl- W A benzyloxy)-3-methoxy-phenyl]-acrylamide 2-Cyano-N- (5-ethyl- [1, 3,4] thiadiazol-2-yl)-3-[4-(5-fluoro-2-trifluoromethyl- W A benzyloxy)-3-methoxy-phenyl]-acrylamide 3- [4- (2, 4-Bis-trifluoromethyl-benzyloxy)-3-methoxy-phenyl]-2-cyano- W B N- (5-methyl- [1. 3, 4] thiadiazol-2-yl)-acrylamide 2-Cyano-3-{4-[2-(2,6-dimethyl-phenoxy)-ethoxy]-3-methoxy-phe nyl}- X A N- (5-ethyl- [1, 3,4] thiadiazol-2-yi)-N-methyl-acrylamide 3- {4- [2- (2-Allyl-phenoxy)-ethoxy]-3-methoxy-phenyl}-2-cyano-N- (5- X A trifluoromethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide 3-{4-[2-(2-Allyl-phenoxy)-ethoxy]-3-methoxy-phenyl}-2-cyano- N-(5- X A methylsulfanyl- [1, 3, 4] thiadiazol-2-yl)-acrylamide 2-Cyano-3-{4-[2-(2,6-dimethyl-phenoxy)-ethoxy]-3-methoxy-phe nyl}- X A N- (5-trifluoromethyl- [1, 3,4] thiadiazol-2-yl)-acrylamide 2-Cyano-3-{4-[2-(2,6-dimethyl-phenoxy)-ethoxy]-3-methoxy-phe nyl}- X A N- [1, 3, 4] thiadiazol-2-yl-acrylamide 3- {4- [2- (2-Allyl-phenoxy)-ethoxy]-3-methoxy-phenyl}-2-cyano-N- X A [1,3, 4] thiadiazol-2-yl-acrylamide 3- (5-Chloro-1H-indol-3-yl)-2-cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-ylf X A acrylamide

Table continued Example ERRa IC50 % control 3- {4- [2- (2-Allyl-phenoxy)-ethoxy]-3-methoxy-phenyl}-N- (5-tert-butyl- Y B [1. 3, 4]thiadiazol-2-yl)-2-cyano-acrylamide 2-Cyano-N-(5-ethyl-[1,3, 4] thiadiazol-2-yl)-3-(4-hexyloxy-phenyl)- Y B acrylamide 2-Cyano-3-{4-[2-(2,6-dimethyl-phenoxy)-ethoxy]-3-methoxy-phe nyl}- Y B N-(5-mercapto-[1, 3,4] thiadiazol-2-yl)-acrylamide 2-Cyano-3-{4-[2-(2,6-dimethyl-phenoxy)-ethoxy]-3-methoxy-phe nyl}- Y B N-[5-(2-morpholin-4-yl-ethylsulfanyl)-[1, 3,4] thiadiazol-2-yl]-acrylamide 2-Cyano-N-[5-(4-dimethylamino-phenyl)- [1,3, 4] thiadiazol-2-yl]-3-{4- Y C [2- (2, 6-dimethyl-phenoxy)-ethoxy]-3-methoxy-phenyl}-acrylamide 3- {4- [2- (2-Allyl-phenoxy)-ethoxy]-3-methoxy-phenyl}-2-cyano-N- [5- Z D (4-dimethylamino-phenyl)- [1, 3,4] thiadiazoi-2-yl]-acrylamide 2-Cyano-3-{4-[2-(2,6-dimethyl-phenoxy)-ethoxy]-3,5-dimethoxy - Z C phenyl}-N-(5-trifluoromethyl-[1,3, 4] thiadiazol-2-yl)-acrylamide 2-Cyano-N- (5-ethyl- [1, 3, 4] thiadiazol-2-yl)-3- (3-methoxy-4-o-tolyloxy- Z D phenyl)-acrylamide 2-Cyano-3-{4-[2-(2,6-dimethyl-phenoxy)-ethoxy]-3-methoxy-phe nyl}- Z D N- (4-methyl-thiazol-2-yl)-acrylamide 3- {4- [2- (2-Allyl-phenoxy)-ethoxy]-3-methoxy-phenyl}-2-cyano-N- (4- Z D methyl-thiazol-2-yl)-acrylamide