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Title:
PPAR MODULATORS
Document Type and Number:
WIPO Patent Application WO/2005/019151
Kind Code:
A1
Abstract:
The present invention is directed to a compound of formula I, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, which is useful in treating or preventing disorders mediated by a peroxisome proliferator activated receptor (PPAR) such as syndrome X, type II diabetes, hyperglycemia, hyperlipidemia, obesity, coagaulopathy, hypertension, arteriosclerosis, and other disorders related to syndrome X and cardiovascular diseases.

Inventors:
Gonzalez Valcarcel, Isabel Cristina (410 North Meridian, Apartment 815 Indianapolis, Indiana, 46204, US)
Mantlo, Nathan Bryan (7325 East County Road 800 North, Brownsburg, Indiana, 46112, US)
Shi, Qing (13138 Penneagle Drive, Carmel, Indiana, 46033, US)
Wang, Minmin (11366 Reflection Point Drive, Fishers, Indiana, 46038, US)
Winneroski, Leonard Larry Junior (587 Thoroughbred Lane, Greenwood, Indiana, 46142, US)
Yanping XU. (13832 Barnett Place, Fishers, Indiana, 46038, US)
York, Jeremy Schulenburg (16095 Tenor Way, Noblesville, Indiana, 46060, US)
Application Number:
PCT/US2004/024381
Publication Date:
March 03, 2005
Filing Date:
August 17, 2004
Export Citation:
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Assignee:
ELI LILLY AND COMPANY (Lilly Corporate Center, Indianapolis, Indiana, 46285, US)
Gonzalez Valcarcel, Isabel Cristina (410 North Meridian, Apartment 815 Indianapolis, Indiana, 46204, US)
Mantlo, Nathan Bryan (7325 East County Road 800 North, Brownsburg, Indiana, 46112, US)
Shi, Qing (13138 Penneagle Drive, Carmel, Indiana, 46033, US)
Wang, Minmin (11366 Reflection Point Drive, Fishers, Indiana, 46038, US)
Winneroski, Leonard Larry Junior (587 Thoroughbred Lane, Greenwood, Indiana, 46142, US)
Yanping XU. (13832 Barnett Place, Fishers, Indiana, 46038, US)
York, Jeremy Schulenburg (16095 Tenor Way, Noblesville, Indiana, 46060, US)
International Classes:
A61K31/095; A61K31/185; A61K45/06; A61P3/04; A61P3/10; C07C59/68; C07C59/90; C07C61/39; C07C251/48; C07C317/22; C07C323/20; C07C323/52; C07C323/62; C07D213/30; C07D213/69; C07D239/26; C07D261/20; C07D263/32; C07D277/24; C07D307/79; (IPC1-7): C07C59/68; A61K31/095; A61K31/185; A61P3/04; A61P3/10
Domestic Patent References:
WO1997028115A11997-08-07
WO2002100813A22002-12-19
WO2002100403A12002-12-19
Attorney, Agent or Firm:
Jang, Soonhee (Eli Lilly and Company, Patent Division P. O. Box 628, Indianapolis Indiana, 46206-6288, US)
Download PDF:
Claims:
WHAT IS CLAIMED IS:
1. A compound having a formula I, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: A1 is : a bond, CH2, 0 or S, and wherein Al and R4 or A1 and RS together being a 3to 6 membered carbocyclyl when Ai is a carbon ; A2 and A3 are independently: CH2, 0 or S; El, E2, E3, E4 and E5 are each CH or substituted carbon bearing A2 and R3 ; or at least one of El, E2, E3, E4 and E5 is nitrogen and each of others being CH or substituted carbon bearing A2 and R3 ; Q is : C (O) OR6, or R6A ; Y is: a bond, ClC6 alkyl or C3C6 cycloalkyl ; Z is: a) aryl; b) a 5to 10membered heteroaryl wherein the heteroaryl containing at least one heteroatom selected from N, O or S, c) biaryl, wherein biaryl being defined as aryl substituted with another aryl or aryl substituted with heteroaryl, or d) biheteroaryl, wherein biheteroaryl being defined as heteroaryl substituted with another heteroaryl, or heteroaryl substituted with aryl, and wherein aryl, heteroaryl, biaryl and biheteroaryl being optionally substituted with one or more groups independently selected from R7 ; n is : 1, 2,3, 4, 5 or 6 p is : 1 or 2; r is : 1,2, 3, or 4; R1 and R2 are each independently: hydrogen, haloalkyl, C1C6 alkyl, (CH2)nC3C8 cycloalkyl, or R1 and R2 form a 4to 8membered nonaromatic carbocyclic ring; and wherein at least one of R1 and R2 is alkyl or cycloalkyl, and; R3 is : hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, C1C6 alkyl, C1C6 alkoxy, or C3C8 cycloalkyl ; R4 and R5 are each independently: hydrogen or C1C6 alkyl ; R6 is: hydrogen, C1C6 alkyl or aminoalkyl ; R6A is : carboxamide, sulfonamide, acylsulfonamide, tetrazole, R7 is : hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, C1C6 alkyl, C1C6 alkoxy, (CH2)nC3C8 cycloalkyl, C (O) R9, C (O) OR9, C(=NOR8)R9, CR8(OH)R9, C[=C(R8)2]R9, OR9, SR9 or S (0) pR" ; R8 is : hydrogen or C1C6 alkyl ; and R9 is: hydrogen, C1C6 alkyl, C3C8 cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of: hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, oxo, C1C6 alkyl, ClC6 alkoxyand C3C8 cycloalkyl.
2. The compound of Claim 1, wherein the compound having a formula II, II or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: A1 is: a bond, CH2, 0 or S, and wherein A1 and R4 or A1 and R5 together being a 3to 6 membered carbocyclyl when A] is a carbon; A2 is : O or S or CH2 ; Q is:C (O) OR6, or R6A ; Y is : a bond, ClC6 alkyl or C3C6 cycloalkyl ; Z is : a) aryl; b) a 5to 10membered heteroaryl wherein the heteroaryl containing at least one heteroatom selected from N, O or S, c) biaryl, wherein biaryl being defined as aryl substituted with another aryl or aryl substituted with heteroaryl, or d) biheteroaryl, wherein biheteroaryl being defined as heteroaryl substituted with another heteroaryl, or heteroaryl substituted with aryl, and wherein aryl, heteroaryl, biaryl and biheteroaryl being optionally substituted with one or more groups independently selected from R7 ; n is : 1, 2,3, 4, 5 or 6 p is: 1 or 2 ; r is : 1,2, 3, or 4; Rl and R2 are each independently: hydrogen, haloalkyl, ClC6 alkyl, (CH2)nC3C8 cycloalkyl, or R'and R2 form a 4to 8membered nonaromatic carbocyclic ring; and wherein at least one of Rl and R2 is alkyl or cycloalkyl, and; R3 is: hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, ClC6 alkyl, CiC6 alkoxy, or C3C8 cycloalkyl ; R4 and R5 are each independently: hydrogen or C1C6 alkyl ; R6 is : hydrogen, C1C6 alkyl or aminoalkyl ; R6A is : carboxamide, sulfonamide, acylsulfonamide, tetrazole, R7 is : hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, CiC6 alkyl, CiC6 alkoxy, (CH2)nC3C8 cycloalkyl, C (O) R9, C (O) OR9, C (=NOR8)R9, CR8 (OH) R9, C[=C(R8)2]R9, OR9, SR9 or S (O) pR9 ; R8 is: hydrogen or C1C6 alkyl ; and R9 is: hydrogen, C1C6 alkyl, C3C8 cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of : hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, oxo, C1C6 alkyl, ClC6 alkoxyand C3C8 cycloalkyl.
3. The compound of Claim 2, wherein Z is optionally substituted phenyl or naphthyl, furanyl, imidazolyl, indolyl, oxazolyl, isoxazolyl, pyridyl, pyrrolyl, thiazolyl, thiophenyl, benzofuranyl, benzothiophenyl, benzoisoxazolyl, quinolinyl, isoquinolinyl or a structural formula selected from following: wherein T is: a bond, (CH2) qO,O (CH2) q,C (O) (CH2) q, (CH2) qC (O), (CH2) qS,S (CH2) q, S[O]p, (C1C3 alkyl), (CH2) qC (=CH2),C (=CH2) (CH2) q, (CH2) qC (=NOH), C(=NOH) (CH2) q, (CH2)qC(=NOCH3), C(=NOCH3)(CH2)q, CH (OH) (CH2) q, or (CH2) qCH (OH), qis : 0, 1, 2 or 3 ; and rings b to 1 are each optionally substituted with one or more groups independently selected from the group consisting of : hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (0) 2R9, ClC6 alkyl, ClC6 alkoxy and (CH2))"C3C8 cycloalkyl.
4. The compound of Claim 2, wherein the compound having a structural formula III, III or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein mis 1,2, 3 or 4.
5. The compound of Claim 4, wherein the compound having a structural formula IV, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: A1 and A2 are respectively: O and O, CH2 and 0, CH2 and S, O and S or S and O ; m is: 1 or 2; RI is : C1C3 alkyl ; R3 is: hydrogen, halo or C1C6 alkyl ; R6 and R9 are each independently: hydrogen or ClC6 alkyl ; T is: a bond,O,C (O),S (O)S (0) 2, C (=CH2),C (=NOH) orCH (OH) ; and rings b and c are each optionally substituted with one or more groups independently selected from : hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (0) 2R9, C1C6 alkyl, ClC6 alkoxy and (CH2) nC3C8 cycloalkyl.
6. The compound of Claim 5, wherein the compound having a structural formula V, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: T is: a bond,OorC (O) ; Rl is : methyl, ethyl or cyclopropyl ; R3 is: methyl or ethyl; and rings b and c are each optionally substituted with one or more substituent independently selected from the group consisting of : hydrogen, Cl, Br, CF3, OCF3, methyl, ethyl, isopropyl, N (CH3) 2, S (0) 2CH3, methoxy and cyclopropyl.
7. The compound of Claim 6, wherein the compound is represented by a structural formula VI, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
8. The compound of Claim 2, wherein the compound having a structural formula VII, VII or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: Z is : A1 and A2 are respectively: bond and S; bond and O ; CH2 and S; or CH2 and 0 ; m is : 1 or 2; R1 is : C1C3 alkyl ; R3 is: hydrogen, halo or CIC6 alkyl ; R6 and R9 are each independently: hydrogen or ClC6 alkyl ; T is: bond,O,C (O),S (O)S (0) 2,C (=CH2) ,C (=NOH) orCH (OH) ; and rings b, c, k and 1 are each optionally substituted with one or more groups independently selected from: hydrogen, oxo, . nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (0) 2R9, C1C6 alkyl, C1C6 alkoxy and (CH2)nC3C8 cycloalkyl.
9. The compound of Claim 8, wherein Ru ils : methyl, ethyl or cyclopropyl ; R3 is: methyl or ethyl; and rings b, c k and 1 are each optionally substituted with one or more substituent independently selected from the group consisting of : hydrogen, Cl, Br, CF3, OCF3, N (CH3) 2, S (0) 2CH3, methyl, ethyl, isopropyl, methoxy and cyclopropyl.
10. The compound of Claim 4, wherein the compound having a structural formula VIII, VIII or a phannaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: A1 and A2 are respectively: O and 0, CH2 and 0, CH2 and S, 0 and S or S and O ; m is: 1 or 2; R1 is : C1C3 alkyl ; and R3 is: hydrogen, halo or C1C6 alkyl ; R6 and R9are each independently: hydrogen or ClC6 alkyl ; T is: a bond,O,C (O),S (O)S (0) 2, C (=CH2),C (=NOH) orCH (OH) ; and ring b is optionally substituted with one or more groups independently selected from: hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (0) 2R9, C1C6 alkyl, ClC6 alkoxy and (CH2) nC3C8 cycloalkyl.
11. The compound of Claim 10, wherein the compound having a structural formula IX, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: R1 is C1C3 alkyl ; R3 is: hydrogen, halo or C1C4 alkyl ; ring b is optionally substituted with one or more groups independently selected from the group consisting of : hydrogen, halo, haloalkyl, haloalkyloxy and C1C6 alkyl.
12. The compound of Claim 11, wherein the compound having a structural formula X, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
13. The compound of Claim 11, wherein the compound having a structural formula XI, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
14. The compound of Claim 4, wherein the compound having a structural formula XII, XII or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein : A1 and A2 are respectively: O and 0, CH2 and 0, CH2 and S, O and S or S and O ; m is: 1 or 2; R1 is : C1C3 alkyl ; and R3 is : hydrogen, halo or C1C6 alkyl ; R4, R5, R6 and R9 are each independently: hydrogen or C1C6 alkyl ; rings k and 1 are each optionally substituted with one or more groups independently selected from: hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (0) 2R9, CiCe alkyl, C1C6 alkoxy and (CH2) nC3C8 cycloalkyl.
15. The compound of Claim 14, wherein R4 and R are each methyl or ethyl; m is 1; rings k and 1 are each optionally substituted with one or more substituent independently selected from the group consisting of hydrogen, Cl, Br, CF3, OCF3, N (CH3) 2, S (0) 2CH3, methyl, ethyl, isopropyl, methoxy and cyclopropyl ; and oxygen atom ofOCH (Rl)(CH2) mmoiety is placed in an ortho position relative to the ring 1.
16. The compound of Claim 2, wherein the compound having a structural formula XIII, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein m is 1,2, 3, or 4.
17. The compound of Claim 16, wherein the compound having a structural formula XIV, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: A1 and A2 are respectively ; O and 0, CH2 and 0, CH2 and S, O and S, or S and O ; mis : 1 or 2 ; R2 is: C1C3 alkyl ; and R3 is: hydrogen, halo or C1C6 alkyl ; R6 and R9 are each independently: hydrogen or C1C6 alkyl; T is: a bond, O, C(O), S(O) S(O)2, C(=CH2), C(=NOH) or CH(OH); and rings b and c are each optionally substituted with one or more groups independently selected from: hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (0) 2R9, C1C6 alkyl, ClC6 alkoxy and (CH2)nC3C8 cycloalkyl.
18. The compound of Claim 17, wherein the compound having a structural formula XV, XV or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein : T is : a bond, O or C (O) ; R2 is: methyl, ethyl or cyclopropyl ; R3 is: methyl or ethyl; and rings b and c are each optionally substituted with one or more substituent independently selected from the group consisting of hydrogen, Cl, Br, CF3, OCF3, N (CH3) 2, S (0) 2CH3, methyl, ethyl, isopropyl, methoxy and cyclopropyl.
19. The compound of Claim 2, wherein the compound having a structural formula XVI, XVI or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein Y is a branched alkyl or C3C6 cycloalkyl.
20. The compound of Claim 19, wherein the compound having a structural formula XVII, XVII or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: A1 and A2 are respectively: O and 0, CH2 and 0, CH2 and S, 0 and S, or S and O ; R3 is: hydrogen, halo or C1C6 alkyl ; R6 and R9 are each independently: hydrogen or C1C6 alkyl ; R9a and R9b are: each independently hydrogen or C1C4 alkyl wherein at least one of R9a and R9b being CiC4 alkyl, or together C3C6 cycloalkyl ; T is: a bond,O,C (O),S (O)S (0) 2,C (=CH2),C (=NOH) orCH (OH) ; and rings b and c are each optionally substituted with one or more groups independently selected from: hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (0) 2R9, C1C6 alkyl, C1C6 alkoxy and (CH2)"C3C8 cycloalkyl.
21. The compound of Claim 20, wherein the compound having a structural formula XVIII, XVIII or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: T is: a bond, O or C (O) ; R3 is: methyl or ethyl; R9a and R9b are each independently hydrogen, methyl or ethyl, wherein at least one of R9a and R9b being methyl or ethyl; rings b and c are each optionally substituted with one or more substituent independently selected from the group consisting of hydrogen, Cl, Br, CF3, OCF3, S (0) 2CH3, N (CH3) 2, methyl, ethyl, isopropyl, methoxy and cyclopropyl.
22. The compound of Claim 21, wherein the compound having a structural formula XIX, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.
23. The compound of Claim 1, wherein the compound having a formula XX, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: A1 is: a bond, CH2, 0 or S, and wherein A, and R4 or Ai and R5 together being a 3to 6 membered carbocyclyl when Ai is a carbon; A2 is : O or S or CH2 ; Q is:C (O) OR6, or R6A ; Y is : a bond, C1C6 alkyl or C3C6 cycloalkyl ; Z is: a) aryl; b) a 5to 10membered heteroaryl wherein the heteroaryl containing at least one heteroatom selected from N, O or S, c) biaryl, wherein biaryl being defined as aryl substituted with another aryl or aryl substituted with heteroaryl, or d) biheteroaryl, wherein biheteroaryl being defined as heteroaryl substituted with another heteroaryl, or heteroaryl substituted with aryl, and wherein aryl, heteroaryl, biaryl and biheteroaryl being optionally substituted with one or more groups independently selected from R7 ; n is : 1, 2,3, 4,5 or 6 p is: 1 or 2; r is : 1,2, 3, or 4; Rl and R2 are each independently: hydrogen, haloalkyl, CiCe alkyl, (CH2)"C3C8 cycloalkyl, or Ri and R2 form a 4to 8membered'nonaromatic carbocyclic ring; and wherein at least one of R'and R 2 is alkyl or cycloalkyl, and; R3 is: hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, CiCe alkyl, C1C6 alkoxy, or C3C8 cycloalkyl ; R4 and R5 are each independently: hydrogen or C1C6 alkyl ; R6 is : hydrogen, ClC6 alkyl or aminoalkyl ; R6A is : carboxamide, sulfonamide, acylsulfonamide, tetrazole, R7 is : hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, CiC6 alkyl, C1C6 alkoxy, (CH2)nC3C8 cycloalkyl, C(O)R9, C(O)OR9, C (=NOR8)R9, CR8 (OH) R9, C[=C(R8)2]R9, OR9, SR9 or S (O)pR9 ; R8 is: hydrogen or C1C6 alkyl ; and R9 is : hydrogen, CiC6 alkyl, C3C8 cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of : hydroxyl 1, haloalkyloxy, aryloxy, oxo, C1C6 alkyl C1C6 alkoxy and C3C8 cycloalkyl.
24. The compound of Claim 23, wherein Z is optionally substituted phenyl or naphthyl, furanyl, imidazolyl, indolyl, oxazolyl, isoxazolyl, pyridyl, pyrrolyl, thiazolyl, thiophenyl, benzofuranyl, benzothiophenyl, benzoisoxazolyl, quinolinyl, isoquinolinyl or a structural formula selected from following: wherein T is: a bond, (CH2) qO,O (CH2) q,C (O) (CH2) q, (CH2) qC (0), (CH2) qS, S (CH2) q, S [O]p, (C1C3 alkyl), (CH2) qC (=CH2),C (=CH2) (CH2) q, (CH2) qC (=NOH), C (=NOH) (CH2) q, (CH2) qC (=NOCH3),C (=NOCH3) (CH2) q, CH(OH)(CH2)q, or (CH2) qCH (OH), qis : 0,1, 2 or 3 ; and rings b to j are each optionally substituted with one or more groups independently selected from the group consisting of : hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (0) 2R9, C1C6 alkyl, C1C6 alkoxy and (CH2)nC3C8 cycloalkyl.
25. The compound of Claim 24, wherein the compound having a structural formula XXI, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: A1 and A2 are respectively: O and 0, CH2 and 0, CH2 and S, 0 and S or S and O ; mis : 1,2, 3 or 4 ; R'is : C1C3 alkyl ; and R3 is: hydrogen, halo or C1C6 alkyl ; R6 and R9 are each independently: hydrogen or C1C6 alkyl ; T is: a bond, O, C (O),S (O)S (0) 2,C (=CH2),C (=NOH) orCH (OH) ; and rings b and c are each optionally substituted with one or more groups independently selected from: hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (0) zur9, C1C6 alkyl, ClC6 alkoxy and (CH2)nC3C8 cycloalkyl.
26. The compound of Claim 25, wherein the compound having a structural formula XXII, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: T is: a bond,OorC (O) ; Rl is : methyl, ethyl or cyclopropyl ; R3 is: methyl or ethyl; and rings b and c are each optionally substituted with one or more substituent independently selected from the group consisting of : hydrogen, Cl, Br, CF3, OCF3, S (0) 2CH3, N (CH3) 2, methyl, ethyl, isopropyl, methoxy and cyclopropyl.
27. The compound of Claim 1, wherein the compound having a structural formula XXIII, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: Ai and A2 are respectively: 0 and 0, CH2 and 0, CH2 and S, O and S or S and O ; m is : 1,2, 3 or 4 ; RI is: ClC3 alkyl ; and R3 is : hydrogen, halo or ClC6 alkyl ; R6 and R9 are each independently: hydrogen or ClC6 alkyl ; T is: a bond,O,C (O),S (O)S (0) 2, C (=CH2),C (=NOH) or CH(OH); and rings b and c are each optionally substituted with one or more groups independently selected from: hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (0) 2R9, C1C6 alkyl, ClC6 alkoxy and (CH2)nC3C8 cycloalkyl.
28. The compound of Claim 27, wherein the compound having a structural formula XXIV, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: T is: a bond,OorC (O) ; Ru ils : methyl, ethyl or cyclopropyl ; R3 is: methyl or ethyl; and rings b and c are each optionally substituted with one or more substituent independently selected from the group consisting of : hydrogen, Cl, Br, CF3, OCF3, S (0) 2CH3, N (CH3) 2, methyl, ethyl, isopropyl, methoxy and cyclopropyl.
29. A compound selected from the group consisting of : No. Structure Name 1 3 [3 (2Benzoyl4 ethylphenoxy)butoxy] f 2methylphenyl} 0 =0 CH3 propionic acid H3C/=\ A O H3C H3c 0 oh H3C' 24 [3 (2Benzoyl4 ethylphenoxy)butoxy] 2metliylphenoxy} cl acetic acid H3c 0 HTC cl3 CH, CH3 3 A [3 (2Benzoyl4 ethylphenoxy)butoxy] 2methyl A0 phenylsulfanyl}acetic Hs acid po H I 3 {4 [3 (2Benzoyl4 ethylphenoxy)butoxy] , 2methyl phenylsulfanyl}acetic H3co cH3 acid s 0 j \ OH 54 [3 (2Benzoyl4 ethylphenoxy) butylsulfanyl]2methyl A0 phenoxy}acetic acid H3C/=d CH3 0 s 0 0 HTC No. Structure Name 6 314 [3 (2Benzoyl4 ethylphenoxy) 'butylsulfanyl]2methyl H3C/=d= CH3 phenyl}propionic acid /cru H3c OH OH OH 7 2f 4 [3 (2Benzoyl4 ethylphenoxy)butoxy] n 2methylphenoxy}2 ooh methylpropionic acid H3c 0 H3C O O OH H3C CH3 3 8 f4 [3 (2Benzoyl4 \L ethylphenoxy)butoxy] phenoxy}acetic acid 0 H3c 0 0 ( HTC 9 3f4 [3 (2Benzoyl4 isopropylphenoxy) butoxy]2methyl o phenyl}propionic acid H3C'CH3 CH3 OH CH3 OH 10/=\ Chiral 3 {4[3(2Benzoyl4 /cyclopropylphenoxy) o butoxy]2methyl / phenyl}propiomcacid cl3 oh Oh OH No. Structure Name 3f4 [3 (2* Benzoyl4 trifluoromethyl phenoxy)butoxy]2 eo methylphenyl} F F propionic acid F 0 0 CHEZ OH OH 12 314 [3 (2Benzoyl4 \ chlorophenoxy) butoxy]2methyl phenyl}propionic acid 3 CH3cO Oh Oh OH 13 3f4 [3 (2Benzoyl4 /chlorophenoxy) butoxy]2methyl phenyl}propionic acid ci Cl3 OH CH3 OH 14 Chiral 314 [3 (2Benzoyl4 methoxyphenoxy) 0 butoxy]2methyl 0 cH phenyl}propionic acid 3 H3CO \/O\ ^ Oh OH OH 15 Chiral 314 [3 (2Benzoyl4 fluorophenoxy) butoxy]2methyl phenyl}propionic acid F<O\r o Xo CH3 F 0 OH No. Structure Name 16 Chiral 3f4 [3 (2Benzoyl4 isopropylphenoxy) butoxy]2methyl H3C/= (CH3 phenyl}propionic acid 3 HaC O \ O cl3// Zou CH3 Chira f4 [3 (2Benzoyl4 t W isopropylphenoxy), butoxy]2methyl H cH3 phenylsulfanyl}acetic 0 acid \/°° \/ 3C CH3 OH 18 14 [3 (2Benzoyl4 chlorophenoxy) butoxy]2methyl phenylsulfanyl}acetic o acrid zu CH3 OH CHg \ /OH 93 (413 [4Etliyl2 (hydroxyphenyl methyl)phenoxy] tOH butoxy}2methyl H CH3 phenyl)propionic acid CH3 OH 20 3 (4 {3 [4Ethyl2 (hydroxyiminophenyl methyl)phenoxy] NOH /CH3 butoxy}2methyl phenyl)propionic acid \ o cH'3 Oh No. Structure Name 21 3 (4 {3 [4Ethyl2 % 8 (methoxyiminophenyl methyl)phenoxy] v=NOCH3 butoxy}2methyl phenyl)propionic acid o CH3 OH 22 H3C\ Chiral 314 [3 (4Isopropyl2 3 ~W°Y~ < phenoxyphenoxy) butoxy]2methyl e OH phenyl}propionic acid 23 Chiral f4 [3 (4Isopropyl2 phenoxyphenoxy) o butoxy]2methyl H 3c e H3 phenylsulfanyl}acetic acrid H3c \f H3C H C} °< S (O 3 oH OH 4HgC CH, 3 {4 [3 (4Ethyl2 isobutyrylphenoxy) butoxy]2methyl 0 CH3 phenyllpropionic acid o o o CH3 OH 25 {4 [3 (2 Cyclopropanecarbonyl4 ethylphenoxy)butoxy] cH3 2methylphenyl} H3C g propionic acid Cl3 oh OH OH No. Structure Name 26 __. Cyclopropanecarbonyl4 ethylphenoxy)butoxy] cH3 2methylphenyl} w Poß _/o propionic acid CH3 OH 27 n 3{4[3(2 Cyclopentanecarbonyl4 ethylphenoxy)butoxy] H3c 2methylphenyl} 0 CH3 propionic acid hic OH OH H3C'CH3 2f{4 [3 (4Ethyl2 isobutyrylphenoxy) o butoxy]phenoxy}2 0 0, metliylpropionic acid F'I3C CH3 3 29 CH, C CH, Cyclopropanecarbonyl4 /G ethylphenoxy)butoxy] H3c phenoxy}2methyl o \/o propionic acid C H3. H3C CH OH 30 0 CH3 3 {4[3(3Benzoyl5 v LoY ethylpyridin2yloxy) 0 CH3 butoxy]2metliyl A OH phenyl}propionic acid iXi 31 14 [3 (3Benzoyl5 /ethylpyridin2yloxy) butoxy]2methyl H3c 3 phenylsulfanyl Iacetic acrid o \/s o CH OH No. Structure Name 32/n Chiraì 3 {4[3(3Benzoyl5 \/chloropyridin2yloxy) butoxy]2methyl C1ß phenyl)propionic acid ci 0 N o 0 OH OH 33/=\ Chiral {4[3(3Benzoyl5 chloropyridin2yloxy) 0 butoxy]2methyl X CH3 phenylsulfanyl}acetic ci 0 acid 0 63 S 0 OH 4/Chirac 3 {4 [3 (3Benzoyl5 trifluoromethylpyridin 2yloxy)butoxy]2 ) = CH methylphenyl} propionic acid F F N O 1 O O CH3 OH CH 3 OH 5cmra) {4 [3 (3Benzoyl5 trifluoromethylpyridin 2yloxy)butoxy]2 o methylphenylsulfanyl} F acetic acid c N S OH H3c 36 Chiral 3f4 [3 (5Chloro3 phenoxypyridin2 yloxy)butoxy]2 methylphenyl} cl Z propionic acid c,/o. =/ cl3 OH OH Jvt No. Structure Name '37/\chiai3 {4 [3 (5Chloro3 phenoxypyridin2 /yloxy)butoxy]2ethyl /o phenyl}propionic acid cl,\ CI OH N CH3 H 8/\chirai {4 [3 (5Chloro3 phenoxypyridin2 p yloxy)butoxy]2 cH3 methylphenylsulfanyl} acetic acid ci > o o \/S o HTC OH 39 F CH Chiral 312Methyl4 [3 (3 F_ 0 0 phenoxy5 \ H trifluoromethylpyridin 2yloxy)butoxy] phenyl}propionic acid w 0/\chira ! 3 {2Ethyl4 [3 (3 phenoxy5 trifluoromethylpyridin 0 0 CH3 2yloxy)butoxy] Fo phenyl}propionic acid F 0 o 0 OH 41 Chiral 312Ethyl4 [3 (3 phenoxy5 trifluoromethylpyridin 2yloxy)butoxy] phenyl}propionic acid 0 OU OH OH No. Structure Name 42 F 0 312Methyl4 [3 (3 phenoxy5 trifluorometliylpyridin 2yloxy)propoxy] phenyl}propionic acid F (trifluoroacetic acid salt) 0 3f3 {4 [3 (5chloro3 phenoxypyridin2 OH yloxy)propoxy]2 methylphenyl 0 propionic acid CH3 CI OUT 44 3 {4[2(5Chloro3 phenoxypyridin2 o ylamino)ethoxy]2 /methylphenyl} cyN H3 propionic acid homo N\p O OH 45 H3cN CH3 3 {4 [3 (3Benzoyl5 \ ethylpyridin2yloxy) n onto propoxy]2methyl phenylpropionic acid QS 46 Chiral 312Methyl4 [3 (6 methyl2phenoxy pyridin3yloxy) butoxy]phenyl} LD AH hic OH OH No. Structure Name 47 3 {4 [3 (5Ethyl biphenyl2yloxy) butoxy]2methyl H cH3 phenyl}propionic acid CH3 OH OH 48 Chiral 314 [3 (4Ethyl2 N o oxazol2ylphenoxy) H C/= (FH3 o butoxy]2methyl phenylpropionic acid OH O CH3 49 H3c CH Chiral 3f4 [3 (4Ethyl2 \/° thiazol4ylphenoxy) ° butoxy]2methyl phenyl}propionic acid s s 50 Chiral 314 [3 (4Ethyl2 pyridin2ylphenoxy) N butoxy]2methyl H3C S CH3 phenyl}propionic acid mon\/y OH H3c OH 1chirai {4 [3 (4Ethyl2pyridin /2ylphenoxy)butoxy] /j 2methyl HsC/SOH phenylsulfanyl}acetic 0 acid o H3C 52 CH3 CH3 0 Chiral 312Ethyl4 [3 (4ethyl 2pyridin2ylphenoxy) N OH butoxy]phenyll propionic acid CH3 CH, No. Structure Name 53 n Chiral 3 {4[3(4Chloro2 a_/pyridin2ylphenoxy) butoxy]2methyl cH3 phenyl}propionic acid H3C <° Hic OH OH 54 F F CH3 0 Chiral 312Methyl4 [3 (2 pyridin2yl4 oH trifluoromethyl Y phenoxy)butoxy] phenyl}propionic acid CH3 55 F H3c 0 Chiral 3f2Ethyl4 [3 (2 pyridin2yl4 F N OH trifluoromethyl phenoxy)butoxy] phenyl}propionic acid CH3 56 Chiral 314 [3 (4Ethyl2 \ N pyridin3ylphenoxy) H 3c butoxy]2methyl \ CH 3 phenyllpropionic acid HgC \ OH OH 57 N Chiral 314 [3 (4Chloro2 pyridin3ylphenoxy) </CH3 butoxy]2methyl /\ phenyl}propiomc acid ci oo o CH3 OH CH3 OH 58 ; cnira 3_43 (4Ethyl2 pyridin4ylphenoxy) H c butoxy]2methyl V ~o phenyl}propionic acid zu OH Oh No. Structure Name 59 chiral CH O 3f 2Methyl4 [3 (2 pyridin4yl4 F OH trifluoromethyl phenoxy)butoxy] phenyl}propionic acid CH3 60 F F/N H3C 0 chiral 3_ f2_Ethyl4 [3 (2 pyridin4yl4 oH trifluoromethyl phenoxy)butoxy] phenyl}propionic acid CH3 '61N"°\CH, 0Chirai 3. {4 [3 (2 cl Benzo [d] isoxazol3yl4 OH chlorophenoxy) \+ < butoxy]2methyl OfO phenyl}propionic acid CH3 62 3f4 [3 (2Benzoyl4 ethylphenoxy)butoxy] A 2methylphenyl} /= CH3 propionic acid HTC OH H3C 63 f4 [3 (2Benzoyl4 ethylphenoxy)butoxy] A 2methylphenoxy} CH acetic acid H3C OU oOH CH3 64 14 [3 (2Benzoyl4 ethylphenoxy)butoxy] 2methyl ho phenylsulfanyl}acetic H3c acid U O S CH3 OH CHg No. Structure Name 65 {4 [3 (2Benzoyl4 ethylphenoxy)butoxy] 0 2methyl phenylsulfanyl}acetic CH3 acid 0 3 acid CH3 0 S O OH 66 {4 [3 (2Benzoyl4 ethylphenoxy) butylsulfanyl]2methyl ==0 phenoxy}acetic acid H3C/t, vCH3 | t A < (OH 3 hic {4 [3 (2Benzoyl4 ethylphenoxy) butylsulfanyl]2methyl H3C/= (= CH3 phenyl}propionic acid CH3 H3C H, XOH OH OH 68 2 {4 [3 (2Benzoyl4 ethylphenoxy)butoxy] X 2methylphenoxy}2 H3c 0 CH3 methylpropionic acid epH CH3 H3C CN3 6H, H, C CH, '69/ {4 [3 (2Benzoyl4 ethylphenoxy)butoxy] phenoxy}acetic acid 0 H 3c 0 0 H3C hic HC 3 No. Structure Name 70/% 3 [3 (2Benzoyl4 isopropylphenoxy) butoxy]2methyl o phenyl}propionic acid H3C/CH3 H3c 0 CH3 OH Chiral 3 {4 3 (2Benzoyl4 \/cyclopropylphenoxy) \ butoxy]2methyl La phenyl)propioll acid CH3 /O CH OH 72/< 3 [3 (2Benzoyl4 trifluoromethyl phenoxy)butoxy]2 0 methylphenyl} F CH3 propionic acid CH3 OH OH 73 314 [3 (2Benzoyl4 chlorophenoxy) butoxy]2methyl phenyl}propionic acid CH3 CH, \ OH OH 74 3 {4 [3 (2Benzoyl4 \/chlorophenoxy) butoxy]2metliyl /'phenyl}propionic acid CH CI O CHg \ OH No. Structure Name 75/=\ Chìral 3 {4[3(2Benzoyl4 /methoxyphenoxy) butoxy]2methyl phenylpropionic acid H3co Cl3 oh Oh OH 76 Chiral 3f4 [3 (2Benzoyl4 fluorophenoxy) butoxy]2methyl cl phenyl}propionic acid CH3 F \/O OH OH OH 77 Chiral 3 {4[3(2Benzoyl4 isopropylphenoxy) 0 butoxy]2methyl H3C X CH3 phenyl}propionic acid 3 CH3 Cl3 OH OH "78/chir {4 [3 (2Benzoyl4 isopropylphenoxy) butoxy]2methyl 0 CH3 phenylsulfanyl}acetic H3c acid o S/° acid HgC OH 79 14 [3 (2Benzoyl4 chlorophenoxy) butoxy]2methyl phenylsulfanyllacetic acid _ o Cl3 CH3 S"H No. Structure Name 80 80 (4 {3 [4Ethyl2 (hydroxyphenyl methyl)phenoxy] OH butoxy}2methyl H3^'CH3 phenyl)propionic acid 0 CH3 OH 8113 (4 {3 [4Ethyl2 / (hydroxyiminophenyl \ methyl)phenoxy] =NOH CH butoxy}2methyl phenyl)propionic acid CHg \/ CH3 OH 82 3 (413 [4Ethyl2 (methoxyiminophenyl ) =NocH3 methyl)phenoxy] butoxy}2methyl o\ o phenyl)propionic acid Cl3 83 H3C OH CH Chira 3 {4 [3 (4Isopropyl2 H3 o phenoxyphenoxy) butoxyl2methyl phenyl}propionic acid '84chira) {4 [3 (4Isopropyl2 phenoxyphenoxy) o butoxy]2methyl phenylsulfanyl}acetic 0 acid H3C \/O \/S O HTC OH No. Structure Name 3 {4 [3 (4Ethyl2 isobutyrylphenoxy) H 3c butoxy]2methyl /phenyl}propionic acid cl3 C3 OH 86 3{4[3(2 Cyclopropanecarbonyl4 < ethylphenoxy)butoxy] H3cCH3 2methylphenyl} 0 propionic acid CH3 OH OH 87 3f4 [3 (2 Cyclopropanecarbonyl4 H 3c ethylphenoxy)butoxy] 0 2methylphenyl propionic acid CH3 OH OH 1 88 3{4[3(2 Cyclopentanecarbonyl4 ethylphenoxy)butoxy] ./ 2methylphenyl} \e For propionic acid H3C OH 89 H3C\4CH3 2 {4[3(4Ethyl2 isobutyrylphenoxy) H3c o o butoxy]phenoxy}2 OxflOH methylpropionic acid CH3 H3C CH3 3 90 2f4 [3 (2 \ Cyclopropanecarbonyl4 /= ethylphenoxy)butoxy] H3C/\ phenoxy}2methyl &o 0 propionic acid cl 3 HC cH. OH No. Structure Name Name 91 H3cN 0 CH3 3f4 [3 (3Benzoyl5 )\O ethylpyridin2yloxy) \F° CH3 r, ° butoxy]2methyl t OH phenyl}propionic acid oh 92 f4 [3 (3Benzoyl5 /ethylpyridin2yloxy) butoxy]2methyl phenylsulfanyl}acetic acid 1° OH OH Chiral 314 [3 (3Benzoyl5 chloropyridin2yloxy) 0 butoxy]2metliyl H3 phenyllpropionic acid CI \ > 0 Cul 0 OH OH '94/==\chirai {4 [3 (3Benzoyl5 chloropyridin2yloxy) 0 butoxy]2methyl 0 phenylsulfanyl}acetic C 3 O _ 1C1C \ N O \/S O C3 OH '95. chira) 3 {4 [3 (3Benzoyl5 trifluoromethylpyridin 2yloxy)butoxy]2 F X CH3 methylphenyl} o propionic acid F F N O CH3 OH EH No. Structure Name 96 Chiral 14 [3 (3Benzoyl5 trifluoromethylpyridin 2yloxy)butoxy]2 =o methylphenylsulfanyl} acetic acid F \/oo hic 3 97 Chiral 3f4 [3 (5Chloro3 phenoxypyridin2 o yloxy)butoxy]2 methylphenyl ci 0 propionic acid N O O CH3 Oh CH3 98 Chiral 3f4 [3 (5Chloro3 phenoxypyridin2 0/yloxy)butoxy]2ethyl cH phenyl}propionic acid 3 CI OH CH3 OH 9/r\chi {4 [3 (5Chloro3 phenoxypyridin2 /yloxy)butoxy]2 methylphenylsulfanyl} acetic acid 3 3 OH 100 FN CH3 cnira 3_ f2Methyl43 (3 F F / oo phenoxy5 0 1H3 vOH trifluoromethylpyridin 2yloxy)butoxy] 0 phenyl Ipropionic acid w No. Structure Name 101/\chira ! 3 {2Ethyl4 [3 (3 phenoxy5 trifluoromethylpyridin 0 cH3 2yloxy)butoxy] /o phenyl}propionic acid c 0 0 HTC NOH 102ca3 {2Ethyl4 [3 (3 phenoxy5 o trifluoromethylpyridin F 2yloxy)butoxy] F 0 phenyl}propionic acid F N H C S QO 3 OH 103 F ° 3 {2Methyl4 [3 (3 F OH phenoxy5 trifluoromethylpyridin F CH3 2yloxy)propoxy] F+ phenyl}propionic acid F 0 (trifluoroacetic acid salt) OH 104 3f4 [3 (5Chloro3 phenoxypyridin2 OH yloxy)propoxy]2 methylphenyl} o propionic acid ci Cl OH 105 3 {4[2(5Chloro3 phenoxypyridin2 o ylamino)ethoxy]2 methylphenyl} propionic acid ouzo OH No. Structure Name 106 H3cN cH3 34 [3 (3Benzoyl5 ~e ethylpyridin2yloxy) d= o vo propoxy]2methyl 0 phenyl}propionic acid 107Chirac3 {2Methyl4 [3 (6 methyl2phenoxy o pyridin3yloxy) NA CH3 butoxy]phenyl} 3 0 0 propionic acid H3C \< OH 108 3 {4 [3 (5Ethyl biphenyl2yloxy) butoxy]2methyl phenyllpropionic acid CH, A= 3 OH 109chirat 3 {4 [3 (4Ethyl2 N cl oxazol2ylphenoxy) cH3 o butoxy]2methyl H (/t/n j o phenyl}propionic acid CH3 CH, 110 H3C/=N CH3 Chiraì 3 {4[3(4Ethyl2 /°o thiazol4ylphenoxy) \, butoxy]2methyl 3 phenyl}propionic acid s Chiral 3f4 [3 (4Ethyl2 pyridin2ylphenoxy) butoxy]2methyl H3c \_S phenyllpropionic acid H ( Oh sC OH No. Structure Name 112 q Chiral {4[3(4Ethyl2pyridin 2ylphenoxy)butoxy] /1 3//2methyl 0 phenylsulfanyllacetic / acid HTC 113 CH 3 CH3 0 Chiral 3 {2Ethyl4 [3 (4etliyl 2pyridin2ylphenoxy) N OH butoxy]phenyll propionic acid c3 CH3 114, Chiral 3 {4 [3(4Chloro2 N pyridin2ylphenoxy) /=d CH3 butoxy]2methyl ci /o\ ^ 3 phenyl}propionic acid Oh OH 115 F v\j CH3 0 Chiral 3 {2Methyl4[3(2 w pyridin2yl4 i °H trifluoromethyl I I Y ou~o phenoxy)butoxy] phenyl}propionic acid CHg 116 F F H3c 0 Chiral 312Ethyl4 [3 (2 i oH pyridin2yl4 trifluoromethyl phenoxy)butoxy] CH3 phenyl}propionic acid CHg 117 Chiral3f4 [3 (4Ethyl2 pyridin3ylphenoxy) Hi3C CH butoxy]2methyl phenyl}propionic acid p 0 OH No. Structure Name Tl§ci3 {4 [3 (4CMoro2 pyridin3ylphenoxy) butoxy]2methyl o phenyl}propionic acid CH3 OH 119 N Chiral 314 [3 (4Ethyl2 pyridin4ylphenoxy) H3C CH butoxy]2methyl 0 phenyl Ipropionic acid OH OH F F N CH 3 0 3f2Methyl4 [3 (2 F pyridin4yl4 trifluoromethyl F r . < OH tnfluoromethyl phenoxy)butoxy] phenyl}propionic acid CH3 121 F F IN H 3c 0 Chiral 312Ethyl4 [3 (2 F OH pyridin4yl4 trifluoromethyl o o phenoxy)butoxy] phenyl}propionic acid CH3 122 NÆo CH3 ° Chiral 3{4[3(2 c 11 OH Benzo [d] isoxazol3yl4 chlorophenoxy) butoxy]2methyl phenyl}propionic acid CH3 123Chiral 123 Chiral (R)14 [3 (4ethyl2 phenoxyphenoxy) butoxy]2methyl H3C, =d aCH3 phenylsulfanyl}acetic ___60,. o__6S 0 acid CH3 OH CHs OH No. Structure Name 124/==\ci (R) {4 [3 (2benzoyl4 methylphenoxy) O C H3 butoxy]2methyl phenylsulfanyl}acetic H3C<Our O<SwO acid CH3 OH CH,'OH 125 Chiral (R) {4 [3 (2benzoyl4 trifluoromethoxy phenoxy)butoxy]2 F) =0 CH3 methylphenylsulfanyl} F b O 6S 0 acetic acid F O<Osr O<SwO CH3 OH CH'OH 126 {4 [3 (2benzoyl4ethyl phenoxy)hexyloxy]2 methylphenylsulfanyl ito CH3 acetic acid HTC O O S'O OH CH3 127 314 [3 (2benzoyl4 ethylphenoxy) hexyloxy]2methyl H3c CH3 phenyl}propionic acid OH OH OH CH3 128 Chiral (R) _34 [3 (4ethyl2 phenoxyphenoxy) O CH3 butoxy]2methyl phenyl}propionic acid wouro mo .. CH3 OH No. Structure Name T29/chiral (R)3 (4 {3 [4ethyl2 t/p (lphenylvinyl) n phenoxy]butoxy}2 CH2 CH3 metliylphenyl) propionic acid wou omo CH3 OH 130 Chiral (R)3 (413 [4ethyl2 (ImethylIphenyl 7 CH ethyl)phenoxy] CH3 butoxy}2methyl phenyl)propionic acid wou o To CH3 OH CHg OH 131 Chiral (R)3f4 [3 (2benzoyl \\/) 4methylphenoxy) butoxy]2methyl S= CH 3 phenyl Ipropionic acid H3C<Ours, O <O CH3 OH CHg OH 132/c (R)3 (4 {3 [4ethyl2 \\ d (lphenylethyl) phenoxy]butoxy}2 CH3 CH3 methylphenyl) H3C propionic acid OnO O CH3 OH 133 Chiral (R)3 (413 [4ethyl2 N (pyridine2carbonyl) phenoxy]butoxy}2 0 CH3 methylphenyl) H3C propionic acid oo o CH3 OH CH3 OH No. Structure Name 134, 3 (2metliyl4 f 3 [2 (thiophene2carbonyl) O CH 4trifluoromethoxy phenoxy]butoxy} F 090\f 0 <0 phenyl)propionic acid CH3 OH 135 s 3 (4 {3 [4ethyl2 (thiophene2carbonyl) \ phenoxy]butoxy}2 methylphenyl) 3 0 0 0 propionic acid CH3 OH CHg OH 136 3 (4f3 [4ethyl2 (naphthalene1 carbonyl)phenoxy] 0 co CH3 butoxy}2methyl H C 3 phenyl)propionic acid 3 / CH3 OH 137/3 (4 {3 [4ethyl2 (l phenylvinyl)phenoxy] A butoxy}2methyl tCH2 CH3 phenyl)propionic acid H3C/ H3C CH3 OH 138 3 {4 [3 (2benzoyl phenoxy)butoxy]2 methylphenyl 0 CH3 propionic acid .. p CH3 OH No. Structure Name 139 3 {4 [3 (2benzoyl4 methylphenoxy) butoxy]2methyl /to CH3 phenyl}propionic acid \/° CH3 OH CH3 OH 140/3 {4 [3 (2benzyl4 ethylphenoxy)butoxy] 2methylphenyl} H3C A/eCH3 propionic acid H3C CH3 OH 141 3f4 [3 (2benzoyl4 bromophenoxy) butoxy]2methyl 0 CH3 phenyl}propionic acid Br 0 0 0 CH3 OH 142/3 {4 [3 (2benzoyl4 butylphenoxy)butoxy] A 2methylphenyl} H3c 0 CH3 propionic acid 0 CH3 OH 143 3f4 [3 (2benzoyl4 propylphenoxy) \ butoxy]2methyl H3c CHg phenyl}propionic acid HTC CH3 OH CHg H No. Structure Name 3f 4 [4 (2benzoyl4 9 ethylphenoxy)1 L CHg 0 methylbutoxy]2 , 3 OH methylphenyll Hr3C/ propionic acid 3 145 3f4 [4 (2benzoyl4 ethylphenoxy) CH3 0 pentyloxy]2methyl phenyl}propionic acid I NOH O O CH 3 146=3 {4 [3 (2benzoyl4 ethylphenoxy)2 methylpropoxy]2 /=0 CHg methylphenyl} metllyl_p d po propionic acid / OH 147 3f4 [3 (2benzoyl4 ethylphenoxy) propoxy]2methyl Hs phenyl}propionic acid OH OH 148 F3 (4f3 [4ethyl2 (4 fluorobenzoyl) W phenoxy]propoxy}2 methylphenyl) /==0 CHg propionic acid H3C OH No. Structure Name 149/3 (4 {3 [4ethyl2 (2 trifluoromethylbenzoyl) F F phenoxy]propoxy}2 H3c 0 CH3 methylphenyl) 0 propionic acid \/ \/ OH 150 F 3 (4 {3 [4ethyl2 (3 FF trifluoromethylbenzoyl) ß phenoxy]propoxy}2 methylphenyl) 0 CH3 propionic acid H3c woNso mo OH OH 151 (4 f 3 [4etliyl2 (thiophene2carbonyl) Y phenoxy]propoxy}2 H3C/= (/=d methylphenyl) 0 propionic acid OH 152 3 {4 [3 (2benzyl4 ethylphenoxy) CH3 propoxy]2methyl H3c phenyl}propionicacid OH Oh OH 153 153 (4 {3 [4ethyl2 /\ (naphthalenel carbonyl)phenoxy] 0 propoxy}2mcthyl H3C H/=e phenyl)propionicacid OH OH No. Structure Name 154 3 (413 [4ethyl2 (l phenylvinyl)phenoxy] A propoxy}2methyl tCH2 CH3 phenyl)propionic acid H3C/=R OH 0 H 155 2 {4 [3 (2benzoyl4 ethylphenoxy)butoxy] phenoxy}2methyl propionic acid H3C zozo HsC O H3 C HO Ha 156 2f4 [3 (2benzoyl4 ethylphenoxy)2 0 methylpropoxy] CH3 phenoxy}2methyl propionic acid o H 3C O H. CO HsCo O HO HO 157 2f4 [3 (2benzyl4 i\ a ethylphenoxy)butoxy] w ß phenoxy}2methyl propionic acid H3C /O Hic Q 0 HO H3 ? 0 HsCs HO No. Structure Name 0 2f4 [3 (2benzoy14 bromophenoxy) A butoxy]phenoxy}2 methylpropionic acid Hic 0 i H3C Q HH33CC$o 0 HO HCO HO 59, \2 {4 [3 (2benzoyl4 butylphenoxy)butoxy] H C S phenoxy}2methyl propionic acid hic Q 0 H3 C H, CO HO T60/=\chM (R)3 {4 [3 (4chloro2 phenoxyphenoxy) o CH butoxy]2methyl phenyl}propionic acid Cl<Our O<O CH3 OH CH3 OH CH3 OH (R)3 {2methyl4 [3 (2 phenoxy4 o CH trifluoromethyl F 3 phenoxy)butoxy] For phenyl}propionic acid F CHg OH 162 Chiral (R)3 {2methyl4 [3 (2 phenoxy4 trifluoromethoxy F 0 CH phenoxy)butoxy] /p phenyl ;propionic acid CH3 OH No. Structure Name 163Chiral '163/==\' (R)3 {2methyl4 [3 (4 methyl2phenoxy o CH3 phenoxy)butoxy] phenyl}propionic acid CH3 OH 164Chiral 3 OH (R)f 4 [3 (4chloro2 phenoxyphenoxy) o CH butoxy]2methyl phenylsulfanyl}acetic CI p_ ^p /S acid CH3 OH CH3 OH 1653f4 [3 (4chloro2 phenoxyphenoxy) propoxy]2methyl phenyl}propionic acid OH OH 166 chiral 166/+\ Chiral (R)3 {4[3(2 s benzo [b] thiophen3yl4 chlorophenoxy) C H3 butoxy]2methyl phenyl}propionic acid ci oo \/° CH3 OH CHg OH T67 N Chiral (R)3f4 [3 (4chloro2 pyridin3ylphenoxy) 3 butoxy]2methyl cl 0 0 0 phenyl}propionic acid CH3 OH i68 Chiral (R)3f4 [3 (4chloro2 phenoxyphenoxy) butoxy]phenyl}2, 2 difluoropropionic acid CH3 F F OH CH3 F F OH No. Structure Name 169Chiral %) (R)3 f 3bromo4 [3 (4chloro2phenoxy o Br phenoxy)butoxy] ci 0 phenyl Ipropionic acid Cl vOurs, O<O CH3 OH CHg OH 170/=\c (R)3 {4 [3 (4chloro2 phenoxyphenoxy) H C butoxy]3methyl phenylpropionic acid CltOurs, O <O CH3 OH CHU OH (R) {3bromo4 [3 (4 chloro2phenoxy phenoxy)butoxy] phenyl}acetic acid Cl___60, f"o.. 0 CH3 HO 172 FF Chiral (R_3_ f4 [3 (4bromo2 trifluoromethoxy phenoxy)butoxy]2 methylphenyl propionic acid CH3 OH 173 = Chlraì (R) {4[3(4chloro2 phenoxyphenoxy) butoxy]3methyl phenyl}acetic acid CI O n, O O CHg HO CH3 HO No. Structure Name Name T74Chiral (R)14 [3 (4chloro2 phenoxyphenoxy) butoxy]phenyl}acetic acid CI On, O CH3" CH3 HO O '175F'f F (R)3 {4 [3 (4chloro2 phenoxyphenoxy) < CH3 w OH butoxy]2 u JU trifluoromethylphenyl} 0 propionic acid 0 i 176/=\ Chiraì (R) {4[3(4chloro2 phenoxyphenoxy) butylsulfanyl]2methyl phenoxy}acetic acid ci 0 0 Cl3 pu CH3 OH 177 Chiral (R)3f4 [3 (4chloro2 phenoxyphenoxy) butylsulfanyl]2methyl //3 phenyl}propionic acid ci os CH3 OH CH3 OH CI O Chiral (R)3f2Cllloro4 [3 (4 Cl chloro2phenoxy phenoxy)butoxy] o o phenyl}propionic acid C I i No. Structure Name 179 F O Chiral (R)3 {4 [3 (4Chloro2 NOH phenoxyphenoxy) butoxy]2fluoro phenyl}propionic acid C i 180 oChira) (R)3 {4 [3 (4Chloro2 phenoxyphenoxy) 9s 9OH butoxy]2ethylphenyl} propionic acid 0 i 181 Cl O Chiral (R)3 {4[3(2Benzoyl OH 4ethylphenoxy) 0 butoxy]2chloro phenyl}propionic acid zizi 182 F 0 Chiral (R)3f4 [3 (2Benzoyl OH 4ethylphenoxy) oo butoxy]2fluoro J "phenyl}propionic acid wo 183 O Chiral (R)3f 4 [3 (4Chloro2 phenoxyphenoxy) butoxy]phenyl} C propionic acid zizi 1840Chirac (R)3 {4 [3 (2Benzoyl oH 4ethylphenoxy) butoxy]phenyl} propionic acid 0 i No. Structure Name 185 O Chiral (R)3f 4 [3 (4Chloro2 (R)3f4 3 (4 Chloro2 OH phenoxyphenoxy) L pentyloxy]2methyl p phenyl}propionic acid Isomer 1 186 O Chiral (R)34 [3 (2Benzoyl m pH 4ethylphenoxy) pentyloxy]2methyl phenyl}propionic acid w ) j J (someri TS 70 Chiral (R)f4 [3 (3Benzoyl naphthalen2yloxy) butoxy]2methyl phenylsulfanyl}acetic acrid O i 88Chiral (R)3f4 [3 (3Benzoyl naphthalen2yloxy) butoxyj2methyl e o o phenyl}propionic acid 0 I 189 O Chiral (R)3 {4 [3 (4Ethyl2 OH phenoxyphenoxy) butylsulfanyl]2methyl phenyl}propionic acid ) 0 190 O Chiral (R)34 [3 (4Isopropyl OH 2phenoxyphenoxy) vs butylsulfanyl]2methyl ~° phenyl}propionic acid w i No. Structure Name 191 Chiral 191 Chiral (R)3 {4 [3 (4Chloro2 0 phenoxyphenoxy) Cl OH butoxy]2propyl phenyl Ipropionic acid o 192 192 O Chiral (R) {4 [3 (4Chloro2 phenoxyphenoxy) butoxy]2ethyl 0, ;, o phenylsulfanyl Iacetic C acid i 193 CI O Chiral (R)3f 4 [3 (2Benzoyl 0 H 4, 5dichlorophenoxy) butoxy]2methyl phenylpropionic acid wo i 194 O Chiral (R)3 {2Methyl4 [3 (2 OH phenoxy4 trifluoromethyl O S phenoxy)butylsulfanyl] phenyl}propionic acid v 195 T950 Chiral (R)3 {2Ethyl4 [3 (4 etliyl2phenoxy OH phenoxy)butoxy] 90 ~0~ phenyl}propionic acid Y p p 0 196 o Chiral (R)3 {2Ethyl4 [3 (2 CF phenoxy4 OH trifluoromethyl o o phenoxy)butoxy] A phenyl}propionic acid W No. Structure Name 197 o Chiral (R)34 [3 (2Benzoyl OH 4ethylphenoxy) WAv OH butoxy]2ethylphenyl} propionic acid zizi 198. 0Chirai (R)3 {2Ethyl4 [l CF OH methyl3 (2phenoxy4 trifluoromethyl Yo vo~ phenoxy)propoxy] phenyl}propionic acid i 199 F O Chiral (R)3 {2Methyl4 [1 t OH methyl3 (2phenoxy4 trifluoromethoxy I s phenoxy) propylsulfanyl]phenyl} propionic acid 2000Chira) (S)3 {4 [3 (4Chloro2 phenoxyphenoxy) OH butoxy]2ethylphenyll propionic acid po 201 3 {4 [3 (4Chloro2 CI phenoxyphenoxy) OH propoxy]2ethyl i Yo~~oW phenyl}propionic acid Aro 202 o Chiral (R)3 4 [3 (2, 4 °vs A Jt Diphenoxyphenoxy) _ oH butoxy]2ethylphenyl} > C° propionic acid 0 I No. Structure Name 203 0chira) 2 {4 [4 (4Chloro2 plphenoxyphenyl)3 methylbutoxy]2 O methylphenyl} cyclopropanecarboxylic CisIsomer 2 acid 204 (R, S)2 {4 [3 (4Ethyl 2phenylsulfanyl °II phenoxy)butoxy] S 03 \ J' phenoxy}2methyl HCr CH, fY r OH .''.' propionic acid 0 \ CH3 205 I 2 {4 [3 (R, S2 Benzenesulfinyl4ethyl cH3 o phenoxy)butoxy] s CH s I'OH 2methyl C/ ^ phenylsulfanyl2 meth 1ro' o y p piomc acid (enamtiomer pair 1) 206 H c Fm CH3 í< vOH Cyclopropylmethyl4 l l l tnfluoromethyl 0) phenoxy)butoxy] t phenoxy}2methyl propionic acid 207 (R, S)2Methyl2 {4 [3 W o (2methyl3phenyl7 H3C propyl benzofuran6yloxy) o \ CH3 butoxy]phenoxy} 0 J propionic acid CH3 No. Structure Name 208 (R, S)2Methyl2f 4 [3 /cl3 0 (4methyl3phenyl7 CH) 3, Upropyl aM CH3 S eOH benzofuran6yloxy) 0 011 CH3 butoxy]phenoxyl propionic acid CHU CH3 209 (R, S)2 {4 [3 (2 F Y C Cyclopropylmethyl4 F CH3 14034e trifluoromethyl 'TUFT phenoxy)butoxy]2 methylphenoxy}2 methylpropionic acid 210 (R, S)314 [3 (2 F 3 Cyclopropylmethyl4 trifluoromethyl ' ru f' nH phenoxy)butoxy]2 wO~ow methylphenyl} propionic acid TI13JR4 [3 (R, S2 t/J Benzenesulfinyl4ethyl oH3 ° phenoxy)butoxy] H3Cn CH3 HOH 2methylphenyl} propionic acid 212 T123f4 [3 (4Ethyl2 phenylsulfanyl T 0 phenoxy)butoxy] H3Cw CH3 vOH 2methylphenyl} propionic acid isomer 2 koo (R, S)2f4 [3 (4Ethyl 2phenylsulfanyl Con3 0 phenoxy) X CH3 H3C ° phenoxy) 3 methylpropionic acid 0)o CH3 No. Structure Name 214 (R, S)3 {4 [3 (R, S2 , Benzenesulfinyl4ethyl CH3 o phenoxy) H C \ SoH/butoxy]2methyl 011o phenyllpropionic acid oxo 215 215 (R, S)2f4 [3 (R,S2 t d Benzenesulfinyl4ethyl CH3 0 phenoxy) 03C, Ubutoxy]2methyl H3c CH3 y OH phenoxyl2methyl olio CH3 propionic acid 216 216 (R, S)314 [3 (2 , Benzenesulfonyl4etliyl X CH3 0 phenoxy)butoxy]2 H3c CH3 OH methylphenyl oxo 217 F/, F 3 {4[3(2Benzoyl4 0 trifluoromethoxy eI CH3 v OH phenoxy)butoxy]2 , methylphenyl} propionic acid wo 30.
30. The compound of Claim 29, wherein the compound is or a pharmaceutically acceptable salt, solvate or hydrate thereof.
31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Claims 130 or a pharmaceutically acceptable salt, solvate or hydrate thereof.
32. A pharmaceutical composition comprising: (1) a compound of Claims 130, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof; (2) a second therapeutic agent selected from the group consisting of : insulin sensitizers, sulfonylureas, biguanides, meglitinides, thiazolidinediones, oc glucosidase inhibitors, insulin secretogogues, insulin, antihyperlipidemic agents, plasma HDLraising agents, HMGCoA reductase inhibitors, statins, acryl CoA: cholestrol acyltransferase inhibitors, antiobesity compounds, antihypercholesterolemic agents, fibrates, vitamins and aspirin; and (3) optionally a pharmaceutically acceptable carrier.
33. A method of modulating a peroxisome proliferator activated receptor (PPAR) comprising the step of contacting the receptor with a compound of Claims 130, or a pharmaceutically acceptable salt, solvate or hydrate thereof.
34. The method of Claim 33, wherein the PPAR is an alpha (ct) receptor.
35. The method of Claim 33, wherein the PPAR is a gamma (y) receptor.
36. The method of Claim 33, wherein the PPAR is a delta (8)receptor.
37. The method of Claim 33, wherein the PPAR is a gamma/delta ()receptor.
38. The method of Claim 33, wherein the PPAR is an alpha/gamma/delta (oc/y/o)receptor.
39. A method for treating or preventing a PPARy mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of Claims 130.
40. A method for treating or preventing a PPAR8 mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of Claims 130.
41. A method for treating or preventing a PPARy/8 mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of Claims 130.
42. A method for treating or preventing a PPARo/y/8 mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of Claims 130.
43. A method for lowering bloodglucose in a mammal comprising the step of administering an effective amount of a compound of Claims 130.
44. A method of treating or preventing disease or condition in a mammal selected from the group consisting of hyperglycemia, dyslipidemia, Type II diabetes, Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other diseases where insulin resistance is a component, comprising the step of administering an effective amount of a compound of Claims 130.
45. A method of treating or preventing diabetes mellitus in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound of Claims 130.
46. A method of treating or preventing cardiovascular disease in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound of Claims 130, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.
47. A method of treating or preventing syndrome X in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of Claims 130, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.
48. A method of treating or preventing disease or condition in a mammal selected from the group consisting of hyperglycemia, dyslipidemia, Type II diabetes, Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other diseases where insulin resistance is a component, comprising the step of administering an effective amount of a compound of Claims 130 and an effective amount of second therapeutic agent selected from the group consisting of : insulin sensitizers, sulfonylureas, biguanides, meglitinides, thiazolidinediones, olglucosidase inhibitors, insulin secretogogues, insulin, antihyperlipidemic agents, plasma HDLraising agents, HMGCoA reductase inhibitors, statins, acryl CoA: cholestrol acyltransferase inhibitors, antiobesity compounds, antihypercholesterolemic agents, fibrates, vitamins and aspirin.
49. Use of a compound of Claims 130 and a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, for the manufacture of a medicament for the treatment of a condition modulated by a PPAR.
Description:
PPAR MODULATORS FIELD OF THE INVENTION The present invention relates to compounds of peroxisome proliferator activated receptor (PPAR) agonists, more specifically compounds of PPAR gamma-delta dual agonists, which are useful for the treatment and/or prevention of disorders modulated by a PPAR agonist.

BACKGROUND OF THE INVENTION The peroxisome proliferator activated receptors (PPARs) are members of the nuclear receptor gene family that are activated by fatty acids and fatty acid metabolites. The PPARs belong to the subset of nuclear receptors that function as heterodimers with the 9-cis retinoic acid receptor (RXR). Three subtypes, designated PPARoc, PPARyand PPAR8, are found in species ranging from Xe7Z0pus to humans.

PPARoc is the main subtype in the liver and has facilitated analysis of the mechanism by which peroxisome proliferators exert their pleiotropic effects. PPARa is activated by a number of medium and long-chain fatty acids, and it is involved in stimulating ß-oxidation of fatty acids. PPARoc is also involved with the activity of fibrates and fatty acids in rodents and humans. Fibric acid derivatives such as clofibrate, fenofibrate, bezafibrate, ciprofibrate, beclofibrate and etofibrate, as well as gemfibrozil, produce a substantial reduction in plasma triglycerides along with moderate reduction in low-density lipoprotein (LDL) cholesterol, and they are used particularly for the treatment of hypertriglyceridemia.

PPARy is the main subtype in adipose tissue and involved in activating the program of adipocyte differentiation. PPAR7 is not involved in stimulating peroxisome proliferation in the liver. There are two isomers of PPAR : PPARyl and PPARy2, which

differ only in that PPARy2 contains an additional 28 amino acids present at the amino terminus. The DNA sequences for the PPARy receptors are described in Elbrecht, et al., BBRC 224: 431-437 (1996). Although peroxisome proliferators, including the fibrates and fatty acids, activate the transcriptional activity of PPAR's, only prostaglandin J2 derivatives have been identified as natural ligands for PPARy, which also binds the anti- diabetic agents thiazolidinediones with high affinity. The physiological functions of PPAR (X and PPARy in lipid and carbohydrate metabolism were uncovered once it was recognized that they were the receptors for the fibrate and glitazone drugs, respectively.

PPARot and PPARy receptors have been implicated in diabetes mellitus, cardiovascular disease, obesity, and gastrointestinal disease, such as inflammatory bowel disease and other inflammation related illnesses. Such inflammation related illnesses include, but are not limited to Alzheimer's disease, Crohn's disease, rheumatoid arthritis, psoriasis, and ischemia reprofusion injury.

By contrast, PPARo (also referred to as PPARß and NUC1) is not reported to be receptor for any known class of drug molecules, and its role in mammalian physiology has remained undefined. The human nuclear receptor gene PPAR8 (hPPARo) has been cloned from a human osteosarcoma cell cDNA library and is fully described in A.

Schmidt et al., Molecular Endocrinology, 6: 1634-1641 (1992).

Diabetes is a disease in which a mammal's ability to regulate glucose levels in the blood is impaired because the mammal has a reduced ability to convert glucose to glycogen for storage in muscle and liver cells. In Type I diabetes, this reduced ability to store glucose is caused by reduced insulin production. "Type II Diabetes"or "non-insulin dependent diabetes mellitus" (NIDDM) is the form of diabetes, which is due to a profound resistance to insulin stimulating or regulatory effect on glucose and lipid metabolism in the main insulin-sensitive tissues, muscle, liver and adipose tissue. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver. When these cells become desensitized to insulin, the body tries to compensate by producing abnormally high levels

of insulin and hyperinsulemia results. Hyperinsulemia is associated with hypertension and elevated body weight. Since insulin is involved in promoting the cellular uptake of glucose, amino acids and triglycerides from the blood by insulin sensitive cells, insulin insensitivity can result in elevated levels of triglycerides and LDL (known as the"bad" cholesterol) which are risk factors in cardiovascular diseases. The constellation of symptoms which includes hyperinsulemia combined with hypertension, elevated body weight, elevated triglycerides and elevated LDL is known as Syndrome X.

Hyperlipidemia is a condition which is characterized by an abnormal increase in serum lipids, such as cholesterol, triglycerides and phospholipids. These lipids do not circulate freely in solution in plasma, but are bound to proteins and transported as macromolecular complexes called lipoproteins. One form of hyperlipidemia is hypercholesterolemia, characterized by the existence of elevated LDL cholesterol levels.

The initial treatment for hypercholesterolemia is often a diet low in fat and cholesterol coupled with appropriate physical exercise. Drug intervention is initiated if LDL- lowering goals are not met by diet and exercise alone. It is desirable to lower elevated levels of LDL cholesterol and increase levels of HDL cholesterol. Generally, it has been found that increased levels of HDL are associated with lower risk for coronary heart disease (CHD). See Gordon, et al., An1. J. Med., 62,707-714 (1977); Stampfer, et al., N.

EnglandJ. Med., 325,373-381 (1991) ; and Kannel, et al., Ann. Internal Med., 90,85-91 (1979). An example of an HDL raising agent is nicotinic acid, but the quantities needed to achieve HDL elevation are associated with undesirable effects, such as flushing.

There are several treatments currently available for treating diabetes mellitus but these treatments still remain unsatisfactory and have limitations. While physical exercise and reduction in dietary intake of calories will improve the diabetic condition, compliance with this approach can be poor because of sedentary lifestyles and excess food consumption, in particular high fat-containing food. Therefore, treatment with hypoglycemics, such as sulfonylureas (e. g. , chlorpropamide, tolbutamide, tolazamide and acetohexamide) and biguanides (e. g. phenfonmin and metfornzin) are often necessary as the disease progresses. Sulfonylureas stimulate the ß cells of the pancreas to secrete more insulin as the disease progresses. However, the response of the (3 cells eventually fails and treatment with insulin injections is necessary. In addition,

both sulfonylurea treatment and insulin injection have the life threatening side effect of hypoglycemic coma, and thus patients using these treatments must carefully control dosage.

It has been well established that improved glycemic control in patients with diabetes (Type I and Type II) is accompanied by decreased microvasclular complications (DCCT and UKPDS). Due to difficulty in maintaining adequate glycemic control over time in patients with Type II diabetes, the use of insulin sensitizers in the therapy of Type II diabetes is growing. There is also a growing body of evidence that PPARy agonist, insulin sensitizer, may have benefits in the treatment of Type II diabetes beyond their effects in improving glycemic control.

In the last decade a class of compounds known as thiazolidinediones (TZD) (e. g. U. S. Pat. Nos. 5,089, 514; 4,342, 771; 4,367, 234; 4,340, 605; and 5,306, 726) have emerged as effective antidiabetic agents that have been shown to increase the sensitivity of insulin sensitive tissues, such as skeletal muscle, liver and adipose, to insulin. Increasing insulin sensitivity rather than the amount of insulin in the blood reduces the likelihood of hypoglycemic coma. Although thiazolidinediones have been shown to increase insulin sensitivity by binding to PPARy receptors, this treatment also produces unwanted side effects such as weight gain and edema and, for troglitazone, liver toxicity. Recently, the compounds that are not TZDs have also been reported as PPAR modulators.

Adams et al. (WO 97/28115, WO 97/28135 and US Patent No. 5,895, 051) discloses acetylphenols, which are useful as antiobesity and antidiabetic compounds.

Leibowitz et al. (WO 97/28149) discloses compounds which are PPAR8 agonists and useful for treating cardiovascular diseases and related conditions.

Brooks et al. (WO 02/100813) discloses compounds of PPAR modulators that are useful for treating type II diabetes and other PPAR-mediated diseases and conditions.

In view of the above, an objective of the present invention is to provide new pharmaceutical agents which modulate PPAR receptors to prevent, treat and/or alleviate these diseases or conditions while reducing and or eliminating one or more of the unwanted side effects associated with the current treatments.

SUMMARY OF THE INVENTION The present invention relates to a compound of novel peroxisome proliferator activated receptor (PPAR) agonist having a structural formula I,

or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: Al is: a bond, CH2, O or S, and wherein Al and R4 or Al and R together being a 3-to 6- membered carbocyclyl when Al is a carbon; A2 and A3 are independently: CH2, O or S; El, E2, E3, E4 and Eg are each CH or substituted carbon bearing A2 and R3 ; or at least one of EJ, E2, E3, E4 and Es is nitrogen and each of others being CH or substituted carbon bearing A2 and R3 ; Q is : -C (O) OR6, or R6A ; Y is: a bond, C1-C6 alkyl or C3-C6 cycloalkyl; Z is: a) aryl; b) a 5-to 10-membered heteroaryl wherein the heteroaryl containing at least one heteroatom selected from N, O or S, c) bi-aryl, wherein biaryl being defined as aryl substituted with another aryl or aryl substituted with heteroaryl, or d) bi-heteroaryl, wherein bi-heteroaryl being defined as heteroaryl substituted with another heteroaryl, or heteroaryl substituted with aryl, and wherein aryl, heteroaryl, bi-aryl and bi-heteroaryl being optionally substituted with one or more groups independently selected from R7 ;

n is : 1, 2,3, 4, 5 or 6 p is : 1 or 2; ris : 1, 2,3, or 4 ; R1 and R2 are each independently: hydrogen, haloalkyl, C1-C6 alkyl, (CH2)nC3-C8 cycloalkyl, or R1 and R2 form a 4-to 8-membered nonaromatic carbocyclic ring; and wherein at least one of Rl and R2 is alkyl or cycloalkyl, and; R3 is : hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, C1-C6 alkyl, C-C6 alkoxy, or C3-C8 cycloalkyl ; R4 anders are each independently: hydrogen or Cl-C6 alkyl ; R is : hydrogen, C1-C6 alkyl or aminoalkyl ;

R6A is : carboxamide, sulfonamide, acylsulfonamide, tetrazole, R7 is : hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, CI-C6 alkyl, Cl-C6 alkoxy, (CH2)nC3-C8 cycloalkyl, C (O) R9, C (O) OR9, <BR> <BR> <BR> <BR> <BR> <BR> C(=NOR8)R9,<BR> CR8(OH)R9,<BR> <BR> <BR> <BR> <BR> OR',<BR> <BR> <BR> <BR> OR', SR9 or

S (0) pR ; R is : hydrogen or Cl-C6 alkyl ; and R9 is : hydrogen, C-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of : hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, oxo, Ci- C6 alkyl, Cl-C6 alkoxyand C3-C8 cycloalkyl.

The compounds of the present invention are useful in the treatment and/or prevention of diseases or condition relates to hyperglycemia, dyslipidemia, Type II diabetes, Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other diseases where insulin resistance is a component.

In one embodiment, the present invention also relates to a pharmaceutical composition which comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof and a pharmaceutically acceptable carrier. Within the scope of this invention also include a pharmaceutical composition containing additional therapeutic agent as well a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof and a pharmaceutically acceptable carrier.

In another embodiment, the present invention relates to a method of modulating a PPAR by contacting the receptor with a compound of the present invention, or a pharmaceutically acceptable salt, solvate and hydrate or stereoisomer thereof.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention are directed to peroxisome proliferator activated receptor (PPAR) agonists, more specifically compounds of PPARy/6 dual agonists, which are useful for the treatment and/or prevention of disorders modulated by a PPAR, such as Type II diabetes, hyperglycemia, dyslipidemia, Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other related diseases.

An embodiment of the present invention is a compound of novel peroxisome proliferator activated receptor (PPAR) agonists having a structural formula I, I or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: Al is: a bond, CH2, O or S, and wherein Al and R4 or Al and R5 together being a 3-to 6- membered carbocyclyl when Al is a carbon; A2 and A3 are independently: CH2, O or S; E1, E2, E3, E4 and Es are each CH or substituted carbon bearing A2 and R3 ; or at least one of E, EZ, E3, E4 and Es is nitrogen and each of others being CH or substituted carbon bearing A2 and R3 ; Q is : -C (O) OR6, or R6A ; Y is : a bond, Cl-C6 alkyl or C3-C6 cycloalkyl ; Z is: a) aryl;

b) a 5-to 10-membered heteroaryl wherein the heteroaryl containing at least one heteroatom selected from N, O or S, c) bi-aryl, wherein biaryl being defined as aryl substituted with another aryl or aryl substituted with heteroaryl, or d) bi-heteroaryl, wherein bi-heteroaryl being defined as heteroaryl substituted with another heteroaryl, or heteroaryl substituted with aryl, and wherein aryl, heteroaryl, bi-aryl and bi-heteroaryl being optionally substituted with one or more groups independently selected from R7 ; n is : 1,2, 3,4, 5 or 6 p is: 1 or 2 ; ris : 1,2, 3, or 4 ; R1 and R2 are each independently: hydrogen, haloalkyl, C-C6 alkyl, (CH2)nC3-C8 cycloalkyl, or R1 and R2 form a 4-to 8-membered nonaromatic carbocyclic ring; and wherein at least one of Rl and R2 is alkyl or cycloalkyl, and; R3 is : hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, Cl-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl ;

R4 and R5 are each independently: hydrogen or Cl-C6 alkyl ; R6 is : hydrogen, C1-C6 alkyl or aminoalkyl ; R6A is : carboxamide, sulfonamide, acylsulfonamide, tetrazole, R7 is : hydrogen, oxo, mod. cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, Cl-C6 alkyl, Ci-Ce alkoxy, (CH2)nC3-C8 cycloalkyl, C (O) R9, C (O) OR9, C (=NOR8) R9,

CR8 (OH) R9, C [=C (R') 2] R', OR', SR9 or S (O) pR9 ; R8 is: hydrogen or C1-C6 alkyl ; and R9 is: hydrogen, C-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of : hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, oxo, Ci- C6 alkyl, C1-C6 alkoxyand C3-C8 cycloalkyl.

A preferred embodiment of the present invention is a compound having a structural formula II, II or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: A1 is: a bond, CH2, O or S, and wherein A1 and R4 or A1 and R5 together being a 3-to 6- membered carbocyclyl when A] is a carbon; A2 is : O or S or CH2 ; Q is : -C (O) OR6, or R6A ;

Y is : a bond, C-C6 alkyl or C3-C6 cycloalkyl ; Z is: a) aryl; b) a 5-to 10-membered heteroaryl wherein the heteroaryl containing at least one heteroatom selected from N, O or S, c) bi-aryl, wherein biaryl being defined as aryl substituted with another aryl or aryl substituted with heteroaryl, or d) bi-heteroaryl, wherein bi-heteroaryl being defined as heteroaryl substituted with another heteroaryl, or heteroaryl substituted with aryl, and wherein aryl, heteroaryl, bi-aryl and bi-heteroaryl being optionally substituted with one or more groups independently selected from R7 ; nis : 1,2, 3,4, 5 or 6 p is: 1 or 2; r is : 1,2, 3, or 4; R'and R2 are each independently: hydrogen, haloalkyl, C I-C6 alkyl, (CH2) nC3-C8 cycloalkyl, or R1 and R2 form a 4-to 8-membered nonaromatic carbocyclic ring; and wherein at least one of R1 and R2 is alkyl or cycloalkyl, and; R3 is: hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, Cl-C6 alkyl,

Cl-C6 alkoxy or C3-C8 cycloalkyl ; R4 andR5 are each independently: hydrogen or Cl-C6 alkyl ; R6 is : hydrogen, C1-C6 alkyl or aminoalkyl ; R6A is : carboxamide, sulfonamide, acylsulfonamide, tetrazole, R7 is : hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, Cl-C6 alkyl, C1-C6 alkoxy, (CH2)nC3-C8 cycloalkyl,

C (O) R9, C (O) OR9, C (=NOR8) R9, CR8 (OH) R9, C [=C (R') 2] R', OR9, SR9 or S (O) pR9 ; R8 is: hydrogen or C1-C6 alkyl ; and R9 is: hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of: hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, oxo, C1- C6 alkyl, C1-C6 alkoxy and C3-C8 cycloalkyl.

The compound as recited above in formula II, wherein Z is optionally substituted phenyl or naphthyl, furanyl, imidazolyl, indolyl, oxazolyl, isoxazolyl, pyridyl, pyrrolyl, thiazolyl, thiophenyl, benzofuranyl, benzothiophenyl, benzoisoxazolyl, quinolinyl, isoquinolinyl or a structural formula selected from following:

wherein T is: a bond, -(CH2)qO-, -O(CH2)q-, -C(O)(CH2)q-, -(CH2)qC(O)-, -(CH2)qS-, -S(CH2)q-, S[O]p, -(C1-C3 alkyl)-, -(CH2)qC(=CH2)-, -C(=CH2)(CH2)q-, -(CH2)qC(=NOH)-, - C (=NOH) (CH2) q-,- (CH2) qC (=NOCH3) -, -C (=NOCH3) (CH2) q-,-CH (OH) (CH2) q-, or- (CH2) qCH (OH)-, qis : 0,1, 2 or 3 ; and rings b to 1 are each optionally substituted with one or more groups independently selected from the group consisting of : hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (O) 2R9, Cl-C6 alkyl, C1-C6 alkoxy and (CH2) nC3-Cs cycloalkyl.

Another preferred embodiment of the present invention is a compound having a structural formula III,

or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein m is 1, 2, 3 or 4.

Yet another preferred embodiment of the present invention is the compound having a structural formula IV, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: A1 and A2 are respectively: O and O, CH2 and O, CH2 and S, O and S or S and O ; m is : 1 or 2; R'is : C1-C3 alkyl ; R3 is : hydrogen, halo or Cj-Ce alkyi ; R6 and R9 are each independently: hydrogen or Cl-C6 alkyl ; T is: a bond, -O-, -C (O)-,-S (O)-S (O) 2-, -C (=CH2)-,-C (=NOH)- or-CH (OH)- ; and

rings b and c are each optionally substituted with one or more groups independently selected from: hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (O) 2R9, Cl-C6 alkyl, C-C6 alkoxy and (CH2) nC3~C8 cycloalkyl.

Yet another preferred embodiment of the present invention is the compound having a structural formula V, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: T is: a bond,-O-or-C (O)- ; Rl is : methyl, ethyl or cyclopropyl ; R3 is: methyl or ethyl; and rings b and c are each optionally substituted with one or more substituent independently selected from the group consisting of : hydrogen, Cl, Br, CF3, OCF3, methyl, ethyl, isopropyl, N (CH3) 2, S (O) 2CH3, methoxy and cyclopropyl.

Yet another preferred embodiment of the present invention is a compound having a structural formula VI, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Yet another preferred embodiment of the present invention is the compound having a structural formula VII, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: Z is : Ai and A2 are respectively: bond and S; bond and O ; CH2 and S; or CH2 and O ; m is : 1 or 2 ; Rl is : C1-C3 alkyl ; R3 is: hydrogen, halo or Cl-C6 alkyl ; R6 and R9 are each independently: hydrogen or C-C6 alkyl ; T is: bond, -O-, -C (O)-,-S (O)-S (O) 2-, -C (=CH2)-,-C (=NOH)- or-CH (OH)- ; and rings b, c, k and 1 are each optionally substituted with one or more groups independently selected from: hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (O) 2R9, Cl-C6 alkyl, C]-C6 alkoxy and (CH2)nC3-C8 cycloalkyl.

The compound as recited above in formula VII, wherein R] is: methyl, ethyl or cyclopropyl ; R3 is: methyl or ethyl ; and rings b, c k and 1 are each optionally substituted with one or more substituent independently selected from the group consisting of : hydrogen, Cl, Br, CF3, OCF3, N (CH3) 2, S (O) 2CH3, methyl, ethyl, isopropyl, methoxy and cyclopropyl.

Yet another preferred embodiment of the present invention is the compound having a structural formula VIII,

or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: Ai and A2 are respectively: O and O, CH2 and O, CH2 and S, hO and S or S and O ; m is: 1 or 2; Rl is : Cl-C3 alkyl ; and R3 is: hydrogen, halo or Cl-C6 alkyl ; R6 and R9 are each independently: hydrogen or C1-C6 alkyl ; T is: a bond,-O-,-C (O)-,-S (O)-S (O) 2-, -C (=CH2)-,-C (=NOH)- or-CH (OH)- ; and ring b is optionally substituted with one or more groups independently selected from: hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (O) 2R9, C1-C6 alkyl, Cl-C6 alkoxy and (CH2)nC3-C8 cycloalkyl.

Yet another preferred embodiment of the present invention is a compound having a structural formula IX, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: Rl is : Cl-C3 alkyl ; R3 is : hydrogen, halo or Cl-C4 alkyl ; ring b is optionally substituted with one or more groups independently selected from the group consisting of : hydrogen, halo, haloalkyl, haloalkyloxy and C-C6 alkyl.

Yet another preferred embodiment of the present invention is the compound having a structural formula X, x or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Yet another preferred embodiment of the present invention is the compound having a structural formula XI, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Yet another preferred embodiment of the present invention is the compound having a structural formula XII,

or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: Al and A2 are respectively: O and O, CH2 and O, CH2 and S, O and S or S and O ; m is : 1 or 2 ; R1 is : Ci-C3 alkyl ; and R3 is : hydrogen, halo or Cl-C6 alkyl ; R4, R5, R6 and R9 are each independently: hydrogen or Cl-C6 alkyl ; rings k and 1 are each optionally substituted with one or more groups independently selected from: hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (O) 2R9, C1-C6 alkyl, C1-C6 alkoxy and (CH2)nC3-C8 cycloalkyl.

The compound as recited above in formula XII, wherein R4 and Rs are each methyl or ethyl; m is 1; rings k and 1 are each optionally substituted with one or more substituent independently selected from the group consisting of : hydrogen, Cl, Br, CF3, OCF3, N (CH3) 2, S (0) 2CH3, methyl, ethyl, isopropyl, methoxy and cyclopropyl ; and oxygen atom oxygen atom of -O-CH (R')- (CH2) m- moiety is placed in an ortho position relative to the ring 1.

Yet another preferred embodiment of the present invention is the compound having a structural formula XIIl,

or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein mis 1, 2,3, or 4.

Yet another preferred embodiment of the present invention is the compound having a structural formula XIV, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: A1 and A2 are respectively: O and O, CH2 and O, CH2 and S, O and S, or S and O ; mis : 1 or 2; R2 is : C1-C3 alkyl ; and R3 is: hydrogen, halo or Cl-C6 alkyl ; R6 and R9 are each independently: hydrogen or C-C6 alkyl ; <BR> <BR> T is: a bond, -O-, -C (O)-,-S (O)-S (O) 2-, -C (=CH2)-,-C (=NOH)- or-CH (OH)- ; and

rings b and c are each optionally substituted with one or more groups independently selected from: hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (O) 2R9, C-C6 alkyl, Cl-C6 alkoxy and (CH2) nC3~C8 cycloalkyl.

Yet another preferred embodiment of the present invention is the compound having a structural formula XV, XV or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein : T is: a bond, O or C (O) ; R is: methyl, ethyl or cyclopropyl ; R3 is: methyl or ethyl; and rings b and c are each optionally substituted with one or more substituent independently selected from the group consisting of : hydrogen, Cl, Br, CF3, OCF3, N (CH3) 2, S (0) 2CH3, methyl, ethyl, isopropyl, methoxy and cyclopropyl.

Yet another preferred embodiment of the present invention is the compound having a structural formula XVI, XVI or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein Y is a branched alkyl or C3-C6 cycloalkyl.

Yet another preferred embodiment of the present invention is the compound having a structural formula XVII,

or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: Al and A2 are respectively: O and O, CH2 and O, CH2 and S, O and S, or S and O ; R3 is: hydrogen, halo or Cl-C6 alkyl ; R6 and R9 are each independently: hydrogen or C]-C4 alkyl ; R9a and R9b are: each independently hydrogen or C1-C4 alkyl wherein at least one of R9a and R9b being C1-C4 alkyl, or together C3-C6 cycloalkyl ; <BR> <BR> <BR> <BR> T is: a bond,-O-,-C (O)-,-S (O)-S (O) 2-, -C (=CH2)-,-C (=NOH)- or-CH (OH)- ; and rings b and c are each optionally substituted with one or more groups independently selected from: hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (0) 2R9, C1-C6 alkyl, C1-C6 alkoxy and (CH2)nC3-C8 cycloalkyl.

Yet another embodiment of the present invention is the compound having a structural formula XVIII, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: T is: a bond, O or C (O) ; R3 is: methyl or ethyl; R9a and R9b are each independently hydrogen, methyl or ethyl, wherein at least one of R9a and R9b being methyl or ethyl; rings b and c are each optionally substituted with one or more substituent independently selected from the group consisting of : hydrogen, Cl, Br, CF3, OCF3, S (O) 2CH3, N (CH3) 2, methyl, ethyl, isopropyl, methoxy and cyclopropyl.

Yet another preferred embodiment of the present invention is the compound having a structural formula XIX, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.

Yet another preferred embodiment of the present invention is the compound having a structural formula XX,

or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: @ Ai is: a bond, CH2, O or S, and wherein Al and R4 or Aj and R together being a 3-to 6-membered carbocyclyl when Al is a carbon; A2 is : O or S or CH2 ; Q is : -C (O) OR6, or R6A ; Y is: a bond, C1-C6 alkyl or C3-C6 cycloalkyl ; Z is: a) aryl; b) a 5-to 10-membered heteroaryl wherein the heteroaryl containing at least one heteroatom selected from N, O or S, c) bi-aryl, wherein biaryl being defined as aryl substituted with another aryl or aryl substituted with heteroaryl, or d) bi-heteroaryl, wherein bi-heteroaryl being defined as heteroaryl substituted with another heteroaryl, or heteroaryl substituted with aryl, and wherein aryl, heteroaryl, bi-aryl and bi-heteroaryl being optionally substituted with one or more groups independently selected from R ; n is : 1,2, 3,4, 5 or 6 p is: 1 or 2; r is : 1,2, 3, or 4;

R'and R2 are each independently: hydrogen, haloalkyl, C1-C6 alkyl, (CH2)nC3-C8 cycloalkyl, or R1 and R2 form a 4-to 8-membered nonaromatic carbocyclic ring; and wherein at least one of Rl and R2 is alkyl or cycloalkyl, and; R3 is : hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, C1-C6 alkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl ; R4 andR5 are each independently: hydrogen or Cl-C6 alkyl ; R6 is : hydrogen, C1-C6 alkyl or aminoalkyl ; R6A is : carboxamide, sulfonamide, acylsulfonamide, tetrazole,

R7 is : hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, C1-C6 alkyl, Cl-C6 alkoxy, (CH2)nC3-C8 cycloalkyl, C (O) R9, C (O) OR9, C (=NOR8) R9, CR8 (OH) R9, C[=C(R8)2]R9, OR9, SR9 or

S (O) pR' ; R8 is: hydrogen or Cl-C6 alkyl ; and R9 is: hydrogen, Cl-C6 alkyl, C3-C8 cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of : hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, oxo, C1- C6 alkyl, Cj-Ce alkoxyand Cs-Cs cycloalkyi.

The compound as recited above in formula XX, wherein Z is optionally substituted phenyl or naphthyl, furanyl, imidazolyl, indolyl, oxazolyl, isoxazolyl, pyridyl, pyrrolyl, thiazolyl, thiophenyl, benzofuranyl, benzothiophenyl, benzoisoxazolyl, quinolinyl, isoquinolinyl or a structural formula selected from following: wherein T is: a bond,- (CH2) qO-,-O (CH2) q-,-C (O) (CH2) q-,- (CH2) qC (O)-,- (CH2) qS-,-S (CH2) q-, S [O] p, -(C1-C3 alkyl)-, -(CH2)qC(=CH2)-, -C(=CH2)(CH2)q-, -(CH2)qC (=NOH) -,

- C (=NOH) (CH2) q-, -(CH2)qC(=NOCH3)-, -C (=NOCH3) (CH2) q-,-CH (OH) (CH2) q-, or -(CH2) qCH (OH)-, qis : 0, 1, 2 or 3 ; and rings b to j are each optionally substituted with one or more groups independently selected from the group consisting of : hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (O) 2R9+ C1-C6 alkyl, Cl-C6 alkoxy and (CH2) nC3~C8 cycloalkyl.

Yet another preferred embodiment of the present invention is the compound having a structural formula XXI, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: Al and A2 are respectively: O and O, CH2 and O, CH2 and S, O and S or S and O ; mis : 1,2, 3 or 4 ; R'is : C1-C3 alkyl ; and R3 is: hydrogen, halo or C1-C6 alkyl ; R6 and R9 are each independently: hydrogen or C1-C6 alkyl ; T is: a bond,-O-,-C (O)-,-S (O)-S (O) 2-, -C (=CH2)-,-C (=NOH)- or-CH (OH)- ; and rings b and c are each optionally substituted with one or more groups independently selected from:

hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyl, aminoalkyl, S (0) 2R9, Cl-C6 alkyl, Cj-Cg alkoxy and (CH2) nC3~C8 cycloalkyl.

Yet another preferred embodiment of the present invention is the compound having a structural formula XXII, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: T is: a bond,-O-or-C (O)- ; R1 is : methyl, ethyl or cyclopropyl ; R3 is: methyl or ethyl; and rings b and c are each optionally substituted with one or more substituent independently selected from the group consisting of hydrogen, Cl, Br, CF3, OCF3, S (O) 2CH3, N (CH3) 2, methyl, ethyl, isopropyl, methoxy and cyclopropyl.

Yet another preferred embodiment of the present invention is the compound having a structural formula XXIII, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: Al and A2 are respectively:

0 and 0, CH2 and O, CH2 and S, O and S or S and O ; mis : 1,2, 3 or 4 ; Rl is : C1-C3 alkyl ; and R3 is : hydrogen, halo or Cl-C6 alkyl ; R6 and R9 are each independently: hydrogen or Cl-C6 alkyl ; T is: a bond,-O-,-C (O)-,-S (O)-S (O) 2-,-C (=CH2)-,-C (=NOH)- or-CH (OH)- ; and rings b and c are each optionally substituted with one or more groups independently selected from: hydrogen, oxo, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, arylalkyL @@ R9-C1-C6 alkyl, C1-C6 alkoxy and (CH2)"C3-C8 cycloalkyl.

Yet another perferred embod@ @@@@ invention is the compound having a structural formula XXIV, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein: T is: a bond, -O- or -C (O)- ; R1 is : methyl, ethyl or cyclopropyl ; R3 is: methyl or ethyl; and rings b and c are each optionally substituted with one or more substituent independently selected from the group consisting of : hydrogen, Cl, Br, CF3, OCF3, S (0) 2CH3, N (CH3) 2, methyl, ethyl, isopropyl, methoxy and cyclopropyl.

The more preferred embodiment of the present invention is the compounds listed below, more specifically the compounds of PPAR gamma/delta dual agonists : No. Structure Name 1 3-f4- [3- (2- Benzoyl-4-ethyl- phenoxy)- =O CH3 butoxy]-2- -- o methyl-phenyl}- I H3C OH propionic acid Oh H, c f4- [3- (2- Benzoyl-4-ethyl- phenoxy)- 0 CH3 butoxy]-2- Ethyl- phenoxy}-acetic oh acid CH3 3 {4-[3-(2- Benzoyl-4-ethyl- phenoxy)- o butoxy]-2- H3C CHs metliyl- phenylsulfanyll 0 OH acetic acid CH3 f4- [3- (2- Benzoyl-4-ethyl- phenoxy)- butoxy]-2- CHa methyl- )-\-O s 0 phenylsulfanyll- CH3-07 \-4 acetic acid OH 5 f4- [3- (2- Benzoyl-4-ethyl- phenoxy)- o butylsulfanyl]-2- HTC methyl- phenoxy-acetic acrid H3C. OH No. Structure Name 6 3- {4- [3- (2- Benzoyl-4-ethyl- phenoxy)- butylsulfanyl]-2- methyl-phenyl}- 0, zozo propionic acid OH OH 7 2-f4- [3- (2- Benzoyl-4-ethyl- phenoxy)- butoxy]-2- H3C 3 o methyl- /o/ phenoxy-2- methyl-propionic CH3 H3C CH3 acid "8. {4- [3- (2- Benzoyl-4-ethyl- phenoxy)- /eo butoxy]- - o phenoxy}-acetic acid OU Hic 3- {4- [3- (2- Benzoyl-4- isopropyl- ° phenoxy)- H3C-CH3 butoxy]-2- H Cz <°<0 <0 methyl-phenyl}- CH3 oH propionic acid CHg OH" 10-chira 3_ f4_3- (2- Benzoyl-4- cyclopropyl- cl phenoxy)- butoxy]-2- 0 methyl-phenyl} CH3 \u/ß propionic acid OH No. Structure Name 11 <\ 3-{4-[3-(2- Benzoyl-4- trifluoromethyl- phenoxy)- F F butoxy]-2- F 0 methyl-phenyl 3 propionic acid oH OH 12 3-f4- [3- (2- Benzoyl-4- chloro-phenoxy)- butoxy]-2- methyl-phenyl}- c o- propionic acid CH3 OH 13-3_ fq. _3__ Benzoyl-4- chloro-phenoxy)- 0 CH3 butoxy]-2- methyl-phenyl)- ci 0 0 propionic acid CH3 OH 14 3-f4- [3- (2- Benzoyl-4- methoxy- /= (CH3 phenoxy)- H3C-O<o w/4 butoxy]-2- 8 °<\ o methyl-phenyl}- CH3 OH propionic acid On 15 Chiral 3-f4- [3- (2- Benzoyl-4-fluoro- phenoxy)- butoxy]-2- F-cH3 methyl-phenyl}- 0 propionic acid C3 OH No. Structure Name 16 i cnira 3-4-3- (2- Benzoyl-4- o isopropyl- H3C = CH phenoxy)- 0 butoxy]-2- H3C \Y t Ov O methyl-phenyl}- CH3 (OH propionic acid OH 17 w Chiral L l Benzoyl-4- isopropyl- H3c CH3 phenoxy)- H butoxy]-2- H c W' S methyl- phenylsulfanyl}- acetic acid 18 \ f4 3 (2 Benzoyl-4- chloro-phenoxy)- butoxy]-2- methyl- s pheiiylsulfanyll CH3 vS\/OH acetic acid 3 19 3- (4- {3- [4-Ethyl- 2- (hydroxy- phenyl-methyl)- OH phenoxy]- H3C/=9 CH3 butoxy}-2- \/o-methyl-phenyl)- propionic acid CH 3 OH 20 3- (4-f3- [4- thyl- 2- (hydroxyimino- phenyl-methyl)- - N-OH H3c CH3 phenoxy]- o-butoxy}-2- o methyl-phenyl)- CH3 C113 OH propionic acid No. Structure Name 21 3- (4- {3- [4-Ethyl- 2- -NOCH (methoxyimino- H3c phenyl-methyl)- 0 3 pllenoxy]- butoxy}-2- CH3 methyl-phenyl)- propionic acid 22 H3C Chiral H3C 0 Isopropyl-2- ou OH phenoxy- -phenoxy)- butoxy]-2- methyl-phenyl}- propionic acid Chiral {4- 3- (4- Isopropyl-2- o phenoxy- H3C phenoxy)- o butoxy]-2- s o methyl- phenylsulfanyl}- OH acetic acid 24 H3C CH3 3-f4- [3- (4-Ethyl 2-isobutyryl- H3c 0 phenoxy)- - o cH3 butoxy]-2- - methyl-phenyl}- 0 propionic acid cl3 OH 25 3- {4-3-2- Cyclopropanecar bonyl-4-ethyl- H3C 1 3 phenoxy)- \/-butoxy]-2- y methyl-phenyll- CH3 OH propionic acid No. Structure Name "263- {4- [3- (2- Cyclopropanecar r° bonyl-4-ethyl- H3C CH3 3 phenoxy)- Y'^'--O 0 butoxy]-2- CH3 methyl-phenyl}- OH propionic acid '27r\3- {4- [3- (2- Cyclopentanecarb onyl-4-ethyl- 0 phenoxy)- 0 3 butoxy]-2- S°< o methyl-phenyl}- propionic acid 3 OH 28 H3C CH, 2-f4- [3- (4-Ethyl- 2-isobutyryl- H3c 0 0 phenoxy)- II butoxy]- o o ooH phenoxy}-2- CH3 H3C CH3 methyl-propionic acid 29 2-f4- [3- (2- \ Cyclopropanecar bonyl-4-ethyl- H3c phenoxy)- 3 o butoxy]- CH3 U >4 phenoxy}-2- H3c CH3 OH methyl-propionic acid 30 H3c-N CH3 3-f4- [3- (3- \/°-Benzoyl-5-ethyl- \fi CH3 pyridin-2-yloxy)- OH butoxy]-2- methyl-phenyl propionic acid No. Structure Name 31/=\ 4- [3- (3- Benzoyl-5-ethyl- pyridin-2-yloxy)- 0 0 butoxy]-2- -methyl- N s 0 phenylsulfanyll \ acetic acid OH 32-Chiral 3_ f4- [3- (3- Benzoyl-5- chloro-pyridin-2- 0 0 H3 yloxy)-butoxy]-2- Cl 0 methyl-phenyl N 0 propionic acid C3 OH 33/=\ Chiral {4-[3-(3- Benzoyl-5- chloro-pyridin-2- H CH3 yloxy)-butoxy]-2- 3 ci 0 methyl- N VS\HO phenylsulfanyl}- 3 acetic acid OH 34 3-f4- [3- (3- /Benzoyl-5- trifluoromethyl- /= CH pyridin-2-yloxy)- F CH3 F butoxy]-2- F 0""o o methyl-phenyl f- F N CH propionic acid OH 35 > Chiral {4-[3-(3- Benzoyl-5- trifluoromethyl- /to pyridin-2-yloxy)- F butoxy]-2- F 0 methyl- S oH phenylsulfanyl}- acetic acid No Structure Name "36/r-\chirai3- {4- [3- (5- Chloro-3- phenoxy-pyridin- 0 2-yloxy)-butoxy]- 2-methyl- --phenyl - CH3 < ~4 propionic acid OH OH 37-Ehira-l-3-f4- [3- (-5- Chloro-3- o phenoxy-pyridin- 2-yloxy)-butoxy]- 3 CI-O/-0 2-ethyl-phenyll- y propionic acid CH3 OH 3 g Chiral 4-3-5 OH '38/-\chirai {4- [3- (5-Chloro- 3-phenoxy- pyridin-2-yloxy)- O CH3 butoxy]-2- --metllyl- /phenylsulfanyl}- N acetic acid OH 39 F-N CH3 chira 3_-Methyl-4- /°-o [3- (3-plienoxy-5- F -O O CH \ ~t trifluoromethyl- pyridin-2-yloxy)- C butoxy]-phenyl}- propionic acid '0chira3- {2-EthyI-4- [3- (3-phenoxy-5- trifluoromethyl- 0 F = (rCH3 pyridin-2-yloxy)- F butoxy]-phenyl}- zozo propionic acid HTC OH No. Structure Name '41chirai3- {2-Ethyl-4- [3- (3-phenoxy-5- trifluoromethyl- 0 F 3 pyridin-2-yloxy)- butoxy]-phenyl}- --o S propionic acid OH OH 42 F 0 3-f2-Methyl-4- F [3- (3-phenoxy-5- trifluoromethyl- F pyridin-2-yloxy)- F-cH3 propoxy]- zon phenyl \//propionic acid OH (trifluoroacetic Un acid salt) 43 0 3-f4- [3- (5- Chloro-3- OH phenoxy-pyridin- 2-yloxy)- propoxy]-2- cH3 methyl-phenyl}- C propionic acid ° \/ OH 44 3-f4- [2- (5- Chloro-3- henoxy-pyridin- o p Y-lYr 2-ylamino)- ci-N ethoxy]-2- N ~\O4~ methyl-phenyl}- propionic acid OH 45 H3c-N CH3 3- {4- [3- (3- 0 B enzoyl-5-ethyl- 0 pyridin-2-yloxy)- OH propoxy]-2- methyl-phenyl}- propionic acid No. Structure Name 46 < Chiraì 3- {2-Methyl-4- [3- (6-methyl-2- o phenoxy-pyndin- N-cH3 3-yloxy)-butoxy]- C_/ o propionic acid OH OH 47/~ 3- [3- (5-Etliyl- biphenyl-2- yloxy)-butoxy]-2- 3 methvl-Dhenyl}- Wot o propionic acid CH3 AoH OH 48 N Chiral 3-14- [3- (4-Ethyl- to 2-oxazol-2-yl- /CH3 O phenoxy)- 0"1"^\-o OH butoxy]-2- -o//°H methyl-phenyl- CH3 propionic acid 49 H3c CH3 Chiral 3-f4- [3- (4-Ethyl- \/°-2-thiazol-4-yl- mN phenoxy)- butoxy]-2- s methyl-phenyl}- propionic acid 50 Chiral 3-14- [3- (4-Ethyl- 2-pyridin-2-yl- phenoxy)- H3c CH3 butoxy]-2- \/°-o methyl-phenyl}- propionic acid HTC OH 51 Chiral 14- [3- (4-Ethyl-2- /pyridin-2-yl- \N ft-) 0 i \ /1 phenoxy)- /SOH butoxy]-2- 0 ethyl- H3C phenylsulfanyl}- acetic acid No. Structure Name 52 H3, cH3 O Chiral 3_ f2_Ethyl-4- [3- wN J/ (4-ethyl-2- N OH pyridin-2-yl- phenoxy) < butoxy]-phenyl}- CH3 propionic acid 3/-chir3. {4. p. (4- N Chloro-2-pyridin- 2-yl-phenoxy)- /=\/CH3 butoxy]-2- methyl-phenyl)- H3C) OH propionic acid OH 54 F F/Chiral F F CH3 0-hiral 3-f2-Methyl-4- [3- (2-pyridin-2- F N OH yl-4- trifluoromethyl- phenoxy)- CH3 butoxy]-phenyl}- propionic acid 55 F F, I H3e o chiral 3- {2-Ethyl-4- [3- (2-pyridin-2-yl-4- trifluoromethyl- o I phenoxy)- butoxy]-phenyl CH propionic acid CHg 6chirai3- {4, [3- (4-EthyI- N 2-pyridin-3-yl- H3C vV phenoxy)- 0 3 butoxy]-2- Y\ on methyl-phenyl}- ° propionic acid OH N-h-iral-3- {4- [3- (4- Chloro-2-pyridin- cH3 3-yl-phenoxy)- /=\/=\ butoxy]-2- methyl-phenyll- propionic acid OH No. Structure Name 58 v \ Chiral 3-{4-[3-(4-Ethyl- 2-pyridin-4-yl- phenoxy)- 0 3 butoxy]-2- o methyl-phenyl}- ° propionic acid OH 59 Chiral 59 4\N CH O Chiral 3- {2-Methyl-4- [3- (2-pyridin-4- F OH yl-4- trifluoromethyl- o o phenoxy)- CH3 butoxy]-phenyl}- propionic acid 60 F F, i H3c cnm 3- {2-Ethyl-4- [3- (2-pyridin-4-yl-4- F OH trifluoromethyl- phenoxy)- butoxy]-phenyl CH propionic acid 3 61 NO CH O Chìral 3-{4-[3-(2- ci Benzo [d] isoxazol OH-3-yl-4-chloro- phenoxy)- butoxy]-2- CH methyl-phenyl}- 3 propionic acid '62/3- {4- [3- (2- Benzoyl-4-ethyl- phenoxy)- 0 CH3 butoxy]-2- H- o methyl-phenyl}- /propionic acid OH 63 HgC Benzoyl-4-ethyl- phenoxy)- /=O CH3 butoxy]-2- methyl- 0 phenoxy}-acetic OH acid 3 CH 3 No. Structure Name 64 f4- [3- (2- Benzoyl-4-ethyl- phenoxy)- Ao butoxy]-2- H3C Ha methyl- 01, 1"- phenylsulfanyll- CH3 OH acetic acid 3 65 65 {4-[3-(2- Benzoyl-4-ethyl- phenoxy)- butoxy]-2- H3c 0 3 methyl- o S o phenylsulfanyl}- CH3 acetic acid OH 66 f4- [3- (2- Benzoyl-4-ethyl- phenoxy)- zozo butylsulfanyl]-2- H3C CH3 methyl- phenoxy}-acetic acid 67 3-f4- [3- (2- Benzoyl-4-ethyl- phenoxy)- t° butylsulfanyl]-2- H XCH3 methyl-phenyl}- propionic acid H3C OH H3c OH 3 OH 68 Benzoyl-4-ethyl- phenoxy)- 0 butoxy]-2- H3c methyl- 0 0 o phenoxy}-2- -eo OH methyl-propionic CH3 H3C CH3 acid No. Structure Name 69 {4-[3-(2- Benzoyl-4-ethyl- phenoxy)- zozo butoxy]- H3c-o phenoxy}-acetic 0 acrid ° \/°oH HTC 3 70 70 3-f4- [3- (2- t ») Benzoyl-4- isopropyl- Ao phenoxy)- H3c CH3 butoxy]-2- o methyl-phenyl}- propionic acid 3 OH 3 OH 71 Chiral 3-f4- [3- (2- /Benzoyl-4- cyclopropyl- /phenoxy)- cH3 butoxy]-2- /°o-o methyl-phenyl- propionic acid 3 OH 72 3-f4- [3- (2- Benzoyl-4- trifluoromethyl- phenoxy)- butoxy]-2- Fez methyl-phenyl}- CH 3 propionic acid 3 OH 73 3-f4- [3- (2- Benzoyl-4- chloro-phenoxy)- butoxy]-2- /=t 3 methyl-phenyl}- cl<o (oAo propionic acid Lez CH3 OH No. Structure Name 74/=\ [3- (2- Benzoyl-4- chloro-phenoxy)- 0 cH butoxy]-2- Cil 3 methyl-phenyl}- propionic acid CH3 OH OH Chiral 3-f4- [3- (2- Benzoyl-4- 0 methoxy- c CH phenoxy)- H3c-o butoxy]-2- o methyl-phenyl}- propionic acid OH 76 {4- [3- (2- /Benzoyl-4-fluoro- 7 phenoxy)- butoxy]-2- cH3 methyl-phenyl}- propionic acid CH CH3 OH 77 Chiral 3-f4- [3- (2- Benzoyl-4- isopropyl- H3C CH phenoxy)- 0 butoxy]-2- c 0 methyl-phenyll- CH3 propionic acid OH Chiral f4- [3- (2- /Benzoyl-4- isopropyl- H3c 0 3 phenoxy)- H3C-- o butoxy]-2- H---J methyl- CH3 OH phenylsulfanyl acetic acid No. Structure Name 79 {4-[3-(2- Benzoyl-4- chloro-phenoxy)- butoxy]-2- Cl 0 3 0 methyl- o S phenylsulfanyl}- CH3 < OH acetic acid 80 (4- {3- [4-Ethyl- 2- (hydroxy- phenyl-methyl)- OH phenoxy]- H3c CH3 butoxyl-2- 0", o 0 methyl-phenyl)- CH3 propionic acid 3 OH 3- (4- {3- [4-Ethyl- 2- (hydroxyimino- phenyl-methyl)- H C CH3 phenoxy]- butoxy-2- 0--rio methyl-phenyl)- CH3 OH propionic acid 82/3- (4- {3- [4-Ethyl- < 2- (methoxyimino- - N-O-CH3 H3c CH3 phenyl-methyl)- < v/=< phenoxy]- C'H 30 0 butoxy}-2- 3 OH methyl-phenyl)- propionic acid CH3 3-f4- [3- (4- H3C 0 Isopropyl-2- o CH3 \D ~t phenoxy- phenoxy)- butoxy]-2- methyl-phenyl}- propionic acid No. Structure Name Chiral q. _ (3- (4- Isopropyl-2- o phenoxy- H3C CH phenoxy)- o butoxy]-2- H3c o S o methyl- phenylsulfanyl}- OH acetic acid 85 H3C CH3 3-f{4- [3- (4-Ethyl- 2-isobutyryl- H 3c 0 phenoxy)- CH3 butoxy]-2- methyl-phenyl}- 0 propionic acid 3 OH OH Cyclopropanecar /= bonyl-4-ethyl- H3C-CH3 phenoxy)- \-o butoxy]-2- methyl-phenyl}- propionic acid 87 3-f4- [3- (2- Cyclopropanecar H C r= CH3 bonyl-4-ethyl- 3 phenoxy)- ° \/° butoxy]-2- CH3 OH methyl-phenyl}- propionic acid 88 3-{4-[3-(2- Cyclopentanecarb onyl-4-ethyl- 0 phenoxy)- cH3 butoxy]-2- 0 methyl-phenyll- propionic acid OH No. Structure Name 89 H3C CH3 2- {4- [3- (4-Ethyl- 2-isobutyryl- H3c o phenoxy)- 0 0 OH butoxy]- phenoxy}-2- 3 CH3 H3C CH3 methyl-propionic acid 90 2- {4- [3- (2- Cyclopropanecar bonyl-4-ethyl- H3C/=\ phenoxy)- ° -butoxy]- CH3 >74 phenoxyl-2- 3 H3c CH3 OH methyl-propionic acid 91 H3c-N cH3 3-f4- [3- (3- - Benzoyl-5-ethyl- =o CH3 pyridin-2-yloxy)- OH butoxy]-2- methyl-phenyl propionic acid f4- [3- (3- Benzoyl-5-ethyl- pyridin-2-yloxy)- butoxy]-2- methyl- N S o phenylsulfanyl}- acetic acid OH OH 93 Chiral 3-f4- [3- (3- Benzoyl-5- chloro-pyridin-2- 0 /= CH3 yloxy)-butoxy]-2- Cl 0 methyl-phenyl N 0 propionic acid CH3 OH No. Structure Name 94 chira 4-3- (3- \/Benzoyl-5- 0 chloro-pyridin-2- yloxy)-butoxy]-2- ci 0 methyl- ci o- o phenylsulfanyl}- CH3 acetic acid OH 95 Chiral 3-f4- [3- (3- Benzoyl-5- trifluoromethyl- ) = CH pyridin-2-yloxy)- butoxy]-2- F N o 0 methyl-phenyll- CH 3 OH propionic acid s OH 96 Chiral {4- [3- (3- , Benzoyl-5- trifluoromethyl- 0 pyridin-2-yloxy)- butoxy]-2- F N metliyl- phenylsulfanyll- acetic acid 7y3- {4- [3- (5- 1 Chloro-3- phenoxy-pyridin- 2-yloxy)-butoxy]- 0 2-methyl- N phenyl CHg -y- propionic acid OH 98 Chiral 3-f4- Chiral Chloro-3- phenoxy-pyridin- O CH 2-yloxy)-butoxy]- - 3 2-ethyl-phenyl}- 0 propionic acid CH3 OH OH No. Structure Name cni / f 4- [3- (5-Chloro- 3-phenoxy- pyridin-2-yloxy)- butoxy]-2- XN HA oS) O methyl- OH acetic acid oh OH 100 F-N CH3 cnira 3_ f 2-Methyl-4- - o [3- (3-phenoxy-5- 0 CH OH trifluoromethyl- pyridin-2-yloxy)- butoxy]-phenyl}- propionic acid 01/-\chjr3- {2-EthyI-4- [3- (3-phenoxy-5- trifluoromethyl- 0 F CH3 pyridin-2-yloxy)- o-butoxy]-phenyl}- F N 0 propionic acid Hic OH 102chir3- {2-Ethyl-4- [3- (3-phenoxy-5- o trifluoromethyl- pyridin-2-yloxy)- F s butoxy]-phenyl F N H3C < \qt propionic acid OH OH 103 F O OH Fuzz trifluoromethyls_ o Y o trifluoromethyl- F CH3 pyridin-2-yloxy)- propoxy]- F-C plienyl}- y Xo propionic acid OH (trifluoroacetic acid salt) No. Structure Name 104 104 3-f 4-3- (5- _ Chloro-3- F OH phenoxy-pyridin- 2-yloxy)- propoxy]-2- cH3 methyl-phenyl}- propionic acid o /o OH 105 1053- __5_ Chloro-3- o phenoxy-pyridin- 2-ylamino)- N ethoxyj-2- N ß ° methyl-phenyl}- propionic acid OH 106 H3c-N cH3 3- {4- [3- (3- - Benzoyl-5-ethyl- 0 pyndin-2-yloxy)- propoxy]-2- 9 methyl-phenyl}- propionic acid 107 3-f2-Methyl-4- [3- (6-methyl-2- o phenoxy-pyridin- - CH3 3-yloxy)-butoxy]- -0 phenyl H3c o propionic acid OH 1083- {4- [3- (5-Ethyl- biphenyl-2- yloxy)-butoxy]-2- inethyl-phenyl) -0 1 propionic acid CH3 OH No. Structure Name 109Chirac3- {4- [3- (4-Ethyl- \\_o 2-oxazol-2-yl- T CH3 O phenoxy)- H3C- 0"1"-", -0 OH butoxy]-2- 0 methyl-phenyl CH3 propionic acid 110 H3C CH3 Chiral 3- {4-[3-(4-Ethyl- 0---,-o 2-thiazol-4-yl- /° phenoxy)- butoxy]-2- OH s methyl-phenyl}- propionic acid 111 chirai 3- {4- [3- (4-Ethyl- 2-pyridin-2-yl- phenoxy)- H3C CH3 butoxy]-2- o-o methyl-phenyl}- /oH propionic acid 112 Chiral f4- [3- (4-Ethyl-2- /pyridin-2-yl- 'N GH3 ° phenoxy)- /S OH butoxy]-2- \Y %/0H methyl- H c pllenylsulfanyl}- acetic acid 113 CH3 CH3 0 Chiral 3-f2-Ethyl-4- [3- (4-ethyl-2- pyridin-2-yl- phenoxy)- o \SX/o butoxy]-phenyl 3- CH3 propionic acid 3 114 Chiral 3-f4- [3- (4- \_/Chloro-2-pyridin- vN CH 2-yl-phenoxy)- butoxy]-2- H3c 0 methyl-phenyll- propionic acid OH No. Structure Name Name 115 F F CH 3 0 Chiral 3-f2-Methyl-4- F N/ L3- (2-pyridin-2- il-4- trifluoromethyl- phenoxy)- CH3 butoxy]-phenyl}- propionic acid 116 F F < H3CA O Chirai 3- {2-Ethyl-4-[3- (2-pyridin-2-yl-4- trifluoromethyl- phenoxy)- CH3 butoxy]-phenyl}- propionic acid 117 Chiral 3- {4- [3- (4-Ethyl- 2-pyridin-3-yl- phenoxy)- \/° butoxy]-2- H3CX ° <40 methyl-phenyl}- propionic acid OH 118 Chiral 3-f4- [3- (4- H3 Chloro-2-pyridin- 3-yl-phenoxy)- o butoxy]-2- CH3 OH methyl-phenyl}- propionic acid 119Nc3- {4- [3- (4-EthyI- 2-pyridin-4-yl- phenoxy)- \/°'butoxy]-2- o methyl-phenyl propionic acid OH 120 F F i IN CH3 o chirai 3- {2-Methyl-4- - (2-pyridin-4- z o o trifluoromethyl- phenoxy)- CH3 butoxy]-phenyl}- propionic acid No. Structure Name 121 F F/IN H3C O Chiral 3_ f2_Ethyl-4- [3- F (2-pyridin-4-yl-4- OH trifluoromethyl- phenoxy)- CH butoxy]-phenyl}- 3 propionic acid 122 0 -Chiral ci Benzo [d] isoxazol 0 OH-3-yl-4-chloro- phenoxy)- butoxy]-2- CH3 methyl-phenyl}- propionic acid 123- Chiral (R_ fq. _3- (4- ethyl-2-phenoxy- IQ phenoxy)- H3C CH3 butoxy]-2- 0 methyl- phenylsulfanyl}- CHU OH acetic acid 124- cnira (R) _ f4_3- (2- benzoyl-4- methyl-phenoxy)- 3 butoxy]-2- H3c s 0 methyl- phenylsulfanyl}- CH3 OH acetic acid 125- ehiral (R)- f4- [3- (2- benzoyl-4- trifluoromethoxy- F O phenoxy)- F 0 0 s 0 butoxy]-2- ethyl- CH3 OH phenylsulfanyl}- acetic acid No. Structure Name 126 126 14- [3- (2-benzoyl- 4-ethyl-phenoxy)- hexyloxy]-2- H C/1=° CH3 methyl- ' 'phenylsulfanyl}- acetic acid OH CH3 127/3- {4- [3- (2- benzoyl-4-ethyl- phenoxy)- YJ=O CH3 hexyloxy]-2- ' methyl-phenyl}- propionic acid v OH H3 3 cnrai (R_3_ f4-3- (4- ethyl-2-phenoxy- o phenoxy)- H3C butoxy]-2- p p methyl-phenyl - propionic acid CHU OH cniral (R)-3- (4- f 3- [4- ethyl-2- (1- phenyl-vinyl)- CH2 CH3 phenoxy]- 3,/=\/= (butoxy}-2- methyl-phenyl)- CH3 OH propionic acid 130 Chira (R)-3- (4-f3- [4- \tW ethyl-2-(1- CH3 methyl-1-phenyl- H C vCH CH3 ethyl)-phenoxy]- - o butoxy-2- methyl-phenyl)- CH3 OH propionic acid No. Structure Name f31/==Chiral (R)-3- {4- [3- (2- benzoyl-4- methyl-phenoxy)- SO CH3 butoxy]-2- methyl-phenyl}- H 3c 0 0 0 propionic acid CH3 OH 132 Chiral (R)-3- (4- {3- [4- ethyl-2- (l- phenyl-ethyl)- ./-CHg CHg phenoxy]- butoxy}-2- methyl-phenyl)- CH3 OH propionic acid 133 Chiral (R)-3- (4- f 3- [4- ethyl-2- (pyridine- 2-carbonyl)- ) CHg phenoxy]- Hs butoxy}-2- methyl-phenyl)- CH3 OH propionic acid 134 A 3-(2-methyl-4- {3- [2- (thiophene-2- F =0 CH carbonyl)-4- F,- trifluoromethoxy- F O O n O O phenoxy]- butoxyl-phenyl)- F UY f butoxy}-phenyl). CHU OH propionic acid 135\3- (4- {3- [4-ethyl- 2- (thiophene-2- carbonyl)- p CH3 phenoxy]- H3C/=\ butoxy}-2- methyl-phenyl)- CH3 OH propionic acid No. Structure Name 136 3- (4-f3- [4-ethyl- 2- (naphthalene-l- carbonyl)- SO CH phenoxy]- butoxy}-2- <°sf zozo methyl-phenyl)- CH3 OH propionic acid OH 137 3- (4-13- [4-ethyl- 2- (l-phenyl- vinyl)-phenoxy]- tCH2 CH3 butoxy}-2- '-'methyl-phenyl)- /0 propionic acid CH3 OH 138 {4- [3- (2- benzoyl- phenoxy)- 0 CH3 butoxy]-2- -'- methyl-phenyl}- O"r,-"-, 0 0 propionic acid 3 OH 139 {4- [3- (2- benzoyl-4- methyl-phenoxy)- 0 CH3 butoxy]-2- methyl-phenyl}- H3c 0 propionic acid CH3 OH 140/3- {4- [3- (2- benzyl-4-ethyl- phenoxy)- CH3 butoxy]-2- meth. methyl-phenyl}- 0 propionic acid CH3 OH No. Structure Name 141/3- {4- [3- (2- benzoyl-4-bromo- phenoxy)- 0 CH3 butoxy]-2- methyl-phenyl BrtO< o Wo propionic acid T CH3 OH 142 {4- [3- (2- benzoyl-4-butyl- phenoxy)- HgC 0 CH3 butoxy]-2- - methyl-phenyl}- propionic acid CH3 OH 143 3-14- [3- (2- benzoyl-4-propyl- phenoxy)- 0 CH3 butoxy]-2- hic methyl-phenyl}- propionic acid CH3 OH 144 3-14- [4- (2- benzoyl-4-ethyl- CH3 O phenoxy)-1- 0 CH3 OH methyl-butoxy]- - 3 2-methyl- Phenyl- propionic acid 145/3- {4- [4- (2- benzoyl-4-ethyl- CH3 O phenoxy)- OH pentyloxy]-2- methyl-phenyl}- H3Cw <°~ propionic acid H3C CH3 No. Structure Name 146 3-14- [3- (2- benzoyl-4-ethyl- phenoxy)-2- /= CH CH3 methyl-propoxy]- rH 3C\ 2-methyl- phenyl- OH propionic acid 147 {4- [3- (2- benzoyl-4-ethyl- phenoxy)- 0 CH3 propoxy]-2- HTC methyl-phenyl}- O propionic acid OH 148 F 3- (4- {3- [4-ethyl- 2- (4-fluoro- 9 benzoyl)- phenoxy]- CH3 propoxy}-2- - methyl-phenyl)- propionic acid OH 149 F 3- (4-f3- [4-ethyl- 2- 2-(2- F F trifluoromethyl- 0 CH3 benzoyl)- H3c 0 0-phenoxy]- 0 propoxy}-2- OH methyl-phenyl)- propionic acid 150 F 3- (4- f 3- [4-ethyl- F 2- (3- trifluoromethyl- benzoyl)- 0 phenoxy]- H3C propoxy}-2- \to o mo methyl-phenyl)- propionic acid OH No. Structure Name 151 s 3- (4-f3- [4-ethyl- 2- (thiophene-2- O C H carbonyl)- phenoxy]- 90 09u 0 propoxy}-2- 4 methyl-phenyl)- OH propionic acid 152 3- {4- [3- (2- benzyl-4-ethyl- phenoxy)- propoxy]-2- methyl-phenyl propionic acid OH 153 - 3- (4- {3- [4-ethyl- 2- (naphthalene-1- carbonyl)- CH3 phenoxy]- H3C propoxy}-2- 0 methyl-phenyl)- propionic acid OH T5-4-3- (4-f3- [4-ethyl- /2- (1-phenyl- vinyl)-phenoxy]- CH2 sCH3 propoxy}-2- - methyl-phenyl)- propionic acid OH -i55- 2-f4- [3- (2- benzoyl-4-ethyl- phenoxy)- butoxy]- H3C<OA phenoxy}-2- methyl-propionic acid _ C-' H3C ( H3C z=O HO HO No. Structure Name 156 T5-6-2-f4- [3- (2- benzoyl-4-ethyl- 0 phenoxy)-2- methyl-propoxy]- phenoxy}-2- O methyl-propionic acid O H, C- HO HO 157. benzyl-4-ethyl- phenoxy)- butoxy]- phenoxy}-2- methyl-propionic acid 0 O H3 C- H3C Q=O HO 0 2-f4- [3- (2- benzoyl-4-bromo- 9 phenoxy)- butoxy]- phenoxy}-2- v methyl-propionic acid 0 O H. coo Zu HO No. Structure Name 159 {4- [3- (2- 0 benzoyl-4-butyl- phenoxy)- 0 butoxy]- phenoxy}-2- \ methyl-propionic acid 0 H3C H3C t° HO 1 () Cnirai (R)-3- {4- [3- (4- chloro-2- O CH phenoxy- 0 CH phenoxy)- 0 butoxy]-2- methyl-phenyll- CH3 OH propionic acid 161 = Chiral (R)-3- {2-methyl- 4- [3- (2-phenoxy- 4-trifluoromethyl- 0 CHq, phenoxy)- F*_6 0 0 butoxy]-phenyl propionic acid CH3 OH 162 = Chiral (R)-3- {2-methyl- Q 4- [3- (2-phenoxy- F 0 CH 4- trifluoromethoxy- F 0<0 09s 0 phenoxy)- CH butoxy]-phenyl}- CH3 OH propionic acid 163 Chiral (R)-3-f2-methyl- 4- [3- (4-methyl-2- phenoxy- U L'r), i phenoxy)- H3C<O O9 O butoxy]-phenyl}- propionic acid CH3 OH No. Structure Name 164 ch oro-3 4- 0 CH3 phenoxy- phenoxy)- oo \/S butoxy]-2- ethyl- CH3 OH phenylsulfanyl}- acetic acid 165- chloro-2- 0 CH 3 phenoxy- phenoxy)- 0 propoxy]-2- methyl-phenyl OH propionic acid 166 Chiral (R)-3-f 4- [3- (2- benzo [b] thiophen CH-3-yl-4-chloro- phenoxy)- CI p p butoxy]-2- methyl-phenyl}- 3 OH propionic acid N (R)-3-f4- [3- (4- =N chloro-2-pyridin- CH3 3-yl-phenoxy)- ci p O 0 butoxy]-2- methyl-phenyl}- OH propionic acid -- chiral (R)-3-f 4- [3- (4- 9'chloro-2- O phenoxy- phenoxy)- 0 butoxy]-phenyll- C'H F 2, 2-difluoro- 3 F F OH propionic acid 169-cnra %) (R)-3- f3- bromo-4- [3- (4- p Br chloro-2- phenoxy- ci 0 phenoxy)- butoxy]-phenyl}- CH3 OH propionic acid No. Structure Name 170 Chiral (R) _3_ f4- [3- (4- chloro-2- 0 H C phenoxy- phenoxy)- 0 butoxy]-3- CH methyl-phenyl}- CHg OH propionic acid 171- TTl/==\chirai (R)- {3-bromo-4- [3- (4-chloro-2- IQ phenoxy- phenoxy)- ci 0,,,-,,-, 0-butoxy]-phenyl 0 acetic acid CH3 HO 172 172Fchi (R)-3- {4- [3- (4- F bromo-2- trifluoromethoxy- Br--0,, 0 phenoxy)- \/butoxy]-2- methyl-phenyl}- propionic acid 173 = Chiral (R)- {4 [3 (4 chloro-2- phenoxy- phenoxy)- c 1 0 0 butoxy]-3- 0 methyl-phenyl}- HO acetic acid 174 l 74 = Chiral l (R)- {4 [3 (4 chloro-2- chloro-2_ O phenoxy- phenoxy)- C'i vO Y O butoxy]-phenyl}- ci 0 0 acetic acid CH3 HO 0 No. Structure Name 175 F F F Chiral (R)-3 {4 [3 (4_ chloro-2- gH 3 OH phenoxy- 0--phenoxy)- 0 butoxy]-2- 0 trifluoromethyl- phenyl}- propionic acid 176 Chiral (R)- {4- [3- (4- chloro-2- phenoxy- phenoxy)- Cl<OfS vOHO butylsulfanyl]-2- cl \-4 methyl- 3 OH phenoxy}-aeetie acid 177 chira (R)-3- {4- [3- (4- chloro-2- phenoxy- phenoxy)- butylsulfanyl]-2- ty P U \ methyl-phenyl}- OH propionic acid 178 ci 0 Chiral (R)-3- {2-Chloro- Cl OH 4- [3- (4-chloro-2- phenol- L ! !'i ! J phenoxy- O phenoxy)- > butoxy]-phenyl}- propionic acid 179 F 0 Chiral (R)-3-f 4- [3- (4- Chloro-2- phenoxy- o phenoxy)- butoxy]-2-fluoro- v phenyl)- propionic acid 180 Chiral (R)-3- {4- [3- (4- Chloro-2- -rDH 1 Cl OH pbenoxy- phenoxy)- 0 butoxy]-2-ethyl- phenyl}- propionic acid No. Structure Name 181, CI O Chiral (R)-3-f 4- [3- (2- OH Benzoyl-4-ethyl- phenoxy)- butoxy]-2-chloro- phenyl}- propionic acid 182 F 0 Chiral (R)-3-f4- [3- (2- i H Benzoyl-4-ethyl- phenoxy)- butoxy]-2-fluoro- phenyl}- propionic acid 183 O Chiral (R)-3- {4- [3- (4- = I oH Chloro-2- phenoxy- OO phenoxy)- m butoxy]-phenyl}- propionic acid 184 O Chiral (R)-3- {4- [3- (2- OH Benzoyl-4-ethyl- phenoxy)- butoxy]-phenyl}- propionic acid i 185 O Chiral (R)-3- {4- [3- (4- Cl OH Chloro-2- It H) N T'n phenoxy- O O O phenoxy)- [ ! Y° fsomen pentyloxy]-2- Isomer 1 pentyloxy]-2- v methyl-phenyl}- propionic acid 186 O Chiral (R)-3- {4-[3-(2- Benzoyl-4-ethyl- phenoxy)- pentyloxy]-2- C ° Isomer 1 methyl-pheny1}- Isomer 1 propionic acid No. Structure Name 187 Chiral (R)- {4- [3- (3- Benzoyl- OH naphthalen-2- 9 O~~O ~ yloxy)-butoxy]-2- 0 methyl- phenylsulfanyl}- acetic acid 188 o Chiral (R)-3- {4- [3- (3- Benzyl- naphthalen-2- yloxy)-butoxy]-2- methyl-phenyl}- o propionic acid 189 O Chiral OH Ethyl-2-phenoxy- phenoxy)- butylsulfanyl]-2- methyl-phenyl}- propionic acid 190 O Chiral (R)-3-f 4- [3- (4- _ I p Isopropyl-2_ phenoxy- o phenoxy)- butylsulfanyl]-2- methyl-phenyl propionic acid 191 Chiral (R)-3- {4- [3- (4- 0 Chloro-2- CI H phenoxy- henoxy)- o'o' butoxy]-2-propyl- o phenyl}- propionic acid 192 0 Chiral (R)-14- [3- (4- Chloro-2- Cl S'-IKOH phenoxy- -phenoxy)- 0 butoxy]-2-ethyl- phenylsulfanyl}- acetic acid No. Structure Name 193 CI O Chiral (R)-3-f 4- [3- (2- Benzoyl-4, 5- dichloro- phenoxy)- O butoxy]-2- 9 methyl-phenyl}- propionic acid 194 O Chiral (R)-3- {2-Methyl- S"OH 4- [3- (2-phenoxy- 4-trifluoromethyl- o phenoxy)- butylsulfanyl]- v phenyl}- propionic acid 195 Chiral (R)-3- {2-Ethyl-4- [3- (4-ethyl-2- OH phenoxy- O'v phenoxy)- butoxy]-phenyl}- propionic acid 196 Ghiral O Chiraì (R)-3- {2-Ethyl-4- CF3 JL : [3- (2-phenoxy-4- OH trifluoromethyl- phenoxy)- A ° butoxy]-phenyl}- propionic acid 197 oCtura ! (R)-3- {4- [3- (2- OH Benzoyl-4-ethyl- phenoxy)- butoxy]-2-ethyl- Ho phenyl}- W propionic acid 198. Chiral (R)-3- {2-Ethyl-4- - 1 A [l-methyl-3- (2- oh phenoxy-4- trifluoromethyl- -phenoxy)- i propoxy]- phenyl}- propionic acid No. Structure Name 199 F F O O Chiral (R)-3- {2-Methyl- 4- [1-methyl-3- (2- phenoxy-4- trifluoromethoxy- phenoxy)- propylsulfanyl]- phenyl}- propionic acid 200 Chiral (S)-3- {4- [3- (4- CI Chloro-2- phenoxy- phenoxy)- 0 butoxy]-2-ethyl- phenyl}- propionic acid 0 3-f4- [3- (4- OU Chloro-2- nH phenoxy- -phenoxy)- 0 propoxy]-2-ethyl- phenyl}- propionic acid 0 Fhiral- (R)-3-f4- [3- (2, 4- phenoxy- phenoxy)- j f jj : n [phcnoxy)- 0 o butoxy]-2-ethyl- A phenyl}- i propionic acid 203 O Chiral 2- {4- [4- (4- Zou Chloro-2- phenoxy-phenyl)- 9 3-methyl- butoxy]-2- Cis-Isomer 2 methyl-phenyl}- y phenyl}- cyclopropanecarb oxylic acid 204 (R, S)-2-f4- [3- (4- Ethyl-2- phenylsulfanyl- H3C H3c s CH 0, U phenoxy)- butoxy]- CH 3 phenoxyl-2- methyl-propionic No. Structure Name acid 2- {4- [3- (R, S-2- Benzenesulfinyl- cl3 0 4-ethyl-phenoxy)- L. O H, C,,"-" 2-methyl- Oz OX CH3 phenylsulfanyl}- 2-methyl- propionic acid (enamtiomer pair 1) 206 F 206Fpo (R, S)-2- {4- [3- (2- H C 11 \ cH Yl_4_ CH 3 trifluoromethyl- p phenoxy)- butoxy]- phenoxy}-2- methyl-propionic acid 207 (R, S)-2-Methyl- 2- {4- [3- (2- \ O3c # methyl-3-phenyl- cl 0'*r OH 7-propyl- 3c 0 CH3 benzofuran-6- yloxy)-butoxy]- phenoxy- CH3 propionic acid CH, (R, S)-2-Methyl- o 2- {4- [3- (4- methyl-3-phenyl- CH, 7-propyl- 0 CH benzofuran-6- yloxy)-butoxy]- phenoxy- CH3 propionic acid CH, No. Structure Name 209 209 (R, S)-2-f4- [3- (2- F F Y 3 H C Cyclopropylmeth o3c, yl-4- trifluoromethyl- o'v'O H3 phenoxy)- butoxy]-2- methyl- phenoxy}-2- methyl-propionic acid 210 (R, S)-3- {4- [3- (2- F F CH3 0 Cyclopropylmeth I \ CH3 , OH 3 trifluoromethyl- phenoxy)- butoxy]-2- methyl-phenyl}- propionic acid 211CM3- {R-4- [3- (R, S- CH3 O Benzenesulfinyl- Uw H C S+. OH3 i oH 4-ethyl-phenoxy)- butoxy]- oxo 2-methyl- phenyl}- propionic acid 212 3-f4- [3- (4-Ethyl- 2-phenylsulfanyl- T CHg o phenoxy)- butoxy]- 3 2-methyl- ovo phenyl}- propionic acid isomer 2 213 (R, S)-2-f4- [3- (4- Ethyl-2- CH3 0 phenylsulfanyl- H3C, U phenoxy)- CH OH butoxy]- wO t~O CH3 phenoxy}-2- methyl-propionic acid No. Structure Name 214 (R, S)-3-f4- [3- (R, S-2- cH3 o Benzenesulfinyl- s° 1 94 4-ethyl-phenoxy)- H3C </, |CH3 S ìl~ OH butoxy]-2- butoxy]-2- o p methyl-phenyl}- propionic acid 215' (R, S)-2- {4- [3- (R, S-2-Benzene- cH3 o sulfinyl-4-ethyl- H 1 3 ii phenoxy) - butoxy]-2- Oz O CH3 methyl- phenoxy}-2- methyl-propionic acid 216 216 ß (R, S)-3- {4 [3 (2 Benzenesulfonyl- 0 CH3 0 4-ethyl-plienoxy)- H3c S, CH3 OH butoxy]-2- ^ methyl-phenyl}- propionic acid 217 {4- [3- (2- Benzoyl-4- O CH3 OH trifluoromethoxy- -phenoxy)- L 1 J phenoxy)- butoxy]-2- eO methyl-phenyl}- i propionic acid The compound as recited above, wherein the compound is

or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Also encompassed by the present invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the present invention or a pharmaceutically acceptable salt, solvate or hydrate thereof.

Also encompassed by the present invention is a pharmaceutical composition comprising: (1) a compound of the present invention or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof; (2) a second therapeutic agent selected from the group consisting of insulin sensitizers, sulfonylureas, biguanides, meglitinides, thiazolidinediones, ot-glucosidase inhibitors, insulin secretogogues, insulin, antihyperlipidemic agents, plasma HDL-raising agents, HMG-CoA reductase inhibitors, statins, acryl CoA: cholestrol acyltransferase inhibitors, antiobesity compounds, antihypercholesterolemic agents, fibrates, vitamins and aspirin; and (3) optionally a pharmaceutically acceptable carrier.

Also encompassed by the present invention is a method of modulating a peroxisome proliferator activated receptor (PPAR) comprising the step of contacting the receptor with a compound of the present invention or a pharmaceutically acceptable salt, solvate or hydrate thereof.

The method recited above, wherein the PPAR is an alpha (a)-receptor.

The method recited above, wherein the PPAR is a gamma (y)-receptor.

The method recited above, wherein the PPAR is a delta (o)-receptor.

The method recited above, wherein the PPAR is a gamma/delta (Y/o)- receptor.

The method recited above, wherein the PPAR is an alpha, gamma and delta (oc/^y/o)-receptor.

Also encompassed by the present invention is a method for treating and/or preventing a PPAR-y mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of the present invention.

Also encompassed by the present invention is a method for treating and/or preventing a PPAR-8 mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of the present invention.

Also encompassed by the present invention is a method for treating and/or preventing a PPAR-y/8 mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of the present invention.

Also encompassed by the present invention is a method for treating and/or preventing a PPAR-oc/y/8 mediated disease or condition in a mammal comprising the step of administering an effective amount of a compound of the present invention.

Also encompassed by the present invention is a method for lowering blood-glucose in a mammal comprising the step of administering an effective amount of a compound of the present invention.

Also encompassed by the present invention is a method of treating and/or preventing disease or condition in a mammal selected from the group consisting of hyperglycemia, dyslipidemia, Type 11 diabetes, Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other diseases where insulin resistance is a component, comprising the step of administering an effective amount of a compound of the present invention.

Also encompassed by the present invention is a method of treating and/or preventing diabetes mellitus in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound of the present invention.

Also encompassed by the present invention is a method of treating and/or preventing cardiovascular disease in a mammal comprising the step of administering to a mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.

Also encompassed by the present invention is a method of treating and/or preventing syndrome X in a mammal comprising the step of administering to the mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof.

Also encompassed by the present invention is a method of treating and/or preventing disease or condition in a mammal selected from the group consisting of hyperglycemia, dyslipidemia, Type II diabetes, Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, hypertension, obesity, anorexia bulimia, anorexia nervosa, cardiovascular disease and other diseases where insulin resistance is a component, comprising the step of administering an effective amount of a compound of the present ) invention, and an effective amount of second therapeutic agent selected from the group consisting of insulin sensitizers, sulfonylureas, biguanides, meglitinides, thiazolidinediones, a-glucosidase inhibitors, insulin secretogogues, insulin, antihyperlipidemic agents, plasma HDL-raising agents, HMG-CoA reductase inhibitors, statins, acryl CoA: cholestrol acyltransferase inhibitors, antiobesity compounds, antihypercholesterolemic agents, fibrates, vitamins and aspirin.

Also encompassed by the present invention is use of a compound of the present invention and a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, for the manufacture of a medicament for the treatment of a condition modulated by a PPAR.

Surprisingly, it is found that the compound having an alkyl branching (e. g., R'shown below) has unexpected activity (and/or selectivity) depending on the type of Rl substituent (H vs. Me) and the conformation of R'substituent (R or S) as shown in Table 1 below.

Table 1: Effect of an alkyl branching (Rl substituent) R1 EC50α EC50γ EC50# Eff%α Eff%γ Eff%# ) (nM) (nM) H 2991 1291 18 35 89 143 Me (R) 2800 102 6 44 79 132 Me (S) NA 2548 368 2 45 101 (NA = Not Active, no EC5o is measured when Eff % is less than 20%) As shown in Table 1, a notable improvement on gamma/delta dual agonist activity is achieved when the compound has an alkyl substituent (Rl = Me) adjacent to the 2,4- disubstituted phenoxy group. Additionally, improvement on gamma/delta dual agonist activity is more significant in R-enantiomer compare to its corresponding S-enantiomer.

Surprisingly, it is also noted that 2,4-disubstituted phenyl (Rc and Rd) of the compound shown below in Table 2 contributes significantly in achieving activity and/or selectivity of gamma/delta dual agonist.

Table 2: Effect of 2,4-disubstitution of phenyl ring Rc Rd EC50a Essay ECsoo Eff% oc Eff% 7 Eff% o (nM) (nM) (nM) H H NA 2697 2952 4 24 43 C1 OPh 2800 102 6 42 76 134 (NA = Not Active, no EC50 is measured when Eff % is less than 20%) As shown in Table 2, a sharp loss of functional activity (>25 fold for EC50γ and >400 fold for ECsoo) is observed in an unsubstituted analog (Rc, Rd = H) compared to the corresponding 2,4-disubstituted analog (Rc =Cl, Rd = OPh).

It is further observed that when A attached to the position 2 of phenoxy group is a hydrogen-bond acceptor, there is an increase in activity (and/or selectivity) of gamma/delta dual agonist. Whereas when A is not a hydrogen-bond acceptor, a loss of activity on both receptors is observed as shown in the Table 3 below.

Table 3: Effect of A attached to the position 2 of phenoxy group A EC50a EC50y EC508 Eff% a Eff% y Eff% 8 (nM) (nM) (nM) CO 1733 9 6 42 98 135 C=NOH 2872 7 6 38 83 131 C=NOMe 2662 644 35 30 139 130 CHOH 2872 7 6 38 83 131 CH2 2650 211 108 21 61 134 C=CH2 NA 272 67 13 75 139 S 2903 77 73 24 64 143 SO 1478 9 8 38 76 115 O 1414 8 5 37 80 121 Surprisingly, it is also found that a certain combination of X and Y are important in achieving the desired activity as shown in Table 4 below. For example, the combination of X/Y being O/CH2 and O/S are more desirable for achieving a potent gamma/delta dual agonist activity.

Table 4: Effect of X/Y X Y EC50a EC50y EC508 Eff% a Eff% y Eff% 5 (nM) (nM) (nM) O CH2 1503 9 7 40 80 120 O S 2822 9 24 37 80 101 O O 3035 89 38 37 76 102 S O 2890 262 23 39 63 112 S CH2 2838 172 39 25 83 121

The terms used to describe the present invention have the following meanings unless otherwise indicated.

The term "alkyl," unless otherwise indicated, refers to those alkyl groups of a designated number of carbon atoms of either a straight or branched saturated configuration, including substituted alkyl. The term"alkyl"used herein also includes "alkylene group"of either straight or branched saturated configuration, including substituted alkylene. Examples of"alkyl"include, but are not limited to: methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl, isopentyl and the like. Examples of"branched alkyl" (or"substituted alkyl") include, but are not limited to-C (R') C (R9a) (R9b)CR2-; -C (RI) C (R9a) (R9b) CH2CR2-;-C (Rl) CH2C (R9a) (R9b) CH2CR2-; -C (Rl) CH2C (R9a) (R9b) (CH2) 2CR2-; and the like where at least one of R9a and R9b is alkyl as defined above. Examples of"alkylene group"is-(CH2) m-, wherein m is a positive integer. Preferably, m is an integer from about 1 to about 6, more preferably from about 1 to about 3. A"branched (or substituted) alkylene group"is an alkylene group in which one or more methylene hydrogen atoms are replaced with a substituent, such as methyl, ethyl or the like. Alkyl as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.

The term"alkoxy"represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, and the like. Alkoxy as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.

The term"cycloalkyl"refers to a saturated or partially saturated carbocycle containing one or more rings of from 3 to 12 carbon atoms, more typically 3 to 6 carbon atoms. Examples of cycloalkyl includes, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like. Cycloalkyl as defined above may also includes a tricycle, such as adamantyl. Cycloalkyl as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.

The term"halo"refers to fluoro, chloro, bromo and iodo.

The term"haloalkyl"is a Cl-C6 alkyl group, which is substituted with one or more halo atoms selected from F, Br, Cl and 1. Examples of haloalkyl group are trifluoromethyl, CH2CF3 and the like.

The term"haloalkyloxy"represents a Cl-C6 haloalkyl group attached through an oxygen bridge, such as OCF3. The"haloalkyloxy"as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.

The term"aryl"includes carbocyclic aromatic ring systems (e. g. phenyl), fused polycyclic aromatic ring systems (e. g. naphthyl and anthracenyl) and aromatic ring systems fused to carbocyclic non-aromatic ring systems (e. g. , 1,2, 3,4- tetrahydronaphthyl). The"aryl"as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.

The term"aryloxy"represents an aryl group attached through an oxygen bridge, such as phenoxy (-O-phenyl). The"aryloxy"as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.

The term"heteroaryl"group, as used herein, is an aromatic ring system having at least one heteroatom such as nitrogen, sulfur or oxygen and includes monocyclic, bicyclic or tricyclic aromatic ring of 5-to 14-carbon atoms containing one or more heteroatoms selected from O, N, or S. The heteroaryl as defined above also includes heteroaryl fused with another heteroaryl, aryl fused with heteroaryl or aryl fused with heterocyclyl (e. g., benzo [1, 4] dioxinyl) as defined herein. The"heteroaryl"may also be optionally substituted with a designated number of substituents as set forth in the embodiment recited above. Examples of heteroaryl are, but are not limited to: furanyl,

thienyl (also referred to as"thiophenyl"), thiazolyl, imidazolyl, indolyl, isoindolyl, isooxazolyl, oxazoyl, pyrazolyl, pyrrolyl, pyrazinyl, pyridyl, pyrimidyl, pyrimidinyl and purinyl, cinnolinyl, benzofuranyl, benzothienyl (or benzothiophenyl), benzotriazolyl, benzoxazolyl, quinoline, isoxazolyl, isoquinoline 1,4 benzodioxan, or 2, 3-' dihydrobenzofuranyl and the like.

The term"bi-aryl"is defined as aryl substituted with another aryl or aryl substituted with heteroaryl as defined above. Examples of"biaryl"are, but are not limited to: bi-phenyl where phenyl is substituted with another phenyl; phenyl-pyridyl where phenyl is substituted with pyridyl; and phenyl-pyrimidinyl where phenyl is substituted with pyrimidinyl. Examples of"biaryl"also include"aryl-T-aryl"or"aryl-T- heteroaryl"where T is a bond,- (CH2) qO-,-O (CH2) q-,-C (O) (CH2) q-,- (CH2) qC (O)-, - (CH2) qS-,-S (CH2) q-, S [Olp,- (CI-C3 alkyl)-,- (CH2) qC (=CH2)-,-C (=CH2) (CH2) q-, - (CH2) qC (=NOH) -,-C (=NOH) (CH2) q-,- (CH2) qC (=NOCH3)-,-C (=NOCH3) (CH2) q-, - CH (OH) (CH2) q- or- (CH2) qCH (OH)- ; and q is 0,1, 2 or 3.

The"bi-aryl"as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.

The term"bi-heteroaryl"is defined as heteroaryl substituted with another heteroaryl, or heteroaryl substituted with aryl or biaryl as defined above. Examples of "bi-heteroaryl"are, but are not limited to: thienyl-pyrazolyl, thienyl-thienyl, thienyl- pyridyl, thienyl-phenyl, thienyl-biphenyl and the like. Examples of"bi-heteroaryl"also include"heteroaryl-T-heteroaryl"or"heteroaryl-T-aryl"where T is a bond,- (CH2) qO-, - (CH2) q-,-C (O) (CH2) q-,-(CH2) qC (O)-,-(CH2) qS-,-S (CH2) q-, S [O] (CI-C3 alkyl)-, - (CH2) qC (=CH2)-,-C (=CH2) (CH2) q-,- (CH2) qC (=NOH)-,-C (=NOH) (CH2) q-, -(CH2) qC (=NOCH3) -, -C (=NOCH3) (CH2) q-,-CH (OH) (CH2) q- or- (CH2) qCH (OH)- ; and q is 0, 1, 2 or 3. The"bi-heteroaryl"as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.

The term"heterocyclyl"refers to a non-aromatic ring which contains one or more heteroatoms selected from O, N or S, which includes a monocyclic, bicyclic or tricyclic ring of 5-to 14-carbon atoms containing one or more heteroatoms selected from O, N or S. The"heterocyclyl"as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.

Examples of heterocyclyl include, but are not limited to, morpholine, piperidine, piperazine, pyrrolidine, and thiomorpholine.

The term"carbocyclyl" (also referred as"nonaromatic carbocyclic ring") refers to a saturated or partially saturated nonaromatic carbocyclic ring. Examples of carbocyclyl are, but are not limited to, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and the like.

An"arylalkyl"as used herein is an aryl substituent that is linked to a compound by an alkyl group having from one to six carbon atoms. The"arylalkyl"as defined above may be optionally substituted with a designated number of substituents as set forth in the embodiment recited above.

The"aminoalkyl"as used herein contains both a basic amino group (NH2) and an alkyl group as defined above.

The term R6A (or acid bioisosteres) as used herein includes, but are not limited to, carboxamide, sulfonamide, acylsulfonamide, tetrazole or the following moiety.

Carboxamide, sulfonamide, acylsulfonamide and tetrazole may be optionally substituted with one or more suitable substituents selected from haloalkyl, aryl, heteroaryl, and Cl-C6 alkyl. The heteroalkyl, aryl, heteroaryl and alkyl may further optionally substituted with one or more substituents selected from the list provided for Rl5. The examples of R6A (or acid bioisosteres) are, but not limited to, hydroxamic acid, acyl cyanamide, tetrazoles, sulfinylazole, sulfonylazole, 3-hydroxyisoxazole, hydroxythiadiazole, sulphonate and acylsulfonamide.

The term"active ingredient"means the compounds generically described by Formula I as well as the salts, solvates and prodrugs of such compounds.

The term"pharmaceutically acceptable"means that the carrier, diluents, excipients and salt must be compatible with the other ingredients of the composition, and not deleterious to the recipient thereof. Pharmaceutical compositions of the present invention are prepared by procedures known in the art using well-known and readily available ingredients.

"Preventing"refers to reducing the likelihood that the recipient will incur or develop any of the pathological conditions described herein.

"Treating"refers to mediating a disease or condition, and preventing or mitigating its further progression or ameliorating the symptoms associated with the disease or condition.

"Pharmaceutically-effective amount"means that amount of a compound of the present invention, or of its salt, solvate, hydrate or prodrug thereof that will elicit the biological or medical response of a tissue, system or mammal. Such an amount can be administered prophylactically to a patient thought to be susceptible to development of a disease or condition. Such amount when administered prophylactically to a patient can also be effective to prevent or lessen the severity of the mediated condition. Such an amount is intended to include an amount, which is sufficient to modulate a PPAR receptor such as a PPARoc, PPARy, PPAR8 or PPARy/8 receptor to mediate a disease or condition. Conditions mediated by PPAR receptors include, for example, diabetes mellitus, cardiovascular disease, Syndrome X, obesity and gastrointestinal disease.

Additional conditions associated with the modulation of a PPAR receptor include inflammation related conditions, which include, for example, IBD (inflammatory bowel disease), rheumatoid arthritis, psoriasis, Alzheimer's disease, Chrohn's disease and ischemia reprofusion injury (stroke and miocardial infarction).

A"mammal"is an individual animal that is a member of the taxonomic class Mammalia. The class Mammalia includes humans, monkeys, chimpanzees, gorillas, cattle, swine, horses, sheep, dogs, cats, mice, rats and the like.

Administration to a human is most preferred. A human to whom the compounds and compositions of the present invention are administered has a disease or condition in which control blood glucose levels are not adequately controlled without medical intervention, but wherein there is endogenous insulin present in the human's blood. Non-insulin dependent diabetes mellitus (NIDDM) is a chronic disease or

condition characterized by the presence of insulin in the blood, even at levels above normal, but resistance or lack of sensitivity to insulin action at the tissues.

Those skilled in the art will recognize that sterocenters exist in compound of the present invention. Accordingly, the present invention includes all possible stereoisomers and geometric isomers of the presently claimed compounds including racemic compounds and the optically active isomers.

The compounds of the present invention contain one or more chiral centers and exist in different optically active forms. When compounds of the present invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as racemic mixtures. Resolution of the final product, an intermediate or a starting material may be effected by any suitable method known in the art, for example by formation of, diastereoisomeric salts which may be separated by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated by crystallization and gas-liquid or liquid chromatography ; selective reaction of one enantiomer with an enantiomer-specific reagent such as enzymatic esterification ; and gas-liquid or liquid chromatography in a chiral environment such as on a chiral support, for example silica with a bound chiral ligand or in the presence of a chiral solvent. See also Sterochemistry of Carbon Compounds by E. L. Eliel (Mcgraw Hill, 1962) and Tables of Resolving Agents by S. H. Wilen. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

When a compound of the present invention has more than one chiral substituents, it may exist in diastereoisomeric forms. The diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. The present invention includes each diastereoisomer of compounds of formula I and mixtures thereof.

Certain compounds of the present invention may exist in different stable conformational forms, which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each confonnational isomer of compounds of formula I and mixtures thereof.

Certain compound of the present invention may exist in zwitterionic form, and the present invention includes each zwitterionic form of compounds of formula I and mixtures thereof.

Certain compounds of the present invention and their salts may exist in more than one crystal form. Polymorphs of compounds of formula I form part of the present invention and may be prepared by crystallization of a compound of formula I under different conditions, such as using different solvents or different solvent mixtures for recrystallization ; crystallization at different temperatures; and various modes of cooling ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting a compound of formula I followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or other available techniques.

Certain compounds of the present invention and their salts may exist in more than one crystal form, which includes each crystal form and mixtures thereof.

Certain compounds of the present invention and their salts may also exist in the form of solvates, for example hydrates, and thus the present invention includes each solvate and mixtures thereof.

"Pharmaceutically-acceptable salt"refers to salts of the compounds of formula I, which are substantially non-toxic to mammals. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral, organic acid : an organic base or inorganic base. Such salts are known as base addition salts, respectively. It should be recognized that the particular counter ! on forming a part of any salt of the present invention is not of a critical nature so long as the salt as a whole is pharmaceutically acceptable and the counterion does not contribute undesired qualities to the salt as a whole.

By virtue of its acidic moiety, a compound of the present invention forms salts with pharmaceutically acceptable bases. Some examples of base addition salts include metal salts such as aluminum; alkali metal salts such as lithium, sodium or potassium; and alkaline earth metal salts such as calcium, magnesium, ammonium, or substituted ammonium salts. Examples of substituted ammonium salts include, for instance, those with lower alkylamines such as trimethylamine and triethylamine ; hydroxyalkylamines such as 2-hydroxyethylamine, bis- (2-hydroxyethyl)-amine or tri- (2- hydroxyethyl)-amine ; cycloalkylamines such as bicyclohexylamine or dibenzylpiperidine, N-benzyl-p-phenethylamine, dehydroabietylamine, N, N'-bisdehydro-abietylamine, glucamine, N-piperazine methylglucamine ; bases of the pyridine type such as pyridine, collidine, quinine or quinoline; and salts of basic amino acids such as lysine and arginine.

Examples of inorganic bases include, without limitation, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

Compounds of the present invention, which are substituted with a basic group, may exist as salts with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [e. g.

(+) -tartrates, (-) -tartrates or mixtures thereof including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.

Certain compounds of the present invention and their salts may also exist in the form of solvates, for example hydrates, and thus the present invention includes each solvate and mixtures thereof.

The compounds of present invention, which bind to and activate the PPARs, lower one or more of glucose, insulin, triglycerides, fatty acids and/or cholesterol, and are therefore useful for the treatment and/or prevention of hyperglycemia, dyslipidemia and in particular Type II diabetes as well as other diseases including syndrome X, Type I diabetes, hypertriglyceridemia, insulin resistance, diabetic dyslipidemia, hyperlipidemia, hypercholesteremia, heart failure, coagaulopathy, hypertension, and cardiovascular diseases, especially arteriosclerosis. In addition, these

compounds are indicated to be useful for the regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia and anorexia nervosa.

The compounds and compositions of the present invention are also useful to treat acute or transient disorders in insulin sensitivity, which sometimes occurs following a surgery, trauma, myocardial infarction and the like. The compounds and compositions of the present invention are also useful for lowering serum triglyceride levels. Elevated triglyceride level, whether caused by genetic predisposition or by a high fat diet, is a risk factor for the development of heart disease, stroke, and circulatory system disorders and diseases. The physician of ordinary skill will know how to identify humans who can benefit from administration of the compounds and compositions of the present invention.

The present invention further provides a method for the treatment and/or prophylaxis of hyperglycemia in a human or non-human mammal which comprises administering an effective, non-toxic amount of a compound of formula I, or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof to a hyperglycemic human or non-human mammal in need thereof.

The compounds of the present invention are useful as therapeutic substances in preventing or treating Syndrome X, diabetes mellitus and related endocrine and cardiovascular disorders and diseases in human or non-human animals.

The present invention also relates to the use of a compound of formula I as described above for the manufacture of a medicament for treating a PPARy or PPAR8 mediated condition, separately or in combination.

A therapeutically effective amount of a compound of the present invention can be used for the preparation of a medicament useful for treating Syndrome X, diabetes, treating obesity, lowering tryglyceride levels, raising the plasma level of high density lipoprotein, and for treating, preventing or reducing the risk of developing arteriosclerosis, and for preventing or reducing the risk of having a first or subsequent atherosclerotic disease event in mammals, particularly in humans. In general, a therapeutically effective amount of a compound of formula I of the present invention could reduce serum glucose level (or HbAlc) of a patient by about 0.7% or more ; and

reduce serum triglyceride level by about 15% or more and increases serum HDL level in a patient by 20% or more.

Additionally, an effective amount of a compound of the present invention and a therapeutically effective amount of one or more active agents selected from antihyperlipidemic agent, plasma HDL-raising agents, antihypercholesterolemic agents, fibrates, vitamins, aspirin, insulin secretogogues, insulin and the like can be used together for the preparation of a medicament useful for the above described treatments.

Advantageously, compositions containing the compound of the present invention or their salts may be provided in dosage unit form, preferably each dosage unit containing from about 1 to about 500 mg. It is understood that the amount of the compounds or compounds of the present invention that will be administered is determined by a physician considering of all the relevant circumstances.

Syndrome X includes pre-diabetic insulin resistance syndrome and the resulting complications thereof, insulin resistance, non-insulin dependent diabetes, dyslipidemia, hyperglycemia obesity, coagulopathy, hypertension and other complications associated with diabetes. The methods and treatments mentioned herein include the above and encompass the treatment and/or prophylaxis of any one of or any combination of the following: pre-diabetic insulin resistance syndrome, the resulting complications thereof, insulin resistance, Type II or non-insulin dependent diabetes, dyslipidemia, hyperglycemia, obesity and the complications associated with diabetes including cardiovascular disease, especially arteriosclerosis.

The compositions are formulated and administered in the same general manner as detailed herein. The compounds of the present invention may be used effectively alone or in combination with one or more additional active agents depending on the desired target therapy. Combination therapy includes administration of a single pharmaceutical dosage composition, which contains a compound of the present invention and one or more additional active agents, as well as administration of a compound of the present invention and each active agent in its own separate pharmaceutical dosage. For example, a compound of the present invention or thereof and an insulin secretogogue such as biguanides, meglitinides, thiazolidinediones, sulfonylureas, insulin or oc- glucosidose inhibitors can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral

dosages. Where separate dosages are used, a compound of the present invention and one or more additional active agents can be administered at essentially the same time, i. e., concurrently or at separately staggered times, i. e. , sequentially; combination therapy is understood to include all these regimens.

An example of combination treatment or prevention of arteriosclerosis may involve administration of a compound of the present invention or salts thereof in combination with one or more of second active therapeutic agents: antihyperlipidemic agents; plasma HDL-raising agents; antihypercholesterolemic agents, fibrates, vitamins, aspirin and the like. As noted above, the compounds of the present invention can be administered in combination with more than one additional active agent.

Another example of combination therapy can be seen in treating diabetes and related disorders wherein the compounds of the present invention or salts thereof can be effectively used in combination with second active therapeutic, such as sulfonylureas, biguanides, meglitinides, thiazolidinediones, o-glucosidase inhibitors, other insulin secretogogues, insulin as well as the active agents discussed above for treating arteriosclerosis.

The examples of second therapeutic agents are insulin sensitizers, PPARy agonists, glitazones, troglitazone, pioglitazone, englitazone, MCC-555, BRL 49653, biguanides, metformin, phenformin, insulin, insulin minetics, sufonylureas, tolbutamide, glipizide, alpha-glucosidase inhibitors, acarbose, cholesterol lowering agent, HMG-CoA reductase inhibitors, lovastatin, simvastatin, pravastatin, fluvastatin, atrovastatin, rivastatin, other statins, sequestrates, cholestyramine, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran, nicotinyl alcohol, nicotinic acid: a nicotinic acid salt, PPARot agonists, fenofibric acid derivatives, gemfibrozil, clofibrate, fenofibrate, benzafibrate, inhibitors of cholesterol absorption, beta-sitosterol, acryl CoA: cholesterol acyltransferase inhibitors, melinamide, probucol, PPAR5 agonists, antiobesity compounds, fenfluramine, dexfenfluramine, phentiramine, sulbitramine, orlistat, neuropeptide Y5 inhibitors, ß3 adrenergic receptor agonists, and ileal bile acid transporter inhibitors.

The compounds of the present invention and the pharmaceutically acceptable salts, solvates and hydrates thereof have valuable pharmacological properties and can be used in pharmaceutical compositions containing a therapeutically effective amount of a compound of the present invention, or pharmaceutically acceptable salts, esters or prodrugs thereof, in combination with one or more pharmaceutically acceptable excipients. Excipients are inert substances such as, without limitation carriers, diluents, fillers, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, wetting agents, binders, disintegrating agents, encapsulating material and other conventional adjuvants. Proper excipient is dependent upon the route of administration chosen.

Pharmaceutical compositions typically contain from about 1 to about 99 weight percent of the active ingredient, which is a compound of the present invention.

Preferably, the pharmaceutical formulation is in unit dosage form. A"unit dosage form"is a physically discrete unit containing a unit dose suitable for administration in human subjects or other mammals. For example, a unit dosage form can be a capsule or tablet, or a number of capsules or tablets. A"unit dose"is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more pharmaceutically acceptable excipients. The quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved.

The dosage regimen utilizing the compounds of the present invention is selected by one of ordinary skill in the medical or veterinary arts considering various factors, such as without limitation, the species, age, weight, sex, medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed, and the like.

Preferably, the compounds of the present invention are administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or more times per day. Where delivery is via transdermal forms, administration is continuous.

Suitable routes of administration of pharmaceutical compositions of the present invention include, for example, oral, eye drop, rectal, transmucosal, topical or

intestinal administration; parenteral delivery (bolus or infusion), including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraven-tricular, intravenous, intraperitoneal, intranasal, or intraocular injections. The compounds of the present invention can also be administered in a targeted drug delivery system, such as in a liposome coated with endothelial cell-specific antibody.

For oral administration, the compounds of the present invention can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the present invention to be Formulated as tablets, pills, powders, sachets, granules, dragees, capsules, liquids, elixirs, tinctures, gels, emulsions, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.

For oral administration in the form of a tablet or capsule, the active ingredient may be combined with an oral, non-toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, methyl cellulose, calcium carbonate, calcium phosphate, calcium sulfate, sodium carbonate, mannitol, sorbitol, and the like; together with, optionally, disintegrating agents, such as, without limitation, cross-linked polyvinyl pyrrolidone, maize, starch, methyl cellulose, agar, bentonite, xanthan gum, alginic acid : or a salt thereof such as sodium alginate, and the like; and, optionally, binding agents, for example, without limitation, gelatin, acacia, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethyl-cellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid : sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Solid forms include powders, tablets and capsules. A solid carrier can be one or more substances, which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material.

In powders, the carrier is a finely divided solid, which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Sterile liquids include suspensions, emulsions, syrups, and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.

The active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.

Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations, which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starch, and/or lubricants such as tale or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

All formulations for oral administration should be in dosages suitable for such administration. Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules.

For parental administration, the compounds of the present invention or salts thereof can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. Formulations for injection may be presented in unit dosage form, such as in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that each syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against any contamination. The carrier can be solvent or dispersion medium containing, for example, water, preferably in physiologically compatible buffers such as Hanks'solution, Ringer's solution, or physiological saline buffer, ethanol, polyol (e. g. glycerol, propylene glycol and liquid polyethylene glycol), propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.

For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

The active compounds can also be administered intranasally as, for example, liquid drops or spray.

For buccal administration, the compositions may take the form of tablets or lozenges Formulated in a conventional manner.

For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of a dry powder inhaler, or an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a

suitable propellant, e. g. , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and crtridges of gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

Pharmaceutical compositions of the present invention can be manufactured in a manner that is itself known, e. g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.

In making the compositions of the present invention, the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, lyophilized solid or paste, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointment, containing for example up to 10% by weight of the active compound. The compounds of the present invention are preferably formulated prior to administration.

Binding and Cotransfection Studies The in vitro potency of compounds in modulating PPARy, PPARoc and PPAR receptors are determined by the procedures detailed below. DNA-dependent binding (ABCD binding) is carried out using Scintillation Proximity Assay (SPA) technology with PPAR receptors. Tritium-labeled PPARot and PPARy agonists are used as radioligands for generating displacement curves and IC50 values with compounds of the present invention. Cotransfection assays are carried out in CV-1 cells. The reporter plasmid contains an acylCoA oxidase (AOX) PPRE and TK promoter upstream of the luciferase reporter cDNA. Appropriate PPARs and RXRoc are constitutively expressed using plasmids containing the CMV promoter. Since for PPARoc and PPARß, interference by endogenous PPARy in CV-1 cells is an issue, in order to eliminate such

interference, a GAL4 cliimeric system is used in which the DNA binding domain of the transfected PPAR is replaced by that of GAL4, and the GAL4 response element is utilized in place of the AOX PPRE. Receptor activation by compounds of the present invention is determined relative to PPARoc agonist and PPARy agonist reference molecules to obtain percent efficacies. EC50 values are determined by computer fit to a concentration-response curve. A typical range for concentration determination is from lnM to 101lM. For binding or cotransfection studies with receptors other than PPARs, similar assays are carried out using appropriate ligands, receptors, reporter constructs and etc. for that particular receptor. In some cases, a single high concentration of agonist (10 , uM) was used.

These studies are carried out to evaluate the ability of compounds of the present invention to bind to and/or activate various nuclear transcription factors, particularly huPPARa ("hu"indicates"human"), huPPARy and huPPAR6. These studies provide in-vitro data concerning efficacy and selectivity of compounds of the present invention. Furthermore, binding and cotransfection data for compounds of the present invention are compared with corresponding data for reference compounds that act on either huPPARorv or huPPARy. The typical range of concentration for binding is from InM to 10µM. The concentration of test compound required to effect 50% maximal activation of PPARα (ICsooc) and PPARy (IC50γ) is determined. The compounds of the present invention are, in general, found to have IC50 in the range of about 1 nM to about 5 uM for PPAR gamma and/or delta.

Evaluation of Triglyceride and Cholesterol Level in HuapoAI Transgenic Mice Five to six week old male mice, transgenic for human apoAI [C57B1/6- tgn (apoal) lrub, Jackson Laboratory, Bar Harbor, ME] are housed five per cage (10"x20"x8"with aspen chip bedding) with food (Purina 5001) and water available at all times. After an acclimation period of 2 weeks, animals are individually identified by ear notches, weighed and assigned to groups based on body weight. Beginning the following morning, mice are dosed daily by oral gavage for 7 days using a 20 gauge, 1 1/2"curved disposable feeding needle. Treatments are test compounds (30 mg/kg), a positive control (fenofibrate, 100 mg/kg) or vehicle [1% carboxymethylcellulose (w/v)/0. 25% Tween80

(w/v); 0.2 ml/mouse]. Prior to termination on day 7, mice are weighed and dosed. Three hours after dosing, animals are anesthetized by inhalation of isoflurane (2-4%) and blood obtained via cardiac puncture (0.7-1. 0 ml). Whole blood is transferred to serum separator tubes (Vacutainer SST), chilled on ice and permitted to clot. Serum is obtained after centrifugation at 4°C and frozen until analysis for triglycerides, total cholesterol, compound levels and serum lipoprotein profile by fast protein liquid chromatography (FPLC) coupled to an inline detection system. After sacrifice by cervical dislocation, the liver, heart and epididymal fat pads are excised and weighed.

The animals dosed with vehicle have average triglycerides values of about 60 to 80 mg/dl, which are reduced by the positive control fenofibrate (33-58 mg/dl with a mean reduction of 37%). The animals dosed with vehicle have average total serum cholesterol values of about 140 to 180 mg/dl, which are increased by fenofibrate (about 190 to 280 mg/dl with a mean elevation of 41%). When subject to FPLC analysis, pooled sera from vehicle-treated hu apoAI transgenic mice have a high-density lipoprotein cholesterol (HDLc) peak area, which ranges from 47v-sec to 62v-sec. Fenofibrate increases the amount of HDLc (68-96v-sec with a mean percent increase of 48%). Test compounds evaluated in terms of percent increase in the area under the curve.

Representative compounds of the present invention are tested using the above methods or substantially similar methods.

Evaluation of Glucose Levels in db/db Mice Five week old male diabetic (db/db) mice [C57BlKs/j-m +/+ Lepr (db), Jackson Laboratory, Bar Harbor, ME] or lean littermates (db+) are housed 6 per cage (10"x20"x8"with aspen chip bedding) with food (Purina 5015) and water available at all times. After an acclimation period of 2 weeks, animals are individually identified by ear notches, weighed and bled via the tail vein for determination of initial glucose levels.

Blood is collected (100 Rl) from unfasted animals by wrapping each mouse in a towel, cutting the tip of the tail with a scalpel, and milking blood from the tail into a heparinized capillary tube balanced on the edge of the bench. Sample is discharged into a heparinized microtainer with gel separator (VWR) and retained on ice. Plasma is obtained after centrifugation at 4°C and glucose is measured immediately. Remaining plasma is frozen until the completion of the experiment, and glucose and triglycerides are assayed in all

samples. Animals are grouped based on initial glucose levels and body weights.

Beginning the following morning, mice are dosed daily by oral gavage for 7 days using a 20 gauge, 1 % 2"curved disposable feeding needle. Treatments are test compounds (30 mg/kg), a positive control agent (30 mg/kg) or vehicle [1% carboxymethylcellulose (w/v) /0.25% Tween80 (w/v); 0.3 ml/mouse]. On day 7, mice are weighed and bled (tail vein) for about 3 hours after dosing. Twenty-four hours after the 7th dose (i. e. , day 8), animals are bled again (tail vein). Samples obtained from conscious animals on days 0,7 and 8 are assayed for glucose. After 24 hour bleed, animals are weighed and dosed for the final time. Three hours after dosing on day 8, animals are anesthetized by inhalation of isoflurane, and blood obtained is via cardiac puncture (0.5-0. 7 ml). Whole blood is transferred to serum separator tubes, chilled on ice and permitted to clot. Serum is obtained after centrifugation at 4°C and frozen until analysis for compound levels. After sacrifice by cervical dislocation, the liver, heart and epididymal fat pads are excised and weighed.

The animals dosed with vehicle have average triglycerides values of about 170 to 230 mg/dl, which are reduced by the positive PPARy control (about 70 to 120 mg/dl with a mean reduction of 50%). Male db/db mice are hyperglycemic (average glucose of about 680 to 730 mg/dl on the 7th day of treatment), while lean animals have average glucose levels between about 190 and 230 mg/dl. Treatment with the positive control agent reduces glucose significantly (about 350 to 550 mg/dl with a mean decrease towards normalization of 56%).

Glucose is measured colorimetrically by using commercially purchased reagents (Sigma #315-500). According to the manufacturers, the procedures are modified from published work (McGowan et al. Clin Cliein, 20: 470-5 (1974) and Keston, A.

Specific colorimetric enzymatic analytical reagents for glucose. Abstract of papers 129th Meeting ACS, 31C (1956). ); and depend on the release of a mole of hydrogen peroxide for each mole of analyte coupled with a color reaction first described by Trinder (Trinder, P. Ann Clin Biochem, 6: 24 (1969) ). The absorbance of the dye produced is linearly related to the analyte in the sample. The assays are further modified for use in a 96 well format. Standards (Sigma &num 339-11, Sigma &num 16-11, and Sigma &num CC0534 for glucose, triglycerides and total cholesterol, respectively), quality control plasma (Sigma # A2034), and samples (2 or 5 pl/well) are measured in duplicate using 200 Rl of reagent. An

additional aliquot of sample, pipetted to a third well and diluted in 200 gel water, provided a blank for each specimen. Plates are incubated at room temperature (18, 15, and 10 minutes for glucose, triglycerides and total cholesterol, respectively) on a plate shaker and absorbance read at 500 nm (glucose and total cholesterol) or 540 nm (triglycerides) on a plate reader. Sample absorbance is compared to a standard curve (100-800, 10-500, and 100-400 mg/dl for glucose, triglycerides and total cholesterol, respectively). Values for the quality control sample are consistently within the expected range and the coefficient of variation for samples is below 10%. All samples from an experiment are assayed at the same time to minimize inter-assay variability.

Serum lipoproteins are separated and cholesterol is quantitated with an in- line detection system. Sample is applied to a Superpose0 6 HR 10/30-size exclusion column (Amersham Pharmacia Biotech) and eluted with phosphate buffered saline- EDTA at 0.5 ml/min. Cholesterol reagent (Roche Diagnostics Chol/HP 704036) at 0.16 ml/min is mixed with the column effluent through a T-connection, and the mixture is passed through a 15 m x 0.5 mm id knitted tubing reactor immersed in a 37°C water bath.

The colored product produced in the presence of cholesterol is monitored in the flow stream at 505 nm, and the analog voltage from the monitor is converted to a digital signal for collection and analysis. The change in voltage corresponding to change in cholesterol concentration is plotted against time, and the area under the curve corresponding to the elution of VLDL, LDL and HDL is calculated (Perkin Elmer Turbochrome software).

The compounds of the present invention can be prepared according to the procedures of the following schemes and examples, which may further illustrate details for the preparation of the compounds of the present invention. The compounds illustrated in the schemes and examples are, however, not to be construed as forming the only genus that is considered as the present invention.

General Reaction Scheme The compounds of the present invention, in general, may be prepared according to the Reaction Schemes described below.

Reaction Scheme 1 CDC03 COOR6 R'R2 I CO RI R2 AZ/\ + -- R4 Rs AcO Y OTs DMF 1 2 1 2 R Rz (R3) r I2C03 AcO /COOR6 MeOH Arc0 y 3 Et3N RI R2 (R3) r Z-A3H XAl COOR6 5 Ms0 Y Az/Ra Rs Cs2C03 or - K m 4 K2CO3 R'R A _/COOR6 hydrolysis \3 Y A2 /R Rs 6 R2 R3) r A _/GOOH A ylA2t A COOH 7 7 R6 = alkyl

As shown in Reaction Scheme 1, treatment of tosylate 2 with a headpiece compound 1 under the basic condition provides intermediate 3. Acetyl group is removed under K2CO3/MeOH condition followed by mesylation of the free alcohol to afford compound 4. Final tailpiece (Z-A3H) is installed by treatment of compound 4 with compound 5 to give ester 6, which is then undergoes a hydrolysis to provide final acid 7.

Reaction Scheme 2 CsZC03 Rl R2 Ri Rz KZC03 Z A3H + 5 Ts0 Y OAc DM \A3 OAc 8 9 (R3) r K2C03 RI R2 H\ (R3), Me /Ra Rs 1 then MsCl JL Y OMs A3 Y OM Et3N 10 Cs2CO3 or K2CO3 R1 R2 (R3) r COOR6 z 1 1 ' J 3 Y A-TJ R4 R ! hydrolysis 6 Aa/R4 6 Rz Rl VA COOH Zu Az /R4 7 R6 = alkyl As shown in Reaction Scheme 2, treatment of tosylate 8 with a tailpiece compound 5 under the basic condition provides intermediate 9. Acetyl group is removed under K2C03/MeOH condition followed by mesylation of the free alcohol to afford compound 10. Final headpiece (compound 1) is installed by treatment of compound 10 with 1 to give ester 6, which is then undergoes a hydrolysis to provide final acid 7.

Reaction Scheme 3 CsZC03 or RI Rz 5 y R2 DMF 3 Z \A Y OH DMF 11 then H+ 12 (R') r MsCI H ,. A, COOR'' Et z, ik y'I oms R4 RI A3 Y OMs 13 Cs2CO3 or K2C03 (ruz hydrolysis As Y \Az/R4 14 R2 (R3) r A3 ylA24/R4 R5 3 R4 R5 15

R6 = alkyl As shown in Reaction Scheme 3, treatment of cyclic sulfate 11 with compound 5 under the basic condition provides alcohol 12. Mesylation of the free alcohol affords compound 13. Final headpiece (compound 1) is installed by treatment of compound 13 with 1 to give ester 14, which is then undergoes, a hydrolysis to provide final acid 15.

Reaction Scheme 4 (R3) % Cs. COor H Al _/COOR6 O KZCO3 R4 Rs Y Rl DMF /a s 1'R DMF R R 1 16 then H+ RI (R3) r MsCl AI /COOR6 Et3N 17 R4 R5 17 Z-A3H RI COOR6 > MsO /RXRS Cs2C03 or mso R4 R5 K2CO3 18 RI (R3), A /COOR6 hydrolysis A3 R4 R5 3 Y A,-1 R4 RS 19 Roi RI (R3) r ZWA3 YA2,/RXRs 3 R4 R5 20

R6 = alkyl As shown in Reaction Scheme 4, treatment of cyclic sulfate 16 with headpiece 1 under the basic condition provides alcohol 17. Mesylation of the free alcohol affords compound 18. Final tailpiece (Z-A3H) is installed by treatment of compound 18 with compound 5 to give ester 19, which is then undergoes a hydrolysis to provide final acid 20.

Reaction Scheme 5 Br RI Rz (R3) r COOR6 ArB (OH) 2 or ArSnBu3 'bd (0) \ AY or ArOH, CuI 7 Cs2CO3 Ar 2, 2, 6, 6-tetramethylheptan-3-5-dione Ar T RI R2 (R3) r x COOR6 hydrolysis \ A YA/\ s A3 A2 R4 R5 - A, Y A,-J R4 R5 21 Ar T Tn RI R2 (R) r ^ 1 A1 _/COOH 3 R4 R5 A, Y Az/R4 Rs 22

R6 = alkyl ; and T = a bond or O Compound 7 is prepared according to the procedure described in Reaction Schemes 1-4. As shown in Reaction Scheme 5, the moiety of-T-Ar such as aryl or aryloxy groups in 21, which is prepared from the parent bromide compound 7, is installed by using standard Suzuki, Stille or Ullmann reaction conditions. A hydrolysis of ester compound 21 provides final acid 22.

In the Schemes, Procedures and Examples below, various reagent symbols and abbreviations have the following meanings.

ACN Acetonitrile BINAP 2, 2'-Bis (diphenylphosphino) -1,1'-binaphthyl Boc t-butoxycarbonyl CBZ benzyloxycarbonyl DCM dichloromethane DEAD diethyl azodicarboxylate DIAD diisopropyl azodicarboxylate DIPEA diisopropylethylamine

DMAP 4-dimethylamino pyridine DMF N, N-dimethylformamide DMSO dimethylsulfoxide eq (equiv) equivalent (s) ESI-MS electron spray ion-mass spectroscopy Et ethyl EtOAc ethyl acetate h hours HOAc acetic acid HPLC high performance liquid chromatography HRMS high resolution mass LRMS low resolution mass LAH lithium aluminum hydride Me methyl Ms methanesulfonyl NBS N-bromosuccinimide Pd2 (dba) 3 tris (dibenzylideneacetone) dipalladium (0) Ph phenyl Pr propyl rt (r. t. ) room temperature TBAI tetrabutylammonium iodide TBS tertbutyldimethylsilyl TFA trifluoroacetic acid TEA triethylamine THF tetrahydrofuran TLC thin-layer chromatography Example 1 <BR> <BR> 2- 4- [3- (2-benzoyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenoxy}-2-meth yl-propionic acid

Step A Acetic acid 3- (toluene-4-sulfonyloxy)-butyl ester TEA (0.88 mL, 3.79 mmol), p-toluenesulfonyl chloride (0.72 g, 3. 79 mmol) and 4-dimethylaminopyridine (0.09 g, 0.79 mmol) are added to acetic acid 3- hydroxy-butyl ester (0.41 g, 3.16 mmol) in dichloromethane (DCM) (4 mL) at 0 °C under N2, and the mixture is stirred for an hour at 0 °C. The mixture is warmed gradually to ambient temperature. After 24 h, the mixture is treated with water and extracted with EtOAc. The organic layers are combined and washed with saturated aqueous sodium chloride, and then dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography, silica, eluting with hexanes : EtOAc (75: 25) afforded the title compound (0.71 g, 2.48 mmol, 78%) as a white solid: ES+ (m/e) 304. 19 (M+NH4) + ; 1H NMR (400 MHz, CDCl3) 7.79 (d, 2H, J= 8 Hz), 7. 33 (d, 2H, J= 8 Hz), 4.65-4. 80 (m, 1H), 3.85-4. 20 (m, 2H), 2.44 (s, 3H), 1.96 (s, 3H), 1.80-1. 95 (m, 2H), 1.34 (d, 3H, J= 6.4 Hz); Ru 0. 40 hexanes: EtOAc (70: 30).

Step B 5-Ethyl-2-hydroxy-phenyl-methanone

Aluminum chloride (0.58 g, 4.4 mmol) is added in portions top- ethylanisole (0.50 g, 3.7 mmol) in DCM (3.4 mL) at 0 °C under N2, and the mixture is stirred for about 10 minutes, and then benzoyl chloride (0.43 mL, 3.9 mmol) is added dropwise. The mixture is stirred at 0 °C for 4 h and poured in ice. The mixture is warmed to ambient temperature and extracted with EtOAc. Organic layers are combined and washed with aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated to obtain yellow oil. Crude mixture is dissolved in toluene (4.3 mL) and aluminum chloride (0.49 g, 3.7 mmol) is added in portions at ambient temperature, and stirred under N2. The mixture is warmed at 80 °C for 3 h and additional 16 h at 55 °C.

The mixture is cooled to ambient temperature and poured in ice. The mixture is extracted with EtOAc. Organic phases are combined and washed with aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduced pressure.

Purification by flash chromatography, silica, eluting with hexanes: EtOAc (98: 2) provides the title compound as a yellow oil that crystallizes with the time: ES+ (m/e) 227.10 (M+H) +, Rf 0. 65 hexanes: EtOAc (90: 10).

Step C Acetic acid 3- (2-benzoyl4-ethyl-phenoxy)-butyl ester Cesium carbonate (0.72 g, 2.22 mmol) is added to (5-ethyl-2-hydroxy- phenyl)-phenyl-methanone (0.50 g, 2.22 mmol) and acetic acid 3- (toluene-4- sulfonyloxy)-butyl ester (0.60 g, 2.09 mmol) in DMF (DMF) (7.5 mL) at ambient

temperature under N2, and the mixture is stirred at 55 °C for 16 h. The mixture is cooled to ambient temperature, diluted with water and extracted with EtOAc. The organic phase is combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, eluting with hexanes: EtOAc (89: 11) provides the title compound as a colorless oil (0.58 g, 1.71 mmol), 82%): ES+ (m/e) 341.24 (M+H) +, 363.24 (M+Na) + ; Rr 0.40 hexanes : EtOAc (80: 20) ; 1H NMR (400 MHz, CDC13) 7.76 (m, 2H), 7.50-7. 54 (m, 1H), 7.39-7. 43 (m, 2H), 7.23-7. 27 (m, 2H), 6.85 (d, 1H, J= 8.4 Hz) 2.62 (q, 2H, J = 7.6 Hz), 1.99 (s, 3H), 1.62-1. 67 (m, 2H), 1.22 (t, 3H, J = 7.6 Hz), 1.11 (d, 3H, J = 6 Hz).

Step D [5-Ethyl-2- (3-hydroxy-l-methyl-propoxy-) phenyl]-phenyl-methanone Potassium carbonate (0.15 g, 1.09 mmol) is added to acetic acid 3- (2- benzoyl4-ethyl-phenoxy) -butyl ester (0.58 g, 1.71 mmol) in methanol (4.5 mL) at room temperature, and the mixture is stirred. After 5 h, the mixture is diluted with water and extracted with EtOAc. Organic layers are combined and washed with saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduced pressure the title compound as a colorless oil (0.50 g, 1.67 mmol, 98%): ES+ (m/e), 299.22 (M+H) +, 321.24 (M+Na) + ; ru 0. 20 hexanes: EtOAc (80: 20) ;'H NMR (400 MHz, CDC13) 7.78-7. 81 (m, 2H), 7.53-7. 58 (m, 1H), 7.40-7. 44 (m, 2H), 7.26 (dd, 1H, Jy = 2.4 Hz, J2 = 8.4 Hz), 7.20 (d, 1H, J = 2.8 Hz), 6.93 (d, 1H,./== 8.4 Hz), 4.50-4. 65 (m, 1H), 3.50-3. 70 (m, 2H), 2.61 (q, 2H, J= 7.2 Hz), 1.78 (bs, lH), 1.62-1. 75 (m, 2H), 1.21 (t, 3H, J = 7. 2 Hz), 1.17 (d, 3H, J = 6. 4 Hz).

Step E <BR> <BR> <BR> <BR> 2- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenoxy}-2-meth yl-propionic acid Triphenylphosphine (46 mg, 0.17 mmol) is added to [5-ethyl-2- (3- hydroxy-l-methyl-propoxy-) phenyl] -phenyl-methanone (34 mg, 0.12 mmol) and 2- (4- hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (42 mg, 0.17 mmol) in toluene (1.3 mL) under N2 at ambient temperature. Diethylazodicarboxilate (34 D, L, 0.17 mol) is added dropwise, and the mixture is stirred for 16 h. The mixture is concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (90: 10) provides 2- {4- [3- (2-benzoyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenoxy}-2- methyl-propionic acid ethyl ester (43 mg, 0.08 mmol, 71%) : ES+ (m/e) 519.3 (M+H) + ; Ru 0. 59 hexanes: EtOAc (80: 20).

Aqueous solution of sodium hydroxide (5M, 0.13 mL, 0.67 mmol) is added to the above propionic acid ethyl ester (35 mg, 0.07 mmol) in ethanol, and the mixture is stirred for 5 h at ambient temperature. The mixture is acidified to pH = 2 with a 1 M HCI, and extracted with EtOAc. Organic layers are combined and washed with saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (33 mg, 0.07 mmol, 100%): ES+ (m/e) 491.3 (M+H) + ;'H NMR (400 MHz, CDC13) 7.76 (d, 2H, J= 7,6 Hz), 7.47-7. 50 (m, 1H), 7.34-7. 37 (m, 2H), 7.20-7. 25 (m, 2H), 6.88 (d, J= 8.4 Hz), 6.70-6. 80 (m, 1H), 6.48-6. 56 (m, 2H), 4.53-4. 60 (m, 1H), 3.66 (m, 2H), 2.61 (q, 2H, J= 7.6 Hz), 2.18 (bs, 3H), 1.61 (bs, 6H), 1.27-1. 50 (m, 2H), 1.22 (t, 3H, J= 7. 6 Hz), 1. 15 (t, 3H, J= 5.6 Hz).

Example 2 3-f 4- [3- (2-benzoyl-4-ethyl-phenoxy)-butoxy] 2-methyl-phenyl} propionic acid

The compound of 3-f4- [3- (2-benzoyl-4-ethyl-phenoxy)-butoxy]-2-methyl- phenyl}-propionic acid methyl ester (21 mg, 0. 05 mmol, 76%) is prepared by following the procedure described in Example 1, Step E by using triphenylphosphine (23 mg, 0.09 mmol), [5-ethyl-2- (3-hydroxy-l-methyl-propoxy-) phenyl] -phenyl-methanone (17 mg, 0.06 mmol) (Example 1, Step D), 3- (4-hydroxy-2-metliyl-phenyl-propionic acid methyl ester (17 mg, 0.09 mmol) and diethylazodicarboxilate (17) lL, 0.09 mmol). ES+ (m/e) 475.29 (M+H) +, 497.29 (M+Na) + ; Rf 0.42 hexanes: EtOAc (80: 20).

Work up of the above propionic acid methyl ester (21 mg, 0.04 mmol) in methanol (0.5 mL) as described in Example 1, Step E provides the title compound (20 mg, 0.04 mmol, 100%): ES+ (m/e) 461.27 (M+H) +, 483.26 (M+Na) + ; 1H NMR (400 MHz, CDCl3) 7.76 (d, 2H, J= 7.6 Hz), 7.48-7. 52 (m, 1H), 7.35-7. 39 (m, 2H), 7.21-7. 25 (m, 2H), 7.00 (d, J= 8.4 Hz), 6.88 (d, 1H, J= 8.4 Hz), 6.58 (d, 1H, J= 6.58 Hz), 6.52 (dd, 1H,. J1 = 2 Hz, J2 = 8.4 Hz), 4.50-4. 60 (m, 1H), 3.68 (t, 2H, J= 6 Hz), 2.87 (t, 2H, J= 8.4 Hz), 2.57-2. 64 (m, 4H), 2.27 (s, 3H), 1.75-1. 81 (m, 2H), 1.21 (t, 3H, J= 7.6 Hz), 1.15 (d, 3H, J= 6. 4 Hz).

Example 3 2- {3- [3- (2-benzoyl-4-ethyl-phenoxy)-butoxy]-phenoxy}-2-methyl-propio nic acid

The compound of 2-13- [3- (2-benzoyl-4-ethyl-phenoxy)-butoxy]- phenoxy}-2-methyl-propionic acid ethyl ester (17 mg, 0.03 mmol, 56%) is prepared by following the procedure described in Example 1, Step E by using triphenylphosphine (24 mg, 0.09 mmol), [5-ethyl-2- (3-hydroxy-l-metliyl-propoxy-) phenyl] -phenyl-methanone (18 mg, 0.06 mmol) (Step D of Example 1), 2- (3-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (20 mg, 0.09 mmol) in toluene (0.5 mL) and diethylazodicarboxilate (18 RL, 0.09 mmol). ES+ (m/e) 505.30 (M+H) +, Rl= 0. 49 hexanes: EtOAc (80 : 20).

Work-up of the above propionic acid ethyl ester (17 mg, 0.04 mmol) in ethanol (0.5 mL) as described in Example 1, Step E provides the title compound as a colorless oil (16 mg, 0.04 mmol, 100%): ES+ (m/e) 477.29 (M+H) +, 499.26 (M+Na) + ;'H NMR (400 MHz, CDC13) 7.78 (d, 2H, J= 6.8 Hz), 7.50-7. 54 (m, 1H), 7.37-7. 41 (m, 2H), 7.19-7. 25 (m, 2H), 7.10-7. 14 (m, 1H), 6. 88 (d, J= 8.4 Hz), 6.49-6. 51 (m, 1H), 6.41-6. 42 (m, 1H), 4. 50-4. 60 (m, 1H), 3.72 (t, 2H, J= 5.6 Hz), 2.61 (q, 2H, J= 8 Hz), 1.72-1. 90 (m, 2H), 1.59 (s, 3H), 1.59 (s, 3H), 1.22 (t, 3H, J= 7.6 Hz), 1.17 (d, 3H, J= 6 Hz).

Example 4 3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-butoxy]-phenyl}-2-methoxy-propio nicacid

The compound of 3-f 4- [3- (2-benzoyl-4-ethyl-phenoxy)-butoxy]-phenyl}- 2-methoxy-propionic acid ethyl ester (24 mg, 0.05 mmol, 46%) is prepared by following the procedure described in Example 1, Step E by using triphenylphosphine (40 mg, 0.15 mmol), [5-ethyl-2- (3-hydroxy-l-methyl-propoxy-) phenyl]-phenyl-methanone (30 mg, 0.10 mmol) (Step D of Example 1), 3- {4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (34 mg, 0.15 mmol) in toluene (1.7 mL) and diethylazodicarboxilate (30 uL, 0.15 mmol). ES+ (m/e) 505.30 (M+H) +, RI--= 0. 40 hexanes: EtOAc (80: 20).

Work-up of the above propionic acid ethyl ester (24 mg, 0.05 mmol) in ethanol (0.5 mL) as described in Example 1, Step E provides the title compound as a colorless oil (22 mg, 0.05 mmol, 100%): ES+ (m/e) 477.3 (M+H) +, 499.3 (M+Na) + ;'H NMR (400 MHz, CDC13) 7.76-7. 78 (m, 2H), 7.49-7. 52 (m, 1H), 7.35-7. 39 (m, 2H), 7.21- 7.26 (m, 2H), 7.11 (d, 1H, J= 8.4 Hz), 6.89 (d, 1H, J= 8.4 Hz), 6.67-6. 69 (m, 2H), 4.52- 4.60 (m, 1H), 3.98 (dd, 1H, J, = 4 Hz, J2 =7.2 Hz), 3.65-3. 73 (m, 2H), 3.40 (s, 3H), 2.93- 3.11 (m, 2H), 2.61 (q, 2H, J= 7.6 Hz), 1.74-1. 82 (m, 2H), 1.22 (t, 3H, J= 7.6 Hz), 1.16 (d, 3H, J= 6. 4 Hz).

Example 5 3- {3- [3- (2-Benzoyl-4-ethyl-phenoxy)-butoxyl]-phenyl}-2-m-ethoxy-prop ionic acid

The compound of 3- {3- [3- (2-benzoyl-4-ethyl-phenoxy)-butoxyl]-phenyl}- 2-m-ethoxy-propionic acid ethyl ester (12 mg, 0.03 mmol, 36%) is prepared by following the procedure described in Example 1, Step E by using rriphenylphosphine (26 mg, 0.10 mmol), [5-ethyl-2- (3-hydroxy-l-methyl-propoxy-) phenyl] -phenyl-methanone (20 mg, 0.07 mmol), 3- (3-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (22 mg, 0.10 mmol) in toluene (0.7 mL) and diethylazodicarboxilate (19 jj, L, 0.10 mmol). ES+ (m/e) 505.3 (M+H)+, Rf= 0.42 hexanes: EtOAc (80: 20).

Work-up of the above propionic acid ethyl ester (12 mg, 0.03 mmol) in ethanol (0.4 mL) as described in Example 1, Step E provides the title compound as a colorless oil (11 mg, 0.03 mmol, 100%): ES+ (m/e) 477.3 (M+H) +, 499.3 (M+Na) + ;'H NMR (400 MHz, CDC13) 7.77-7. 79 (m, 2H), 7.50-7. 54 (m, 1H), 7.37-7. 41 (m, 2H), 7.14- 7.26 (m, 3H), 6.89 (d, 1H, J= 8.4 Hz), 6.80 (d, 1H, J= 7.6 Hz), 6.63-6. 73 (m, 2H), 4.54- 4.60 (m, 1H), 3.99-4. 03 (m, 1H), 3.73-3. 76 (m, 2H), 3.39 (s, 3H), 2.9-3. 12 (m, 2H), 2.61 (q, 2H, J= 7.6 Hz), 1.74-1. 88 (m, 2H), 1.22 (t, 3H, J= 7.6 Hz), 1.17 (d, 3H, J= 6.4 Hz).

Example 6 {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenoxy}-acetic acid

The compound of3- {4- [3- (2-benzoyl-4-ethyl-phenoxy)-butoxy]-2-methyl- phenoxy}-acetic acid methyl ester (41 mg, 0.09 mmol, 86%) is prepared by following the procedure described in Step E of Example 1 by using triphenylphosphine (39 mg, 0.15 mmol), [5-ethyl-2- (3-hydroxy-l-methyl-propoxy-) phenyl] -phenyl-methanone (30 mg, 0.10 mmol), (4-hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (29 mg, 0.15 mmol) in toluene (1.2 mL) and diethylazodicarboxilate (30 1L, 0.15 mmol). ES+ (m/e) 477.27 (M+H) +, 499.26 (M+Na) + ; Rf 0. 35 hexanes: EtOAc (80: 20).

Work-up of the above acetic acid methyl ester (40 mg, 0.08 mmol) in methanol (1.0 mL) as described in Example 1, Step E provides the title compound as a colorless oil (38 mg, 0.08 mmol, 100%): ES+ (m/e) 463.26 (M+H) + ;'H NMR (400 MHz, CDCl3) 7.76-7. 78 (m, 2H), 7.48-7. 52 (m, 2H), 7.34-7. 39 (m, 2H), 7.21-7. 25 (m, 2H), 6.89 (d, 1H, J= 8.4 Hz), 6.61-6. 66 (m, 2H), 6.51 (dd, 1H, J1 = 2.8 Hz, J2 = 8.4 Hz), 4.61 (s, 2H), 4.54-4. 60 (m, 1H), 3.65-3. 68 (m, 2H), 2.61 (q, 2H, J= 8 Hz), 2.25 (s, 3H), 1.73-1. 82 (m, 2H), 1.22 (t, 3H, J= 8 Hz), 1.16 (d, 3H, J= 6 Hz).

Example 7 f4- [3- (2-Benzoyl-4-ethyl-phenoxy)-butoxy]-phenoxy} acetic acid

The compound of f4- [3- (2-benzoyl-4-ethyl-phenoxy)-butoxy]- phenoxy} acetic acid ethyl ester (29 mg, 0.06 mmol, 61%) is prepared by following the procedure described in Step E of Example 1 by using triphenylphosphine (39 mg, 0.15 mmol), [5-ethyl-2- (3-hydroxy-l-methyl-propoxy-) phenyl] -phenyl-methanone (30 mg, 0.10 mmol), (4-hydroxy-phenoxy)-acetic acid ethyl ester (29 mg, 0.15 mmol) in toluene (1.2 mL) and diethylazodicarboxilate (30 JL, 0.15 mmol). ES+ (m/e) 477.3 (M+H) +, Rr 0.39 hexanes: EtOAc (80: 20).

Work up of the above acetic acid ethyl ester (29 mg, 0.06 mmol) in ethanol (1.0 mL) as described in Example 1, Step E provides the title compound as a colorless oil (27 mg, 0.06 mmol, 100%): ES+ (m/e) 449.28 (M+H) + ; 1H NMR (400 MHz, CDCl3) 7.76-7. 78 (m, 2H), 7.48-7. 52 (m, 1H), 7.36-7. 39 (m, 2H), 7.21-7. 25 (m, 2H), 6.89 (d, 1H, J= 8.4 Hz), 6.82-6. 84 (m, 2H), 6.68-6. 71 (m, 2H), 4.62 (s, 2H), 4.54-4. 58 (m, 1H), 3.67- 3.70 (m, 2H), 2.61 (q, 2H, J= 7.6 Hz), 1.75-1. 84 (m, 2H), 1.22 (t, 3H, J= 7.6 Hz), 1.16 (d, 3H, J = 6.4 Hz).

Example 8 f 4- [3- (2-Benzoyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenyl-sulfanyl }-acetic acid The compound of {4- [3- (2-benzoyl-4-ethyl-phenoxy)-butoxy]-2-methyl- phenylsulfanyl}-acetic acid ethyl ester (37 mg, 0.07 mmol, 72%) is prepared by following

@ the procedure described in Step E of Example 1 by using rriphenylphosphine (39 mg, 0.15 mmol), [5-ethyl-2-(3-hydroxy-1-methyl-propoxy-) phenyl] -phenyl-methanone (30 mg, 0.10 mmol), (4-hydroxy-2-methyl-nphenylsulfanyl) -acetic acid ethyl ester (34 mg, 0.15 mmol) in toluene (1.2 mL) and diethylazodicarboxilate (30 IL, 0.15 mmol). ES+ (m/e) 507.26 (M+H) +, 0. 43 hexanes : EtOAc (80: 20).

Work up of the above acetic acid ethyl ester (37 mg, 0.08 mmol) in ethanol (1.0 mL) as described in Example 1, Step E provides the title compound as a colorless oil (34 mg, 0.06 mmol, 100%): ES+ (m/e) 479. 23 (M+H) + ; 1H NMR (400 MHz, CDCl3) 7.76-7. 78 (m, 2H), 7.45-7. 52 (m, 1H), 7.35-7. 39 (m, 2H), 7.205-7. 25 (m, 2H), 6.86 (d, 1H, J= 8. 4 Hz), 6.64 (d, 1H, J= 2. 4 Hz), 6.54 (dd, 1H, Jl = 2.4 Hz, J2 = 8.8 Hz), 4. 52- 4.59 (m, 1H), 3.67-3. 71 (m, 1H), 3. 48 (s, 2H), 2.61 (q, 2H, J = 7.6 Hz), 2.42 (s, 3H), 1.74- 1.85 (m, 1H), 1.22 (t, 3H, J= 7.6 Hz), 1.16 (d, J= 6 Hz).

Example 9 {4-[3-(2-Benzoyl-4-ethyl-phenoxy)-butyl]-2-methyl-phenoxy}-a cetic acid Step A Triethyl amine (46 µL, 0.33 mmol) and methanosulfonyl chloride (24 µL, 0.30 mmol) is added to [5-ethyl-2- (3-hydroxy-l-methyl-propoxy-) phenyl] -phenyl- methanone (Example 1 Step B) (83 mg, 0.28 mmol) in DCM (1 ml) at 0 °C under N2.

The mixture is stirred for 3 h at 0 °C, and HCl (1M) is added and extracted with EtOAc.

Organic phase is combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain title compound (84 mg, 0.23 mmol). ES+ (m/e) 377.22 (M+H) + ; 1H NMR (400 MHz, CDC13) 7.77-7. 79 (m, 2H), 7.53-7. 57 (m, 1H), 7.41-7. 45 (m, 2H), 7.26-7. 28 (m, 1H), 7.20 (d, 1H, J= 2. 4 Hz), 6.89 (d, 1H, J= 8 Hz), 4.48-4. 52 (m, 1H), 4.051 (m, 2H), 2.62 (q, 2H, J= 7.6 Hz), 2.87 (s, 3H), 1.68-1. 93 (m, 2H), 1.22 (t, 3H, J = 7.6 Hz), 1.18 (d, 3H, J= 6.4 Hz).

Step B {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-butyl]-2-methyl-phenoxy}-acetic acid Cesium carbonate (30 mg, 93 Rmol) is added to methanosulfonic acid 2- (2-benzoyl-4-ethyl-phenoxy) -propylester (29 mg, 78 mol) and (4-mercapto-2-methyl- phenoxy)-acetic acid ethyl ester (21.2 mg, 93 jjmol) in DMF (0.6 mL), and the mixture is stirred under N2 at 55 °C. After 18 h, the mixture is cooled to ambient temperature and filtered. Solids are washed with EtOAc. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate and filtered. The organic phase is concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (86: 14) gives {4- [3- (2-benzoyl-4-ethyl- phenoxy)-butyl]-2-methyl-phenoxy}-acetic acid ethyl ester (18 mg, 36 Rmol, 45%): ES+ (m/e) 507.26 ; Ru 0. 40 hexanes: EtOAc (80: 20).

Aqueous solution of sodium hydroxide (5M, 0.07 mL, 0.35 mmol) is added to the above acetic acid ethyl ester (18 mg, 0.03 mmol) in ethanol (0.6 mL) and stirred at ambient temperature for 3 h. The mixture is acidified to pH = 2 with a 1 M aqueous solution of HCl and extracted with EtOAc. The organic layers are combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a colorless oil (16 mg, 0.03 mmol, 100%): ES+ (m/e) 479.22 (M+H) +, 501.20 (M+Na) +.

Example 10 3-{4-[3-(2-Benzoyl-4-ethyl-phenoxy)-butylsulfanyl]-2-methyl- phenyl}-propionic acid

Cesium carbonate (40 mg, 123 Rmol) is added to methanosulfonic acid 2- (2-benzoyl-4-ethyl-phenoxy) -propylester (Example 9, Step A) (39 mg, 102 llmol) and 3- {4-mercapto-2-methyl-phenyl)-propionic acid methyl ester (26 mg, 123) J, mol) in DMF (0.7 mL), and the mixture is stirred under N2 at 55 °C. After 18 h, the mixture is cooled to ambient temperature and filtered. Solid is washed with EtOAc. Filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate and filtered. The organic phase is concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (85: 15) provides 3-f4- [3- (2-benzoyl-4-ethyl- phenoxy)-butylsulfanyl]-2-methyl-phenyl}-propionic acid methyl ester (32 mg, 65 4mol, 64%): ES+ (m/e) 491.26 ; Rj= 0. 36 hexanes: EtOAc (80: 20).

Aqueous solution of sodium hydroxide (5M, 0.13 mL, 0.64 mmol) is added to the above propionic acid methyl ester (32 mg, 0.06 mmol) in methanol (0.7 mL), and the mixture is stirred at ambient temperature for 3 h. The mixture is acidified to pH = 2 with a 1 M aqueous solution of HCl and extracted with EtOAc. Organic layers are combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give title compound as a colorless oil (30 mg, 0.06 mmol, 100%): ES+ (m/e) 477.24 (M+H) +.

Example 11 2-f4- [3-ethyl-2-isobutyryl-phenoxy)-butoxy]-phenoxy}-2-methyl-pro pionic acid

Step A<BR> <BR> 1- (5-ethyl-2-hydroxy-phenyl)-2-methyl-propan-1-one Aluminum chloride (0.35 g, 2.6 mmol) is added in portions top- ethylanisole (0.30 g, 2.2 mmol) in DCM (2.2 mL) at 0 °C under N2. After stirring the mixture for 10 min. , isobutyryl chloride (0.25 mL, 2.4 mmol) is added dropwise. The mixture is stirred at 0 °C for 4 h and then poured in ice. The mixture is warmed to ambient temperature and then extracted with EtOAc. Organic layers are combined, washed with aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain a yellow oil. The crude mixture is dissolved in toluene (2.6 mL), and aluminum chloride (0.29 g, 2.2 mmol) is added in portions at ambient temperature, and then stirred under N2. The mixture is warmed at 80°C for 3 h and for 16 h at 55 °C. The mixture is cooled to ambient temperature and poured in ice. The mixture is extracted with EtOAc. Organic phase is combined and washed with aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash silica gel chromatography, eluting with hexanes : EtOAc (97: 3) provides the title compound as a yellow oil (0.35 g, 1.82 mmol, 83%): ES+ (m/e) 193.16 (M+H) +, Rf = 0.37 hexanes: EtOAc (90: 10).

Step B<BR> 2-14- [3-ethyl-2-isobutyryl-phenoxy)-butoxy]-phenoxyl-2-methyl-pro pionic acid Cesium carbonate (96 mg, 0.29 mmol) is added to 1- (5-ethyl-2-hydroxy- phenyl)-2-methyl-propan-1-one (56 mg, 0.29 mmol) and 2- [4- (3-methanesulfonyloxy- butoxy)-phenoxy]-2-methyl-propionic acid ethyl ester (100 mg, 0.26 mmol) in DMF (1 mL), and the mixture is stirred under N2 at 55 °C. After 16 h, the mixture is cooled to ambient temperature and filtered. The solid is washed with EtOAc. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated organic phase under reduce pressure.

Purification by flash chromatography, silica, hexanes : EtOAc (85: 15) provides 2-14- [3- ethyl-2-isobutyryl-phenoxy)-butoxy]-phenoxy}-2-methyl-propio nic acid ethyl ester (40 mg, 0.12 mmol, 44%): ES (m/e) 471.37 (M+H) +, Rn 0. 32 hexanes: EtOAc (80: 20).

Aqueous solution of sodium hydroxide (5M, 0.24 mL, 1.2 mmol) is added to the above propionic acid ethyl ester (28 mg, 0.06 mmol) in ethanol (0.8 mL), and the mixture is stirred at ambient temperature for 3 h. The mixture is acidified to pH = 2 with a 1 M aqueous solution of HCl and extracted with EtOAc. Organic layers are combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a colorless oil (26 mg, 0.06 mmol, 100%): ES+ (m/e) 443.34 (M+H) +, 465.32 (M+Na) +.

Example 12 3- {4- [3-Ethyl-2-isobutyryl)-phenoxy]-2-methyl-phenyl}-propionic acid The compound of 3- [3-ethyl-2-isobutyryl)-phenoxy]-2-methyl- phenyl}-propionic acid methyl ester (77 mg, 0.17 mmol, 51%) is prepared according to the procedure described in Example 11 using cesium carbonate (113 mg, 0.34 mmol), 1- (5-ethyl-2-hydroxy-phenyl)-2-methyl-propan-1-one (66 mg, 0.34 mmol) and 3- [4- (3- methanesulfonyloxy-butoxy)-phenyl]-propionic acid methyl ester (100 mg, 0.29 mmol) in

DMF (1.1 mL). ES+ (m/e) 441.39 (M+H) +, R 0. 30 hexanes: EtOAc (80 : 20). Work up of the above propionic acid methyl ester (91 mg, 0.21 mmol) in methanol (1.5 mL) as described in Example 11, Step B provides the title compound as a colorless oil (89 mg, 0.21 mmol, 100%). ES+ (m/e) 427. 34 (M+H) +.

Example 13 <BR> 2- {4- [3- (2-cyclohexanecarbonyl-4-ethyl-phenoxy)-butoxy]-phenoxy-2-me thyl-propionic acid Step A Cyclohexyl- (5-ethyl-2-hydroxy-phenyl)-methanone Aluminum chloride (0. 35 g, 2.6 mmol) is added in portions top- ethylanisole (0.30 g, 2.2 mmol) in DCM (2.2 mL) at 0 °C under N2. After stirring the mixture forlO min. , cyclohexanecarbonyl chloride (0.32 mL, 2.4 mmol) is added dropwise. The mixture is stirred at 0 °C for 4 h and poured in ice. The mixture is warmed to ambient temperature and extracted with EtOAc. Organic layers are combined, washed with aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated to obtain a yellow oil. The crude mixture is dissolved in toluene (2.6 mL) and aluminum chloride (0.29 g, 2.2 mmol) is added in portions at ambient temperature.

The mixture is stirred under N2, and warmed at 80 °C for 3 h and for 16 h at 55 °C. The mixture is cooled to ambient temperature and poured in ice. It is extracted with EtOAc, and organic phase is combined, washed with aqueous sodium chloride, dried over

magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash silica gel chromatography, eluting with hexanes: EtOAc (97: 3) provides the title compound as a yellow oil: ES+ (m/e) 233.15 (M+H) +, Rr 0. 68 hexanes: EtOAc (90: 10). <BR> <BR> <P> Step B<BR> <BR> 2- {4- [3- (2-cyclohexanecarbonyl-4-ethyl-phenoxy)-butoxy]-phenoxy-2-me thyl-propionic acid Cesium carbonate (96 mg, 0.29 mmol) is added to cyclohexyl- (5-ethyl-2- hydroxy-phenyl)-methanone (68 mg, 0.29 mmol) and 2- [4- (3-methanesulfonyloxy- butoxy)-phenoxy]-2-methyl-propionic acid ethyl ester (100 mg, 0.26 mmol) in DMF (1 mL), stir under N2 at 55 °C. After 16 h, the mixture is cooled to ambient temperature, filtered and washed solid with EtOAc. The filtrate is washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and filtered. The organic phase is concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: EtOAc (90: 10) provides 2- {4- [3- (2-cyclohexanecarbonyl-4-ethyl-phenoxy)- butoxy]-phenoxy-2-methyl-propionic acid ethyl ester (43 mg, 0.09 mmol, 32%): ES+ (m/e) 511.35 (M+H) +, Rr 0. 45 hexanes: EtOAc (80: 20). Work up of the above propionic acid ethyl ester (43 mg, 0.09 mmol) in ethanol (0.8 mL) as described in Example 11, Step B provides the title compound as a colorless oil (41 mg, 0.09 mmol, 100%): ES+ (m/e) 483.33 (M+H) +, 505.32 (M+Na) +.

Example 14 <BR> <BR> 3- {4- [3- (2-Cyclopentanecarbonyl-4-etliyl-phenoxy)-butoxy]-2-methyl-p henyl}-propionic acid

Step A<BR> <BR> Cyclopentyl- (5-ethyl-2-hydroxy-phenyl)-methanone The above compound is prepared by following the procedure described in Step A, Example 13 using aluminum chloride (0.35 g, 2.6 mmol), p-ethylanisole (0.30 g, 2.2 mmol) in DCM (2.2 mL) and cyclopentylcarbonyl chloride (0.29 mL, 2.4 mmol). ES+ (m/e) 219.13 (M+H) +, Rm 0.72 hexanes: EtOAc (90: 10). <BR> <BR> <P> Step B<BR> <BR> 3-f{4- [3- (2-Cyclopentanecarbonyl-4-ethyl-phenoxy)-butoxy]-2-methyl-ph enyl}-propionic acid The compound of 3- {4- [3- (2-cyclopentanecarbonyl-4-ethyl-phenoxy)- butoxy]-2-methyl-phenyl}-propionic acid methyl ester (34 mg, 0.07 mmol, 43%) is prepare by following the procedure described in Example 13, Step B by using cesium carbonate (66 mg, 0.20 mmol), cyclopentyl- (5-ethyl-2-hydroxy-phenyl)-methanone (36 mg, 0.17 mmol) and 3- [4- (3-methanesulfonyloxy-butoxy)-phenyl]-propionic acid methyl ester (70 mg, 0.20 mmol) in DMF (0. 8 mL). ES+ (m/e) 467.33 (M+H) +, Rn 0.48 hexanes: EtOAc (80: 20). Work up of the above propionic acid methyl ester (9 mg, 0.02 mmol) in methanol (0.3 mL) as described in Example 11, Step B provides the title

compound of the propionic acid as a colorless oil (8 mg, 0.02 mmol, 100%: ES+ (m/e) 453.35 (M+H) +.

Example 15 2- {4- [3- (2-Cyclopropanecarbonyl-4-ethyl-phenoxy)-butoxy]-phenoxy}-2- methyl- propionic acid Step A<BR> <BR> Cyclopropyl- (5-ethyl-2-hydroxy-phenyl)-methanone The above compound is prepared by following the procedure described in Example 13, Step A by using aluminum chloride (0.59 g, 4.4 mmol), p-ethylanisole (0.50 g, 3.7 mmol) in dichloromethane (3.6 mL) and cyclopropylcarbonyl chloride (0.36 mL, 3.9 mmol) to afford the compound as a yellow oil: ES+ (m/e) 191.02 (M+H) + ; ray= 0. 49 hexanes: EtOAc (90 : 10). <BR> <BR> <P> Step B<BR> <BR> 2- {4- [3- (2-Cyclopropanecarbonyl-4-ethyl-phenoxy)-butoxy]-phenoxy}-2- methyl- propionic acid The compound of 2- {4- [3- (2-cyclopropanecarbonyl-4-ethyl-phenoxy)- butoxy]-phenoxy}-2-methyl-propionic acid ethyl ester (0.09 g, 0.19 mmol, 43%) is prepared by following the procedure described in Example 13, Step B by using cesium carbonate (0.17 g, 0.53 mmol), cyclopropyl- (5-ethyl-2-hydroxy-phenyl)-methanone (0.09 g, 0.45 mmol) and 2- [4- (3-metlianesulfonyloxy-butoxy)-phenoxy]-2-methyl-propionic acid ethyl ester (0.20 g, 0.53 mmol) in DMF (2 mL). ES+ (m/e) 469.31 (M+H) + ; 491.30

(M+Na) +. Work up of the above propionic acid ethyl ester (0.14 g, 0.32 mmol) in ethanol (2.5 mL) as described in Example 11, Step B provides the title compound as a colorless oil: ES+ (m/e) 441.28 (M+H) +, 463.26 (M+Na) +.

Example 16 3-f4- [3- (R)- (2-Cyclopropanecarbonyl-4-ethyl-phenoxy)-butoxy)]-2-metliyl- phenyl}- propionic acid The compound of 3-f4- [3- (R)- (2-cyclopropanecarbonyl-4-ethyl-phenoxy)- butoxy)]-2-methyl-phenyl}-propionic acid methyl ester (0.14 g, 0.32 mmol, 66%) is prepared by following the procedure described in Example 13 by using cesium carbonate (0.19 g, 0.58 mmol), cyclopropyl- (5-ethyl-2-hydroxy-plienyl)-methanone (0.09 g, 0.48 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]-propionic acid methyl ester (0.20, 0. 58 mmol) in DMF (2 mL). ES+ (m/e) 439. 3 (M+H) +, 461.29 (M+Na) + ; 0. 45 hexanes: EtOAc (80: 20).

Work up of the above propionic acid methyl ester (0.14, 0.32 mmol) in methanol (2.5 mL) as described in Example 11, Step B provides the title compound as a colorless oil (0.13 g, 0.32 mmol, 100%): ES+ (m/e) 425.29 (M+H) +, 447.27 (M+Na) +.

Example 17 3-14- [3- (2-benzoyl-4-trifluoromethyl-phenoxy)-butoxy]-2-methyl-pheny ll-propionic acid Step A (2-Methoxy-5-trifluoromethyl-phenyl)-phenyl-methanone A 1.6 M solution of n-BuLi in hexanes (0.51 mL, 0.82 mmol) is added dropwise for about 20 min to N, N, N, N-tetramethylenediamine (0.12 mL, 0. 80 mmol) at -20°C under N2 After 20 min, p-trifluoromethylanisole (0.10 g, 0.57 mmol) in THF (0.2 mL) is added dropwise for 15 min at-20 °C under N2. After Ih, N-methoxy-N-methyl- benzamide (0.12 mL, 0.79 mL) is added dropwise in 10 min at-20 °C underN2. After 2h, a 1 M HCl (0.9 mL) is added. The mixture is extracted with EtOAc, and organic phases are combined and washed with saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (90: 10) provides the title compound (0.09 g, 0.32 mmol, 57%): ES+ (m/e) 281.08 (M+H) + ; Rr 0.20 hexanes : EtOAc (90: 10).

Step B (2-Hydroxy-5-trifluoromethyl-phenyl)-phenyl-methanone

Pyridine hydrochloride (0.55 g, 4. 8 mmol) is added to (2-methoxy-5- trifluoromethyl-phenyl) -phenyl-methanone (0.09 g, 0.32 mmol), and the mixture is warmed to 200 °C for 3 h under N2. The mixture is cooled to room temperature, treated with 1 M HCl (10 mL), and then extracted with EtOAc. Organic phases are combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, eluting with hexanes: EtOAc (98: 2) provides the title compound (0.031 g, 0.11 mmol, 36%): ES- (m/e) 265.06 (M-H) + ; Ri 0. 45 hexanes: EtOAc (90: 10).

Step C 3-14- [3- (2-benzoyl-4-trifluoromethyl-phenoxy)-butoxy]-2-methyl-pheny ll-propionic acid Cesium carbonate (45 mg ; 0. 19 mmol) is added to (2-hydroxy-5- trifluoromethyl-phenyl) -phenyl-methanone (31 mg, 0.12 mmol) and 3- [4- (3- methanesulfonyloxy-butoxy)-phenyl]-propionic acid methyl ester (48 mg, 0.14 mmol) in DMF (0.5 mL), and the mixture is stirred under N2 at 55 °C. After 16 h, the mixture is cooled to ambient temperature, and then filtered and washed solid with EtOAc. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: EtOAc (88: 12) provides 3- {4- [3- (2-benzoyl-4- trifluoromethyl-phenoxy)-butoxy]-2-methyl-phenyl}-propionic acid methyl ester (33 mg, 0.06 mmol, 55%): ES+ (m/e) 515.26 (M+H) + ; 0. 31 hexanes: EtOAc (80: 20). Work up of the above propionic acid methyl ester (33 mg, 0.06 mmol) in methanol (0.5 mL) as described in Example 11, Step B provides the title compound as a colorless oil (30 mg, 0.06 mmol, 100%): ES+ (m/e) 501.24 (M+H) +.

Example 18 3- {4- [3- (2-Benzoyl-4-isopropyl-phenoxy)-butoxy]-2-methyl-phenyl}-pro pionic acid

Step A (2-Hydroxy-5-isopropyl-phenyl)-phenyl-methanone Aluminum chloride (0.32 g, 2.3 mmol) is added in portions to p- isopropylanisole (0.30 g, 1.9 mmol) in DCM (2.2 mL) at 0 °C under N2. The mixture is stirred for 10 min and then benzoyl chloride (0.24 mL, 2.1 mmol) is added dropwise. The mixture is stirred at 0 °C for 4 h and poured in ice. The mixture is warmed to ambient temperature and extracted with EtOAc. Organic layers are combined and washed with aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography, silica, hexanes: EtOAc (97: 3) provides (5-isopropyl-2-methoxy-phenyl)-phenyl-methanone (0.53 g, 2.1 mmol, 100%). Pyridine hydrochloride (3.6 g, 31 mmol) is added to (5- isopropyl-2-methoxy-phenyl) -phenyl-methanone and the mixture is stirred at 200 °C for 3h. The mixture is cooled to ambient temperature and a 1 M HCl is added. The mixture is extracted with EtOAc. Organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated to afford the title compound. ES+ (m/e) 241.02 (M+H) + ; Rr 0.59 hexanes : EtOAc (9: 1).

Step B<BR> 3-4- [3- (2-Benzoyl-4-isopropyl-phenoxy)-butoxy]-2-methyl-phenyl}-pro pionic acid Cesium carbonate (85 mg, 0.26 mmol) is added to (2-hydroxy-5-isopropyl- phenyl)-phenyl-methanone (42 mg, 0.17 mmol) and 3- [4- (3-methanesulfonyloxy- butoxy)-phenyl]-propionic acid methyl ester (72 mg, 0.21 mmol) in DMF (0.7 mL), and the mixture is stirred under N2 at 55 °C. After 16 h, the mixture is cooled to ambient temperature, filtered and washed solid with EtOAc. The filtrate is washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated organic phase under reduce pressure. Purification by flash chromatography, silica, hexanes: EtOAc (88 : 12) provides 3- {4- [3- (2-Benzoyl-4-isopropyl-phenoxy)- butoxy]-2-methyl-phenyl}-propionic acid methyl ester (45 mg, 0.09 mmol, 52%): ES+ (m/e) 489.39 (M+H) + ; Rr 0. 45 hexanes: EtOAc (85: 15). Work up of the above propionic acid methyl ester (31 mg, 0.06 mmol) in methanol (0.6 mL) as described Example 11, Step B provides the title compound: ES+ (m/e) 475.36 (M+H) +.

Example 19 {4- [3- (R)- (2-Benzoyl-4-isopropyl-phenoxy)-butoxy]-2-methyl-phenylsulfa nyl}-acetic acid The compound of f4- [3- (R)- (2-Benzoyl-4-isopropyl-phenoxy)-butoxy]-2- methyl-phenylsulfanyl}-acetic acid ethyl ester (0.11 g, 0.21 mmol, 66%) is prepared according to Example 18 by using cesium carbonate (0.14 g, 0.43 mmol), (2-hydroxy-5- isopropyl-phenyl) -phenyl-methanone (75 mg, 0.31 mmol) and [4-(3-(59- methanesulfonyloxy-butoxy) -2-methyl-phenylsulfanyl] acetic acid ethyl ester (0.14 g, 0.37 mmol) in DMF (1.2 mL). ES+ (m/e) 521.39 (M+H) + ; 0. 35 hexanes: EtOAc (80: 20). Work up of the above acetic acid ethyl ester (0.11 g, 0.21 mmol) in ethanol (1. 8 mL) provides the title compound: ES+ (m/e) 493.30 (M+H) +.

Example 20 <BR> <BR> 3- {4- [3- (R)- (2-Benzoyl-4-cyclopropyl-phenoxy)-butoxy]-2-methyl-phenyl}-p ropionic acid

Step A<BR> <BR> 1-Cyclopropyl-4-methoxy-benzene

AIM solution of diethylzinc in hexanes (2.07 mL. 2.07 mmol) is added dropwise to a solution of l-methoxy-4-vinyl-benzene (0.14 g, 1.03 mmol) in toluene (0.5 mL) followed by a dropwise addition of iodomethane (0.25 mL, 3.09 munol) for 30 min.

The mixture is warmed to 50 °C and the reaction is completed after about 30 min. The mixture is warmed to room temperature, diluted with water and extracted with ether.

Organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica flash chromatography hexanes: EtOAc (90: 10) provided the title compound (0.11 g, 0.76 mmol, 74%): MS (m/e) 148 (M); R 0. 60 hexanes : EtOAc (90: 10).

Step B<BR> <BR> (5-Cyclopropyl-2-methoxy-phenyl)-phenyl-methanone

A 1.6 M solution of n-Butyl lithium in hexanes (0.63 mL, 1.0 mmol) is added dropwise for 20 min to N, N, N, N-tetramethylenediamine (0.15 mL, 0.97 mmol) in THF (0.3 mL) at-20 °C under N2. After 20 min, 1-cyclopropyl-4-methoxy-benzene (Example 18, Step 1) (0.10 g, 0.69 mmol) in THF (1.0 mL) is added dropwise for 15 min at-20 °C under N2. After 1 h, N-methoxy-N-methyl-benzamide (0.15 mL, 0.97 mL) is added dropwise for 10 min at-20 °C under N2. After 2 h, a 1 M solution of aqueous HCl (0.9 mL) is added. The mixture is extracted with EtOAc, and then organic phases were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (90: 10) provides the title compound (0.02 g, 0.07 mmol, 27%): M (m/e) 252 (M); Rr 0. 25 hexanes: EtOAc (90: 10). <BR> <BR> <P> Step C<BR> <BR> (5-Cyclopropyl-2-liydroxy-phenyl)-phenyl-methanone A1. 6 M solution of boron tribromide (175 J. L, 0.28 mmol) in DCM (1.2 mL) is added to (5-cyclopropyl-2-methoxy-phenyl)-phenyl-methanone (0.04 g, 0.16 mmol) in DCM (0.7 mL) at-78 °C under N2. After 1 h, the mixture is cooled to 0 °C and diluted with water. Aqueous phase is extracted with additional DCM. Organic phase is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, concentrated. Purification by silica flash chromatography hexanes: EtOAc (90: 10)

provides the title compound (0.02 g, 0.07 mol, 48%): Rf= 0.59 hexanes: EtOAc (80: 20); IH NMR (400 MHz, CDC13) 11.81 (s, 1H), 7.67-7. 69 (m, 2H), 7.58-7. 62 (m, 1H), 7.507. 54 (m, 2H), 7.31 (d, 1H, J= 2. 8 Hz), 7.22 (dd, 1H, Jl= 2. 8 Hz, J2=8. 4 Hz), 6. 98 (d, 1H, 1.77-1. 85 (m, 1H), 0.85-0. 90 (m, 2H), 0.52-0. 56 (m, 2H).

Step D <BR> <BR> <BR> <BR> 3- {4- [3- (R)- (2-Benzoyl-4-cyclopropyl-phenoxy)-butoxy]-2-methyl-phenyl}-p ropionic acid Cesium carbonate (38 mg, 0.17 mmol) is added to (5-cyclopropyl-2- hydroxy-phenyl)-phenyl-methanone (17 mg, 0.07 mmol) and 3- [4- (3- (S)- methanesulfonyloxy-butoxy) -phenyl] -propionic acid methyl ester (33 mg, 0.09 mmol) in DMF (0.80 mL), and the mixture is stirred under N2 at 55 °C. After 16 h, the mixture is cooled to ambient temperature and then filtered and washed solid with EtOAc. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered, and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: EtOAc (89: 11) provides 3-14- [3- (R)- (2-benzoyl-4- cyclopropyl-phenoxy)-butoxy]-2-methyl-phenyl}-propionic acid methyl ester (19 mg, 0.04 mmol, 54%): ES+ (m/e) 487.16 (M+H) + ; 0.36 hexanes: EtOAc (80: 20).

Aqueous solution of sodium hydroxide (0.12 mL, 0.59 mmol) is added to the above propionic acid methyl ester (19 mg, 0.04 mmol) in methanol (0.7 mL) and the mixture is stirred at ambient temperature for 5 h. The mixture is acidified to pH = 2 with a 1 M aqueous solution of HCI, and extract with EtOAc. Organic layers are combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford the title compound as a colorless oil (30 mg, 0.06 mmol, 100%): ES+ (m/e) 473.44 (M+H) +.

Example 21 3-14- [3- (R)- (2-Benzoyl-4-chloro-phenoxy)-butoxy]-2-methyl-phenyll-propio nic acid

The compound of 3-14- [3- (R)- (2-Benzoyl-4-chloro-phenoxy)-butoxy]-2- methyl-phenyl}-propionic acid methyl ester (0.41 g, 0.85 mmol, 75%) is prepared according to the procedure described in Example 20, Step D by using cesium carbonate (0.55 g, 1.69 mmol), (5-chloro-2-hydroxy) -phenyl-methanone (0.26 g, 1.13 mmol) and 3- [4-(3-($-methanesulfonyloxy-butoxy)-phenyl]-propionic acid methyl ester (0.47 g, 1.35 mmol) in DMF (4.8 mL). ES+ (m/e) 481.35 (M+H) +, 503.34 (M+Na) + ; Ru 0. 42 hexanes: EtOAc (80 : 20). Work up of the above propionic acid methyl ester (0.41 g, 0.85 mmol) in methanol (9 mL) as described in Example 20, Step D provides the title compound as a colorless oil (0.39 g, 0.85 mmol, 100%): ES+ (m/e) 467.2 (M+H) +, 489.2 (M+Na) +.

Example 22 {4- [3- (R)- (2-Benzoyl-4-chloro-phenoxy)-butoxy]-2-methyl-phenylsulfanyl }-acetic acid The compound of {4-[3-(R)-(2-benzoyl-4-chloro-phenoxy)-butoxy]-2- methyl-phenylsulfanyl}-acetic acid ethyl ester (0.17 g, 0.33 mmol, 77%) is prepared according to the procedure described in Example 20, Step D by using cesium carbonate (0.21 g, 0.64 mmol), (5-chloro-2-hydroxy) -phenyl-methanone (0.10 g, 0.43 mmol) and [4-(3-(S)-methanesulfonyloxy-butoxy)-2-methyl-phenylSulfanyl ] acetic acid ethyl ester

(0.19 g, 0.52 mmol) in DMF (1. 8 mL). ES+ (m/e) 513.33 (M+H) + ; Rif-0. 46 hexanes: EtOAc (80: 20). Work up of the above acetic acid ethyl ester (0.17 g, 0.33 mmol) in ethanol (3.5 mL) as described in Example 20, Step D provides the title compound as a colorless oil (0.16 g, 0.33 mmol, 100%): ES+ (m/e) 507.16 (M+Na) +.

Example 23 3- (4- {3- (R)- [4-Ethyl-2- (hydroxy-phenyl-methyl)-phenoxy]-butoxy}-2-methyl-phenyl)- propionic acid Step A 3- {4- [3- (R)- (2-benzoyl-4-ethy-phenoxy)-butoxy]-2-methyl-phenyl}-propioni c acid methyl ester The compound of 3- {4- [3- (R)- (2-benzoyl-4-ethy-phenoxy)-butoxy]-2- methyl-phenyl}-propionic acid methyl ester (0. 56 g, 1. 18 mmol, 58%) is prepared according to the procedure described in Example 20, Step D by using cesium carbonate (0.82 g, 2.53 mmol), (5-ethyl-2-hydroxy-phenyl-methanone (0. 38 g, 1.69 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]-propionic acid methyl ester (0.70 g, 2.03 mmol) in DMF (6.5 mL). ES+ (m/e) 475.24 (M+H) +, 497.24 (M+Na) +; Rf= 0. 42 hexanes: EtOAc (80: 20).

Step B<BR> <BR> 3- (4-f3- (R)- [4-Ethyl-2- (hydroxy-phenyl_methyl)-phenoxy]-butoxyl-2-methyl-phenyl)- propionic acid Sodium borohydride (3. 8 mg, 0.10 mmol) is added to the above propionic acid methyl ester (44 mg, 0.09 mmol) in methanol (0.50 mL) at 0 °C under N2. The mixture is warmed to ambient temperature. After 2 h, the mixture is cooled to 0 °C and water is added. The mixture is extracted with EtOAc and organic phase is combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrate under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (85: 15) provides 3- (4-f3- (R)- [4-ethyl-2- (hydroxy-phenyl-methyl)- phenoxy]-butoxy}-2-methyl-phenyl)-propionic acid methyl ester (31 mg, 0.07 mmol, 70%) : ES+ (m/e) 459.48 (M-H20+H) +, 494.51 (M+Na) + ; Ru 0. 36 hexanes: EtOAc (80: 20).

Work up of the above propionic acid methyl ester (31 mg, 0.07 mmol) in methanol (0.60 mL) as described in Example 20, Step D provides the title compound as a colorless oil (30 mg g, 0.07 mmol, 100%): ES- (m/e) 461.1 (M-H)-, ES+ (m/e) 485.42 (M+H) +.

Example 24 3- (4- {3- (R)- 4-Ethyl-2- (hydroxyimino-phenyl-methyl)-phenoxy)-butoxy}-2-methyl- phenyl)-propionic acid Hydroxylamine hydrochloride (26.9 mg, 0.39 mmol) is added to 3- {4- [3- (2-benzoyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenyl}-propion ic acid methyl ester (Example 23, Step A) (46 mg, 0.09 mmol) in pyridine (0.3 mL) and ethanol (0.3 mL).

The mixture is warmed to reflux under N2. After 3 h, the mixture is cooled to ambient temperature and then diluted with water and extracted with EtOAc. Organic phase is

combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (70: 30) provides 3- (4- {3- (R)- [4-ethyl-2- (hydroxyimino-phenyl-methyl)-phenoxy)-butoxy}-2-methyl-pheny l)-propionic acid methyl ester (30 mg, 0.06 mmol, 63%): ES+ (m/e) 490.50 (M+H) + ; 0. 26 hexanes: EtOAc (75: 25). Work up of the above propionic acid methyl ester (30 mg, 0.06 mmol) in methanol (0.5 mL) as described in Example 20, Step D provides the title compound as a colorless oil (29 mg g, 0.06 mmol, 100%): ES+ (m/e) 476.44 (M+H) +.

Example 25 3- (4- {3- (R)- [4-Ethyl-2- (methoxyimino-phenyl-methyl)-phenoxy]-butoxy}-2-methyl- phenyl) -propionic acid The compound of 3- (4- {3- (R)- [4-ethyl-2- (methoxyimino-phenyl-methyl)- phenoxy)-butoxy}-2-methyl-phenyl)-propionic acid methyl ester (13 mg, 0.03 mmol, 47%) is prepared according to the procedure described in Example 24 by using o-methyl- hydroxylamine hydrochloride (19 mg, 0.23 mmol), and 3- {4- [3- (2-benzoyl-4-ethyl- phenoxy)-butoxy]-2-methyl-phenyl}-propionic acid methyl ester (Example 23, Step A) (27 mg, 0.06 mmol) in pyridine (0.25 mL) and ethanol (0.25 mL). ES+ (m/e) 504.22 (M+H) +. Work up of the above propionic acid methyl ester (13 mg, 0.03 mmol) in methanol (0.40 mL) as described in Example 20, Step D provides the title compound as a colorless oil (11 mg, 0.04 mmol, 100%): ES+ (m/e) 490.22 (M+H) +.

Example 26 <BR> <BR> 3-f4- [3- (Benzoyl-5-ethyl-pyridin-2-yloxy)-butoxy]-2-methyl-phenyll-p ropionic acid

Step A 5-Ethyl-2-methoxy-pyridine

A 1.7 M solution of tert-butyllithium in pentane (16.3 mmol, 9.6 mL) is added to 5-bromo-2-methoxy-pyridine (1.50 g, 7.97) and after 1 h, ethyl iodide (1.90 mL, 23.9 mmol) is added dropwise. The mixture is warmed to ambient temperature, and after 3 h, water is added and extracted with diethyl ether. Organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a yellow oil: Rf= 0. 39 hexanes: EtOAc (90: 10) ; 1H NMR (400 MHz, CDC13) 7.98 (d, 1H, J=2 Hz), 7.41 (dd, 1H, J1= 2 Hz, J2= 8.4 Hz), 6.67 (d, J= 8. 4 Hz), 3.91 (s, 3H), 2.56 (q, 2H, J= 7. 6 Hz), 1.21 (t, 3H, J= 7. 6 Hz).

Step B (5-Ethyl-2-methoxy-pyridin-3-yl)-phenyl-methanol

A 1.4 M solution of sec-butyllithium in cyclohexane (7.74 mL, 10.8 mmol) is added dropwise for 20 min to N, N, N, N-tetramethylenediamine (1.60 mL, 10.6 mmol) in THF (3 mL) at-78 °C under N2 and stir. After 30 min, 5-ethyl-2-methoxy- pyridine (1.23 g, 9.68 mmol) in THF (3 mL) is added dropwise in 10 min. After lh, benzaldehyde (1.28 mL, 12.5 mmol) is added dropwise in 10 min. After 1 h at-78 °C, the mixture is warmed to-20 °C. After 90 min, water is added and the mixture is extracted with EtOAc. Organic phase is washed with aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure.

Purification by flash chromatography, silica, hexanes: EtOAc (85: 15) provides the title compound (1.5 g, 6.17 mmol, 64%): ES+ (m/e) 244.04 (M+H) + ; Rf-0. 27 hexanes: EtOAc (80: 20).

Step C (5-Ethyl-2-methoxy-pyridin-3-yl)-phenyl-methanone Pyridinium chlorocromate (1.73 g, 8.00 mmol) is added to 5-ethyl-2- methoxy-pyridin-3-yl)-phenyl-methanol (Example 26, Step B) (1.50 g, 6.20 mmol) in DCM (35 mL). The mixture is stirred under N2 at ambient temperature for 2 h. The mixture is filtered through a pad of celite. Purification by flash chromatography, silica, hexanes: EtOAc (85 : 15) provides the title compound (0.96 g, 3.90 mmol, 64%) as a yellow oil: ES+ (m/e) 242.27 (M+H) + ; Rj= 0.48 hexanes: EtOAc (80: 20).

Step D (5-Ethyl-2-hydroxy-pyridin-3-yl)-phenyl-methanone

A 5.1 M solution of boron tribromide in DCM is added dropwise to (5- ethyl-2-methoxy-pyridin-3-yl)-phenyl-methanone (0.96 g, 4.0 mmol) in DCM (30 mL) at - 78 °C and the mixture is stirred. The mixture is slowly warmed to ambient temperature.

After 2 h, the mixture is cooled to 0 °C and water is added carefully. The mixture is extracted with EtOAc, and organic phase is combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as a yellow solid (0.95 g, 4.0 mmol): ES+ (m/e) 228.22 (M+H) +.

Step E 3- {4- [3- (Benzoyl-5-ethyl-pyridin-2-yloxy)-butoxy]-2-methyl-phenyl}-p ropionic acid Cesium carbonate (0.46 g, 1.41 mmol) is added to 5-ethyl-2-hydroxy- pyridin-3-yl) -phenyl-methanone (0.20 g, 0. 88 mmol) and 3- [4- (3- (, S)- methanesulfonyloxy-butoxy)-phenyl]-propionic acid methyl ester (0.39 g, 1.14 mmol) in DMF (3. 8 mL), and the mixture is stirred under N2 at 55 °C. After 16 h, the mixture is cooled to ambient temperature, and then filtered and washed solid with EtOAc. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: EtOAc (92 : 8) provides 3-f4- [3- (benzoyl-5-ethyl- pyridin-2-yloxy)-butoxy]-2-methyl-phenyl}-propionic acid methyl ester (0.16 g, 0.34 mmol, 38%): ES+ (m/e) 476.2 (M+H) + ; 0. 35 hexanes: EtOAc (80: 20).

Aqueous solution of sodium hydroxide (5M, 1.20 mL, 5.0 mmol) is added to the above propionic acid methyl ester (0.16 g, 0.34 mmol) in methanol (3 mL), and the mixture is stirred at ambient temperature for 6 h. The mixture is acidified to pH = 7 with

a 1 M aqueous solution of HCl and extracted with EtOAc. Organic layers are combined and washed with saturated aqueous sodium chloride, which is then dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound as an oil. ES+ (m/e) 462.17 (M+H) +.

Example 27 {4- [3- (3-Benzoyl-5-ethyl-pyridin-2-yloxy)-butoxy]-2-methyl-phenyls ulfanyl}-acetic acid The compound of f4- [3- (3-benzoyl-5-ethyl-pyridin-2-yloxy)-butoxy]-2- methyl-phenylsulfanyl}-acetic acid ethyl ester (0.07 g, 0.14 mmol, 26%) is prepared according to the procedure described in Example 26 by using cesium carbonate (0.26 g, 0.79 mmol), 5-ethyl-2-hydroxy-pyridin-3-yl)-phenyl-methanone (Example 26, Step D) (0.12 g, 0.53 mmol) and [4-(3-(S)-methanesulfonyloxy-butoxy)-2-methyl- phenylsulfanyl] acetic acid ethyl ester (0.24 g, 0.63 mmol) in ACN (2.3 mL). ES+ (m/e) 508.15 (M+H) + ; Rr 0. 62 hexanes: EtOAc (50: 50). Work up of the above acetic acid ethyl ester (0.07 g, 0.14 mmol) in ethanol (1.5 mL) as described in Example 20, Step D provides the title compound as an oil: ES+ (m/e) 480.15 (M+H) +.

Example 28 3- {4- [3- (5-Ethyl-biphenyl-2-yloxy)-butoxy]-2-methyl-phenyl}-propioni c acid 2-Bromo-4-ethyl-1-methoxy-benzene Step A N-bromosuccinimide (0.72 g, 4.03 mmol) is added to 1-ethyl-4-methoxy- benzene (0.50 g, 3.67 mmol) in ACN (15 mL), and the mixture is stirred under N2 at ambient temperature. After 24 h, the mixture is concentrated under reduced pressure and diluted with water. The mixture is extracted with EtOAc, and organic phases is washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (95: 5) provides the title compound (0.74 g, 3.44 mmol, 94%): ES+ (m/e) 228. 92 (M (79Br) +H) +, 230.85 (M (89Br) +H) + ;'H NMR (400 MHz, CDCl3) 7. 38 (d, 1H, J= 1. 6 Hz), 7.08 (dd, 1H, Jl= 1.6 Hz, J2= 8.4 Hz), 6.81 (d, 1H, J= 8. 4 Hz); 3. 86 (s, 3H), 2.57 (q, 2H, J= 7. 6 Hz), 1.21 (t, 3H, J= 7. 6 Hz).

Step B 5-Ethyl-2-methoxy-biphenyl

Tetrakis (triphenyl phosphine) palladium (0) (54 mg, 0.05 mmol) is added to 2-bromo-4-ethyl-1-methoxy-benzene (0.20 g, 0.94 mmol) in dimethoxyethane (3.5 mL) under N2, and the mixture is stirred. After 10 min, phenylboronic acid (0.17 g, 1. 39 mmol) and sodium carbonate (0.29 g, 2.79 mmol) in water (1.7 mL) are added. The mixture is warmed to 80°C for 18 h and then cooled to room temperature. Water is added and the mixture is extracted with EtOAc. Organic phase is combined and washed with saturated aqueous sodium chloride. Organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (85: 15) provides the title compound as an oil (0.18 g, 0.85 mmol, 92%): ES+ (m/e) 213.08 (M+H) + ; Rj= 0.50 hexanes: EtOAc (90: 10).

Step C 5-Ethyl-biphenyl-2-ol A 1.65 M solution of boron tribromide in DCM (0.86 mL, 1.41 mmol) is added to 5-ethyl-2-methoxy-biphenyl (0.1 g, 0.47 mmol) in DCM (4 mL) under N2 at-78 °C, and the mixture is stirred. The mixture is warmed to-10 °C, and after 2 h, water is added and then extracted with DCM. Organic phases are combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes : EtOAc (95: 5) provides the title compound (0.08 g, 0.44 mmol, 93%): ES- (m/e) 197.11 (M-H)-; R 0. 18 hexanes: EtOAc (90: 10).

Step D 3- {4- [3- (5-Ethyl-biphenyl-2-yloxy)-butoxy]-2-methyl-phenyl}-propioni c acid Cesium carbonate (0.11 g, 0.33 mmol) is added to 5-ethyl-biphenyl-2-ol (0.04 g, 0.20 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]-propionic acid methyl ester (0.09 g, 0.26 mmol) in DMF (0.65 mL), and the mixture is stirred under N2 at 55 °C. After 16 h, the mixture is cooled to ambient temperature, filtered and washed solid with EtOAc. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: EtOAc (93: 7) provides 3- {4- [3- (5-ethyl-biphenyl-2-yloxy)-butoxy]-2-methyl-phenyl}-propioni c acid methyl ester (0.05 g, 0.11 mmol, 55%): ES+ (m/e) 464.3 (M+NH4) + ; Rf 0. 29 hexanes: EtOAc (80 : 20). Work up of the above propionic acid methyl ester (0.05 g, 0.11 mmol) in methanol (1 mL) as described in Example 20, Step D provides the title compound (0.04, 0.11 mmol, 100%): ES+ (m/e) 433.31 (M+H) +, 455.28 (M+Na) +.

Example 29 3- (4-{3-(S)-[4-ethyl-2-(1H-pyrrol-2-yl)-phenoxy]-butoxy}-2-met hyl-phenyl-propionic acid Step A 2-(5-Ethyl-2-methoxy-phenyl)-pyrlole-l-carboxilic acid ter-butyl ester Tetrakis (triphenyl phosphine) palladium (0) (54 mg, 0.05 mmol) is added to 2-bromo-4-ethyl-1-methoxy-benzene (0. 20 g, 0.93 mmol) in dimethoxyethane (3.5

mL) under N2 and the mixture is stirred. After 10 min, N-terbutoxycarbonyl-pyrrole-2- boronic acid (0.25 g, 1.20 mmol) and sodium carbonate (0.26 g, 2.42 mmol) in water (1.7 mL) are added. The mixture is warmed to 80 °C for 18 h. The mixture is cooled to room temperature, and then water is added and extracted with EtOAc. Organic phases are combined and washed with saturated aqueous sodium chloride. Organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (92: 8) provides the title compound as an oil (0.21 g, 0.69 mmol, 74%): ES+ (m/e) 202.23 (M-COOC (CH3) 3+2H) +. <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> 4-Ethyl-2- (1 H-pyrrol-2-yl)-phenol A 1.65 M solution of boron tribromide in DCM (0.63 mL, 1.0 mmol) is added to 2- (5-ethyl-2-methoxy-phenyl)-pyrrole-1-carboxilic acid tert-butyl ester (0.1 g, 0.35 mmol) in DCM (3 mL) under N2 at-78 °C, and the mixture is stirred. The mixture is warmed to 0 °C. After 2 h, water is added and extracted with DCM. Organic phases are combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (80: 20) provides the title compound (0.01 g, 0.06 mmol, 16%): ES+ (m/e) 188.00 (M+H) + ; Rf 0.30 hexanes: EtOAc (85: 15).

Step C <BR> <BR> 3- {3-(@-[4-Ethyl-2-(1 H-pyrrol-2-yl)-phenoxy]-butoxy}-2-methyl-phenyl-propionic acid Cesium carbonate (23 mg, 0.07 mmol) is added to 4-ethyl-2-(lH-pyrrol-2- yl) -phenol (11 mg, 0.06 mmol) and 3- [4- (3- ()-methanesulfonyloxy-butoxy)-phenyl]- propionic acid methyl ester (24 mg, 0.07 mmol) in DMF (0.5 mL), and the mixture is stirred under N2 at 55 °C. After 16 h, the mixture is cooled to ambient temperature, filtered and washed solid with EtOAc. The filtrate is washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under

reduce pressure. Purification by flash chromatography, silica, hexanes: EtOAc (95: 5) gives 3- (4- {3- ()- [4-Ethyl-2- (lH-pyrrol-2-yl)-phenoxy]-butoxy}-2-methyl-phenyl- propionic acid methyl ester (5 mg, 0.01 mmol, 19%): ES+ (m/e) 436.19 (M+H) + ; Ru 0. 43 hexanes: EtOAc (80: 20). Work up of the above propionic acid methyl ester (5 mg, 0.01 mmol) in methanol (0.5 mL) as described in Example 20, Step D provides the title compound (3 mg, 0. 01 mmol, 100%): ES+ (m/e) 422.2 (M+H) +.

Example 30 3-f 4- [3- ()- (4-Ethyl-2-thiophen-2-yl-phenoxy)-butoxy]-2-methyl-phenyl}-p ropionic acid Step A 2-Bromo-4-ethyl-phenol N-bromosuccinimide (1. 58 g, 8.92 mmol) is added to a solution of 4-ethyl phenol (1.0 g, 8.19 mmol) in ACN (35 mL), and the mixture is stirred under N2 at ambient temperature. After 24 h, the mixture is concentrated under reduced pressure and diluted with water. The mixture is extracted with EtOAc, and organic phases are washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (95: 5) yields title compound (1.01 g, 4.9 mmol, 61%): Rf 0.34 hexanes: EtOAc (90: 10), 1H NMR (400 MHz, CDC13) 7.28 (d, 1H, J= 2. 4 Hz), 7.03 (dd, 1H, Jl= 2.4 Hz, J2= 8.4 Hz), 6. 92 (d, 1H, J= 8. 4 Hz), 5.34 (s, 1H), 2.56 (q, 2H, J = 7.6 Hz), 1.20 (t, 3H, J= 7. 6 Hz).

Step B 4-Ethyl-2-thiophen-2-yl-phenol

Tetrakis (triphenyl phosphine) palladium (0) (57 mg, 0.05 mmol) is to 2- bromo-4-ethyl-phenol (0.20 g, 0.99 mmol) in dimethoxyethane (3.3 mL) under N2, and the mixture is stirred. After 10 min, 2-thiophene boronic acid (0.16 g, 1.29 mmol) and sodium carbonate (0.27 g, 2.57 mmol) in water (1.6 mL) are added. The mixture is warmed to 80°C for 18 h. The mixture is cooled to room temperature and then water is added and extracted with EtOAc. Organic phases are combined and washed with saturated aqueous sodium chloride. Organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (90: 10) provides the title compound as an oil (0.08 g, 0.39 mmol, 40%): Rif 0. 44 hexanes: EtOAc (90: 10), 1H NMR (400 MHz, CDCl3) 7.39 (dd, 1H, J= 1.6 Hz, J2= 5.4 Hz), 7. 28 (dd, 1H, J= 1.6, J2= 3.4 Hz), 7.23 (d, 1H, J= 2. 4 Hz), 7.14 (dd, 1H, J1= 3. 4, J2= 5.4 Hz, 7.07 (dd, 1H, J1= 2.4 Hz, J2= 8.4 Hz), 6.89 (d, 1H, J= 8. 4 Hz), 5.32 (s, 1H), 2.61 (q, 2H, J= 7. 6 Hz), 1.24 (t, 3H, J= 7. 6 Hz).

Step C 3-4- [3- (S- (4-Ethyl-2-thiophen-2-yl-phenoxy)-butoxy]-2-methyl-phenyl}-p ropionic acid Cesium carbonate (0.13 g, 0.40 mmol) is added to 4-ethyl-2-thiophen-2-yl- phenol (51 mg, 0.25 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]- propionic acid methyl ester (0.10, 0.30 mmol) in DMF (1.4 mL), and the mixture is stirred under N2 at 55 °C. After 16 h, the mixture is cooled to ambient temperature and filtered. The solids are washed with EtOAc. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: EtOAc (95: 5) provides 3-f 4- [3- (- (4-ethyl-2-thiophen-2-yl-phenoxy)-butoxy]- 2-methyl-phenyl}-propionic acid methyl ester (60 mg, 0.13 mmol, 53%): ES+ (m/e) 453.25 (M+H)+; Rf= 0.26 hexanes : EtOAc (95: 5). Work up of the above propionic acid

methyl. ester (60 mg, 0.13 mmol) in methanol (1.0 mL) as described in Example 20, Step D provides the title compound (57 mg, 0.13 mmol, 100%): ES+ (m/e) 439.35 (M+H) +.

Example 31 {4- [3- (6')- (4-Ethyl-2-thiazol-2-yl-phenoxy)-butoxy]-2-methyl-phenoxy}-p ropionicacid Step A 4-Ethyl-2-thiazol-2-yl-phenol Tetrakis (triphenyl phosphine) palladium (0) (25 mg, 0.02 mmol) is added to 2-bromo-thiazole (38 RL, 0.43 mmol) in dimethoxyethane (1.4 mL) under N2, and the mixture is stirred. After 10 min, 2-methoxy-5-ethylbenzeneboronic acid (0.10 g, 0.56 mmol) and sodium carbonate (0.12 g, 1.10 mmol) in water (0.7 mL) are added. The mixture is warmed to 95 °C for 18 h. The mixture is cooled to room temperature, and water is added and extract with EtOAc. Organic phases are combined and washed with saturated aqueous sodium chloride. Organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (93: 7) provides 2- (5-ethyl-2-methoxy-phenyl)-thiazole compound as an oil (0.07 g, 0. 30 mmol, 55%): ES+ (m/e) 220.25 (M+H) +, Rr 0. 30 hexanes: EtOAc (90: 10).

A 4.1 M solution of boron tribromide in DMF (0.15 mL, 0.60 mmol) is added to 2- (5-ethyl-2-methoxy-phenyl)-tliiazole (0.08 g, 0.30 mmol) in DCM (0.7 mL) under N2 at-78 °C, and the mixture is stirred. The mixture is warmed to 0 °C. After 3 h, water is added and extracted with DCM. Organic phases are combined, washed with

saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (98: 2) provides the title compound (0.02 g, 0.11 mmol, 37%): ES+ (m/e) 206.18 (M+H) + ; Rl= 0.51 hexanes: EtOAc (90: 10).

Step B<BR> {4- [3- (S)- (4-Etliyl-2-thiazol-2-yl-phenoxy)-butoxy]-2-methyl-phenoxy}- propionic acid Cesium carbonate (58 mg g, 0.18 mmol) is added to 4-ethyl-2-thiazol-2-yl- phenol (23 mg, 0.11 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]- propionic acid methyl ester (50 mg, 0.14 mmol) in DMF (0.7 mL), and the mixture is stirred under N2 at 55 °C. After 16 h, the mixture is cooled to ambient temperature, filtered and solid is washed with EtOAc. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: EtOAc (90: 10) gives 14- [3- (, S)- (4-ethyl-2-thiazol-2-yl-phenoxy)-butoxy]-2- methyl-phenoxy}-propionic acid methyl ester (37 mg, 0.08 mmol, 73%): ES+ (m/e) 454.40 (M+H) + ; Rr 0. 24 hexanes: EtOAc (80: 20). Work up of the above propionic acid methyl ester (37 mg, 0.08 mmol) in methanol (0.7 mL) as described in Example 20, Step D provides the title compound (35 mg, 0.08 mmol, 98%): ES+ (m/e) 440.34 (M+H) +.

Example 32 3- {4- [3- (S)- (4-Ethyl-2-thiazol-4-yl-phenoxy)-butoxy]-2-methyl-phenyl}-pr opionic acid Cesium carbonate (101 mg, 0.31 mmol) is added to 4-ethyl-2-thiazol-4-yl- phenol (40 mg, 0.19 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]- propionic acid methyl ester (87 mg, 0.25 mmol) in DMF (1.2 mL), and the mixture is stirred under N2 at 55 °C. After 24 h, the mixture is cooled to ambient temperature and filtered. The solid is with washed with ethyl acetate. The filtrate is washed with water

and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: ethyl acetate (91: 9) gives 3-14- [3- (S)- (4-Ethyl-2-thiazol-4-yl-phenoxy)-butoxy]- 2-methyl-phenyl}-propionic acid methyl ester (64 mg, 0.14 mmol, 73%): ES+ (m/e) 454.43 (M+H) + ; Ru 0. 33 hexanes: ethyl acetate (80: 20).

A 5 M aqueous solution of sodium hydroxide (0.42 mL, 2.11 mmol) is added to the above propionic acid methyl ester (64 mg, 0.14 mmol) in methanol (1.2 mL), and the mixture is stirred at ambient temperature for 9 h. The mixture is acidified to pH = 2 with a 1M HCl and extracted with ethyl acetate. Organic layers are combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford title compound (60 mg, 0.13 mmol, 98%): ES+ (m/e) 440.28 (M+H) +.

Example 33 3-14- [3- (S)- (4-Ethyl-2-furan-2-yl-phenoxy)-butoxy]-2-methyl-phenyll-prop ionic acid Cesium carbonate (110 mg, 0.34 mmol) is added to 4-ethyl-2-furan-2-yl- phenol (40 mg, 0.21 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]- propionic acid methyl ester (95 mg, 0.27 mmol) in DMF (1.2 mL), and the mixture is stirred under N2 at 55 °C. After 24 h, the mixture is cooled to ambient temperature and filtered. The solid is washed with ethyl acetate. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: ethyl acetate (90: 10) gives 3-14- [3- (S)- (4-Ethyl-2-furan-2-yl-phenoxy)-butoxy]- 2-methyl-phenyl}-propionic acid methyl ester (62 mg, 0.14 mmol, 66%): ES+ (m/e) 437.36 (M+H) + ; Rj-= 0.37 hexanes: ethyl acetate (80: 20).

A 5 M aqueous solution of sodium hydroxide (0.42 mL, 2.11 mmol) is added to 3-f 4- [3- (S)- (4-ethyl-2-furan-2-yl-phenoxy)-butoxy]-2-methyl-phenyll-prop ionic acid (62 mg, 0.14 mmol) in methanol (1.3 mL), and the mixture is stirred at ambient temperature for 9 h. The mixture is acidified to pH = 2 with a 1 M aqueous solution of HCl and extracted with ethyl acetate. Organic layers are combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated at reduced pressure to obtain title compound (60 mg, 0.13 mmol, 98%): ES+ (m/e) 423.33 (M+H) +.

Example 34 3-f 4- [3- (S)- (4-Ethyl-2-thiophen-3-yl-phenoxy)-butoxy]-2-methyl-phenyl}-p ropionic acid Step A 4-Ethyl-2-thiophen-3-yl-phenol Tetrakis (triphenyl phosphine) palladium (0) (28 mg, 0.02 mmol) is added to 2-bromo-4-ethyl-phenol (0.10 g, 0.49 mmol) in dimethoxyethane (1.6 mL) under N2 and the mixture is stirred. After 10 min, 3-thiophene boronic acid (0.08 g, 0.65 mmol) and sodium carbonate (0.14 g, 1.29 mmol) in water (0.8 mL) are added. The mixture is warmed to 80°C for 18 h. The mixture is cooled to room temperature, and water is added.

The mixture is extracted with EtOAc. Organic phases are combined and washed with saturated aqueous sodium chloride. Organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography,

silica, hexanes: EtOAc (90: 10) gives title compound as an oil (0.05 g, 0.21 mmol, 43%): Rj= 0.40 hexanes: EtOAc (90: 10), 1H NMR (400 MHz, CDC13) ; ES+ (m/e) 205.10 (M+H) +.

Step B 3- {4- [3- (S- (4-Ethyl-2-thiophen-3-yl-phenoxy)-butoxy]-2-methyl-phenyl}-p ropionic acid The compound of 3-f{4- [3- (S)- (4-Ethyl-2-thiophen-3-yl-phenoxy)-butoxy]- 2-methyl-phenyl}-propionic acid methyl ester (62 mg, 0.14 mmol, 64%) is prepared according to the procedure described in Example 31, Step B by using cesium carbonate (97 mg, 0.30 mmol), 4-ethyl-2-thiophen-3-yl-phenol (44 mg, 0.21 mmol) and 3- [4- (3- (S)- methanesulfonyloxy-butoxy)-phenyl]-propionic acid methyl ester (88 mg, 0.26 mmol) in DMF (1. 0 mL). ES+ (m/e) 437.36 (M+H) + ; Rf 0. 36 hexanes : EtOAc (90: 10). Work up of the above propionic acid methyl ester (62 mg, 0.14 mmol) in methanol (1.0 mL) provides the title compound (60 mg, 0.13 mmol, 98%): ES+ (m/e) 439.26 (M+H) +.

Example 35 3-{4-3-(S)-(4-Ethyl-2-oxazol-4-yl-phenoxy)-butoxy]-2-methyl- phenyl}-propionic acid Cesium carbonate (72 mg, 0.22 mmol) is added to 4-ethyl-2-oxazol-4-yl- phenol (30 mg, 0.16 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]- propionic acid methyl ester (65 mg, 0.19 mmol) in DMF (0.8 mL), and the mixture was stirred under N2 at 55 °C. After 24 h, the mixture is cooled to ambient temperature and filtered. The solid is washed with ethyl acetate. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: ethyl acetate (91: 9) gives 3-14-3- (S)- (4-ethyl-2-oxazol-4-yl-phenoxy)-butoxy]- 2-methyl-phenyl}-propionic acid methyl ester (38 mg, 0.87 mmol, 56%): ES+ (m/e) 438.30 (M+H) + ; /= 0.30 hexanes: ethyl acetate (80: 20).

A 5 M aqueous solution of sodium hydroxide (0.26 mL, 1.30 mmol) is added to the above propionic acid methyl ester (38 mg, 0. 87 mmol) in methanol (0.7 mL), and the mixture is stirred at ambient temperature for 9 h. The mixture is acidified to pH = 2 with a 1M aqueous solution of HCL and extracted with ethyl acetate. Organic layers are combined, washed with saturated wash with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated at reduced pressure to obtain title compound (34 mg, 0.82 mmol, 95%): ES+ (m/e) 424.27 (M+H) +.

Example 36 3-f 4- [3- (S)- (4-Ethyl-2-oxazol-2-yl-phenoxy)-butoxy]-2-methyl-phenyl}-pro pionic acid Cesium carbonate (39 mg, 0.12 mmol) is added to 4-ethyl-2-oxazol-2-yl- phenol (16 mg, 0.08 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]- propionic acid methyl ester (35 mg, 0.10 mmol) in DMF (0.7 mL), and the mixture is stirred under N2 at 55 °C. After 24 h, the mixture is cooled to ambient temperature and filtered. The solid is washed with ethyl acetate. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes : ethyl acetate (80: 20) gives 3-14- [3- (, S)- (4-ethyl-2-oxazol-2-yl-phenoxy)- butoxy]-2-methyl-phenyl}-propionic acid methyl ester (14 mg, 0.03 mmol, 37%) : ES+ (m/e) 438.35 (M+H) + ; Rr 0. 23 hexanes : ethyl acetate (70: 30).

A 5 M aqueous solution of sodium hydroxide (0.13 mL, 0.63 mmol) is added to the above propionic acid methyl ester (13 mg, 0.03 mmol) in methanol (0.3 mL) and the mixture is stirred at ambient temperature for 9 h. The mixture is acidified to pH = 2 with a 1M aqueous solution of hydrochloric acid and extracted with ethyl acetate.

Organic layers are combined, washed with saturated aqueous sodium chloride, dried over

magnesium sulfate, filtered and concentrated at reduced pressure to obtain title compound (10 mg, 0.02 mmol, 95%): ES+ (m/e) 424.31 (M+H) +.

Example 37 3-t4- [3- (S)- (4-Chloro-2-thiazol-4-yl-phenoxy)-butoxy]-2-methyl-phenyll-p ropionic acid

Cesium carbonate (107 mg, 0.33 mmol) is added to 4-chloro-2-thiazol-4- yl-phenol (50 mg, 0.24 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]- propionic acid methyl ester (97 mg, 0.28 mmol) in DMF (0.8 mL), and the mixture is stirred under N2 at 55 °C. After 24 h, a 5 M aqueous solution of NaOH (1 mL) is added, and the mixture is cooled to ambient temperature for 5 h. The mixture is acidified to pH = 2 with a 1M HC1 and extracted with EtOAc. Organic layers are combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtrated and concentrated at reduced pressure. Oil is purified in HTC to obtain title compound (43 mg, 0.96 mmol, 41%): ES (m/e) 445.90 (M+H) +.

Example 38 3- {4- [3- (S)- (4-Ethyl-2-pyridin-2-yl-phenoxy)-butoxy]-2-methyl-phenyl}-pr opionic acid

Cesium carbonate (115 mg, 0. 35 mmol) is added to 4-ethyl-2-pyridin-2-yl- phenol (50 mg, 0.25 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]- propionic acid methyl ester (103 mg, 0.30 mmol) in DMF (0.7 mL), and the mixture is stirred under N2 at 55 °C. After 24 h, the mixture is cooled to ambient temperature and

filtered. The solid is washed with ethyl acetate. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: ethyl acetate (87: 13) gives 3-14- [3- (S)- (4-ethyl-2-pyridin-2-yl-phenoxy)- butoxy]-2-methyl-phenyl}-propionic acid methyl ester (64 mg, 0.14 mmol, 67%): ES+ (m/e) 448.56 (M+H) + ; Ru 0. 20 hexanes: ethyl acetate (80: 20).

A 5 M aqueous solution of sodium hydroxide (0.43 mL, 2.14 mmol) is added to the above propionic acid methyl ester (64 mg, 0.14 mmol) in methanol (1. 1 mL), and the mixture is stirred at ambient temperature for 9 h. The mixture is neutralized to pH = 7 with a 1 M HCl and extracted with ethyl acetate. Organic layers are combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated at reduced pressure to obtain title compound (60 mg, 0.13 mmol, 95%): ES+ (m/e) 434.45 (M+H) +.

Example 39 3-f 4- [3- ()- (4-Ethyl-2-pyridin-3-yl-phenoxy)-butoxy]-2-methyl-phenyl}-pr opionic acid Step A 4-Ethyl-2-pyridin-3-yl-phenol Tetrakis (triphenylphosphine) palladium (0) (57 mg, 0.05 mmol) is added to 2-bromo-4-ethyl-phenol (0.20 g, 0.99 mmol) in dimethoxyethane (3.3 mL) under N2, and the mixture is stirred. After 10 min, pyridin-3-yl-boronic acid (0.16 g, 1.29 mmol) and

sodium carbonate (0.27 g, 2.59 mmol) in water (1.6 mL) are added. The mixture is warmed to 80°C for 18 h. The mixture is cooled to room temperature, and water is added and then extracted with EtOAc. Organic phase is combined and washed with saturated aqueous sodium chloride. Organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (70: 30) gives title compound as an oil Rf 0. 20 hexanes: EtOAc (50: 50); ES+ (m/e) 200.19 (M+H) +.

Step B 3-f 4- [3- (S)- (4-Ethyl-2-pyridin-3-yl-phenoxy)-butoxy]-2-methyl-phenyl}-pr opionic acid The compound of 3-f4- [3- (S)- (4-ethyl-2-pyridin-3-yl-phenoxy)-butoxy]-2- methyl-phenyl}-propionic acid methyl ester (45 mg, 0.10 mmol, 62%) is prepared according to the procedure described in Example 31, Step B by using cesium carbonate (75 mg, 0.23 mmol), 4-ethyl-2-pyridin-3-yl-phenol (33 mg, 0.16 mmol) and 3- [4- (3- (S)- metlianesulfonyloxy-butoxy)-phenyl]-propionic acid methyl ester (103 mg, 0.30 mmol) in DMF (0.7 mL). ES+ (m/e) 448. 48 (M+H) + ; Rn 0. 15 hexanes: EtOAc (70: 30). Work up of the above propionic acid methyl ester (45 mg, 0.10 mmol) in methanol (0.9 mL) as described in Example 26, Step E provides the title compound (62 mg, 0.09 mmol, 95%): ES+ (m/e) 434.40 (M+H) +.

Example 40 3- {4- [3- (S)- (4-Ethyl-2-pyridin-4-yl-phenoxy]-2-methyl-phenyl}-propionic acid Cesium carbonate (68 mg, 0.21 mmol) is added to 4-ethyl-2-pyridin-4-yl- phenol (30 mg, 0.15 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]- propionic acid methyl ester (62 mg, 0. 28 mmol) in DMF (0.5 mL), and the mixture is stirred under N2 at 55 °C. After 24 h, a 5 M aqueous solution of sodium hydroxide (1 mL) is added, and the mixture is cooled to ambient temperature for 5 h. The mixture is

neutralized to pH = 7 with a 1 M HCl and extracted with ethyl acetate. Organic layers are combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated at reduced pressure. Oil was purified in HTC to obtain title compound (17 mg, 0.04 mmol, 26%): ES+ (m/e) 434.3 (M+H) +.

Example 41 3- {4- [3- (S)- (4-Chloro-2-pyridin-2-yl-phenoxy)-butoxy]-2-methyl-phenyl}-p ropionic acid Cesium carbonate (720 mg, 2.21 mmol) is added to 4-chloro-2-pyridin-2- yl-phenol (350 mg, 1.70 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]- propionic acid methyl ester (702 mg, 2.04 mmol) in DMF (5.8 mL), and the mixture is stirred under N2 at 55 °C. After 24 h, the mixture is cooled to ambient temperature and filtered. The solid is washed with ethyl acetate. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes : ethyl acetate (85: 15) gives 3-14- [3- (S)- (4-Chloro-2-pyridin-2-yl-phenoxy)- butoxy]-2-methyl-phenyl}-propionic acid methyl ester (440 mg, 0.97 mmol, 57%): ES+ (m/e) 454.13 (M+H) + ; Rf 0. 35 hexanes: ethyl acetate (80: 20).

A 5 M aqueous solution of sodium hydroxide (2.91 mL, 14 mmol) is added to the above propionic acid methyl ester (440 mg, 0.97 mmol) in methanol (7.0 mL), and the mixture is stirred at ambient temperature for 3 h. The mixture is neutralized to pH = 7 with a 1 M HCl and extract with ethyl acetate. Organic layers are combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated at reduced pressure to obtain title compound (62 mg, 0.09 mmol, 95%): ES+ (m/e) 434.40 (M+H) +.

Example 42 3-f 4- [3- (2-Benzoyl-4-methoxy-phenoxy)-butoxy]-2-methyl-phenyl}-propi onic acid

Cesium carbonate (58 mg, 0.18 mmol) is added to (2-hydroxy-5-methoxy- phenyl)-phenyl-methanone (30 mg, 0.13 mmol) and 3- [4- (3- (6)-methanesulfbnyloxy- butoxy) -phenyl] -propionic acid methyl ester (54 mg, 0.16 mmol) in DMF (l. OmL), and the mixture is stirred under N2 at 55 °C. After 24 h, a 5 M aqueous solution of sodium hydroxide (1 mL) is added and the mixture is cooled to ambient temperature in 5 h. The mixture is acidified to pH = 2 with HCl (1M) and extracted with EtOAc. Organic layers are combined and washed with saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtrated and concentrated at reduced pressure. Oil is purified in HTC to obtain the title compound: ES+ (m/e) 463.3 (M+H) +.

Example 43 3-14- [3- (S)- (2-Benzoyl-4-fluoro-phyenoxy)-butoxy]-2-methyl-phenyll-propi onic acid The title compound is prepared according to the procedure described in Example 42 using cesium carbonate (63 mg, 0.19 mmol), (5-fluoro-2-hydroxy-phenyl)- phenyl) -phenyl-methanone (30 mg, 0.16 mmol) and 3- [4- (3- ()-methanesulfonyloxy- butoxy) -phenyl] -propionic acid methyl ester (57 mg, 0.16 mmol). ES+ (m/e) 451.3 (M+H) +.

Example 44 3- {4- [3- (S)- (4-Isopropyl-2-phenoxy-phenoxy)-butoxy]-2-methyl-phenyl}-pro pionic acid

Step A<BR> <BR> 4-Isopropyl-2-phenoxy-phenol Cesium carbonate (4.3 g, 13.3 mmol) is added to phenol (1.05 g, 13.3 mmol) and 2-bromo-4-isopropyl-1-methoxy-benzene (lg, 4. 3 mmol) in 1-methyl-2- pyrrolidinone (15 mL). After 5 min. , cupper chloride (I) (0. 33 g, 3.3 mmol) and 2,2, 6,6- tetramethyl-heptane-3,5-dione (0.30 g, 1.7 mmol) are added and the mixture is stirred at 120 °C under N2. After 24 h, the mixture is cooled to ambient temperature and filtered and the solids are washed with EtOAc. Organic phase is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (95: 5) provides 4-isopropyl-l-methoxy-2-phenoxy-benzene (1.0 g, 4.0 mmol, 94%): ES+ (m/e) 243.09 (M+H) +. A 4 M solution of boron tribromide (2.0 mL, 8.0 mmol) is added to 4-isopropyl-l-methoxy-2-phenoxy-benzene (1.0 g, 4.0 mmol) in DCM (4 mL) at-78 °C under N2. The mixture is warmed to-5 °C, and after 2h, the mixture is cooled to 0 °C and diluted with water. Aqueous phase is extracted with additional DCM. Organic phase is washed with saturated aqueous sodium chloride, dried

over magnesium sulfate, and concentrated. Purification by silica flash chromatography hexanes: EtOAc (95: 5) provided the title compound (0.7 g, 3.3 mmol, 82%): ES+ (m/e) 227.02 (M-H)-, Rif 0. 53 hexanes: EtOAc (90: 10).

Step B 3- {4- [3- (S)- (4-Isopropyl-2-phenoxy-phenoxy)-butoxy]-2-methyl-phenyl}-pro pionic acid The compound of 3-f4- [3- (S)- (4-isopropyl-2-phenoxy-phenoxy)-butoxy]- 2-methyl-phenyl}-propionic acid methyl ester (67 mg, 0.14 mmol, 73%) is prepared according to the procedure described in Example 31, Step B by using cesium carbonate (130 mg, 0.40 mmol), 4-isopropyl-2-phenoxy-phenol (44 mg, 0.19 mmol) and 3- [4- (3- ()-methanesulfonyloxy-butoxy)-phenyl]-propionic acid methyl ester (86 mg, 0.25 mmol) in DMF (0.7 mL). ES+ (m/e) 499.36 (M+Na) + ; Rf 0. 51 hexanes: EtOAc (80: 20). Work up of the above propionic acid methyl ester (67 mg, 0.14 mmol) in methanol (1.1 mL) as described in Example 20, Step D provides the title compound (63 mg, 0.13 mmol, 95%) : ES+ (m/e) 463.31 (M+H) +.

Example 45 {4- [3- (- (4-Isopropyl-2-phenoxy-phenoxy)-butoxy]-2-methyl-phenylsulfa nyl}-acetic acid The compound of {4- [3- ()- (4-isopropyl-2-phenoxy-phenoxy)-butoxy]-2- methyl-phenylsulfanyl}-acetic acid ethyl ester (0.39 g, 0.77 mmol, 70%) is prepared according to the procedure described in Example 31, Step B by using cesium carbonate (0.57 g, 1.74 mmol), 4-isopropyl-2-phenoxy-phenol (0.25 g, 1.09 mmol) and [4- (3- (S)- methanesulfonyloxy-butoxy) -2-methyl-phenylsulfanyl] acetic acid ethyl ester (0.53 g, 1.40 mmol) in DMF (7.0 mL). ES+ (m/e) 531.30 (M+Na) + ; Rf 0. 27 hexanes : EtOAc

(80 : 20). Work up of the above acetic acid ethyl ester (0.39 g, 0.77 mmol) in ethanol (6.0 mL) as described in Example 20, Step D provides the title compound as a colorless oil (0.37 g, 0.77 mmol, 99%): ES+ (m/e) 503.29 (M+Na) +.

Example 46 3- {4- [3- (6)- (5-Chloro-3-phenoxy-pyridin-2-yloxy)-butoxy]-2-methyl-phenyl }-propionic acid Step A 5-Chloro-3-phenoxy-pyridin-2-ol Cesium carbonate (8.1 g, 25 mmol) is added to phenol (2.35 g, 25 mmol) and 3-bromo-5-chloro-2-methoxy-pyridine (2.8 g, 12 mmol) in 1-methyl-2-pyrrolidinone (27 mL). After 5 min, cupper chloride (I) (0.62 g, 6.2 mmol) and 2,2, 6,6-tetramethyl- heptane-3,5-dione (0.58 g, 3.1 mmol) are added and the mixture is stirred at 120 °C under N2. After 24 h, the mixture is cooled to ambient temperature and filtered, and the solids are washed with EtOAc. Organic solution is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, silica, hexanes: EtOAc (95: 5) provides 5-chloro-2-methoxy-3-phenoxy-pyridine (3 g, 12 mmol, 99%): ES+ (m/e) 235.98 (M+H) + ; Rr 0. 45 hexanes: EtOAc (90: 10). HBr 48% (8 mL) is added to 5-chloro-2-

methoxy-3-phenoxy-pyridine (3 g, 12 mmol) in acetic acid (20 mL), and the mixture is stirred at 105 °C for 10 min. The mixture is cooled to room temperature and neutralized to pH = 7 with a 5 M aqueous solution of sodium hydroxide, and then extracted with EtOAc. Organic layers are combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain title compound as a colorless oil (0.37 g, 0.77 mmol, 99%): ES+ (m/e) 222.07 (M+H) + ; IH NMR (400 MHz, CDC13) 7.39-7. 43 (m, 2H), 7.22-7. 26 (m, 2H), 7.09-7. 10 (d, 2H, J=8 Hz), 6. 80 (s, 1H). <BR> <BR> <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3- 4- [3- (S)- (5-Chloro-3-phenoxy-pyridin-2-yloxy)-butoxy]-2-methyl-phenyl }-propionic acid Potassium carbonate (131 mg, 0.94 mmol) is added to 5-chloro-3- phenoxy-pyridin-2-ol (150 mg, 0.68 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)- phenyl] -propionic acid methyl ester (279 mg, 0.81 mmol) in DMF (2.5 mL), and the mixture is stirred under N2 at 55 °C. After 20 h, the mixture is cooled to ambient temperature and filtered and washed solid with EtOAc. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: EtOAc (95: 5) gives 3- {4- [3- (S)- (5-chloro-3-phenoxy-pyridin-2-yloxy)-butoxy]- 2-methyl-phenyl}-propionic acid methyl ester (100 mg, 0.21 mmol, 31%) : ES+ (m/e) 470.27 (M+H) + ; Rj= 0.48 hexanes: EtOAc (80: 20). Work up of the above propionic acid methyl ester (100 mg, 0.21 mmol) in methanol (1.5 mL) as described in Example 26, Step D provides the title compound (98 mg, 0.21 mmol, 95%): ES+ (m/e) 456.28 (M+H) +.

Example 47 <BR> <BR> f4- [3- (S)- (5-Chloro-3-phenoxy-pyridin-2-yloxy)-butoxy]-2-methyl-phenyl sulfanyll- acetic acid

The compound of f4- [3- (S)- (5-chloro-3-phenoxy-pyridin-2-yloxy)- butoxy]-2-methyl-phenylsulfanyl}-acetic acid ethyl ester (0.10 g, 0.19 mmol, 32%) is prepared according to the procedure described in Example 46, Step B by using cesium carbonate (0.31 g, 0.96 mmol), 5-chloro-3-phenoxy-pyridin-2-ol (0.13 g, 0.60 mmol) and [4-(3-(@-methanesulfonyloxy-butoxy)-2-methyl-phenylSulfanyl] acetic acid ethyl ester (0.29 g, 0.78 mmol) in DMF (3.0 mL). ES+ (m/e) 502.32 (M+H) + ; Ru 0. 51 hexanes: EtOAc (80: 20).

Add a 5 M aqueous solution of sodium hydroxide (0.57 mL, 0.29 mmol) to the above acetic acid ethyl ester (0.10 g, 0.19 mmol) in ethanol (1.2 mL), and the mixture is stirred at ambient temperature for 8 h. The mixture is neutralized to pH = 7 with a 1M HC1 and then extracted with EtOAc. Organic layers are combined and washed with saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain title compound as a colorless oil (0.09 g, 0.18 mmol, 95%): ES+ (m/e) 474.20 (M+H) +.

Example 48 <BR> <BR> 3-f4- [3- (S)- (5-Chloro-3-phenoxy-pyridin-2-yloxy)-butoxy]-2-ethyl-phenyll -propionic acid

The compound of 3- {4- [3- (S)- (5-Chloro-3-phenoxy-pyridin-2-yloxy)- butoxy]-2-ethyl-phenyl}-propionic acid ethyl ester (0.18 g, 0. 35 mmol, 52%) is prepared according to the procedure described in Example 46, Step B by using cesium carbonate (0.29 g, 0.88 mmol), 5-chloro-3-phenoxy-pyridin-2-ol (0.15 g, 0.67 mmol) and 3- [2- ethyl-4-3- (S)-methanesulfonyloxy-butoxy)-phenyl]-propionic acid ethyl ester (0.30 g, 0.81 mmol) in DMF (2.6 mL). ES+ (m/e) 520.11 (M+Na) + ; Rf 0. 56 hexanes : EtOAc (80: 20). Work up of the above propionic acid ethyl ester (0.17 g, 0.35 mmol) in ethanol (2.5 mL) as described in Example 47 provides the title compound as a colorless oil (0.16 g, 0.34 mmol, 95%): ES+ (m/e) 492.06 (M+Na) +.

Example 49 <BR> <BR> 3- {4- [3- (S- (3-Benzoyl-5-chloro-pyridin-2-yloxy)-butoxy]-2-methyl-phenyl }-propionic acid

Step A (5-Chloro-2-hydroxy-pyridin-3-yl)-phenyl-methanone A 1.4 M solution of sec-BuLi in cyclohexane (1. 1 mL, 1.5 mmol) is added dropwise for 20 min to 5-chloro-2-methoxy-pyridine (200 mg, 1.4 mmol) in THF (2.5 mL) at-78 °C under N2. After stirring for 45 min., N-methoxy-N-methyl-benzamide (0.29 mL, 1.9 mmol) is added dropwise. After 1 h, a 1M solution of aqueous HCl (1 mL) is added, and the mixture is warmed to room temperature. The mixture is diluted with water and extracted with EtOAc. Organic phases are combined and washed with saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain an oil. Purification by flash chromatography, silica, hexanes: EtOAc (96: 4) provides (5-chloro-2-methoxy-pyridin-3- <BR> yl) -phenyl-methanone: ES+ (m/e) 247.92 (M+H) +, Rj= 0.35 hexanes: EtOAc (90: 10). A 5.1 M solution of boron tribromide in DCM (0.15 mL, 0.81 mmol) is added dropwise to (5-chloro-2-methoxy-pyridin-3-yl) -phenyl-methanone (0.10 g, 0.40 mmol) in DCM (3 mL) at-78 °C, and the mixture is stirred. The mixture is warmed slowly to ambient

temperature, and after 8 h, the mixture is cooled to 0 °C and water is added carefully. The mixture is extracted with EtOAc. Organic phases are combined and washed with saturated aqueous sodium chloride, and then dried over magnesium sulfate and concentrated under reduced pressure to obtain title compound as a yellow solid (0.09 g, 0.38 mmol, 98%). ES+ (m/e) 232 (M) +.

Step B<BR> 3-f{4- [3- ()- (3-Benzoyl-5-chloro-pyridin-2-yloxy)-butoxy]-2-methyl-phenyl }-propionic acid The compound of 3-{4-[3-(S)-(3-Benzoyl-5-chloro-pyridin-2-yloxy)- butoxy]-2-methyl-phenyl}-propionic acid methyl ester (48 mg, 0.10 mmol, 50%) is prepared according to the procedure described in Example 46, Step B by using cesium carbonate (104 mg, 0.32 mmol), (5-chloro-2-hydroxy-pyridin-3-yl)-phenyl-methanone (47 mg, 0.20 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]-propionic acid methyl ester (89 mg, 0.26 mmol) in DMF (1.5 mL). ES+ (m/e) 504.17 (M+Na) + ; Rm 0.46 hexanes: EtOAc (80: 20). Work up of the above propionic acid methyl ester (47 mg, 0.10 mmol) in methanol (1.0 mL) as described in Example 47 provides the title compound (45 mg, 0.09 mmol, 95%): ES+ (m/e) 468.24 (M+H) +.

Example 50 {4- [3- (tS)- (3-Benzoyl-4-chloro-pyridin-2-yloxy)-butoxy]-2-methyl-phenyl sulianyl}-acetic acid The compound of f4- [3- (, S)- (3-benzoyl-4-chloro-pyridin-2-yloxy)- butoxy]-2-methyl-phenylsulfanyl}-acetic acid ethyl ester (43 mg, 0.08 mmol, 39%) is prepared according to the procedure described in Example 46, Step B by using cesium

carbonate (0.11 g, 0.34 mmol), (5-chloro-2-hydroxy-pyridin-3-yl)-phenyl-methanone (0.05 g, 0.21 mmol) and [4-(3-(2-methanesulfonyloxy-butoxy)-2-methyl- phenylsulfanyl] acetic acid ethyl ester (0.10 g, 0.27 mmol) in DMF (1.4 mL). ES+ (m/e) 514.17 (M+H) + ; Rf 0. 39 hexanes: EtOAc (80: 20). Work up of the above acetic acid ethyl ester (43 mg, 0.08 mmol) in ethanol (1.0 mL) as described in Example 47 provides the title compound as a colorless oil (40 mg, 0.07 mmol, 95%). ES+ (m/e) 486.20 (M+H) +.

Example 51 3- {4- [3- (S)- (3-Benzoyl-5-trifluoromethyl-pyridin-2-yloxy)-butoxy]-2-meth yl-phenyl}- propionic acid Cesium carbonate (114 mg, 0.35 mmol) is added to (2-hydroxy-5- trifluoromethyl-pyridin-3-yl) -phenyl-methanone (67 mg, 0.25 mmol) and 3- [4- (3- (, S)- methanesulfonyloxy-butoxy) -phenyl] -propionic acid methyl ester (105 mg, 0.30 mmol) in DMF (1.2 mL), and the mixture is stirred under N2 at 55 °C. After 24 h, the mixture is cooled to ambient temperature, filtered and washed solid with ethyl acetate. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: ethyl acetate (95: 5) gives 3-f4- [3- (S)- (3-benzoyl-5- trifluoromethyl-pyridin-2-yloxy)-butoxy]-2-methyl-phenyl}-pr opionic acid methyl ester (37 mg, 0.07 mmol, 30%): ES+ (m/e) 516.29 (M+H) + ; Rf 0.21 hexanes: ethyl acetate (90: 10).

A 5 M aqueous solution of sodium hydroxide (0.22 mL, 1. 1 mmol) is added to the above propionic acid methyl ester (37 mg, 0.07 mmol) in methanol (0.6 mL), and the mixture is stirred at ambient temperature for 4 h. The mixture is neutralized to pH = 7 with a 1 M HC1 and extracted with ethyl acetate. Organic layers are combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated at reduced pressure to obtain title compound (35 mg, 0.06 mmol, 95%): ES+ (m/e) 502.13 (M+H) +.

Example 52 {4- [3- (S)- (3-Benzoyl-5-trifluoromethyl-pyridin-2-yloxy)-butoxy]-2-meth yl- phenylsulfanyl}-acetic acid The compound of {4- [3- (S)- (3-benzoyl-5-trifluoromethyl-pyridin-2- yloxy)-butoxy]-2-methyl-phenylsulfanyl}-acetic acid ethyl ester (10 mg, 0.02 mmol, 12%) is prepared according to the procedure described in Example 46, Step B by using cesium carbonate (72 mg, 0.22 mmol), (2-hydroxy-5-trifluoromethyl-pyridin-3-yl)- phenyl-methanone (40 mg, 0.15 mmol) and [4- (3- (S)-methanesulfonyloxy-butoxy)-2- methyl-phenylsulfanyl] acetic acid ethyl ester (67 mg, 0.18 mmol) in DMF (0.7 mL). ES+ (m/e) 548.25 (M+H) + ; Rf 0.36 hexanes: EtOAc (90: 10). Work up of the above acetic acid ethyl ester (10 mg, 0.02 mmol) in ethanol (0.5 mL) as described in Example 47 provides the title compound as a colorless oil (9 mg, 0.02 mmol, 95%). ES+ (m/e) 520. 08 (M+Na) +.

Example 53 <BR> <BR> 3- 2-Methyl-4- [3- (S)- (3-phenoxy-5-trifluoromethyl-pyridin-2-yloxy)-butoxy]-phenyl }- propionic acid

Cesium carbonate (83 mg, 0.25 mmol) is added to 3-phenoxy-5- trifluoromethyl-pyridin-2-ol (50 mg, 0.20 mmol) and 3- [4- (3- (S)-methanesulfonyloxy- butoxy) -phenyl] -propionic acid methyl ester (87 mg, 0.25 mmol) in DMF (0.9 mL), and the mixture is stirred under N2 at 55 °C. After 18 h, the mixture is cooled to ambient temperature, filtered and washed solid with ethyl acetate. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes : ethyl acetate (93: 7) gives 3- {2-methyl-4- [3- (tS)- (3-phenoxy-5- trifluoromethyl-pyridin-2-yloxy)-butoxy]-phenyl}-propionic acid methyl ester (26 mg, 0.05 mmol, 27%): ES+ (m/e) 526.27 (M+Na) + ; R 0. 56 hexanes: ethyl acetate (80: 20).

A 5 M aqueous solution of sodium hydroxide (0.30 mL, 1.5 mmol) is added to the above propionic acid methyl ester (50 mg, 0.10 mmol) in methanol (0.8 mL), and the mixture is stirred at ambient temperature for 4 h. The mixture is neutralized to pH = 7 with a 1 M HCl and extracted with ethyl acetate. Organic layers are combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated at reduced pressure to obtain title compound (47 mg, 0.08 mmol, 95%): ES+ (m/e) 512.23 (M+Na) +.

Example 54 <BR> <BR> f2-Methyl-4- [3- (S)- (3-phenoxy-5-trifluoromethyl-pyridin-2-yloxy)-butoxy]- phenylsulfanyl}-acetic acid

The compound of f2-Methyl-4- [3- (S)- (3-phenoxy-5-trifluoromethyl- pyridin-2-yloxy)-butoxy]-phenylsulfanyl}-acetic acid ethyl ester (33 mg, 0.06 mmol, 30%) is prepared according to the procedure described in Example 46, Step B by using cesium carbonate (81 mg, 0.25 mmol), 3-phenoxy-5-trifluoromethyl-pyridin-2-ol (53 mg, 0.21 mmol) and [4- (3- (S)-methanesulfonyloxy-butoxy)-2-methyl-phenylsulfanyl] acetic acid ethyl ester (93 mg, 0.25 mmol) in DMF (1.0 mL). ES+ (m/e) 558.22 (M+Na) + ; Rm 0.61 hexanes : EtOAc (80: 20). Work up of the above acetic acid ethyl ester (33 mg, 0.06 mmol) in ethanol (0.6 mL) as described in Example 47 provides the title compound as a colorless oil (30 mg, 0.06 mmol, 95%). ES+ (m/e) 530.26 (M+Na)+.

Example 55 <BR> <BR> 3- {2-Ethyl-4- [3- (- (3-phenoxy-5-trifluoromethyl-pyridin-2-yloxy)-butoxy]-phenyl }- propionic acid

The compound of 3- {2-ethyl-4- [3- (S)- (3-phenoxy-5-trifluoromethyl- pyridin-2-yloxy)-butoxy]-phenyl}-propionic acid ethyl ester (0.07 g, 0.14 mmol, 22%) is prepared according to the procedure described in Example 46, Step B by using potassium carbonate (0.11 g, 0.81 mmol), 3-phenoxy-5-trifluoromethyl-pyridin-2-ol (0.16 g, 0.63 mmol) and 3-[2-ethyl-4-3-(S)-methanesulfonyloxy-butoxy)-phenyl]-propio nic acid ethyl ester (0.27 g, 0.75 mmol) in DMF (4 mL). ES+ (m/e) 543.1 (M+Na) + ; Ru 0. 44 hexanes: EtOAc (80: 20). Work up of the above propionic acid ethyl ester (0.07 g, 0.14 mmol) in ethanol (1.0 mL) as described in Example 47 provides the title compound as a colorless oil (0.06 g, 0.12 mmol, 95%). ES+ (m/e) 526.11 (M+Na) +.

Example 56 <BR> <BR> 3- {2-Methyl-4- [3- ()- (6-methyl-2-phenoxy-pyridin-3-yloxy)-butoxy]-phenyl}-propion ic acid

Cesium carbonate (227 mg, 0.49 mmol) is added to 6-methyl-2-phenoxy- pyridin-3-ol (100 mg, 0.20 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)-phenyl]- propionic acid methyl ester (205 mg, 0.59 mmol) in DMF (2.4 mL), and the mixture is stirred under N2 at 55 °C. After 24 h, the mixture is cooled to ambient temperature and filtered. The solid is washed with ethyl acetate. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: ethyl acetate (84: 16) gives 3- {2-methyl-4- [3- (- (6-methyl-2-phenoxy-pyridin- 3-yloxy)-butoxy]-phenyl}-propionic acid methyl ester (11 mg, 0.24 mmol, 48%): ES+ (m/e) 450.40 (M+H) + ; 0. 0. 31 hexanes : ethyl acetate (80: 20).

A 5 M aqueous solution of sodium hydroxide (0.72 mL, 3.6 mmol) is added to the above propionic acid methyl ester (100 mg, 0.240 mmol) in methanol (0.8 mL), and the mixture is stirred at ambient temperature for 4 h. The mixture is neutralized to pH = 7 with a 1 M HC1 and extracted with ethyl acetate. Organic layers are combined and washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrate at reduced pressure to obtain title compound (47 mg, 0.08 mmol, 95%): ES+ (m/e) 436.48 (M+H) +.

Example 57 <BR> <BR> 3-f4- [3- (S)- (3-Benzoyl-5-ethyl-pyridin-2-yloxy)-propoxy]-2-methyl-phenyl l-propionic acid

The compound of 3-14- [3- (S)- (3-benzoyl-5-ethyl-pyridin-2-yloxy)- propoxy]-2-methyl-phenyl}-propionic acid methyl ester (40 mg, 0.09 mmol, 56%) is prepared according to the procedure described in Example 46, Step B by using cesium carbonate (80 mg, 0.25 mmol), (5-ethyl-2-hydroxy-pyridin-3-yl)-phenyl-methanone (35 mg, 0.15 mmol) and 3- [4- (3-methanesulfonyloxy-propoxy)-2-methyl-phenyl]-propionic acid methyl ester (66 mg, 0.20 mmol) in DMF (0.9 mL). ES+ (m/e) 462.15 (M+H) + ; Rr 0.27 hexanes: EtOAc (80: 20). Work up of the above propionic acid methyl ester (40 mg, 0.09 mmol) in methanol (1.5 mL) as described in Example 47 provides the title compound (38 mg, 0.08 mmol, 95%). ES+ (m/e) 448.24 (M+H) +.

Example 58 <BR> <BR> 3- {2-Methyl-4- [3-(S)- (3-phenoxy-5-trifluoromethyl-pyridin-2-yloxy)-propoxy]-pheny l}- propionic acid

Cesium carbonate (46 mg, 0.14 mmol) is added to 3-phenoxy-5- trifluoromethyl-pyridin-2-ol (21 mg, 0. 08 mmol) and 3- [4- (3-methanesulfonyloxy- propoxy)-2-methyl-phenyl]-propionic acid methyl ester methyl ester (33 mg, 0.10 mmol) in DMF (0.5 mL), and the mixture is stirred under N2 at 55 °C. After 24 h, a 5 M aqueous solution of sodium hydroxide (1 mL) is added and the mixture is cooled to ambient temperature for 5 h. The mixture is neutralized to pH = 7 with a 1 M HCl and extracted with EtOAc. Organic layers are combined and washed with saturated aqueous sodium chloride and then dried over magnesium sulfate, filtrated and concentrated at reduced pressure. Oil is purified in HTC to obtain title compound as trifluoroacetate salt. ES+ (m/e) 476.1 (M+H) +.

Example 59 <BR> <BR> 3- {4- [3- (S)- (5-Chloro-3-phenoxy-pyridin-2-yloxy)-propoxy]-2-methyl-pheny l}-propionic acid

The title compound is prepared according to the procedure described in Example 58 by using cesium carbonate (34 mg, 0.14 mmol), 5-chloro-3-phenoxy-pyridin- 2-ol (21 mg, 0.10 mmol) and 3- [4- (3-methanesulfonyloxy-propoxy)-2-methyl-phenyl]- propionic acid methyl ester methyl ester (30 mg, 0.09 mmol) in DMF (0.5 mL). ES+ (m/e) 442.0 (M+H) +.

Example 60 3-f2-Methyl-4- [3- (S)- (5-trifluoromethyl- [3, 3'] bipyridinyl-2-yloxy)-butoxy]-phenyl}- propionic acid Cesium carbonate (38 mg, 0.11 mmol) is added to 5-trifluoromethyl- [3, 3'] bipyridinyl-2-ol (22 mg, 0.09 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)- phenyl] -propionic acid methyl ester (38 mg, 0.11 mmol) in DMF (0. 7 mL), and the mixture is stirred under N2 at 55 °C. After 18 h, the mixture is cooled to ambient temperature and filtered. The solid is washed with ethyl acetate. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium

sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: ethyl acetate (70: 30) gives 3-12-methyl-4- [3- (S)- (5- trifluoromethyl- [3, 3'] bipyridinyl-2-yloxy)-butoxy]-phenyl}-propionic methyl ester (24 mg, 0.05 mmol, 52%): ES+ (m/e) 489. 15 (M+H) + ; Rif 0. 18 hexanes: ethyl acetate (70: 30).

A 5M aqueous solution of sodium hydroxide (0.17 mL, 0. 84 mmol) is added to the above propionic methyl ester (23 mg, 0.05 mmol) in methanol (0.5 mL) and the mixture is stirred at ambient temperature for 4 h. The mixture is neutralized to pH = 7 with a 1 M HC1 and extracted with ethyl acetate. Organic layers are combined and. washed with saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated at reduced pressure to obtain title compound (20 mg, 0.04 mmol, 95%) ES+ (m/e) 475.16 (M+H) +.

Example 61 3-f4- [3- (S)- (5-Chloro- [3, 3'] bipyridinyl-2-yloxy)-butoxy]-2-methyl-phenyl}-propionic acid Cesium carbonate (67 mg, 0.21 mmol) is added to 5-chloro- [3, 3'] bipyridinyl-2-ol (21 mg, 0.10 mmol) and 3- [4- (3- (S)-methanesulfonyloxy-butoxy)- phenyl] -propionic acid methyl ester (42 mg, 0.12 mmol) in DMF (0.7 mL), and the mixture is stirred under N2 at 55 °C. After 18 h, the mixture is cooled to ambient temperature and filtered. Solid is washed with ethyl acetate. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: ethyl acetate (60: 40) gives 3-f4- [3- (S)- (5-chloro- [3, 3'] bipyridinyl-2- yloxy)-butoxy]-2-methyl-phenyl}-propionic acid methyl ester (18 mg, 0.04 mmol, 40%): ES+ (m/e) 455.15 (M+H) + ; Ru 0. 32 hexanes : ethyl acetate (60: 40).

A 5 M aqueous solution of sodium hydroxide (0.15 mL, 0.70 mmol) is added to the above propionic acid methyl ester (18 mg, 0.04 mmol) in methanol (0.6 mL), and the mixture is stirred at ambient temperature for 4 h. The mixture is neutralized to pH = 7 with a 1 M HCl and extracted with ethyl acetate. Organic layers are combined and washed with saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated at reduced pressure to obtain title compound (15 mg, 0.03 mmol, 90%) ES+ (m/e) 441.08 (M+H) +.

Example 62 3-12-Ethyl-4- [3- (S)- (5-trifluoromethyl- [3, 3'] bipyridinyl-2-yloxy)-butoxy]-phenyl}- propionic acid The compound of 3-f2-ethyl-4- [3- (S)- (5-trifluoromethyl- [3, 3'] bipyridinyl- 2-yloxy)-butoxy]-phenyl}-propionic acid ethyl ester (0.10 g, 0.19 mmol, 47%) is prepared according to the procedure described in Example 46, Step B by using cesium carbonate (0.19 g, 0.58 mmol), 5-trifluoromethyl- [3, 3'] bipyridinyl-2-ol (0.10 g, 0.41 mmol) and 3- [2-ethyl-4-3- (S)-methanesulfonyloxy-butoxy)-phenyl]-propionic acid ethyl ester (0.18 g, 0.49 mmol) in DMF (3 mL). ES+ (m/e) 517.2 (M+H) +, Rf 0.33 hexanes : EtOAc (80: 20). Work up of the above propionic acid ethyl ester (0.10 g, 0.19 mmol) in ethanol (1.0 mL) as described in Example 47 provides the title compound as a colorless oil (0.09 g, 0.17 mmol, 90%). ES+ (m/e) 489.13 (M+H) +.

Example 63 (R)-3- {2-Chloro-4- [3- (4-chloro-2-phenoxy-phenoxy)-butoxy]-phenyl}-propionic acid Step A (S) -Acetic acid 3-hydroxy-butyl ester A mixture of (S)- (+)-1, 3-butanediol (10.0 g, 0.1 mol) and 2,4, 6-collidine (27 g, 0.2 mol) in DCM (100 mL) is cooled to-78 °C. The reaction is then treated dropwise with acetyl chloride (10.4 g, 0.13 mol), and stirred for 2hr at-78 °C. The reaction is then allowed to warm to rt and stir for an additional hour. The reaction is then quenched with IN HCl and extracted with DCM. The organic layer is separated, washed with brine, and dried over Na2SO4. The organic is filtered, and the solvent is removed to afford 9.77 g (66%) of acetic acid 3-hydroxy-butyl ester. IH NMR (400 MHz, CDC13) ; MS (ES+) nilz mass calcd for C6HI203 132, found 133 (M + 1).

Step B (S) -Acetic acid 3- (toluene-4-sulfonyloxy)-butyl ester: A solution of acetic acid 3-hydroxy-butyl ester (9. 8 g, 70 mmol) in DCM (50 mL) is cooled to 0 °C. The solution is treated withp-toluenesulfonyl chloride (16.9 g, 90 mmol), TEA (9 g, 90 mmol), and DMAP (2.3 g, 18.5 mmol). The mixture is stirred for 1 hr at 0 °C, and then warmed to rt. The reaction is stirred overnight at rt. The

reaction is then diluted in water and extracted with DCM. The organic layer is separated, washed with brine, and dried over sodium sulfate. The organic is filtered, and the solvent is removed to afford the crude product. The crude is purified by silica gel column chromatography using 9/1 hexanes/EtOAc to elute the pure product. The solvent is removed to afford 11.6 g (55%) of the desired product. 1H NMR (400 MHz, CDC13) ; MS (ES+) ti7lz mass calcd for C13HI805S 286, found 287 (M + 1,100%). <BR> <BR> <P> Step C<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (R)-3- (4-Chloro-2-phenoxy-phenoxy)-butan-1-ol A solution of (R) -acetic acid 3- (toluene-4-sulfonyloxy)-butyl ester (5.89 g, 21 mmol) and 4-chloro-2-phenoxy-phenol (5.0 g, 23 mmol) in DMF (50 mL) is treated with cesium carbonate (7.4 g, 23 mmol). The solution is heated to 60 °C and stirred overnight. The reaction is cooled and quenched with IN HCI. The solution is partitioned in EtOAc and water. The organic is separated, washed with brine, and dried over sodium sulfate. The organic is filtered, and the solvent is removed to afford acetic acid 3- (4- chloro-2-phenoxy-phenoxy)-butyl ester, which is then diluted in methanol (100 mL) and treated with potassium carbonate (5.68 g, 40 mol). The reaction is stirred for 2 hours at rt. The reaction is then partitioned in EtOAc and water. The organic layer is separated, washed with brine, and dried over sodium sulfate. The organic is filtered and the solvent is removed to afford the crude product. The crude is purified by silica gel column chromatography using 1/1 hexanes/EtOAc to elute the pure product. The solvent is removed to afford 4.35 g (72%) of the desired product NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C16Hl7CIO3 292, found 293 (M + 1,100%).

Step D (R)-Methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-butyl ester

A solution of 3- (4-chloro-2-phenoxy-phenoxy)-butan-1-ol (4.35 g, 15 mmol) in DCM (50 mL) is cooled to 0 °C. The solution is then treated with TEA (1.8 g, 18 mmol), MsCl (2.0 g, 18 mmol), and DMAP (0.454 g, 4 mmol). The reaction is stirred for 2 hours at 0 °C. The reaction is then diluted in water and extracted with DCM. The organic is separated, washed with brine, and dried over sodium sulfate. The organic is filtered and the solvent is removed to afford 5.4g (98%) of the desired product NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C17H, gCI05S 370, found 371 (M + 1, 100%).

Step E (R)-3- {2-Chloro-4- [3- (4-chloro-2-phenoxy-phenoxy)-butoxy]-phenyl}-propionic acid A solution of methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-butyl ester (89 mg, 0.24 mmol) and 3- (2-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (50 mg, 0.22 mmol) in DMF (5 mL) is treated with cesium carbonate (85 mg, 0.26 mmol). The reaction is heated to 50 °C and stirred overnight. The reaction is treated with aqueous 5N NaOH (0.4 mL, 2.2 mmol) and stirred for 2 additional hours at 50 °C. The reaction is cooled and quenched with 1N HCl to pH=4. The reaction is extracted with Et20. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The crude product is purified by prep HPLC to afford 70 mg (67%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) n ? lz mass calcd for C25H24C1205 370, found 371 (M + 1,100%).

Example 64 (R)-3-f 4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-fluoro-phenyl}-propio nic acid

The procedure from Example 63, Step E is utilized with 3- (2-fluoro-4- hydroxy-phenyl)-propionic acid ethyl ester to afford 73 mg (66%) of desired product NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C25H24ClF05 458, found 459 (M+1, 100%).

Example 65 (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propion ic acid

The procedure from Example 63, Step E is utilized with 3- (2-ethyl-4- hydroxy-phenyl) -propionic acid ethyl ester to afford 4 mg (4%@ desired product. ¹H NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for 27 105 468, found 469 (M+1, 100%).

Example 66 (R)-4-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-methyl-ph enyl}-butyric acid

The procedure from Example 63, Step E is utilized with 4- (4-hydroxy-2- methyl-phenyl) -butyric acid ethyl ester to afford 54 mg (50%) of desired product NMR (400 MHz, CDC13) ; MS (ES+) 7n/z mass calcd for C27H29C105 468, found 469 (M+1, 100%).

Example 67 (R)-3-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-butoxy]-phenyl}-pro pionic acid

The procedure from Example 63, Step E is utilized with 3- (4-hydroxy- phenyl)-propionic acid ethyl ester to afford 53 mg (44%) of desired product NMR (400 MHz, CDC13) ; MS (ES+) nilz mass calcd for C25H25C105 440, found 441 (M + 1, 100%).

Example 68 (R)-3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-butoxy]-2-chloro-phenyl}-propion ic acid

Step A (R)- [5-Ethyl-2- (3-hydroxy-1-methyl-propoxy)-phenyl]-phenyl-methanone : The procedure from Example 63, Step C is utilized with (5-ethyl-2- hydroxy-phenyl) -phenyl-methanone to afford 1.4 g (69%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) n/z mass calcd for Cz9H2203 298, found 299 (M + 1, 100%).

Step B (R)-Methanesulfonic acid 3- (2-benzoyl-4-ethyl-phenoxy)-butyl ester: The procedure from Example 63, Step D is utilized with [5-ethyl-2- (3- hydroxy-l-methyl-propoxy)-phenyl]-phenyl-methanone (1.4 g, 5 mmol) to afford 1.7 g (98%) of the desired product NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C2oH2405S 376, found 377 (M + 1,100%).

Step C (R)-3- 4- [3- (2-Benzoyl-4-ethyl-phenoxy)-butoxy]-2-chloro-phenyl}-propion ic acid The procedure from Example 63, Step E is utilized with 3- (2-chloro-4- hydroxy-phenyl) -propionic acid ethyl ester to afford 61 mg (58%) of desired product NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C28H29ClO5 480, found 481 (M + 1, 100%).

Example 69 (R)-3-{4-[3-(2-Benzoyl-4-ethyl-phenoxy)-butoxy]-2-fluoro-phe nyl}-propionic acid The procedure from Example 63, Step E is utilized with 3- (2-Fluoro-4- hydroxy-phenyl) -propionic acid ethyl ester to afford 61 mg (58%) of desired product NMR (400 MHz, CDCl3) ; MS (ES+) nilz mass calcd for C2gH29F05 464, found 465 (M+1, 100%).

Example 70 (R)-3-{4-[3-(2-Benzoyl-4-ethyl-phenoxy)-butoxyl]-phenyl}-pro pionic acid The procedure from Example 63, Step E is utilized with 3- (4-hydroxy- phenyl)-propionic acid ethyl ester to afford 59 mg (49%) of desired product NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C28H30Os 464, found 465 (M + 1, 100%).

Example 71 (R)-3-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-butoxy]-phenyl}-3-m ethyl-butyric acid

Step A 3- (4-Hydroxy-phenyl)-3-methyl-butyric acid methyl ester: A solution of 3- (4-hydroxy-phenyl)-3-methyl-butyric acid (1.0 g, 5.15 mmol) in MeOH (25 mL) is treated with concentrated sulfuric acid (8 mL). The reaction is stirred overnight at rt. The reaction is cooled to 0 °C and quenched with 5. ON aqueous sodium hydroxide to pH=8. The aqueous layer is extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered, and the solvent is removed to afford 780 mg (73%) of the title compound. 1H NMR (400 MHz, CDCIs) ; MS (ES+) nilz mass calcd for Cl IHI403 194, found 195 (M + 1,100%).

Step B (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-phenyl}-3-methyl-butyri c acid methyl ester

A solution of methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-butyl ester (100 mg, 0.27 mmol) and 3- (4-hydroxy-phenyl)-3-methyl-butyric acid methyl ester (62 mg, 0. 30 mmol) in DMF (10 mL) is treated with cesium carbonate (105 mg, 0.32 mmol). The reaction is heated to 50 °C and stirred overnight. The reaction is then cooled and quenched with IN HCl to pH=7. The reaction is extracted with Et20. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The crude is purified by silica gel column chromatography using 3/1 hexanes/EtOAc to elute the pure product. The solvent is removed to afford 80 mg (62%) of desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C2gH3iClO5 482, found 483 (M + 1, 100%).

Step C (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-phenyl}-3-methyl-butyri c acid A solution of 3-14- [3- (4-chloro-2-pbenoxy-phenoxy)-butoxy]-phenyll-3- methyl-butyric acid methyl ester (80 mg, 0.17 mmol) in MeOH (15 mL) is treated with 5N aqueous sodium hydroxide (0.3 mL). The reaction is heated to reflux and stirred for 3 hours. The reaction is then cooled and adjusted to pH=4 with IN aqueous hydrochloric acid. The solution is extracted with EtOAc. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed to afford 61 mg (78%) of desired product NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C27H29CIO5 468, found 469 (M + 1, 100%).

Example 72 (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-propyl-phenyl}-propio nicacid

Step A (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-propyl-phenyl}-propio nic acid ethyl ester

The procedure from Example 71, Step B is utilized with 3- (4-hydroxy-2- propyl-phenyl)-propionic acid ethyl ester (2159493) to afford 90 mg (78%) of desired product NMR (400 MHz, CDC13) ; MS (ES+) snlz mass calcd for C3oH35ClO5 510, found 511 (M + 1, 100%).

Step B (R)-3-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-propyl-ph enyl}-propionic acid A solution of (R)-3- {4- [3- (4-chloro-2-phenoxy-phenoxy)-butoxy]-2- propyl-phenyl}-propionic acid ethyl ester (90 mg, 0.18 mmol) in EtOH (5 mL) is treated with 5. ON aqueous sodium hydroxide. The reaction is heated to 80 °C and stirred for 4 hours. The reaction is cooled to rt and quenched with 1. ON aqueous hydrochloric acid to pH=4. The aqueous is extracted with diethyl ether. The organic layer is washed with brine, and then dried over sodium sulfate and filtered. The solvent is removed to afford

81 mg (95%) of desired product. IH NMR (400 MHz, CDCl3) ; MS (ES+) only mass calcd for C28H31CIO5 482, found 483 (M + 1,100%).

Example 73 (R)-3-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-butoxy]-2,6-dimethy l-phenyl}-propionic acid Step A <BR> <BR> (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2, 6-dimethyl-phenyl}-propionic acid ethyl ester: The procedure from Example 71, Step B is utilized with 3- (4-hydroxy-2, 6- dimethyl-phenyl) -propionic acid ethyl ester (2190971) to afford 102 mg (91%) of desired product. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calc@@ C29H33ClO5 496, found 497 (M + 1, 100%).

Step B (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2, 6-dimethyl-phenyl}-propionic acid The procedure from Example 72, Step C is utilized with (R)-3-{4-[3-(4- chloro-2-phenoxy-phenoxy) -butoxy]-2, 6-dimethyl-phenyl}-propionic acid ethyl ester to afford 82 mg (87%) of desired product NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C27H29ClO5 468, found 469 (M + 1, 100%).

Example 74 (R)-f 4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenylsulfanyl} -acetic acid Step A (R)- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenylsulfanyl} -acetic acid ethyl ester The procedure from Example 71, Step B is utilized with (2-ethyl-4- hydroxy-phenylsulfanyl) -acetic acid ethyl ester to afford 42 mg (39%) of desired product.

'H NMR (400 MHz, CDCl3) ; MS (ES+) inlz mass calcd for C28H31ClO5S 514, found 515 (M + 1, 100%).

Step B (R)-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-pheny lsulfanyl}-acetic acid The procedure from Example 72, Step C is utilized with (R)- {4- [3- (4- chloro-2-phenoxy-phenoxy)-butoxy]-2-etliyl-phenylsulfanyl}-a cetic acid ethyl ester to afford 25 mg (63%) of desired product NMR (400 MHz, CDC13) ; MS (ES+) into mass calcd for C26H27ClOsS 486, found 487 (M + 1,100%).

Example 75 (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-pentyloxy]-2-methyl-phenyl}-pro pionic acid Step A (R, S)-Toluene-4-sulfonic acid 3-hydroxy-pentyl esterluene-4-sulfonic acid 3-hydroxy- pentyl ester A solution of (R, S)-pentane-1, 3-diol (20.0 g, 0.19 mol, 2148539) and TEA (23.3 g, 0.23 mol) in methylene chloride (400 mL) is treated with dibutyltin oxide (0.96 g, 3.8 mmol). The reaction is stirred at rt and treated portion wise withp-toluenesulfonyl chloride (36.6 g, 0.19 mol). The reaction is stirred overnight at rt. The reaction is diluted in water and neutralized to pH=7 with 1N aqueous hydrochloric acid. The aqueous is extracted with methylene chloride. The organic is dried over sodium sulfate, filtered, and the solvent removed to afford the crude product. The crude product is purified by silica gel column chromatography using 3/2 hexanes/EtOAc to elute the pure product. The solvent is removed to afford 34.3 g (69%) of desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for Cl2Hl804S 258, found 259 (M + 1).

Step B (R, S)-3- [4- (3-Hydroxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester

A solution of (R, S)-toluene-4-sulfonic acid 3-hydroxy-pentyl esterluene-4- sulfonic acid 3-hydroxy-pentyl ester (34.3 g, 0.13 mol) and 3- (4-hydroxy-2-methyl- phenyl) -propionic acid methyl ester (28.4 g, 0.15 mol) are combined in DMF (300 mL).

The solution is treated with cesium carbonate (52 g, 0.16 mol) and heated to 55 °C. The reaction is stirred overnight. The reaction is cooled and quenched with 1N HC1. The reaction is extracted with EtOAc. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The crude is purified by silica gel column chromatography using 4/1 hexanes/EtOAc to elute the pure product. The solvent is removed to afford 5.4 g (15%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) nilz mass calcd for C16H2404 280, found 281 (M + 1,100%).

Step C (S)-3- [4- (3-Hydroxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester: The compound of (R, S)-3- [4- (3-hydroxy-pentyloxy)-2-methyl-phenyl]- propionic acid methyl ester is purified by HPLC using a 4.6 x 250 mm Chiralpak AD column. The pure chiral compound is eluted using 5/5/90 NPA/methanol/heptane. The solvent is removed to afford the desired product (95.6% ee). IH NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C16H24O4 280, found 281 (M + 1,100%).

Step D (S)-3- [4- (3-Methanesulfonyloxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester

A solution of (S)-3- [4- (3-hydroxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester (0.2 g, 0.7 mmol) and TEA (0.108 g, 1.07 mmol) are combined in methylene chloride (10 mL) and cooled to 0 °C. The solution is then treated with MsCI (0. 098 g, 0.86 mmol) and stirred for 2 hours at 0 °C. The reaction is then quenched with water and extracted with methylene chloride. The organic is dried over sodium sulfate, filtered, and the solvent removed to afford 0.25 g (quantitative) of the desired product NMR (400 MHz, CDCl3) ; MS (ES+) nalz mass calcd for C17H2606S 358, found 359 (M + 1, 100%).

Step E (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-pentyloxy]-2-methyl-phenyl}-pro pionic acid A solution of (S)-3- [4- (3-methanesulfonyloxy-pentyloxy)-2-methyl- phenyl] -propionic acid methyl ester (125 mg, 0.35 mmol) and 4-Chloro-2-phenoxy- phenol (70 mg, 0.32 mmol) in DMF (5 mL) is treated with cesium carbonate (124 mg, 0.38 mmol). The reaction is heated to 60 °C and stirred overnight. The reaction is then treated with aqueous 5N NaOH (0.4 mL, 2.2 mmol) and stirred for 2 additional hours at 50 °C. The reaction is then cooled and quenched with 1N HCl to pH=4. The reaction is then extracted with Et20. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent removed. The crude product is purified by prep HPLC to afford 63 mg (42%) of the desired product NMR (400 MHz, CDC) ; MS (ES+) inlz mass calcd for C27H29C105 468, found 469 (M + 1,100%).

Example 76 (R)-3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-pentyloxy]-2-methyl-phenyl}-prop ionic acid The procedure from Example 75, Step E is utilized with (5-ethyl-2- hydroxy-phenyl) -phenyl-methanone to afford 77 mg (50%) of the desired product. H NMR (400 MHz, CDCl3) ; MS (ES+) nzlz mass calcd for C30H34Os 474, found 475 (M + 1, 100%).

Example 77 (S)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-pentyloxy]-2-methyl-phenyl}-pro pionic acid (R)-3- [4- (3-Hydroxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester: Step A The compound of (R, S)-3- [4- (3-hydroxy-pentyloxy)-2-methyl-phenyl]- propionic acid methyl ester is purified by HPLC using a 4.6 x 250 mm Chiralpak AD column. The chiral pure compound is eluted using 5/5/90 NPA/methanol/heptane. The solvent is removed to afford the desired product (95.7% ee). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for Cl6H2404 280, found 281 (M + 1,100%).

Step B (R)-3- [4- (3-Methanesulfonyloxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester

The procedure for Example 75, Step D is utilized with (R)-3- [4- (3- hydroxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester to afford 0.25 g (quantitative) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C17H2696S 358, found 359 (M + 1, 100%).

Step C (S)-3-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-pentyloxy]-2-methyl -phenyl}-propionic acid The procedure for Example 75, Step E is utilized with (R)-3- [4- (3- methanesulfonyloxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester to afford 66 mg (44%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C27H29C1O5 468, found 469 (M + 1,100%).

Example 78 (S)-3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-pentyloxy]-2-methyl-phenyl}-prop ionic acid The procedure from Example 77, Step C is utilized with (5-ethyl-2- hydroxy-phenyl) -phenyl-methanone to afford 77 mg (50%) of the desired product NMR (400 MHz, CDCl3) ; MS (ES+) rnlz mass calcd for C3oH3405 474, found 475 (M + 1, 100%).

Example 79 (R)-3-14- [3- (3-Benzoyl-naphthalen-2-yloxy)-butoxy]-2-methyl-phenyll-prop ionic acid

Step A (3-Hydroxy-naphthalen-2-yl)-phenyl-methanone

A solution of 3-hydroxy-2-naptlioic acid (5.0 g, 26.6 mmol) in THF (200 mL) is cooled to-78 °C. The solution is then treated dropwise with 1.8M phenyllithium in cyclohexane/ether (118 mL, 0.21 mol). The reaction is allowed to warm to rt and stir for 3 hours. The reaction is cooled and quenched with water. The reaction is neutralized to pH=6 with IN aqueous hydrochloric acid, and extracted with ethyl ether. The organic is dried over sodium sulfate, filtered, and the solvent is removed to afford the crude product. The crude is purified by silica gel column chromatography using 9/1 hexanes/EtOAc to elute the pure product. The solvent is removed to afford 2.4 g (36%) of desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for Cl7Hl202 248, found 249 (M + 1,100%).

Step B (R)-3- {4- [3- (3-Benzoyl-naphthalen-2-yloxy)-butoxy]-2-methyl-phenyl}-prop ionicacid methyl ester

A solution of (3-hydroxy-naphthalen-2-yl) -phenyl-methanone (76 mg, 0.3 mmol) and (R)-3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.1 g, 0. 28 mmol) are combined in DMF (10 mL) and treated with cesium carbonate (0.109 g, 0.34 mmol). The reaction is heated to 60 °C and stirred overnight.

The reaction is cooled and quenched with 1N aqueous hydrochloric acid. The aqueous is extracted with EtOAc. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed to afford the crude product. The crude is purified by silica gel column chromatography using 9/1 Hexanes/EtOAc to elute the pure product.

The solvent is removed to afford 99 mg (71 %) of the desired product. 1H NMR (400 MHz, CDCl3) ; MS (ES+) into mass calcd for C17H2606S 496, found 497 (M + 1,100%).

Step C (R)-3- {4- [3- (3-Benzoyl-naphthalen-2-yloxy)-butoxy]-2-methyl-phenyl}-prop ionic acid The procedure from Example 71, Step C is utilized with (R)-3- {4- [3- (3- benzoyl-naphthalen-2-yloxy)-butoxy]-2-methyl-phenyl}-propion ic acid methyl ester to afford 93 mg (quantitative) of desired product NMR (400 MHz, CDCl3) ; MS (ES+) iiilz mass calcd for C31H30O5 482, found 483 (M + 1, 100%).

Example 80 (R)-14- [3- (3-Benzoyl-naphthalen-2-yloxy)-butoxy]-2-methyl-phenyisulfan yl}-acetic acid Step A (R)-f 4- [3- (3-Benzoyl-naphthalen-2-yloxy)-butoxy]-2-methyl-phenylsulfan yl}-acetic acid methyl ester The procedure from Example 79, Step B is utilized with (R)- [4- (3- methanesulfonyloxy-butoxy) -2-methyl-phenylsulfanyl] -acetic acid methyl ester to afford 50 mg (36%) of the desired product NMR (400 MHz, CDCl3) ; MS (ES+) inlz mass calcd for C31H30O5S 514, found 515 (M + 1,100%).

Step B (R)-14- [3- (3-Benzoyl-naphthalen-2-yloxy)-butoxy]-2-methyl-phenylsulfan yll-acetic acid The procedure from Example 71, Step C is utilized with (R)-{4-[3-(3- benzoyl-naphthalen-2-yloxy)-butoxy]-2-methyl-phenylsulfanyl} -acetic acid methyl ester to afford 47 mg (quantitative) of desired product NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C30H28OsS 500, found 501 (M + 1, 100%).

Example 81 <BR> <BR> (R)-3- {4- [3- (4-Ethyl-2-phenoxy-phenoxy)-butylsulfanyl]-2-methyl-phenyl}- propionic acid Step A (R)-Methanesulfonic acid 3- (4-ethyl-2-phenoxy-phenoxy)-butyl ester The procedure for Example 75, Step D is utilized with (R)-3- (4-ethyl-2- phenoxy-phenoxy)-butan-l-ol to afford 0.24 g (quantitative) of the desired product NMR (400 MHz, CDCl3) ; MS (ES+) 7nlz mass calcd for Cl9H2405S 364, found 365 (M + 1,100%). <BR> <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> (R)-3-f{4- [3- (4-Ethyl-2-phenoxy-phenoxy)-butylsulfanyl]-2-methyl-phenyl}- propionic acid methyl ester A solution of 3- (4-mercapto-2-methyl-phenyl)-propionic acid methyl ester (0.167 g, 0.8 mmol) in DMF (5 mL) is purged with nitrogen. The solution is treated with potassium carbonate (0.14 g, 1.0 mmol) and purged with nitrogen. The solution is then

treated with (R) -methanesulfonic acid 3- (4-ethyl-2-phenoxy-phenoxy)-butyl ester (0.24 g, 0.66 mmol) and stirred overnight under nitrogen. The reaction is quenched with IN aqueous hydrochloric acid. The aqueous is extracted with ethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent removed to afford the crude product. The crude is purified by silica gel column chromatography using 9/1 Hexanes/Acetone to elute the pure product. The solvent is removed to afford 0.2 g (63%) of the desired product NMR (400 MHz, CDC13) ; MS (E$+) m/z mass calcd for C29H3404S 478, found 479 (M + 1,100%).

Step C <BR> <BR> <BR> <BR> <BR> (R)-3- {4- [3- (4-Ethyl-2-phenoxy-phenoxy)-butylsulfanyl]-2-methyl-phenyl}- propionic acid The procedure for Example 71, Step C is utilized with (R)-3- {4- [3- (4- ethyl-2-phenoxy-phenoxy)-butylsulfanyl]-2-methyl-phenyl}-pro pionic acid methyl ester to afford 0.175 g (95%) of the desired product. 1H NMR (400 MHz, CDCl3) ; MS (ES+) n/z mass calcd for C28H3204S 464, found 465 (M + 1,100%).

Example 82 (R)-3-{4-[3-(4-Isopropyl-2-phenoxy-phenoxy)-butylsulfanyl]-2 -methyl-phenyl}- propionic acid

Step A (R)-3- (4-Isopropyl-2-phenoxy-phenoxy)-butan-1-ol The procedure for Example 63, Step C is utilized with 4-isopropyl-2- phenoxy-phenol to afford 0.126 g (69%) of the desired product. I NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C19H24O3 300, found 301 (M + 1,100%).

Step B (R)-Methanesulfonic acid 3- (4-Isopropyl-2-phenoxy-phenoxy)-butyl ester The procedure for Example 63, Step D is utilized with (R)-3- (4-isopropyl- 2-phenoxy-phenoxy)-butan-1-ol to afford 0.100 g (63%) of the desired product. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C2oH2605S 378, found 379 (M+1, 100%).

Step C (R)-3- {4- [3- (4-Isopropyl-2-phenoxy-phenoxy)-butylsulfanyl]-2-methyl-phen yl}- propionic acid methyl ester:

The procedure for Example 81, Step B is utilized with (R)- methanesulfonic acid 3- (4-Isopropyl-2-phenoxy-phenoxy)-butyl ester to afford 0.105 g (81 %) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C3oH3604S 492, found 493 (M + 1,100%).

Step D (R)-3-f{4- [3- (4-Isopropyl-2-phenoxy-phenoxy)-butylsulfanyl]-2-methyl-phen yl}- propionic acid The procedure for Example 71, Step C is utilized with (R)-3- {4- [3- (4- Isopropyl-2-phenoxy-phenoxy)-butylsulfanyl]-2-methyl-phenyl} -propionic acid methyl ester to afford 0.091 g (89%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C29H3404S 478, found 479 (M + 1,100%).

Example 83 (R)-3- {4- [3- (2-Benzoyl-4, 5-dichloro-phenoxy)-butoxy]-2-methyl-phenyl}-propionic acid

Step A (S)-3- [4- (3-Hydroxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester

A solution of (S)-toluene-4-sulfonic acid 3-hydroxy-butyl ester (2.08 g, 8.5 mmol) and 3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (1.5 g, 7.7 mmol) in DMF (20 mL) is treated with cesium carbonate (3.0 g, 9.3 mmol). The reaction is heated to 55 °C and stirred overnight. The reaction is cooled and quenched with IN aqueous hydrochloric acid. The aqueous is extracted with ethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed to afford the crude product. The crude is purified by silica gel column chromatography using 9/1 hexanes/EtOAc to elute the pure product. The solvent is removed to afford 0.67 g (33%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) ryzlz mass calcd for Cl5H2204 266, found 267 (M + 1, 100%).

Step B (S)-3- [4- (3-Methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester

The procedure for Example 63, Step D is utilized with (S)-3- [4- (3- hydroxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester to afford 0.87 g (quantitative) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for Cl6H2406S 344, found 345 (M + 1,100%).

Step C (R)-3-4- [3- (2-Benzoyl-4, 5-dichloro-phenoxy)-butoxy]-2-methyl-phenyl}-propionic acid A solution of (S)-3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]- propionic acid methyl ester (0.1 g, 0.29 mmol) and (4,5-dichloro-2-hydroxy-phenyl)- phenyl-methanone (85 mg, 0.32 mmol) in DMF (3 mL) is treated with cesium carbonate (113 mg, 0.35 mmol). The reaction is heated to 60 °C and stirred overnight. The reaction is treated with aqueous 5N NaOH (0.6 mL, 2.9 mmol) and stirred for 2 additional hours at 60 °C. The reaction is cooled and quenched with IN HC1 to pH=4. The reaction is extracted with Et20. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The crude product is purified by prep HPLC to afford 48 mg (33%) of the desired product NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C27H26Cl205 500, found 501 (M + 1,100%).

Example 84 (R)-3- {2-Ethyl-4- [3- (4-ethyl-2-phenoxy-phenoxy)-butoxy]-phenyl}-propionic acid

Step A (S)-3- [2-Ethyl-4- (3-hydroxy-butoxy)-phenyl]-propionic acid ethyl ester The procedure from Example 83, Step A is utilized with 3- (2-ethyl-4- hydroxy-phenyl) -propionic acid methyl ester to afford 1.12 g (56%) of the desired product. 1H NMR (400 MHz, CDCl3) ; MS (ES+) fnlz mass calcd for CI7H2604 294, found 295 (M + 1, 100%).

Step B (S)-3- [2-Ethyl-4- (3-methanesulfonyloxy-butoxy)-phenyl]-propionic acid ethyl ester The procedure for Example 63, Step D is utilized with (S)-3- [2-Ethyl-4- (3- hydroxy-butoxy) -phenyl] -propionic acid ethyl ester to afford 1.17 g (84%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C18H2806S 372, found 373 (M + 1, 100%).

Step C (R)-3- {2-Ethyl-4- [3- (4-ethyl-2-phenoxy-phenoxy)-butoxy]-phenyl}-propionic acid A solution of (S)-3- [2-ethyl-4- (3-methanesulfonyloxy-butoxy)-phenyl]- propionic acid ethyl ester (0.1 g, 0.27 mmol) and 4-ethyl-2-phenoxy-phenol (64 mg, 0.3 mmol) in DMF (3 mL) is treated with cesium carbonate (105 mg, 0.32 mmol). The reaction is heated to 60 °C and stirred overnight. The reaction is then treated with aqueous 5N NaOH (0.6 mL, 2.9 mmol) and stirred for 2 additional hours at 60 °C. The reaction is cooled and quenched with IN HCl to pH=4. The reaction is extracted with Et20. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The crude product is purified by prep HPLC to afford 60 mg (48%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) into mass calcd for C29H3405 462, found 463 (M + 1, 100%).

Example 85 (R)-3- {2-Ethyl-4- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butoxy]-phenyl}-propio nic acid The procedure from Example 84, Step C is utilized with 2-phenoxy-4- trifluoromethyl-phenol to afford 63 mg (47%) of the desired product. 1H NMR (400 MHz, CDCl3) ; MS (ES+) 7m/Z mass calcd for C2sH29F3O5 502, found 503 (M + 1, 100%).

Example 86 (R)-3-{4-[3-(2-Benzoyl-4-ethyl-phenoxy)-butoxy]-2-ethyl-phen yl}-propionic acid The procedure from Example 84, Step C is utilized with (5-ethyl-2- hydroxy-phenyl)-phenyl-methanone to afford 63 mg (49%) of the desired product. 1H NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C3pH3405 474, found 475 (M + 1, 100%).

Example 87 (R)-3-{4-[3-(2,4-Diphenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}- propionic acid The procedure from Example 84, Step C is utilized with 2,4-diphenoxy- phenol to afford 105 g (50%) of the desired product NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C33H3406 526, found 527 (M + 1, 100%).

Example 88 <BR> <BR> (R)-3- {2-Methyl-4- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phenyl} - propionic acid Step A (S)-3- [4- (3-Hydroxy-butylsulfanyl)-2-methyl-phenyl]-propionic acid methyl ester A solution of 3- (4-mercapto-2-methyl-phenyl)-propionic acid methyl ester (1.0 g, 7.1 mmol) in DMF (20 mL) is purged with nitrogen. The solution is treated with potassium carbonate (1.48 g, 10.7 mmol) and purged again with nitrogen. The reaction is then treated with (S) -toluene-4-sulfonic acid 3-hydroxy-butyl ester (1.28 g, 7.9 mmol) and stirred overnight at rt under nitrogen. The reaction is quenched with 1N aqueous hydrochloric acid. The aqueous is extracted with ethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed to afford the crude product. The crude is purified by silica gel column chromatography using 9/1 hexanes/acetone to elute the pure product. The solvent is removed to afford 0.96 g (72%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for CisH2203S 282, found 283 (M + 1,100%).

Step B (S)-3- [4- (3-Methanesulfonyloxy-butylsulfanyl)-2-methyl-phenyl]-propio nic acid methyl ester

The procedure for Example 63, Step D is utilized with (S)-3- [4- (3- hydroxy-butylsulfanyl) -2-methyl-phenyl] -propionic acid methyl ester to afford 1.2 g (quantitative) of the desired product. 1H NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C16H2405S2 360, found 361 (M + 1, 100%). <BR> <BR> <P> Step C<BR> <BR> (R)-3- {2-Methyl-4- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phenyl} - propionic acid A solution of (S)-3- [4- (3-methanesulfonyloxy-butylsulfanyl)-2-methyl- phenyl]-propionic acid methyl ester (0.1 g, 0.28 mmol) and 2-phenoxy-4-trifluoromethyl- phenol (78 mg, 0.31 mmol) in DMF (3 mL) is treated with cesium carbonate (108 mg, 0.33 mmol). The reaction is heated to 60 °C and stirred overnight. The reaction is then treated with aqueous 5N NaOH (0.6 mL, 2.9 mmol) and stirred for 2 additional hours at 60 °C. The reaction is then cooled and quenched with IN HCl to pH=4. The reaction is then extracted with Et20. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The crude product is purified by prep HPLC to afford 18 mg (13%) of the desired product.'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C27H27F305S 504, found 505 (M + 1, 100%).

Example 89 (R)-3-{4-[3-(4-Ethyl-2-phenoxy-phenoxy)-butoxy]-2,6-dimethyl -phenyl}-propionic acid

Step A (R)-3-(4-Ethyl-2-phenoxy-phenoxy)-butan-1-ol The procedure from Example 63, Step C is utilized with 4-ethyl-2- phenoxy-phenol to afford 0. 52 g (78%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C18H2203 286, found 287 (M + 1,100%).

Step B (R)-Methanesulfonic acid 3- (4-ethyl-2-phenoxy-phenoxy)-butyl ester The procedure from Example 63, Step D is utilized with (R)-3- (4-ethyl-2- phenoxy-phenoxy)-butan-l-ol to afford 0.64 g (96%) of the desired product. 1H NMR (400 MHz, CDCl3) ; MS (ES+) nilz mass calcd for Cl9H2405S 364, found 365 (M + 1, 100%).

Step C (R)-3-f4- [3- (4-Ethyl-2-phenoxy-phenoxy)-butoxy]-2, 6-dimethyl-phenyl}-propionic acid A solution of (R)-methanesulfonic acid 3- (4-ethyl-2-phenoxy-phenoxy)- butyl ester (0.1 g, 0.27 mmol) and 3- (4-hydroxy-2, 6-dimethyl-phenyl) -propionic acid methyl ester (67 mg, 0.3 mmol) in DMF (5 mL) is treated with cesium carbonate (107 mg, 0.33 mmol). The reaction is heated to 50 °C and stirred overnight. The reaction is then treated with aqueous 5N NaOH (0.54 mL, 2.7 mmol) and stirred for 2 additional hours at 50 °C. The reaction is then cooled and quenched with IN HC1 to pH=4. The reaction is then extracted with Et20. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The crude product is purified by prep HPLC to afford 31 mg (25%) of the desired product NMR (400 MHz, CDCl3) ; MS (ES+) filz mass calcd for C29H3405 462, found 463 (M + 1,100%).

Example 90 (R)-3- {2-Ethyl-4- [1-methyl-3-(2-phenoxy-4-trifluoromethyl-phenoxy)-propoxy]-p henyl}- propionic acid Step A (S)-4- (2-Phenoxy-4-trifluoromethyl-phenoxy)-butan-2-ol A mixture of 2-phenoxy-4-trifluoromethyl-phenol (502 mg, 1.97 mmol), (S)-toluene-4-sulfonic acid 3-hydroxy-butyl ester (531 mg, 2.17 mmol) and Cs2CO3 (965

mg, 2.96 mmol) in 20 mL of dry DMF is heated to 55°C for overnight. The mixture is then cooled to rt and diluted with Et20 and filtered through a pad of celite. Organic layer is washed with 1N HCI, H20, brine and dried over Na2S04, filtered and concentrated.

Crude material is purified by chromatography (hexanes/acetone = 8: 1) to afford the title compound as a colorless oil in 79% yield. Rf= 0.31 (8/1 hexanes/acetone). IH NMR (400 MHz, CDC13).

Step B (S)-methanesulfonic acid 1-methyl-3- (2-phenoxy-4-trifluoromethyl-phenoxy)-propyl ester A mixture of (S)-4-(2-phenoxy-4-trifluoromethyl-phenoxy)-butan-2-ol (360 mg, 1.10 mmol), mathanesulfonyl chloride (0.13 mL, 1.65 mmol) and Et3N (0.38 mL, 2.76 mmol) in 15 mL of dry CH2CI2 is allowed to stand at 0°C for 30 min and then slowly wann up to rt for 2 h. The mixture is then diluted with Et2O and is washed with 1N HCI, H20, brine and dried over Na2S04, filtered and concentrated. The crude material is used for next step without further purification. Rf= 03 (1511 hexanes/acetone). 1H NMR (400 MHz, CDC13).

Step C <BR> <BR> (R)-3- {2-Ethyl-4- [1-methyl-3- (2-phenoxy-4-trifluorometliyl-phenoxy)-propoxy]-phenyl}- propionic acid A solution of (R) -methanesulfonic acid 1-methyl-3- (2-phenoxy-4- trifluoromethyl-phenoxy)-propyl ester (0.1 g, 0.25 mmol) and 3- (2-ethyl-4-hydroxy- phenyl) -propionic acid ethyl ester (60 mg, 0.27 mmol) in DMF (3 mL) is treated with cesium carbonate (98 mg, 0.3 mmol). The reaction is heated to 50 °C and stirred overnight. The reaction is treated with aqueous 5N NaOH (0.5 mL, 2.7 mmol) and stirred for 2 additional hours at 50 °C. The reaction is cooled and quenched with 1N HC1 to pH=4. The reaction is extracted with Et20. The organic is washed with brine, dried over

sodium sulfate, filtered, and the solvent is removed. The crude product is purified by prep HPLC to afford 27 mg (21%) of the desired product NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C28H29F305 502, found 503 (M + 1,100%).

Example 91 (R)-3- {2-Methyl-4- [1-methyl-3-(2-phenoxy-4-trifluoromethyl-phenoxy)-propylsulf anyl]- phenyl}-propionic acid Step A (S)-4- (2-Phenoxy-4-trifluoromethyl-phenoxy)-butan-2-ol A mixture of 2-phenoxy-4-trifluoromethyl-phenol (502 mg, 1.97 mmol), (S)-toluene-4-sulfonic acid 3-hydroxy-butyl ester (531 mg, 2.17 mmol) and Cs2CO3 (965 mg, 2.96 mmol) in 20 mL of dry DMF is heated to 55°C for overnight. The mixture is then cooled to rt and diluted with Et20 and filtered through a pad of celite. Organic layer is washed with IN HCI, H2O, brine and dried over Na2SO4, filtered and concentrated.

Crude material is purified by chromatography (hexanes/acetone = 8: 1) to afford the title compound as a colorless oil in 79% yield. Rf = 0.31 (8/lhexanes/acetone). IH NMR (400 MHz, CDCl3).

Step B (S)-methanesulfonic acid 1-methyl-3- (2-phenoxy-4-trifluoromethyl-phenoxy)-propyl ester

A mixture of (e-4-(2-phenoxy-4-trifluoromethyl-phenoxy)-butan-2-ol (360 mg, 1.10 mmol), mathanesulfonyl chloride (0.13 mL, 1.65 mmol) and Et3N (0. 38 mL, 2.76 mmol) in 15 mL of dry CH2C12 is allowed to stand at 0°C for 30 min and then slowly warm up to rt for 2 h. The mixture is then diluted with Et2O and is washed with IN HCI, H20, brine and dried over Na2S04, filtered and concentrated. The crude material is used for next step without further purification. Rf= 0.3 (15/1 hexanes/acetone). 1H NMR (400 MHz, CDCl3).

Step C <BR> <BR> <BR> <BR> (R)-3- {2-Methyl-4- [1-methyl-3- (2-phenoxy-4-trifluoromethyl-phenoxy)-propylsulfanyl]- phenyl}-propionic acid A solution of methanesulfonic acid 1-methyl-3- (2-phenoxy-4- trifluoromethyl-phenoxy) -propyl ester (0.1 g, 0.25 mmol) in DMF (5 mL) is purged with nitrogen. The solution is treated with potassium carbonate (51 mg, 0.37 mmol) and purged again with nitrogen. The solution is then treated with 3- (4-Mercapto-2-methyl- phenyl) -propionic acid methyl ester (57 mg, 0.27 mmol) and stirred at rt overnight. The reaction is quenched with IN aqueous hydrochloric acid. The aqueous is extracted with ethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent removed to afford the crude product. The crude is purified by silica gel column chromatography using 9/1 hexanes/acetone to elute the methyl ester intermediate. The intermediate is treated with 5N NaOH (0.5 mL, 2.5 mmol) in MeOH (5 mL) and heated to reflux. The reaction stirred at reflux for 2 hours and then is cooled. The reaction is quenched with IN aqueous hydrochloric acid to pH=4. The aqueous is extracted with

ethyl ether. The organic is washed with brine, dried over sodium sulfate, and filtered.

The solvent is removed to afford 0.032 g (26%) of desired product. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C27H27F304S 504, found 505 (M + 1, 100%).

Example 92 (R)-3- {2-Methyl-4- [1-methyl-3- (2-phenoxy-4-trifluoromethoxy-phenoxy)- propylsulfanyl]-phenyl}-propionic acid

Step A (æ-4-(2-Bromo-4-trifluoromethoxy-phenoxy)-butan-2-ol

A mixture of 2-bromo-4-trifluoromethoxy-phenol (1.0 g, 3.9 mmol), (S)- toluene-4-sulfonic acid 3-hydroxy-butyl ester (1.05 g, 4.3 mmol) and Cs2CO3 (1.9 g, 5. 8 mmol) in 20 mL of dry DMF is heated to 60°C for overnight. The mixture is then cooled to rt and diluted with Et2O and filtered through a pad of celite. Organic layer is washed with IN HCI, H20, brine and dried over Na2SO4, filtered and concentrated. Crude material is purified by chromatography (hexanes/acetone = 15: 1) to afford the title compound as a colorless oil in 83% yield. Rf= 0.3 (15/1 hexanes/acetone).'H NMR (400 MHz, CDCl3).

Step B (S)-Methanesulfonic acid 3-(2-bromo-4-trifluoromethoxy-phenoxy)-1-methyl-propyl ester

A mixture of ()-4- (2-bromo-4-trifluoromethoxy-phenoxy)-butan-2-ol (900 mg, 2.73 mmol), mathanesulfonyl chloride (0. 32 mL, 4.10 mmol) and Et3N (0.95 mL, 6.84 mmol) in 30 mL of dry CH2Cl2 is allowed to stand at 0°C for 30 min and then slowly warm up to rt for 2 h. The mixture is then diluted with Et20 and is washed with IN HC1, H20, brine and dried over Na2S04, filtered and concentrated. The crude material is used for next step without further purification. Rf = 0.33 (13/1 hexanes/acetone). 1H NMR (400 MHz, CDCl3).

Step C <BR> <BR> <BR> <BR> (R)-3-f{4- [3- (2-Bromo-4-trifluoromethoxy-phenoxy)-1-methyl-propylsulfanyl ]-2-methyl- phenyl}-propionic acid methyl ester A mixture of (S)-methanesulfonic acid 3- (2-bromo-4-trifluoromethoxy- phenoxy)-l-methyl-propyl ester (210 mg, 0.52 mmol), 3- (4-mercapto-2-methyl-phenyl)- propionic acid methyl ester (90.4 mg, 0.43 mmol) and K2C03 (89. 1 mg, 0.65 mmol) in 10 mL of dry DMF is allowed to stand at rt for overnight. The mixture is diluted with Et20 and filtered through a pad of celite. Organic layer is washed with IN HCI, H2O, brine and dried over Na2SO4, filtered and concentrated. Crude material is purified by chromatography (hexanes/acetone = 10: 1) to afford the title compound as a colorless oil in 83% yield. Rf = 0.26 (10/1 hexanes/acetone).'H NMR (400 MHz, CDCl3).

Step D (R)-3- {2-Methyl-4- [1-methyl-3- (2-phenoxy-4-trifluoromethoxy-phenoxy)- propylsulfanyl]-phenyl-propionic acid A solution of 3-14- [3- (2-bromo-4-trifluoromethoxy-phenoxy)-l-methyl- propylsulfanyl]-2-methyl-phenyl}-propionic acid methyl ester (0.117 g, 0.22 mmol), phenol (63 mg, 0.67 mmol), copper (II) chloride (11 mg, 0.11 mmol), 2,2, 6,6-

Tetramethyl-3,5-heptanedione (5 mg, 0.03 mmol), and cesium carbonate (0.219 g, 0.67 mmol) in NMP (5 mL) is heated to 120 °C. The reaction stirred overnight, and then is cooled to room temperature. The reaction is then quenched with IN aqueous hydrochloric acid and extracted with ethyl ether. The organic is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude ester intermediate. The intermediate is treated with 5N NaOH (0.4 mL, 2.2 mmol) in MeOH (5 mL) and heated to reflux. The reaction stirred at reflux for 2 hours and then is cooled.

The reaction is quenched with IN aqueous hydrochloric acid to pH=4. The aqueous is extracted with ethyl ether. The organic is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude product. The crude is purified by prep HPLC to afford 30 mg (26%) of desired product NMR (400 MHz, CDC13) ; MS (ES+) 7nlz mass calcd for C27H27F305S 520, found 521 (M+1, 100%).

Example 93 (S)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propion ic acid Step A (S)-3- (4-Chloro-2-phenoxy-phenoxy)-butan-1-ol A solution of (R) -acetic acid 3- (toluene-4-sulfonyloxy)-butyl ester (1.43 g, 5 mmol) and 4-chloro-2-phenoxy-phenol (1.0 g, 4.5 mmol) in DMF (20 mL) is treated with cesium carbonate (1.77 g, 5.4 mmol). The solution is heated to 60 °C and stirred

overnight. The reaction is cooled and quenched with 1N HC1. The solution is partitioned in EtOAc and water. The organic is separated, washed with brine, and dried over sodium sulfate. The organic is filtered and the solvent is removed to afford acetic acid 3- (4- chloro-2-phenoxy-phenoxy) -butyl ester, which is then diluted in methanol (20 mL) and treated with potassium carbonate (1.5 g, 10.9 mmol). The reaction is stirred for 3 hours at room temperature. The reaction is partitioned in ethyl ether and water. The organic layer is separated, washed with brine, and dried over sodium sulfate. The organic is filtered and the solvent is removed to afford the crude product. The crude is purified by silica gel column chromatography using 1/1 hexanes/EtOAc to elute the pure product. The solvent is removed to afford 0.99 g (88%) of the desired product. 1H NMR (400 MHz, CDC13) ; MS (ES+) 7n/z mass calcd for C16H17ClO3 292, found 293 (M + 1,100%).

Step B (S)-Methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-butyl ester A solution of (S)-3- (4-chloro-2-phenoxy-phenoxy)-butan-l-ol (0.99 g, 3.2 mmol) in CH2C12 (20 mL) is cooled to 0 °C. The solution is then treated with TEA (0.38 g, 3.8 mmol) and MsCI (0.44 g, 3.8 mmol). The reaction stirred for 2 hours at 0 °C. The reaction is diluted in water and extracted with CH2Cl2. The organic is separated, washed with brine, and dried over sodium sulfate. The organic is filtered and the solvent is removed to afford 1.28 g (100%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for Cl7Hl9ClOss 370, found 371 (M + 1, 100%).

Step C (S)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propion ic acid A solution of (S)-methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)- butyl ester (0.15 g, 0.4 mmol) and 3- (2-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.099 g, 0.44 mmol) in DMF (5 mL) is treated with cesium carbonate (0.158 g, 0.49 mmol). The reaction is heated to 50 °C and stirred overnight. The reaction is cooled and

quenched with 1N HCI. The solution is partitioned in EtOAc and water. The organic is separated, washed with brine, and dried over sodium sulfate. The organic is filtered and the solvent removed to afford the crude product. The crude is purified by silica gel column chromatography using 9/1 hexanes/EtOAc to elute the pure product. The solvent is removed to afford (S)-3- {4- [3- (4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl- phenyl}-propionic acid ethyl ester. This intermediate is treated with 5N aqueous sodium hydroxide in ethanol and heated to reflux. The reaction stirred for 3 hours and then is cooled to rt. The reaction is quenched with 1N aqueous hydrochloric acid and pH adjusted to pH=3. The aqueous is extracted with ether and washed with brine. The organic is dried over sodium sulfate, filtered, and the solvent is removed to afford 0.096 g (51%) of desired product. 1H NMR (400 MHz, CDCl3) ; MS (ES+) mlz mass calcd for C27H29ClO5 468, found 469 (M + 1,100%).

Example 94 3-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-propoxy]-2-ethyl-phenyl }-propionic acid Step A 3- (4-Chloro-2-phenoxy-phenoxy)-propan-l-ol The procedure from Example 93, Step A is utilized with 3-brom-1- propanol to afford 0.3 g (48%) of desired product NMR (400 MHz, CDCl3) ; MS (ES+) 7nlz mass calcd for Cl5Hl5ClO3 278, found 279 (M + 1,100%).

Step B Methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-propyl ester

The procedure for Example 93, Step B is utilized with 3- (4-chloro-2- phenoxy-phenoxy)-propan-l-ol to afford 0.319 g (83%) of the desired product. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for Cl6Hl7ClOss 356, found 357 (M + 1, 100%).

Step C 3-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-propoxy]-2-ethyl-phenyl }-propionic acid ethyl ester A solution of mthanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)- propyl ester (0.319 g, 0.9 mmol) and 3- (2-ehyl-4-hydroxy-phenyl)-propionic acid ethyl ester (0.218 g, 0.98 mmol) in DMF (10 mL) is treated with cesium carbonate (0.349 g, 1.07 mmol). The reaction is heated to 60 °C and stirred overnight. The reaction is cooled and quenched with 1N aqueous hydrochloric acid. he solution is partitioned in ethyl ether and water. The organic is separated, washed with brine, and dried over sodium sulfate.

The organic is filtered and the solvent is removed to afford the crude product. The crude is purified by silica gel column chromatography using 9/1 hexanes/EtOAc to elute the pure product. The solvent is removed to afford 0.337 g (78%) of the desired product NMR (400 MHz, CDC13); MS (ES+) m/z mass calcd for C2sH3iC105 482, found 483 (M + 1, 100%).

Step D 3-f 4- [3- (4-Chloro-2-phenoxy-phenoxy)-propoxy]-2-ethyl-phenyl}-propio nic acid A solution of 3- {4- [3- (4-chloro-2-phenoxy-phenoxy)-propoxy]-2-ethyl- phenyl}-propionic acid ethyl ester (0.337 g, 0.7 mmol) in ethanol (10 mL) is treated with 5N aqueous sodium hydroxide (1.4 mL). The reaction is heated to reflux and stirred for 2 hours. The reaction is then cooled and the pH adjusted to pH=4 with IN aqueous hydrochloric acid. The solution is extracted with EtOAc. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed to afford 0.28 g (88%) of desired product NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C26H27C105 454, found 455 (M + 1,100%).

Example 95 2- {4- [4- (4-Chloro-2-phenoxy-phenyl)-3-methyl-butoxy]-2-methyl-phenyl }- cyclopropanecarboxylic acid Step A 2- (4-Hydroxy-2-metliyl-phenyl)-cyclopropanecarboxylic acid ethyl ester A solution of 2- (4-benzyloxy-2-methyl-phenyl)-cyclopropanecarboxylic acid ethyl ester (2.0 g, 6.75 mmol) in EtOAc (100 mL) is treated with 10% Palladium on carbon (0.5 g) and stirred under hydrogen (1 atm). The reaction stirred for 3 hours. The reaction is filtered through celite, and the filtrate is concentrated to afford 1.3 g (94%) of

title compound. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C2oH2203 310, found 311 (M+1, 100%). <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> 2- 4- [4- (4-Chloro-2-phenoxy-phenyl)-3-methyl-butoxy]-2-methyl-phenyl }- cyclopropanecarboxylic acid ethyl ester A solution of (R)-methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)- butyl ester (0.8 g, 2.16 mmol) and 2- (4-hydroxy-2-methyl-phenyl)- cyclopropanecarboxylic acid ethyl ester (0.48 g, 2.16 mmol) in DMF (10 mL) is treated with cesium carbonate (0.77 g, 2.4 mmol). The reaction is heated to 50 °C and stirred overnight. The reaction is cooled and quenched with IN aqueous hydrochloric acid. The solution is partitioned in ethyl ether and water. The organic is separated, washed with brine, and dried over sodium sulfate. The organic is filtered and the solvent is removed to afford the crude product. The crude is purified by silica gel column chromatography using 9/1 Hexanes/EtOAc to elute two products. The solvent is removed to afford isomer 1 (0.33 g, 31%) and isomer 2 (0.345 g, 32%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) 771/Z mass calcd for C30H33C104 492, found 493 (M + 1,100%).

Step C 2- {4- [4- (4-Chloro-2-phenoxy-phenyl)-3-methyl-butoxy]-2-methyl-phenyl }- cyclopropanecarboxylic acid A solution of 2- {4- [4- (4-chloro-2-phenoxy-phenyl)-3-methyl-butoxy]-2- methyl-phenyl}-cyclopropanecarboxylic acid ethyl ester (0. 330 g, 0.7 mmol, Isomer 1) in ethanol (10 mL) is treated with 5N aqueous sodium hydroxide (1.3 mL). The reaction is heated to reflux and stirred for 3 hours. The reaction is cooled and the pH adjusted to pH=4 with IN aqueous hydrochloric acid. The solution is extracted with EtOAc. The organic is washed with brine, dried over sodium sulfate and filtered. The solvent is

removed to afford 0.26 g (84%) of title compound. 1H NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C28H29ClO4 464, found 465 (M + 1,100%).

Example 96 2- {4- [4- (4-Chloro-2-phenoxy-phenyl)-3-methyl-butoxy]-2-methyl-phenyl }- cyclopropanecarboxylic acid A solution of 2-14- [4- (4-chloro-2-phenoxy-phenyl)-3-methyl-butoxy]-2- methyl-phenyl}-cyclopropanecarboxylic acid ethyl ester (0.345 g, 0.7 mmol, Isomer 2) in ethanol (15 mL) is treated with 5N aqueous sodium hydroxide (1.4 mL). The reaction is heated to reflux and stirred for 3 hours. The reaction is cooled and the pH adjusted to pH=4 with IN aqueous hydrochloric acid. The solution is extracted with EtOAc. The organic is washed with brine, dried over sodium sulfate and filtered. The solvent is removed to afford 0.27 g (83%) of title compound. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C28H29C1O4 464, found 465 (M + 1,100%).

Example 97 (S)- [4- (3-Methanesulfonyloxy-butoxy)-2-methyl-phenylsulfanyl]-aceti c acid ethyl ester Step A 4-Benzyloxy-2-methyl-1-methylsulfanyl-benzene A mixture of 4-(methylthio)-m-cresol (10 g, 64.8 mmol) and 325 mesh K2C03 (11.65 g, 84. 3 mmol) in DMF (100 mL) is treated with benzyl bromide (12.22 g, 71.5 mmol) and stirred at room temperature for 17 hr under N2. The mixture is filtered using Et20 to rinse the solids, and the filtrate is acidified with 1 N HC1 (65 mL). The filtrate is diluted with more Et20 and then extracted twice with water and brine. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 17. 03 g (100%) of crude title compound that is carried on without purification. Rf= 0. 66 (1/1 hexanes/acetone).'H NMR (400 MHz, CDCl3). <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> 1-Methanesulfinyl-4-benzyloxy-2-methyl-benzene A 0 OC solution of crude 4-benzyloxy-2-methyl-1-methylsulfanyl-benzene (17.03 g, 64. 8 mmol) in chloroform (300 mL) is treated with about 77% m-

chloroperbenzoic acid (14.53 g, 64.8 mmol) in portions over 10 minutes. The reaction is stirred at 0 °C for 20 minutes and monitored closely by TLC (1/1 hexanes/acetone) until the crude material is gone (Rf = 0.66) and the sulfoxide formed (Rf = 0.27). The mixture is extracted with saturated NaHCO3 and then saturated NaHSO3. The organic layer is dried (MgS04), and the solvent is removed in vacuo to afford 18.32 g (100%) of crude title compound that is carried on without purification. Rf = 0.27 (1/1 hexanes/acetone). IH NMR (400 MHz, CDC13) ; MS (ES+) inlz mass calcd for ClsHIgO2S 260, found 261 (M + 1,100%).

Step C (4-Benzyloxy-2-methyl-phenylsulfanyl) -acetic acid ethyl ester A solution of crude material from Step B (18.32 g, 64.8 mmol) in CH2C12 (250 mL) is treated with trifluoroacetic anhydride (27.2 g, 0. 130 mol, ) and the resultant purple solution is heated to reflux for 30 minutes under N2. The reaction is cooled, and the solvent is removed in vacuo to give 25.21 g (100%) of an intermediate that is carried on without purification. Rf= 0.66 (1/1 hexanes/acetone). The crude ot-trifluoroacetoxy sulfide (25.21 g, assume 64.8 mmol) is combined with bromoEtOAc (59.02 g, 0.353 mol) in EtOH (230 mL) and purged with N2 for 5 minutes. Potassium carbonate (325 mesh, 32.56 g, 0.236 mol) is added, and the mixture is stirred for 17 hours at rt under N2, The mixture is filtered using Et20 to rinse the solids, and the filtrate is acidified with 1 N HC1 (100 mL). The filtrate is diluted with more Et20 and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 10/1 hexanes/acetone to afford 6.45 g (35%) of the title compound. Rf = 0.43 (2/1 hexanes/acetone).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for CI8H2oO3S 316, found 317 (M + 1, 100%).

Step D (4-Hydroxy-2-methyl-phenylsulfanyl) -acetic acid ethyl ester

A solution (-78 °C) of material obtained in Step C (6.44 g, 20.4 mmol) and dimethylethylsilane (17.96 g, 0.203 mol) in CH2C12 (150 mL) is treated dropwise with a 1 M solution of TiCl4 in CH2C12 (20.4 mL, 20.4 mmol). The mixture is warmed to 0°C and then rt for 3 hours. The reaction is quenched with water and extracted with EtOAc. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 98/2 CH2C12/ACN to afford 2.96 g (64%) of the title compound. Rf= 0. 28 (2/1 hexanes/acetone).'H NMR (400 MHz, CDC13) ; MS (ES-) niez mass calcd for C11H14O3S 226, found 325 (M-1,100%).

Step E (2-Toluene-4-sulfonic acid 3-hydroxy-butyl ester A solution of (S)- (+)-1, 3-butanediol (9.5 g, 0.105 mol) and Et3N (12.8 g, 0.126 mol) in CH2C12 (200 mL) is treated with dibutyltin oxide (0.52 g, 2.08 mmol) and thenp-toluenesulfonyl chloride (20.09 g, 0.105 mol) is added as a solid in portions over 30 minutes at rt. The resultant mixture is stirred at rt for 17 hours under N2. The reaction is quenched with 1 N HC1 (50 mL), diluted with water and extracted with EtOAc. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 98/2 CH2C12/ACN (to elute the unreactedp-toluenesulfonyl chloride) and then 2/1 hexanes/acetone to afford 18. 67 g (73%) the title compound. Rf== 0.23, Rf bis-tosylate = 0.53 (98/2 CH2C12/ACN).

Step F ()- [4- (3-Hydroxy-butoxy)-2-methyl-phenylsulfanyl]-acetic acid ethyl ester

A mixture of (4-hydroxy-2-methyl-phenylsulfanyl) -acetic acid ethyl ester (2.96 g, 13.1 mmol), (S)-toluene-4-sulfonic acid 3-hydroxy-butyl ester (3.83 g, 15.7 mmol) and cesium carbonate (5.54 g, 0.169 mol) in dry DMF (55 mL) is heated to 50°C for 17 hours under N2. The reaction is cooled, quenched with 1 N HC1 (40 mL), diluted with Et20 and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using a gradient of 6/1 to 2/1 hexanes/EtOAc to afford 2.30 g (59%) of the title compound. Rf = 0.28 (1/1 hexanes/EtOAc).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C15H22O4S 298, found 321 (M+Na, 100%).

Step G (6- [4- (3-Methanesulfonyloxy-butoxy)-2-methyl-phenylsulfanyl]-aceti c acid ethyl ester A 0 °C solution of (S)- [4- (3-hydroxy-butoxy)-2-methyl-phenylsulfanyl]- acetic acid ethyl ester (2.29 g, 7.67 mmol) and Et3N (1.94 g, 19.2 mmol) in CH2Cl2 (40 mL) is treated dropwise with MsCI (1.32 g, 11.5 mmol) and stirred at 0 °C for 2 hours under N2. The reaction is quenched with 1 N HC1 (23 mL), diluted with CH2C12 and then extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 3.20 g (100%) of the title compound. Rf= 0.37 (1/1 hexanes/EtOAc). IH NMR (400 MHz, CDC13) ; MS (ES+) nilz mass calcd for C16H24O6S2 376, found 377 (M + 1,100%).

Example 98 (R)-{4-[3-(4-Ethyl-2-phenoxy-phenoxy)-butoxy]-2-methyl-pheny lsulfanyl}-acetic acid Step A<BR> <BR> 4-Ethyl X 1-methoxy-2-phenoxy-benzene A mixture of 2-bromo-4-ethyl-1-methoxy-benzene (0.60 g, 2.79 mmol), phenol (0.525 g, 5. 57 mmol), cesium carbonate (1.82 g, 5.58 mmol), copper (I) chloride (0.138 g, 1.39 mmol) and 2,2, 6,6-tetramethyl-3, 5-heptanedione (0.13 g, 0.706 mmol) in dry 1-methyl-2-pyrrolidinone (5 mL) is heated to 120 °C for 17 hours under N2. The reaction is cooled, quenched with 1 N HC1 (20 mL), diluted with Et20 and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/EtOAc to afford 0.604 g (95%) of the title compound. Rf = 0.46 (4/1 hexanes/EtOAc). IH NMR (400 MHz, CDC13) ; MS (ES+) nalz mass calcd for Cj5H2204S 298, found 321 (M + Na, 100%).

Step B 4-Ethyl-2-phenoxy-phenol

A-40 °C solution of 4-ethyl-1-methoxy-2-phenoxy-benzene (0.60 g, 2.62 mmol) in dry CH2C12 (5 mL) is treated dropwise with borontribromide (1.96 g, 7.83 mmol) and then warmed to 0 °C and stirred for 30 minutes under N2. The reaction is diluted with Et20 and quenched with water. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 2/1 hexanes/acetone to afford 0.448 g (80%) 4- ethyl-2-phenoxy-phenol. Rf= 0.44 (2/1 hexanes/acetone). JH NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C14H14O4 214, found 213 (M-1,100%).

Step C (R)-({4-[3-(4-Ethyl-2-phenoxy-phenoxy)-butoxy]-2-methyl-phen ylsulfanyl}-acetic acid ethyl ester A mixture of 4-ethyl-2-phenoxy-phenol (0.141 g, 0. 658 mmol), (, S)- [4- (3- methanesulfonyloxy-butoxy)-2-methyl-phenylsulfanyl]-acetic acid ethyl ester (0.297 g, 0.789 mmol) (Example 97, Step G) and Cs2CO3 (0.279 g, 0.856 mmol) in dry DMF (10 mL) is heated to 60 °C and stirred for 17 hours under N2. The mixture is cooled and acidified with 1 N HC1 (20 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford

crude product that is absorbed on silica gel and purified by column chromatography using 9/1 hexanes/EtOAc to afford 0.230 g (71%) of the title compound. Rf = 0.30 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDC13) ; MS (ES+) 7n/z mass calcd for C29H3405S 494, found 495 (M + 1,100%).

Step D (R)- {4- [3- (4-Ethyl-2-phenoxy-phenoxy)-butoxy]-2-methyl-phenylsulfanyl} -acetic acid A solution of ()- ( {4- [3- (4-ethyl-2-phenoxy-phenoxy)-butoxy]-2-methyl- phenylsulfanyl}-acetic acid ethyl ester (0.230, 0.465 mmol) in ethanol (6 mL) is treated with 5 N NaOH (1 mL) and stirred at room temperature until saponification complete.

The solvent removed in vacuo to afford a residue that is acidified with 1 N HC1. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 0.206 g (95%) of the title compound.'H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z exact mass calcd for C27H30O5S 466, found 467 (M + 1,100%).

Example 99 (R)-{4-[3-(2-Benzoyl-4-methyl-phenoxy)-butoxy]-2-methyl-phen ylsulfanyl}-acetic acid Step A (R)-f 4- [3- (2-Benzoyl-4-methyl-phenoxy)-butoxy]-2-methyl-phenylsulfanyl }-acetic acid ethyl ester

A mixture of (2-hydroxy-5-methyl-phenyl)-phenyl-methanone (0.189 g, 0.891 mmol), (S)- [4- (3-methanesulfonyloxy-butoxy)-2-methyl-phenylsulfanyl]-aceti c acid ethyl ester (0.402 g, 1.07 mmol) (Example 97, Step G) and Cs2CO3 (0.377 g, 1.16 mmol) in dry DMF (15 mL) is heated to 60 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (20 mL). The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 9/1 hexanes/EtOAc to afford 0.326 g (74%) of the title compound.

Rf= 0.53 (98/2 CH2C12/ACN).'H NMR (400 MHz, CDC13) ; MS (ES+) walz mass calcd for C29H3205S 492, found 493 (M + 1,100%).

Step B (R)- {4- [3- (2-Benzoyl-4-methyl-phenoxy)-butoxy]-2-methyl-phenylsulfanyl }-acetic acid A solution of (R)- {4- [3- (2-benzoyl-4-methyl-phenoxy)-butoxy]-2-methyl- phenylsulfanyl}-acetic acid ethyl ester (0.326, 0.662 mmol) in ethanol (10 mL) is treated with 5 N NaOH (2 mL) and stirred at rt until saponification complete. The solvent is removed in vacuo to afford a residue that is acidified with 1 N HC1. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford 0.321 g (100%) of the title compound. IH NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C27H2805S 464, found 465 (M + 1, 100%).

Example 100 <BR> <BR> (R)-f 4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-2-methyl-phen ylsulfanyl}- acetic acid

Step A <BR> <BR> (R)- {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-2-methyl-phen ylsulfanyl}- acetic acid ethyl ester

A mixture of (2-hydroxy-5-trifluoromethoxy-phenyl)-phenyl-methanone (0.286 g, 1.01 mmol), (S)-[4-(3-methanesulfonyloxy-butoxy)-2-methyl-phenylsulfanyl ]- acetic acid ethyl ester (0.460 g, 1.22 mmol) (Example 97, Step G) and Cs2CO3 (0.40 g, 1.23 mmol) in dry DMF (25 mL) is heated to 50 °C and stirred for 17 hours under N2.

The reaction is cooled and acidified with 1 N HCI (20 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by

column chromatography using 6/1 hexanes/EtOAc to afford 0.291 g (51 %) of the title compound. Rf= 0.51 (1/1 hexanes/EtOAc). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C29H2906SF3 562, found 563 (M + 1,100%).

Step B (R)-{4-[3-(2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-2-m ethyl-phenylsulfanyl}- acetic acid A solution of (R)- {4- [3- (2-benzoyl-4-methyl-phenoxy)-butoxy]-2-methyl- phenylsulfanyl}-acetic acid ethyl ester (0.291, 0. 517 mmol) in ethanol (10 mL) is treated with 5 N NaOH (1 mL) and stirred at room temperature until saponification complete.

The solvent is removed in vacuo to afford a residue that is acidified with IN HCI. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford 0.280 g (100%) of the title compound. 1H NMR (400 MHz, CDCl3) ; HRMS (ES+) m/z exact mass calcd for C27H2606SF3 535.1402, found 535.1396.

Example 101 {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-hexyloxy]-2-methyl-phenylsulfany l}-acetic acid Step A (5-Ethyl-2-methoxy-phenyl)-phenyl-methanone

A 0 °C solution of 4-etliylanisole (10.0 g, 73.4 mmol) in dry CH2Cl2 (100 mL) is treated portion wise with aluminum chloride (11.7 g, 87.7 mmol). The 0 °C reaction mixture is then treated dropwise with benzoyl chloride (11. 38 g, 81. 0 mmol) and the reaction is stirred at 0 °C for 1 hour under N2. The reaction is poured into ice water and extracted with CH2C12. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/EtOAc to afford 14.72 g (83%) of the title compound. Rf= 0.34 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDC13) ; MS (ES+) nzlz mass calcd for Cl6Hl6o2 240, found 241 (M + 1, 100%). <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> (5-Ethyl-2-methoxy-phenyl)-phenyl-methanone A mixture of (5-ethyl-2-methoxy-phenyl) -phenyl-methanone 2120203 (10.0 g, 41.6 mmol) and pyridine hydrochloride (48.1 g, 0.416 mol) is heated to 200 °C in an oil bath stirred for 30 minutes under N2. The reaction is cooled diluted with Et20 and washed twice with 1 N HC1 and brine. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 8.90 g (95%) of the title compound. Rf = 0.55 (2/1 hexanes/EtOAc).'H NMR (400 MHz, CDC13) ; MS (ES-) inlz mass calcd for C15H14O2 226, found 225 (M-1,100%).

Step C 3-Bromo-hexan-1-ol

A-78 °C solution of ethyl p-bromocaproate (5.0 g, 22.4 mmol) in dry THF (50 mL) is treated dropwise with a 1 M solution of diisobutylaluminum hydride in cyclohexane (47 mL, 47.0 mmol). The mixture is stirred for 15 minutes at-78 °C and then warmed to 0 OC and stirred for 45 minutes under N2. The reaction is slowly quenched with 1 N HC1 (100 mL) and then diluted with water and extracted with Et2O.

The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford 4.04 g (99%) of crude 3-bromo-hexan-1-ol that is utilized without purification.

Step D {5-Ethyl-2-[1-(2-hydroxy-ethyl)-butoxy]-phenyl}-phenyl-metha none A mixture of (5-ethyl-2-methoxy-phenyl) -phenyl-methanone (1.00 g, 4.42 mmol), 3-bromo-hexan-1-ol (2.00 g, 11.0 mmol) and Cs2C03 (4.32 g, 13.3 mmol) in dry DMF (20 mL) is heated to 50 °C and stirred for 17 hours under N2. The reaction is cooled, filtered, and the filtrate is acidified with 1 N HC1 (20 mL). The filtrate is diluted with water and extracted with Et20. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using a gradient of 6/1 then 3/1 hexanes/acetone to afford 1.03 g (71%) of the title compound. Rf= 0.24 (2/1 hexanes/acetone).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C2, H2603 326, found 327 (M + 1,100%).

Step E Methanesulfonic acid 3- (2-benzoyl-4-ethyl-phenoxy)-hexyl ester

A 0 °C solution of {5-ethyl-2- [l- (2-hydroxy-ethyl)-butoxy]-phenyl}- phenyl-methanone (1.03 g, 3.16 mmol) and TEA (0.64 g, 6.32 mmol) in CH2C12 (25 mL) is treated with MsCI (0.592 g, 5.17 mmol), and the reaction is stirred for 1 hour at 0 °C under N2. The reaction is quenched with 1 N HC1 (7 mL) and diluted with more CH2Cl2 and extracted with water. The organic layer is dried (MgS04), and the solvent is removed in vacuo to afford 1. 30 g (100%) of the title compound that is utilized without purification. IH NMR (400 MHz, CDC13).

Step F {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-hexyloxy]-2-methyl-phenylsulfany l}-acetic acid A mixture of (4-hydroxy-2-methyl-phenylsulfanyl) -acetic acid ethyl ester (0.081 g, 0.358 mmol), methanesulfonic acid 3- (2-benzoyl-4-ethyl-phenoxy)-hexyl ester (0.145 g, 0. 359 mmol) and Cs2CO3 (0.140 g, 0. 430 mmol) in dry DMF (7 mL) is heated to 50 °C and stirred for 17 hours under N2. The reaction is treated with 5 N NaOH (2 mL) and cooled to room temperature and stirred 2 hours. The mixture is acidified with 1 N HC1 (25 mL), diluted with water and extracted with Et20. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford 0. 387 g of crude acid that is purified by preparative HPLC to afford 0.060 g (33%) of the title compound.'H NMR (400 MHz, CDC13) ; MS (ES+) 7n/z mass calcd for C3oH34OsS 506, found 507 (M + 1, 100%).

Example 102 3-{4-[3-(2-Benzoyl-4-ethyl-phenoxy)-hexyloxy]-2-methyl-pheny l}-propionic acid

The title compound is prepared by following the procedure described in Example 101, Step F by utilizing 3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester to afford 0.314 g (57%). 1H NMR (400 MHz, CDCl3) ; HRMS (ES+) m/z exact mass calcd for C3, H3705 489.2641, found 489.2618.

Example 103 {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-hexyloxy]-2-methyl-phenoxy}-acet ic acid

The title compound is prepared by following the procedure described in Example 101, Step F by utilizing (4-hydroxy-2-methyl-phenoxy) -acetic acid methyl ester to afford 0.062 g (54%). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C30H34O6 490, found 491.

Example 104 3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-hexylsulfanyl]-2-methyl-phenyl}- propionic acid The title compound is prepared by following the procedure described in Example 101, Step F by utilizing 3- (4-mercapto-2-methyl-phenyl)-propionic acid methyl ester to afford 0.069 g (38%). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C31H36O4S 504, found 505.

Example 105 {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-hexylsulfanyl]-2-methyl-phenoxy} -acetic acid The title compound is prepared by following the procedure described in Example 101, Step F by utilizing (4-mercapto-2-methyl-phenoxy) -acetic acid ethyl ester to afford 0.069 g (38%). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C3oH3405S 506, found 507.

Example 106 <BR> <BR> (R)-3- {4- [3- (4-Ethyl-2-phenoxy-phenoxy)-1-methyl-propoxy]-2-methyl-pheny l}- propionic acid Step A (S)- [5-Ethyl-2- (3-hydroxy-butoxy)-phenyl]-phenyl-methanone A mixture of (5-ethyl-2-methoxy-phenyl) -phenyl-methanone (2.96 g, 13.1 mmol), ()-toluene-4-sulfonic acid 3-hydroxy-butyl ester (1.19 g, 4. 87 mmol) and cesium carbonate (1.73 g, 5.31 mol) in dry DMF (25 mL) is heated to 55 °C for 17 hours under N2. The reaction is cooled, quenched with 1 N HC1 (20 mL), diluted with Et20 and extracted with water. The organic layer is dried (Na2S04), and the solvent is removed il7 vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using a gradient of 4/1 to 2/1 hexanes/EtOAc to afford 0.860g (65%) of the title compound. Rf= 0.29 (1/1 hexanes/EtOAc). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for Cl9H2203 298, found 321 (M + Na, 100%).

Step B (S)-Methanesulfonic acid 3- (2-benzoyl-4-ethyl-phenoxy)-l-methyl-propyl ester

A 0 °C solution of (S)- [5-ethyl-2- (3-hydroxy-butoxy)-phenyl]-phenyl- methanone (0.86 g, 2. 88 mmol) and Et3N (0.73 g, 7.21 mmol) in CH2Cl2 (15 mL) is treated dropwise with MsCI (0. 488 g, 4.26 mmol) and stirred at 0 °C for 2 hours under N2.

The reaction is quenched with 1 N HC1 (9 mL), diluted with CH2C12 and then extracted with water. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford 1.12 g (100%) of the title compound. Rf = 0.38 (1/1 hexanes/EtOAc).'H NMR (400 MHz, CDC13) ; MS (ES+) inlz mass calcd for C2oH2405S 376, found 377 (M + 1, 100%). step C (R)-3-{4-[3-(4-Ethyl-2-phenoxy-phenoxy)-1-methyl-propoxy]-2- methyl-phenyl}- propionic acid methyl ester

A mixture of 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0. 281 g, 1.45 mmol), (S)-methanesulfonic acid 3- (2-benzoyl-4-ethyl-phenoxy)-l-methyl- propyl ester (0.600 g, 1.59 mmol) and Cs2CO3 (0.570 g, 1.75 mmol) in dry DMF (15 mL) is heated to 60 °C and stirred for 17 hours under N2. The reaction is cooled and acidified

with 1 N HC1 (20 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 98/2 98/2 CH2C12/ACN to afford 0.411 g (60%) of the title compound. Rf= 0.46 (98/2 CH2C12/ACN).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C3pH3405 474, found 475 (M + 1, 100%).

Step D (R)-3-{4-[3-(4-Ethyl-2-phenoxy-phenoxy)-1-methyl-propoxy]-2- methyl-phenyl}- propionic acid A solution of (R)-3-f4- [3- (4-ethyl-2-phenoxy-phenoxy)-l-methyl- propoxy]-2-methyl-phenyl}-propionic acid methyl ester (0.411, 0.866 mmol) in methanol (12 mL) is treated with 5 N NaOH (3 mL) and stirred at rt until saponification complete.

The solvent removed in vacuo to afford a residue that is acidified with 1 N HCI. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2S04, and the solvent is removed in vacuo to afford 0.418 g (100%) of the title compound.'H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z exact mass calcd for C29H3305 461.2328, found 461.2335.

Example 107 (R)-3-{4-[3-(4-Ethyl-2-phenoxy-phenoxy)-butoxy]-2-methyl-phe nyl}-propionic acid Step A (S)-3- [4- (3-Hydroxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester

A mixture of 3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (3.47 g, 17.9 mmol), (X-toluene-4-sulfonic acid 3-hydroxy-butyl ester (5.23 g, 21.4 mmol) and cesium carbonate (7.57 g, 23.2 mol) in dry DMF (70 mL) is heated to 50 °C for 17 hours under N2. The reaction is cooled, filtered, and the filtrate is quenched with 1 N HC1 (50 mL). The filtrate is then diluted with Et20 and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 4/1 hexanes/EtOAc to afford 3.07 g (65%) of the title compound. Rf = 0.33 (1/1 hexanes/EtOAc).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C15H22O4 266, found 367 (M + 1, 100%).

Step B (6)-3- [4- (3-Methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester A 0 °C solution of ()-3- [4- (3-hydroxy-butoxy)-2-methyl-phenyl]- propionic acid methyl ester (3.07 g, 11.5 mmol) and Et3N (2.92 g, 28. 9 mmol) in CH2C12 (50 mL) is treated dropwise with MsCI (1.98 g, 17.3 mmol) and stirred at 0 °C for 1.5 hours under N2. The reaction is quenched with 1 N HC1 (30 mL), diluted with CH2Cl2

and then extracted with water. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford 4.17 g (100%) of the title compound. Rf= 0.45 (1/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C16H2406S2 344, found 362 (M + NH4, 100%).

Step C ()-3- {4- [3- (4-Ethyl-2-phenoxy-phenoxy)-butoxy]-2-methyl-phenyl}-propion ic acid methyl ester A mixture of 4-ethyl-2-phenoxy-phenol (0.214 g, 0.726 mmol), (S)-3- [4- (3-methanesulfonyloxy-butoxy) -2-methyl-phenyl] -propionic acid methyl ester (0.300 g, 0.871 mmol) and Cs2CO3 (0.308 g, 0.945 mmol) in dry DMF (10 mL) is heated to 60 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (20 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 9/1 hexanes/EtOAc to afford 0.216 g (64%) of the title compound. Rf= 0.30 (4/1 hexanes/EtOAc).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C29H3405 462, found 463 (M + 1, 100%).

Step D (R)-3-f 4- [3- (4-Ethyl-2-phenoxy-phenoxy)-butoxy]-2-methyl-phenyl}-propion ic acid A solution of (R)-3- {4- [3- (4-ethyl-2-phenoxy-phenoxy)-butoxy]-2-methyl- phenyl}-propionic acid methyl ester 0.216, 0.467 mmol) in methanol (6 mL) is treated with 5 N NaOH (1 mL) and stirred at rt until saponification complete. The solvent

removed in vacuo to afford a residue that is acidified with 1 N HCI. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 0.195 g (93%) of the title compound.'H NMR (400 MHz, CDC13) ; HRMS (ES+) inlz exact mass calcd for C28H3205 448, found 449 (M + 1, 100%).

Example 108 (R)-3- (4-{3-[4-Ethyl-2-(1-phenyl-vinyl)-phenoxy]-butoxy}-2-methyl- phenyl)-propionic acid Step A 4-Ethyl-2- (1-phenyl-vinyl)-benzene A 0 °C solution of (5-ethyl-2-methoxy-phenyl)-phenyl-methanone (1.00 g, 4.16 mmol) in anhydrous Et20 (10 mL) is treated dropwise with a 3 M solution of methylmagnesium bromide in Et20 (2.10 g, 6. 30 mmol) and stirred at 0 OC for 1 hour under N2. The reaction is acidified with 1 N HC1, diluted with Et20 and then extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to

afford 1.06 g (100%) of crude 1- (5-ethyl-2-methoxy-phenyl)-1-phenyl-ethanol. Rf= 0.43 (2/1 hexanes/acetone).

The alcohol intermediate is dissolved dissolved in toluene (20 mL), treated with p-toluenesulfonic acid monohydrate (0.160 g, 0.841 mmol) and is heated to reflux to remove the water generated in the reaction. Upon completion, the mixture is cooled and diluted with EtOAc, which is then extracted with water and saturated NaHCO3. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford 1.47 g crude product that is purified by column chromatography using 5/1 hexanes acetone to afford 1.17 g (100%) of the title compound. Rf= 0.65 (2/1 hexanes/acetone).'H NMR (400 MHz, CDC13); MS (ES+) m/z mass calcd for Cl7Hl8O 338, found 239 (M + 1,100%). <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> 4-Ethyl-2- (l-phenyl-vinyl)-phenol A mixture of 4-ethyl-2- (1-phenyl-vinyl)-benzene (0. 638 g, 2.68 mmol) and pyridine hydrochloride (6.20 g, 53.7 mol) is heated to 200 °C in an oil bath and stirred for 5 hours under N2. The reaction is cooled, diluted with Et20 and washed twice with 1 N HC1 and brine. The organic layer is dried (Na2SO4), and the solvent is removed ! vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 3/1 hexanes acetone to afford 0.378 g (63%) of the title compound.

Rf= 0.33 (2/1 hexanes/acetone).'H NMR (400 MHz, CDC13) ; MS (ES+) only mass calcd for C16HI60 224, found 225 (M + 1,100%).

Step C (R)-3- (4-{3-[4-Ethyl-2-(1-phenyl-vinyl)-phenoxy]-butoxy}-2-methyl- phenyl)-propionic acid methyl ester

A mixture of 4-ethyl-2- (l-phenyl-vinyl)-phenol (0. 188 g, 0. 838 mmol), (S)-3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.346 g, 1.00 mmol) and Cs2CO3 (0.330 g, 1. 01 mmol) in dry DMF (15 mL) is heated to 60 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with IN HC1 (20 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 6/1 hexanes/EtOAc to afford 0.155 g (39%) of the title compound. Rf= 0.44 (2/1 hexanes/acetone).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C3lH36o4 472, found 490 (M + NH4, 100%).

Step D (R)-3- (4-{3-[4-Ethyl-2-(1-phenyl-vinyl)-phenoxy]-butoxy}-2-methyl- phenyl)-propionic acid A solution of (R)-3-(4-{3-[4-ethyl-2-(1-phenyl-vinyl)-phenoxy]-butoxy}- 2-methyl-phenyl) -propionic acid methyl ester (0.150, 0.317 mmol) in methanol (6 mL) is treated with 5 N NaOH (1 mL) and stirred at room temperature until saponification complete. The solvent is removed in vacuum to afford a residue that is acidified with IN HC1. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford 0.118 g of crude acid that is

purified by preparative HPLC to afford 0.028 g (19%) of the title compound. 1H NMR (400 MHz, CDC13); HRMS (ES+) n ? lz exact mass calcd for C29H33Os 461.2328, found 461. 2350.

Example 109 (R)-3- (4-{3-[4-Ethyl-2-(1-methyl-1-phenyl-ethyl)-phenoxy]-butoxy}- 2-methyl-phenyl)- propionic acid Step A 4-Ethyl-2- (l-methyl-l-phenyl-ethyl)-benzene A 1M solution of titanium (IV) chloride (3.75 mL, 7.49 mmol) is cooled to -30 °C and treated dropwise with a 2 M solution dimethylzinc in toluene (3.75 g, 7.49 mmol). The mixture is stirred at-30 °C for 20 minutes under N2. A solution of (5-ethyl- 2-methoxy-phenyl) -phenyl-methanone (0.60 g, 2.50 mmol) in CH2C12 (4 mL) is added dropwise, and the reaction is stirred for 15 minutes at-30 OC and then warmed to rt and stirred for 1.5 hours. The mixture is slowly poured into a dry ice/methanol mixture, stirred and warmed to rt for 2 hours. The mixture is diluted with Et20 and then extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 9/1 hexanes/EtOAc to afford 0.601 g (95%) of the title compound.

Rf= 0.60 (4/1 hexanes/EtOAc). lH NMR (400 MHz, CDCl3). <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> 4-Ethyl-2- (1-methyl-1-phenyl-ethyl)-phenol

A-40 °C solution of 4-ethyl-2-(1-methyl-1-phenyl-ethyl)-benzene (0.600 g, 2. 36 mmol) in CH2C12 (10 mL) is treated dropwise with borontribromide (1.78 g, 7.09 mmol) and then warmed to 0 °C and stirred for 1 hour under N2. The reaction is diluted with Et20 and quenched with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuum to afford crude product that is absorbed on silica gel and purified by column chromatography using 2/1 hexane/acetone to afford 0.545 g (96%) of the title compound. Rf= 0.44 (2/1 hexane/acetone). IH NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C17H20O 240, found 239 (M-1, 100%).

Step C (R)-3- (4-[3-[4-Ethyl-2-(1-methyl-1-phenyl-ethyl)-phenoxy]-butoxy}- 2-methyl-phenyl)- propionic acid methyl ester A mixture of 4-ethyl-2- (l-methyl-1-phenyl-ethyl)-phenol (0.100 g, 0.416 mmol), (S)-3-[4-(3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]-prop ionic acid methyl ester (0.172 g, 0.499 mmol) and Cs2CO3 (0.176 g, 0.540 mmol) in dry DMF (8 mL) is heated to 60 °C and stirred for 17 hours under N2. The reaction is cooled and acidified

with 1 N HC1 (20 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2SO4), and the solvent is removed ill vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 7/1 hexanes/EtOAc to afford 0.097 g (48%) of the title compound. Rf= 0.48 (1/1 hexanes/EtOAc).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C32H4004 488, found 506 (M + NH4, 100%).

Step D (R)-3- (4-{3-[4-Ethyl-2-(1-methyl-1-phenyl-ethyl)-phenoxy]-butoxy}- 2-methyl-phenyl)- propionic acid A solution of (R)-3- (4- {3- [4-ethyl-2- (1-methyl-1-phenyl-ethyl)-phenoxy]- butoxy}-2-methyl-phenyl)-propionic acid methyl ester (0.097, 0.199 mmol) in methanol (10 mL) is treated with 5 N NaOH (2 mL) and stirred at rt until saponification is complete. The solvent is removed in vacuo to afford a residue that is acidified with 1N HC1. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford 0.095 g of crude acid that is purified by preparative HPLC to afford 0.043 g (46%) of the title compound.'H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z exact mass calcd for C3lH42NO4 (M + NH4) 492.3114, found 492.3128.

Example 110 (R)-3- {4- [3- (2-Benzoyl-4-methyl-phenoxy)-butoxy]-2-methyl-phenyl}-propio nic acid Step A (R)-3- {4- [3- (2-Benzoyl-4-methyl-phenoxy)-butoxy]-2-methyl-phenyl}-propio nic acid methyl ester

A mixture of (2-hydroxy-5-methyl-phenyl) -phenyl-methanone (0.200 g, 0.942 mmol), (S)-3-[4-(3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]-prop ionic acid methyl ester (0.390 g, 1.13 mmol) and Cs2CO3 (0.400 g, 1.23 mmol) in dry DMF (12 mL) is heated to 60 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (20 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 7/1 hexanes/EtOAc to afford 0.332 g (76%) of the title compound. Rf= 0.45 (1/1 hexanes/EtOAc). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C29H3205 460, found 461 (M + 1,100%).

Step B (R)-3-f 4- [3- (2-Benzoyl-4-methyl-phenoxy)-butoxy]-2-methyl-phenyl}-propio nic acid A solution of (R)-3- {4- [3- (2-benzoyl-4-methyl-phenoxy)-butoxy]-2- methyl-phenyl}-propionic acid methyl ester (0.332, 0.721 mmol) in methanol (10 mL) is treated with 5 N NaOH (2 mL) and stirred at rt until saponification is completed. The solvent is removed in vacuo to afford a residue that is acidified with 1 N HC1. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford 0.318 g (99%) of the title compound.'H NMR (400 MHz, CDC13) ; HRMS (ES+) nilz exact mass calcd for C28H3105 447. 2171, found 447.2174.

Example 111 <BR> <BR> (R)-3- (4- {3- [4-Ethyl-2- (l-phenyl-ethyl)-phenoxy]-butoxy}-2-methyl-phenyl)-propionic acid

Step A 4-Ethyl-2- (1-phenyl-ethyl)-benzene

A mixture of 4-ethyl-2- (1-phenyl-vinyl)-benzene (1.00 g, 4.20 mmol) and 10% palladium on carbon in anhydrous ethanol (40 mL) is purged with N2, purged with hydrogen and then stirred at rt under a hydrogen balloon for 7 hours. The reaction is filtered through hyflo, and the solvent is removed in vacuo to afford a residue that is dissolved in Et20 and dried (Na2S04). The organic layer is filtered, and the solvent is removed in vacuo to afford 0.952 g (95%) of the title compound. Rf= 0.58 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).

Step B<BR> <BR> 4-Ethyl-2- (l-phenyl-ethyl)-phenol

A-40 °C solution of 4-ethyl-2- (1-phenyl-ethyl)-benzene (0.950 g, 3.95 mmol) in CH2C12 (15 mL) is treated dropwise with borontribromide (2.97 g, 11.8 mmol) and then warmed to 0 °C and stirred for 1.5 hours under N2. The reaction is diluted with Et20 and quenched with water. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 3/1 hexanes/acetone to afford 0.860 g (96%) of the title compound. Rf= 0.59 (1/1 hexanes/EtOAc). 1H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for Cl6Hl8O 226, found 225 (M-1,100%).

Step C (R)-3- (4-{3-[4-Ethyl-2-(1-phenyl-ethyl)-phenoxy]-butoxy}-2-methyl- phenyl)-propionic acid A mixture of 4-ethyl-2- (1-phenyl-ethyl)-phenol (0.102 g, 0.451 mmol), ()-3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.170 g, 0.494 mmol) and Cs2CO3 (0.175 g, 0.537 mmol) in dry DMF (7 mL) is heated to 60 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (20 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude ester that is dissolved in methanol (6 mL) is treated with 5 N NaOH (2 mL) and stirred at rt until saponification complete. The solvent is removed in vacuo to afford a residue that is acidified with 1 N HC1. The mixture is diluted with water and extracted with EtOAc.

The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 0. 587 g of crude acid that is purified by preparative HPLC to afford 0.063 g (30%) of the title compound. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z exact mass calcd for C30H37O4 461.2692, found 461.2705.

Example 112 (R)-3- (4-{3-[4-Ethyl-2-(pyridine-2-carbonyl)-phenoxy]-butoxy}-2-me thyl-phenyl)- propionic acid

Step A Pyridine-2-carboxylic acid methoxy-methyl-amide

A 0 °C mixture of picolinoyl chloride hydrochloride (2.00 g, 11.2 mmol) and N, O-dimethylhydroxylamine (1.32 g, 13.5 mmol) in CH2C12 (50 mL) is treated dropwise with TEA (3.41 g, 33.7 mmol), and the reaction is stirred at 0 °C for 15 minutes is then warmed to rt and stirred for 1 hour under N2. The mixture is diluted with CH2Cl2 and washed with water. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford 1.44 g (77%) the title compound that is utilized without purification.

Rf= 0.10 (1/1 hexanes/EtOAc). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C8HIoO2N2 166, found 167 (M + 1, 100%).

Step B (5-Ethyl-2-methoxy-phenyl)-pyridin-2-yl-methanone

A-10 °C solution of N, N, N', N'-tetramethylethylenediamine (1.31 g, 11.3 mmol) is treated dropwise with a 1.6 M solution of n-butyllithium in hexanes (7.2 mL, 11. 5 mmol), and the reaction is stirred at-10 °C under N2. 4-Ethylanisole (1. 08 g, 7.93 mmol) is then added dropwise, and the mixture is stirred at-10 °C under N2, Pyridine-2- carboxylic acid methoxy-methyl-amide (1.47 g, 8.85 mmol) is added and the mixture is stirred at-10 °C for 40 minutes under N2. The mixture is quenched with water and extracted with Et20. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 7/1 hexanes/acetone to afford 0.132 g (6%) of the title compound.

Rf= 0.38 (1/1 hexanes/EtOAc). 1H NMR (400 MHz, CDC13) ; MS (ES+) 7n/z mass calcd for Cl5HI502N 241, found 242 (M+1, 100%).

Step C (5-Ethyl-2-hydroxy-phenyl)-pyridin-2-yl-methanone A-40 °C solution of (5-ethyl-2-methoxy-phenyl)-pyridin-2-yl-methanone (0.132 g, 0.547 mmol) in CH2C12 (5 mL) is treated dropwise with borontribromide (0.424 g, 1.69 mmol) and warmed to 0 °C and then rt, which is then stirred under N2 until the reaction is completed. The reaction is cooled to 0 °C, diluted with Et2O, quenched with water and the pH is adjusted to pH = 7 with 1 N NaOH. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford 0.102 g (82%) of the title compound that is utilized without purification. Rf= 0.55 (1/1 hexanes/EtOAc). 1H NMR

(400 MHz, CDC13) ; MS (ES+) 7i7lz mass calcd for C14Hl3NO2 227, found 228 (M + 1, 100%).

Step D (R)-3- (4-{3-[4-Ethyl-2-(pyridine-2-carbonyl)-phenoxy]-butoxy}-2-me thyl-phenyl)- propionic acid methyl ester A mixture of 5-ethyl-2-hydroxy-phenyl)-pyridin-2-yl-methanone (0.102 g, 0.449 mmol), (S)-3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.170 g, 0.494 mmol) and Cs2CO3 (0.175 g, 0.537 mmol) in dry DMF (7 mL) is heated to 60 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (20 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 98/2 CH2C12/ACN to afford 0.054 g (25%) of the title compound. Rf= 0.15 (98/2 CH2C12/ACN).'H NMR (400 MHz, CDC13) ; MS (ES+) 7n/z mass calcd for C29H33NO5 475, found 476 (M + 1,100%).

StepE (R)-3- (4-{3-[4-Ethyl-2-(pyridine-2-carbonyl)-phenoxy]-butoxy}-2-me thyl-phenyl)- propionic acid A solution of (R)-3- (4-{3-[4-ethyl-2-(pyridine-2-carbonyl)-phenoxy] butoxy}-2-methyl-phenyl)-propionic acid methyl ester (0.054, 0.114 mmol) in methanol (6 mL) is treated with 5 N NaOH (1 mL) and stirred at rt until saponification is completed. The solvent is removed in vacuum to afford a residue that is neutralized to pH

= 7 with 1 N HC1. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2SO4), and the solvent is removed ill vacuo to afford 0.052 g (100%) of the title compound.'H NMR (400 MHz, CDC13) ; HRMS (ES+) inlz exact mass calcd for C28H32NO5 462.2280, found 462.2281.

Example 113 3-(2-Methyl-4- {3-[2-(thiophene-2-carbonyl)-4-trifluoromethoxy-phenoxy]-but oxy}- phenyl) -propionic acid

Step A Thiophene-2-carboxylic acid methoxy-methyl-amide

The procedure from Example 112, Step A is utilized with thiophene-2- carbonyl chloride to afford 4.09 g (92%) of the title compound. Rf= 0. 28 (2/1 hexanes/acetone). 1H NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C7H902NS 171, found 172 (M + 1, 100%).

Step B (2-Methoxy-5-trifluoromethoxy-phenyl)-thiophen-2-yl-methanon e The procedure from Example 112, Step B is utilized with thiophene-2- carboxylic acid methoxy-methyl-amide to afford 1.52 g (24%) of the title compound.

Rf=0. 51 (98/2 CH2C12/ACN).'H NMR (400 MHz, CDCl3).

Step C (2-Hydroxy-5-trifluoromethoxy-phenyl)-thiophen-2-yl-methanon e The procedure from Example 112, Step C is utilized with (2-methoxy-5- trifluoromethoxy-phenyl)-thiophen-2-yl-methanone to afford 1. 18 g (82%) of the title compound after column purification with 98/2 CH2Cl2/ACN. Rf= 0.76 (98/2 CH2C12/ACN).'H NMR (400 MHz, CDC13) ; MS (ES-) ii7lz mass calcd for C12H7O3F3S 288, found 287 (M-1,100%).

Step D<BR> <BR> 3-(2-Methyl-4- {3-[2-(thiophene-2-carbonyl)-4-trifluoromethoxy-phenoxy]-but oxy}- phenyl) -propionic acid methyl ester

A mixture of (2-hydroxy-5-trifluoromethoxy-phenyl)-thiophen-2-yl- methanone (0.100 g, 0.347 mmol), 3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl- phenyl] -propionic acid methyl ester (0.144 g, 0.418 mmol) and Cs2C03 (0. 136 g, 0.417 mmol) in dry DMF (10 mL) is heated to 50 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (25 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 10/1 hexanes/acetone to afford 0. 085 g (45%) of the title compound. Rf= 0.26 (2/1 hexanes/acetone). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C27H27SO6F3 536, found 537 (M + 1,100%).

Step E 3-(2-Methyl-4- {3-[2-(thiophene-2-carbonyl)-4-trifluoromethoxy-phenoxy]-but oxy}- phenyl) -propionic acid A solution of 3- (2-methyl-4- {3- [2- (thiophene-2-carbonyl)-4- trifluoromethoxy-phenoxy]-butoxy}-phenyl)-propionic acid methyl ester (0. 085, 0.158 mmol) in methanol (6 mL) is treated with 5 N NaOH (1 mL) and stirred at rt until saponification complete. The solvent is removed in vacuo to afford a residue that is neutralized to pH = 7 with 1 N HC1. The mixture is diluted with water and extracted with

EtOAc. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford 0.075 g (90%) of the title compound. IH NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C26H25SO6F3 522, found 523 (M + 1,100%).

Example 114 3- (4-{3-[4-Ethyl-2-(thiophene-2-carbonyl)-phenoxy]-butoxy}-2-m ethyl-phenyl)- propionic acid

Step A (5-Ethyl-2-methoxy-phenyl)-thiophen-2-yl-methanone

The procedure from Example 101, Step A is utilized with thiophene-2- carbonyl chloride to afford 8.61 g (95%) of the title compound.'H NMR (400 MHz, CDCIs) ; MS (ES+) inlz mass calcd for C14H14O2S 246, found 247 (M + 1, 100%).

Step B<BR> <BR> (5-Ethyl-2-hydroxy-phenyl)-thiophen-2-yl-methanone

The procedure from Example 101, Step B is utilized with (5-ethyl-2- methoxy-phenyl) -thiophen-2-yl-methanone to afford 7.34 g (91%) of the title compound.

'H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for Cl3Hl202S 232, found 231 (M-1, 100%).

Step C 3- (4-{3-[4-Ethyl-2-(thiophene-2-carbonyl)-phenoxy]-butoxy}-2-m ethyl-phenyl)- propionic acid methyl ester

A mixture of (5-ethyl-2-hydroxy-phenyl) -thiophen-2-yl-methanone (0.111 g, 0.478 mmol), 3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.206 g, 0. 598 mmol) and Cs2CO3 (0.187 g, 0.574 mmol) in dry DMF (8 mL) is heated to 50 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (20 mL). The mixture is diluted with water and extracted with Et2O. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 10/1 hexanes/acetone to afford 0.165 g (72%) of the title compound. Rf= 0.22 (2/1

hexanes/acetone). IH NMR (400 MHz, CDCl3) ; MS (ES+) iiilz mass calcd for C28H3205S 480, found 481 (M+ 1, 100%).

Step D 3- (4-{3-[4-Ethyl-2-(thiophene-2-carbonyl)-phenoxy]-butoxy}-2-m ethyl-phenyl)- propionic acid A solution of 3-(4-{3-[4-ethyl-2-(thiophene-2-carbonyl)-phenoxy]- butoxy}-2-methyl-phenyl)-propionic acid methyl ester (0.165, 0.343 mmol) in methanol (6 mL) is treated with 5 N NaOH (1 mL) and stirred at rt until saponification is completed. The solvent is removed in vacuo to afford a residue that is acidified with 1 N HCl. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford 0.170 g (100%) of the title compound. 1H NMR (400 MHz, CDCl3) ; HRMS (ES+) m/z exact mass calcd for C27H3105S 467.1892, found 467.1887.

Example 115 3- (4- {3- [2- (Benzo [b] thiophene-2-carbonyl)-4-ethyl-phenoxy]-butoxy}-2-methyl-phen yl)- propionic acid Step A Benzo [b] thiophen-2-yl- (5-ethyl-2-metlioxy-phenyl)-methanone

The procedure from Example 101, Step A is utilized with benzo [b] thiophene-2-carbonyl chloride to afford 1.29 g (91%) of the title compound. 1H NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C18H16O2S 296, found 297 (M+1, 100%).

Step B Benzo [b] thiophen-2-yl- (5-ethyl-2-hydroxy-phenyl)-metlianone The procedure from Example 101, Step B is utilized with benzo [b] thiophen-2-yl- (5-ethyl-2-methoxy-phenyl)-methanone to afford 0.91 g (74%) of the title compound.'H NMR (400 MHz, CDCl3) ; MS (ES-) 7n/z mass calcd for C17H1402S 282, found 281 (M-1,100%).

Step C 3- {3-[2-(Benzo [b] thiophene-2-carbonyl)-4-ethyl-phenoxy]-butoxy}-2-methyl-phen yl)- propionic acid A mixture of benzo [b] thiophen-2-yl- (5-ethyl-2-hydroxy-phenyl)- methanone (0.082 g, 0.290 mmol), 3-[4-(3-methanesulfonyloxy-butoxy)-2-methyl- phenyl] -propionic acid methyl ester (0.105 g, 0.305 mmol) and Cs2CO3 (0.119 g, 0.365 mmol) in dry DMF (7 mL) is heated to 50 °C and stirred for 17 hours under N2. The reaction is treated with 5 N NaOH (2 mL), and then cooled and stirred at rt for 3 hours.

The mixture is acidified with 1 N HCI, diluted with water, and then extracted with Et20.

The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 0.427 g crude acid that is purified by preparative HPLC to give 0.024 g (16%) of the title

compound. 1H NMR (400 MHz, CDC13) ; MS (ES+) inlz mass calcd for C3lH3205S 516, found 517.

Example 116 3- (4- {3- [4-Ethyl-2- (naphthalene-1-carbonyl)-phenoxy]-butoxy}-2-methyl-phenyl)- propionic acid Step A (5-Ethyl-2-methoxy-phenyl)-naphthalen-1-yl-methanone The procedure from Example 101, Step A is utilized with naphthalene-1- carbonyl chloride to afford 10.42 g (98%) of the title compound.'H NMR (400 MHz, CDCl3) ; MS (ES+) 7nlz mass calcd for C20H18O2 290, found 291 (M + 1, 100%).

Step B (5-Ethyl-2-hydroxy-phenyl)-naphthalen-1-yl-methanone

The procedure from Example 101, Step B is utilized with (5-ethyl-2- methoxy-phenyl)-naphthalen-1-yl-methanone to afford 9.63 g (97%) of the title compound.'H NMR (400 MHz, CDCl3) ; MS (ES-) 7n/z mass calcd for C19H16O2 276, found 275 (M-1,100%).

Step C 3- (4-{3-[4-Ethyl-2-(naphthalene-1-carbonyl)-phenoxy]-butoxy}-2 -methyl-phenyl)- propionic acid The procedure from Example 115, Step C is utilized with (5-ethyl-2- hydroxy-phenyl)-naphthalen-1-yl-methanone to afford 0.056 g (47%) of the title compound. 1H NMR (400 MHz, CDC13) ; MS (ES-) mass calcd for C33H3405 510, found 509 (M-1).

Example 117 3-(4-{3-[4-Ethyl-2-(1-phenyl-vinyl)-phenoxy]-butoxy)-2-methy l-phenyl)-propionic acid

The title compound is prepared according to the procedure described in Example 115, Step C by utilizing 4-ethyl-2- (l-phenyl-vinyl)-phenol to afford 0.009 g (6%). 1H NMR (400 MHz, CDC13) ; MS (ES-) n7/z mass calcd for C3oH3404 458, found 457 (M-1).

Example 118 3- {4- [3- (2-Benzoyl-phenoxy)-butoxy]-2-methyl-phenyl}-propionic acid

The title compound is prepared according to the procedure described in Example 115, Step C by utilizing (2-hydroxy-phenyl)-phenyl-methanone to afford 0.034 g (35%). 1H NMR (400 MHz, CDCl3) ; HRMS (ES+) m/z exact mass calcd for C27H2905 433.2015, found 433.2003.

Example 119 3- {4- [3- (2-Benzoyl-4-methyl-phenoxy)-butoxy]-2-methyl-phenyl}-propio nic acid The title compound is prepared according to the procedure described in Example 115, Step C by utilizing (2-hydroxy-5-methyl-phenyl)-phenyl-methanone to afford 0.025 g (30%). 1H NMR (400 MHz, CDCl3) ; HRMS (ES+) m/z exact mass calcd for C2sH3t05 447.2171, found 447.2150.

Example 120 (R)-3-f 2-Methyl-4- [3- (quinolin-5-yloxy)-butoxy]-phenyl}-propionic acid hydrochloride The title compound is prepared according to the procedure described in Example 115, Step C by utilizing (S)-3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl- phenyl] -propionic acid methyl ester and quinolin-5-ol to afford 0.029 g (24%). 1H NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C23H25NO4 379, found 380 (M + 1, 100%).

Example 121 (R)-3-{2-Methyl-4-[3-(2-methyl-quinolin-8-yloxy)-butoxy]-phe nyl}-propionic acid hydrochloride

The title compound is prepared according to the procedure described in Example 115, Step C by utilizing ()-3- [4- (3-methanesulfonyloxy-butoxy)-2-metliyl- phenyl] -propionic acid methyl ester and 2-methyl-quinolin-8-ol to afford 0.007 g (6%).

'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C24H27NO4 393, found 394 (M + 1, 100%).

Example 122 (R)-3- {2-Methyl-4- [3- (quinolin-8-yloxy)-butoxy]-phenyl}-propionic acid hydrochloride

The title compound is prepared according to the procedure described in Example 115, Step C by utilizing (S)-3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl- phenyl]-propionic acid methyl ester and quinolin-8-ol to afford 0.025 g (21%). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C23H25NO4 379, found 380 (M + 1, 100%).

Example 123 (R)-3-{4-[3-(Isoquinolin-5-yloxy)-butoxy]-2-methyl-phenyl}-p ropionic acid hydrochloride The title compound is prepared according to the procedure described in Example 115, Step C by utilizing ()-3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl- phenyl] -propionic acid methyl ester and isoquinolin-5-ol to afford 0.037 g (31%). 1H NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C23H25NO4 379, found 380 (M + 1,100%).

Example 124 (R)-3- {4- [3- (5-Chloro-quinolin-8-yloxy)-butoxy]-2-methyl-phenyl}-propion ic acid The title compound is prepared according to the procedure described in Example 115, Step C by utilizing (S)-3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl- phenyl] -propionic acid methyl ester and 5-chloro-quinolin-8-ol to afford 0.088 g (49%).

1H NMR (400 MHz, (CDCl3) ; MS (ES+) m/z mass calcd for C23H24N04C1413, found 414 and 415 (M + 1 and M + 3,100%).

Example 125 3-14- [3- (2-Benzyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenyll-propioni c acid Step A 2-Benzyl-4-ethyl-phenol A mixture of (5-ethyl-2-methoxy-phenyl)-phenyl-methanone (1.0 g, 4.16 mmol) and triethylsilane (2. 90 g, 24.9 mmol) is treated with TFA (10 mL), and the reaction is stirred at rt for 5 hours under N2. The solvent is removed in vacuo to afford a residue that is diluted with EtOAc and extracted with water and saturated NaHCO3. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford 1.27 g of an oil. The oil is dissolved in CH2C12 (15 mL), cooled to-40 °C and treated dropwise with borontribromide (6.36 g, 25.4 mmol), which then warmed to 0 OC and stirred for 1.5 hours under N2. The reaction is diluted with Et20 and quenched with water. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 6/1 hexanes/acetone to give 0.657 g (74%) of the title compound. Rf= 0.27 (2/1 hexanes/acetone).'H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C15H16O 212, found 211 (M-1,100%).

Step B 3- {4- [3- (2-Benzyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenyl}-propioni c acid The procedure from Example 115, Step C is utilized with 2-benzyl-4- ethyl-phenol to afford 0.037 g (34%) of the title compound. 1H NMR (400 MHz, CDCl3) ; HRMS (ES+) nilz exact mass calcd for C29H3504 447.2535, found 447.2525.

Example 126 3-{4-[3-(2-Benzoyl-4-bromo-phenoxy)-butoxy]-2-methyl-phenyl} -propionic acid Step A 3-{4-{3-(2-Benzoyl-4-bromo-phenoxy)-butoxy]-2-methyl-phenyl} -propionic acid methyl ester A mixture of (5-bromo-2-hydroxy-phenyl)-phenyl-methanone (0.285 g, 1.03 mmol), 3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid

methyl ester (0.393 g, 1.14 mmol) and Cs2CO3 (0.402 g, 1.23 mmol) in dry DMF (10 mL) is heated to 50 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (25 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 10/1 hexanes/acetone to afford 0. 357 g (66%) of the title compound. Rf= 0.25 (2/1 hexanes/acetone). 1H NMR (400 MHz, CDCl3) ; MS (ES+) ? mass calcd for C28H2905Br 524, found 525 and 527 (M + 1 and M + 3,100%).

Step B 3- {4- [3- (2-Benzoyl-4-bromo-phenoxy)-butoxy]-2-methyl-phenyl}-propion ic acid A solution of 3- {4- [3- (2-benzoyl-4-bromo-phenoxy)-butoxy]-2-methyl- phenyl}-propionic acid methyl ester (0.064, 0.122 mmol) in methanol (6 mL) is treated with 5 N NaOH (0.5 mL) and stirred at rt until saponification is completed. The solvent is removed in vacuo to afford a residue that is acidified with 1 N HCI. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford 0.073 g (100%) of the title compound. 1H NMR (400 MHz, CDCl3) ; HRMS (ES+) mlz exact mass calcd for C27H2705BrNa 533.0940, found 533.0949.

Example 127 3-14- [3- (2-Benzoyl-4-butyl-phenoxy)-butoxy]-2-methyl-phenyll-propion ic acid Step A 3- {4- [3- (2-Benzoyl-4-butyl-phenoxy)-butoxy]-2-methyl-phenyl}-propion ic acid methyl ester

The compounds of 3- {4- [3- (2-benzoyl-4-bromo-phenoxy)-butoxy]-2- methyl-phenyl}-propionic acid methyl ester (0.128 g, 0.244 mmol) (Example 126, Step A), 77-butylboronic acid (0.075 g, 0.736 mmol) and cesium fluoride (0.130 g, 0.856 mmol) are combined in 1,4-dioxane (6 mL) and purged with N2. The reaction is treated with 1, 1'-bis (diphenylphosphino) ferrocene palladium (II) chloride and CH2C12 complex (0.027 g, 0.037 mmol) and then heated in an oil bath at 80 °C for 10 hours under N2. The reaction is cooled, and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and column purified using 10/1 hexanes/acetone to afford 0.066 g (54%) of the title compound. Rf= 0.26 (2/1 hexanes/acetone). IH NMR (400 MHz, CDC13) ; MS (ES+) inlz mass calcd for C32H3805 502, found 503 (M + 1,100%).

Step B 3-{4-[3-(2-Benzoyl-4-butyl-phenoxy)-butoxy]-2-methyl-phenyl} -propionic acid A solution of 3-14- [3- (2-benzoyl-4-butyl-phenoxy)-butoxy]-2-methyl- phenyl}-propionic acid methyl ester (0.066, 0.131 mmol) in methanol (6 mL) is treated with 5 N NaOH (0.7 mL) and stirred at rt until saponification is completed. The solvent is removed in vacuo to afford a residue that is acidified with 1 N HCI. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford 0.060 g (94%) of the title compound. 1H NMR (400 MHz, CDCl3), MS (ES+) m/z mass calcd for C3lH3605 488, found 489.

Example 128 3-f 4- [3- (2-Benzoyl-4-propyl-phenoxy)-butoxy]-2-methyl-phenyl}-propio nic acid Step A 3-f 4- [3- (2-Benzoyl-4-propyl-phenoxy)-butoxy]-2-methyl-phenyl}-propio nic acid methyl ester The procedure from Example 127, Step A is utilized with 71-propylboronic acid to afford 0.055 g (54%) the title compound. Rf= 0.34 (2/1 hexanes/acetone). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C31H36O5 488, found 485 (M + 1, 100%).

Step B 3- {4- [3- (2-Benzoyl-4-propyl-phenoxy)-butoxy]-2-methyl-phenyl}-propio nicacid The procedure from Example 127, Step B is utilized with 3- {4- [3- (2- benzoyl-4-propyl-phenoxy)-butoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford 0.052 g (98%) of the title compound.'H NMR (400 MHz, CDCl3) ; HRMS (ES+) m/z exact mass calcd for C3pH3505 475. 2484, found 475.2485.

Example 129 3-f 4- [4- (2-Benzoyl-4-ethyl-phenoxy)-1-methyl-butoxy]-2-methyl-phenyl }-propionic acid Step A Toluene-4-sulfonic acid 4-hydroxy-pentyl ester A solution of 1,4-pentanediol (4.60 g, 44.2 mmol) and Et3N (5.36 g, 52.9 mmol) in CH2Cl2 (100 mL) is treated with dibutyltin oxide (0.22 g, 0.884 mmol), and thenp-toluenesulfonyl chloride (8.42 g, 44. 2 mmol) is added as a solid in portions over 30 minutes at rt. The resultant mixture is stirred at rt for 6 hours under N2. The reaction is quenched with 1 N HC1 (25 mL), diluted with water and extracted with CH2Cl2. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 98/2 CH2C12/ACN (to elute the unreactedp-toluenesulfonyl chloride) and then 2/1 hexanes/acetone to afford 2.70 g (24%) of the title compound. Rf=0. 10 (98/2 CH2C12/ACN).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C2H1704S 258, found 259 (M + 1,100%).

Step B Acetic acid 1-methyl-4- (toluene-4-sulfonyloxy)-butyl ester

A solution of toluene-4-sulfonic acid 4-hydroxy-pentyl ester (1.21 g, 4.68 mmol), Et3N (0.947 g, 9. 36 mmol) and N, N-dimethylaminopyridine (0.114 g, 0. 933 mmol) in CH2Cl (20 mL) is treated dropwise with acetic anhydride (0.572 g, 5.61 mmol), and the resultant mixture is stirred at rt for 2 hours under N2. The reaction is quenched with 1 N HC1 (15 mL), diluted with water and extracted with CH2C12. The organic layer is dried (Na2SO4) and the solvent is removed i7i vacuo to afford 0.803 g (57%) of the title compound that is utilized without purification. Rf = 0.43 (1/1 hexanes/EtOAc). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C14H2oO5S 300, found 318 (M + NH4,100%).

Step C [5-Ethyl-2- (4-hydroxy-pentyloxy)-phenyl]-phenyl-methanone A mixture of (5-ethyl-2-methoxy-phenyl)-phenyl-methanone (0.248 g, 1.09 mmol), acetic acid 1-methyl-4- (toluene-4-sulfonyloxy)-butyl ester (0.362 g, 1.21 mmol) and Cs2CO3 (0.535 g, 1.64 mmol) in dry DMF (15 mL) is heated to 50 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (20 mL).

The mixture is diluted with water and extracted with Et20. The organic layer is dried

(Na2S04) and the solvent is removed in vacuo to afford 0.750 g of crude product that is dissolved in methanol (10 mL) and treated with 325 mesh K2CO3 (0.302 g, 2.19 mmol).

The mixture is stirred at rt until O-acyl protected intermediate Rf= 0.23 (4/1 hexanes/EtOAc) is converted to product. The reaction is acidified with IN HCI, diluted with water and extracted with EtOAc. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using a gradient of 3/1 then 1/1 hexanes/EtOAc to afford 0.233 g (68%) of the title compound. 1H NMR (400 MHz, CDCl3) ; MS (ES+) 7m/z mass calcd for C20H2403 312, found 313 (M + 1, 100%).

Step D Methanesulfonic acid 4- (2-benzoyl-4-ethyl-phenoxy)-1-methyl-butyl ester A 0 °C solution of [5-ethyl-2- (4-hydroxy-pentyloxy)-phenyl]-phenyl- methanone (0.233 g, 0.746 mmol) and TEA (0.189 g, 1.87 mmol) in CH2C12 (10 mL) is treated with MsCl (0. 127 g, 1.11 mmol), and the reaction stirred for 2 hours at 0 °C under N2. The reaction is quenched with 1 N HC1 (4 mL) and diluted with additional CH2C12 and extracted with water. The organic layer is dried (MgS04), and the solvent is removed in vacuo to afford 0. 310 g (100%) of the title compound that is utilized without purification. Rf= 0. 35 (1/1 hexanes/EtOAc).'H NMR (400 MHz, CDC13) ; MS (ES+) nz/z mass calcd for C2lH2605S 390, found 391 (M + 1, 100%).

Step E 3- {4- [4- (2-Benzoyl-4-ethyl-phenoxy)-1-methyl-butoxy]-2-methyl-phenyl }-propionic acid methyl ester

A mixture of 3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.135 g, 0.695 mmol), methanesulfonic acid 4-(2-benzoyl-4-ethyl-phenoxy)-1-methyl- butyl ester (0.30 g, 0.768 mmol) and cesium carbonate (0.341 g, 1.05 mol) in dry DMF (10 mL) is heated to 60 OC for 17 hours under N2. The reaction is cooled and quenched with 1 N HC1 (20 mL). The mixture is diluted with Et20 and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 98/2 CH2C12/ACN to afford 0.208 g (61%) of the title compound. Rf= 0.52 (98/2 CH2C12/ACN). 1H NMR (400 MHz, CDC13) ; MS (ES+) into mass calcd for C31H36O5 488, found 489 (M + 1, 100%).

Step F 3- {4- [4- (2-Benzoyl-4-ethyl-phenoxy)-1-methyl-butoxy]-2-methyl-phenyl }-propionic acid A solution of 3-{4-[4-(2-benzoyl-4-ethyl-phenoxy)-1-methyl-butoxy]-2- methyl-phenyl}-propionic acid methyl ester (0.208, 0.426 mmol) in methanol (8 mL) is treated with 5 N NaOH (2 mL) and stirred at rt until saponification complete. The solvent is removed in vacuo to afford a residue that is acidified with 1 N HC1. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 0. 168 g of acid that is purified by preparative HPLC to give 0.099 g (49%) of the title compound.'H NMR (400 MHz, CDC13) ; MS (ES+) n/z mass calcd for C30H340s 474, found 475 (M + 1, 100%).

Example 130 3- {4- [4- (2-Benzoyl-4-ethyl-phenoxy)-pentyloxy]-2-methyl-phenyl}-prop ionicacid Step A 3- [4- (4-Hydroxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester A mixture of 3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.247 g, 1.27 mmol), acetic acid 1-metliyl-4- (toluene-4-sulfonyloxy)-butyl ester (0.421g, 1.40 mmol) and Cs2CO3 (0.622 g, 1.91 mmol) in dry DMF (15 mL) is heated to 50 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (20 mL).

The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford 0.735 g of crude product that is dissolved in methanol (10 mL) and treated with 325 mesh K2CO3 (0.351 g, 2.549 mmol).

The mixture is stirred at it until O-acyl protected intermediate Rf= 0.53 (1/1 hexanes/EtOAc) is converted to product. The reaction is acidified with 1 N HC1, diluted with water and extracted with EtOAc. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using a gradient of 3/1 then 1/1 hexanes/EtOAc to afford 0.150 g (42%) of the title compound. Rf = 0.27 (1/1 hexanes/EtOAc).'H NMR (400 MHz, CDC13); MS (ES+) i77/z mass calcd for Cl6H2404 280, found 303 (M + Na, 100%).

Step B 3- [4- (4-Methanesulfonyloxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester

A 0 OC solution of 3- [4- (4-hydroxy-pentyloxy)-2-methyl-phenyl]- propionic acid methyl ester (0.150 g, 0.535 mmol) and TEA (0.135 g, 1.33 mmol) in CH2C12 (8 mL) is treated with MsCI (0.092 g, 0.801 mmol), and the reaction stirred for 2 hours at 0 °C under N2. The reaction is quenched with 1 N HC1 (4 mL) and diluted with more CH2C12 and extracted with water. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford 0. 185 g (96%) of the title compound that is utilized without purification. Rf= 0.38 (1/1 hexanes/EtOAc).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C17H2606S 358, found 376 (M + NH4,100%). step C 3- {4- [4- (2-Benzoyl-4-ethyl-phenoxy)-pentyloxy]-2-methyl-phenyl}-prop ionic acid methyl ester A mixture of (5-ethyl-2-methoxy-phenyl)-phenyl-methanone (0.106 g, 0.469 mmol), 3- [4- (4-methanesulfonyloxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester (0.185 g, 0.516 mmol) and cesium carbonate (0.229 g, 0.703 mol) in dry DMF (10 mL) is heated to 60 °C for 17 hours under N2. The reaction is cooled and quenched with 1 N HC1 (20 mL). The mixture is diluted with Et20 and extracted with

water. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/EtOAc to afford 0.114 g of the title compound. Rf= 0.50 (98/2 CH2C12/ACN).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C3lH3605 488, found 489 (M + 1, 100%).

Step D 3-{4-[4-(2-Benzoyl-4-ethyl-phenoxy)-pentyloxy]-2-methyl-phen yl}-propionic acid A solution of 3- {4- [4- (2-benzoyl-4-ethyl-phenoxy)-pentyloxy]-2-methyl- phenyl}-propionic acid methyl ester (0.114, 0. 233 mmol) in methanol (8 mL) is treated with 5 N NaOH (2 mL) and stirred at rt until saponification is completed. The solvent is removed in vacuo to afford a residue that is acidified with 1 N HCI. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford 0.111 g (100%) of the title compound. IH NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C3pH3405 474, found 475 (M + 1, 100%).

Example 131 3- 4- [3- (2-Benzoyl-4-ethyl-phenoxy)-2-methyl-propoxy]-2-methyl-pheny l}-propionic acid Step A Methanesulfonic acid 3-methanesulfonyloxy-2-methyl-propyl ester A 0 °C solution of 2-methyl-propane-1, 3-diol (10.0 g, 0.111 mol) and Et3N (39.3 g, 0. 388 mol) in CH2C12 (200 mL) is treated dropwise with MsCI (33.0 g, 0.228 mol) and stirred at 0 OC for 3 hours under N2. The reaction is quenched with 1 N HC1 (300 mL), diluted with CH2Cl2 and then extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 26.74 g (98%) of the title compound. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C6HI406S2 246, found 264 (M + NH4, 100%).

Step B Methanesulfonic acid 3-(2-benzoyl-4-ethyl-phenoxy)-2-methyl-propyl ester

A mixture of (5-ethyl-2-methoxy-phenyl) -phenyl-methanone (1.00 g, 4.42 mmol) methanesulfonic acid 3-metlianesulfonyloxy-2-methyl-propyl ester (8.71 g, 35.4 mmol) and cesium carbonate (2.16 g, 6.63 mol) in dry DMF (30 mL) is heated to 50 °C for 17 hours under N2. The reaction is cooled and acidified with 1 N HCI. The mixture is diluted with Et20 and extracted with water. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 6/1 hexanes/acetone to afford 1.76 g (100%) of the title compound. Rf= 0.10 (2/1 hexanes/acetone).'H NMR (400 MHz, CDC13) ; MS (ES+) nzlz mass calcd for C2oH2405S 376, found 377 (M + 1,100%). step C 3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-2-methyl-propoxy]-2-methyl-pheny l}-propionic acid methyl ester

A mixture of 3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.102 g, 0.525 mmol, methanesulfonic acid 3- (2-benzoyl-4-ethyl-phenoxy)-2-methyl- propyl ester (0.197 g, 0.523 mmol) and cesium carbonate (0.205 g, 0.629 mmol) in dry DMF (10 mL) is heated to 50 °C for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (25 mL). The mixture is diluted with Et20 and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed ill vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 10/1 hexanes/acetone to afford 0.105 g (42%) of the title compound. Rf= 0.23 (2/1 hexanes/acetone).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C30H34O5 474, found 475 (M + 1, 100%).

Step D <BR> <BR> <BR> <BR> 3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-2-methyl-propoxy]-2-methyl-pheny l}-propionic acid A solution of 3-f4- [3- (2-benzoyl-4-ethyl-phenoxy)-2-methyl-propoxy]-2- methyl-phenyl}-propionic acid methyl ester (0.105 g, 0.221 mmol) in methanol (6 mL) is treated with 5 N NaOH (1 mL) and stirred at rt until saponification is completed. The mixture is acidified with 1 N HC1, diluted with water, and extracted with Et20. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 0.116 g (100%) of the title compound.'H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z exact mass calcd for C29H3305 461. 2328, found 461.2328.

Example 132 3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-propoxy]-2-methyl-phenyl}-propio nic acid Step A 3- [4- (3-Hydroxy-propoxy)-2-methyl-phenyl]-propionic acid methyl ester A mixture of 3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (5.00 g, 25.7 mmol) 3-bromo-propan-1-ol (5. 37 g, 38.6 mmol) and cesium carbonate (12.6 g, 38. 7 mol) in dry DMF (50 mL) is heated to 50 °C for 17 hours under N2. The reaction is cooled and filtered, and the filtrate is quenched with 1 N HC1 (50 mL). The filtrate is then diluted with Et20 and extracted with water. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 6/1 hexanes/EtOAc to afford 2.08 g (32%) of the title compound. Rf= 0.30 (1/1 hexanes/acetone).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for (2004 252, found 253 (M + 1,100%). step B 3- [4- (3-Methanesulfonyloxy-propoxy)-2-methyl-phenyl]-propionic acid methyl ester

A 0 °C solution of 3- [4- (3-hydroxy-propoxy)-2-methyl-phenyl]-propionic acid methyl ester (2.05 g, 8.12 mmol) and Et3N (1.23 g, 12.2 mmol) in CH2C12 (30 mL) is treated dropwise with MsCI (1. 11 g, 9.69 mmol) and stirred at 0 OC for 1 hour under N2.

The reaction is quenched with 1 N HC1 (15 mL), diluted with CH2C12 and then extracted with water. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford 2.73 g (100%) of the title compound.'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C15H2206S 330, found 348 (M + NH4,100%).

Step C 3-{4-[3-(2-Benzoyl-4-ethyl-phenoxy)-propoxy]-2-methyl-phenyl }-propionic acid A mixture of (5-ethyl-2-methoxy-phenyl)-phenyl-methanone (0.068 g, 0.301 mmol), 3- [4- (3-methanesulfonyloxy-propoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.100 g, 0.303 mmol) and Cs2CO3 (0.118 g, 0.362 mmol) in dry DMF (7 mL) is heated to 50 °C and stirred for 17 hours under N2. The reaction is treated with 5 N NaOH (2 mL), cooled and stirred at rt until saponification is completed. The mixture is acidified with 1 N HC1, diluted with water, and extracted with Et20. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford 0.479 g of crude acid that is purified by preparative HPLC to give 0.063 g (47%) of the title compound.'H NMR (400 MHz, CDC13); MS (ES+) m/z mass calcd for C28H3o05 446, found 447 (M + 1, 100%).

Example 133 3- (4-{3-[4-Ethyl-2-(4-fluoro-benzoyl)-phenoxy]-propoxy}-2-meth yl-phenyl)-propionic acid

Step A (5-Ethyl-2-methoxy-phenyl)- (4-fluoro-phenyl)-methanone The procedure from Example 101, Step A is utilized with 4-fluoromethyl- benzoyl chloride to afford 10.2 g (100%) of the title compound. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C16HI502F 258, found 259 (M + 1, 100%). <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> (5-Ethyl-2-hydroxy-phenyl)- (4-fluoro-phenyl)-metlianone The procedure from Example 101, Step B is utilized with (5-ethyl-2- methoxy-phenyl)- (4-fluoro-phenyl)-methanone to afford 4.15 g (88%) of the title

compound. 1H NMR (400 MHz, CDC13) ; MS (ES-) rnlz mass calcd for C15H13O2F 244, found 243 (M - 1, 100%).

Step C 3- (4-{3-[4-Ethyl-2-(4-fluoro-benzoyl)-phenoxy]-propoxy}-2-meth yl-phenyl)-propionic acid The procedure from Example 132, Step C is utilized with (5-ethyl-2- hydroxy-phenyl)- (4-fluoro-phenyl)-methanone to afford 0.081 g (48%) of the title compound. 1H NMR (400 MHz, CDC13) ; MS (ES+) nzlz mass calcd for C28H2905F 464, found 465 (M + 1, 100%).

Example 134 3- (4-{3-[4-Ethyl-2-(4-trifluoromethyl-benzoyl)-phenoxy]-propox y}-2-methyl-phenyl)- propionic acid Step A (5-Ethyl-2-methoxy-phenyl)- (4-trifluoromethyl-phenyl)-methanone The procedure from Example 101, Step A is utilized with 4- trifluoromethyl-benzoyl chloride to afford 3.39 g (75%) of the title compound.'H NMR (400 MHz, CDC13) ; MS (ES+) 7n/z mass calcd for C17H15O2F3 308, found 309 (M+1, 100%).

Step B<BR> <BR> (5-Ethyl-2-hydroxy-phenyl)- (4-trifluoromethyl-phenyl)-methanone

The procedure from Example 101, Step B is utilized with (5-ethyl-2- methoxy-phenyl)- (4-trifluoromethyl-phenyl)-methanone to afford 3.2 g (100%) of the title compound. 1H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C16H13O2F3 294, found 293 (M-1,100%).

Step C 3- (4-{3-[4-Ethyl-2-(4-trifluoromethyl-benzoyl)-phenoxy]-propox y}-2-methyl-phenyl)- propionic acid The procedure from Example 132, Step C is utilized with (5-ethyl-2- hydroxy-phenyl)- (4-trifluorometliyl-phenyl)-methanone to afford 0.079 g (51%) of the title compound.'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C29H2905F3 514, found 515 (M + 1, 100%).

Example 135 3- (4-{3-[4-Ethyl-2-(3-trifluoromethyl-benzoyl)-phenoxy]-propox y}-2-methyl-phenyl)- propionic acid Step A (5-Ethyl-2-methoxy-phenyl)- (3-trifluoromethyl-phenyl)-methanone

The procedure from Example 101, Step A is utilized with 3- . trifluoromethyl-benzoyl chloride to afford 3.90 g (45%) of the title compound. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C17HI502F3 308, found 309 (M + 1, 100%). <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> (5-Ethyl-2-hydroxy-phenyl)- (3-trifluoromethyl-phenyl)-methanone The procedure from Example 101, Step B is utilized with (5-ethyl-2- methoxy-phenyl)- (3-trifluoromethyl-phenyl)-methanone to prepare 3.46 g (93%) of the title compound.'H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C16H13O2F3 294, found 293 (M-1,100%).

Step C 3- (4-{3-[4-Ethyl-2-(3-trifluoromethyl-benzoyl)-phenoxy]-propox y}-2-methyl-phenyl)- propionic acid The procedure from Example 132, Step C is utilized with (5-ethyl-2- hydroxy-phenyl)- (3-trifluoromethyl-phenyl)-methanone to afford 0.069 g (30%) of the title compound. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C29H2905F3 514, found 515 (M + 1, 100%).

Example 136 3- (4-{3-[4-Ethyl-2-(2-trifluoromethyl-benzoyl)jk-phenoxy]-prop oxy}-2-methyl-phenyl)- propionic acid

Step A (5-Ethyl-2-methoxy-phenyl)- (2-trifluoromethyl-phenyl)-methanone The procedure from Example 101, Step A is utilized with 2- trifluorometliyl-benzoyl chloride to prepare 5.18 g (100%) of the title compound. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C17H15O2F3 308, found 309 (M+1, 100%). <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> (5-Ethyl-2-hydroxy-phenyl)- (2-trifluoromethyl-phenyl)-methanone The procedure from Example 101, Step B is utilized with (5-ethyl-2- methoxy-phenyl)-(2-trifluoromethyl-phenyl)-methanone to afford 4.17 g (93%) of the

title compound. 1H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C16H13O2F3 294, found 293 (M-1,100%).

Step C 3- (4-{3-[4-Ethyl-2-(2-trifluoromethyl-benzoyl)-phenoxy]-propox y}-2-methyl-phenyl)- propionic acid The procedure from Example 132, Step C is utilized with (5-ethyl-2- hydroxy-phenyl)-(2-trifluoromethyl-phenyl)-methanone to afford 0.025 g (16%) of the title compound. 1H NMR (400 MHz, CDC13) ; MS (ES+) 777lz mass calcd for C29H2905F3 514, found 515 (M + 1, 100%).

Example 137 3- (4-{3-[4-Ethyl-2-(thiophene-2-carbonyl)-phenoxy]-propoxy}-2- methyl-phenyl)- propionic acid The title compound is prepared according to the procedure described in Example 132, Step C by utilizing (5-ethyl-2-hydroxy-phenyl)-thiophen-2-yl-methanone to afford 0.101 g (66%). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C26H2805S 452, found 453 (M + 1,100%).

Example 138 3-14- [3- (2-Benzyl-4-ethyl-phenoxy)-propoxy]-2-methyl-phenyll-propion ic acid The title compound is prepared according to the procedure described in Example 132, Step C by utilizing 2-benzyl-4-ethyl-phenol to afford 0.063 g (49%). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C2gH3204 432, found 433 (M + 1, 100%).

Example 139 3- (4-{3-[4-Ethyl-2-(naphthalene-1-carbonyl)-phenoxy]-propoxy}- 2-methyl-phenyl)- propionic acid The title compound is prepared according to the procedure described in Example 132, Step C by utilizing (5-ethyl-2-hydroxy-phenyl)-naphthalen-1-yl-methanone to afford 0.067 g (48%). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C32H3205 496, found 497 (M + 1, 100%).

Example 140 3- (4- {3- [4-Ethyl-2- (l-phenyl-vinyl)-phenoxy]-propoxy}-2-methyl-phenyl)-propioni c acid

The title compound is prepared according to the procedure described in Example 132, Step C by utilizing 4-ethyl-2- (1-phenyl-vinyl)-phenol to afford 0.030 g (21%). 1H NMR (400 MHz, CDC13) ; MS (ES-)/ mass calcd for C29H3204 444, found 443 (M-1,100%).

Example 141 3- (4- {3- [2- (Benzo [b] thiophene-2-carbonyl)-4-ethyl-phenoxy]-propoxy}-2-methyl- phenyl) -propionic acid The title compound is prepared according to the procedure described in Example 132, Step C by utilizing benzo [b] thiophen-2-yl- (5-ethyl-2-hydroxy-phenyl)-

methanone to afford 0.119 g (88%).'H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z exact mass calcd for C3oH3105S 503.1892, found 503.1890.

Example 142 2-{4-[3-(2-Benzoyl-4-ethyl-phenoxy)-butoxy]-phenoxy}-2-methy l-propionic acid A mixture of (5-ethyl-2-methoxy-phenyl)-phenyl-methanone (0.070 g, 0.309 mmol), 2- [4- (3-methanesulfonyloxy-butoxy)-phenoxy]-2-methyl-propionic acid ethyl ester (0.115 g, 0.307 mmol) and Cs2CO3 (0.121 g, 0.371 mmol) in dry DMF (7 mL) is heated to 50 °C and stirred for 17 hours under N2. The reaction is cooled to rt and acidified with 1 N HC1. The mixture is diluted with Et20 and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude ester that is dissolved in ethanol (6 mL) and treated with 5 N NaOH (0.50 mL). The mixture is stirred at rt until saponification is completed. The mixture is acidified with 1 N HC1, diluted with water, and the mixture extracted with EtOAc. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude acid that is purified by preparative HPLC to give 0.024 g (16%) of the title compound.'H NMR (400 MHz, CDC13) ; HRMS (ES+) 7izlz exact mass calcd for C29H3306 477.2277, found 477.2264.

Example 143 2-{4-[3-(2-Benzoyl-4-ethyl-phenoxy)-2-methyl-propoxy]-phenox y}-2-methyl-propionic acid The title compound is prepared according to the procedure described in Example 142 by utilizing 2- [4- (3-methanesulfonyloxy-2-methyl-propoxy)-phenoxy]-2- methyl-propionic acid ethyl ester to afford 0.059 g (41%). 1H NMR (400 MHz, CDCl3) ; HRMS (ES+) mlz exact mass calcd for C29H3306 477. 2277, found 477. 2258.

Example 144 2-14- [3- (2-Benzyl-4-ethyl-phenoxy)-butoxy]-phenoxyl-2-methyl-propion ic acid The title compound is prepared according to the procedure described in Example 142 by utilizing 2- [4- (3-methanesulfonyloxy-butoxy)-phenoxy]-2-methyl- propionic acid ethyl ester and 2-benzyl-4-ethyl-phenol to afford 0.048 g (20%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) rnlz exact mass calcd for C29H3405Na 485.2304, found 485.2299.

Example 145 2-f4- [3- (2-Benzoyl-4-bromo-phenoxy)-butoxy]-phenoxyl-2-methyl-propio nic acid Step A 2- {4- [3- (2-Benzoyl-4-bromo-phenoxy)-butoxy]-phenoxy}-2-methyl-propio nic acid ethyl ester A mixture of 2- [4- (3-methanesulfonyloxy-butoxy)-phenoxy]-2-methyl- propionic acid ethyl ester (0.405 g, 1. 08 mmol), (5-bromo-2-hydroxy-phenyl)-phenyl- methanone (0.250 g, 0.902 mmol) and cesium carbonate (0. 382 g, 1.17 mmol) in dry DMF (25 mL) is heated to 50 °C for 6 hours under N2. The reaction is cooled and acidified with 1 N HC1 (30 mL). The mixture is diluted with Et20 and extracted with water. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 8/1 hexanes/acetone to afford 0.184 g (30%) of the title compound. Rf= 0.35 (2/1 hexanes/acetone).'H NMR (400 MHz, CDC13).

Step B 2- {4- [3- (2-Benzoyl-4-bromo-phenoxy)-butoxy]-phenoxy}-2-methyl-propio nic acid A solution of 2- {4- [3- (2-benzoyl-4-bromo-phenoxy)-butoxy]-phenoxy}-2- methyl-propionic acid ethyl ester (0.059 g, 0.106 mmol) in ethanol (6 mL) is treated with 5 N NaOH (0.5 mL) and stirred at rt until saponification is completed. The solvent is removed in vacuo to afford a residue that is acidified with 1 N HC1, diluted with water, and extracted with EtOAc. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford 0.049 g of acid that is purified by preparative HPLC to give 0.044 g (79%) of the title compound.'H NMR (400 MHz, CDC13) ; MS (ES+) mlz mass calcd for C27H2706Br 526, found 527 and 529 (M + 1 and M+3,100%).

Example 146 2- {4- [3- (2-Benzoyl-4-butyl-phenoxy)-butoxy]-phenoxy}-2-methyl-propio nic acid

Step A 2-f 4- [3- (2-Benzoyl-4-butyl-phenoxy)-butoxy]-phenoxy}-2-methyl-propio nic acid ethyl ester

The compounds of2- {4- [3- (2-benzoyl-4-bromo-phenoxy)-butoxy]- phenoxy}-2-methyl-propionic acid ethyl ester (Example 145, Step A) (0.118 g, 0.212 mmol), n-butylboronic acid (0.065 g, 0. 638 mmol) and cesium fluoride (0.113 g, 0.744 mmol) are combined in 1,4-dioxane (6 mL) and purged with N2. The reaction is treated with 1, 1'-bis (diphenylphosphino) ferrocene palladium (II) chloride, CH2C12 complex (0.023 g, 0.031 mmol) and heated in an oil bath at 80 °C for 10 hours under N2. The reaction is cooled and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and column purified using 8/1 hexanes/acetone to afford 0.078 g (69%) of the title compound. Rf= 0.28 (2/1 hexanes/acetone).'H NMR (400 MHz, CDC13); MS (ES+) ç/z mass calcd for C33H4006 532, found 533 (M + 1,100%).

Step B 2- {4- [3-(2-Benzoyl-4-butyl-phenoxy)-butoxy]-phenoxy}-2-methyl-pro pionic acid A solution of 2-f 4- [3- (2-benzoyl-4-butyl-phenoxy)-butoxy]-phenoxy}-2- methyl-propionic acid ethyl ester (0.078, 0.146 mmol) in ethanol (6 mL) is treated with 5 N NaOH (0.5 mL) and stirred at it until saponification complete. The solvent is removed in vacuo to afford a residue that is acidified with 1 N HC1. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2S04) and the solvent is

removed in vacuo to afford 0.084 g (100%) of the title compound. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z exact mass calcd for C31H37O6 505.2590, found 505.2617.

Example 147 2-Methyl-2- {4- [3- (3-phenyl-benzofuran-6-yloxy)-hexyloxy]-phenoxy}-propionic acid Step A 3- (3-Phenyl-benzofuran-6-yloxy)-hexan-l-ol A mixture of (3-phenyl-benzofuran-6-ol (0.36 g, 1.71 mmol), 3-bromo- hexanol (0.403 g, 2.23 mmol) (Example 101, Step C) and Cs2C03 (0.837 g, 2.57 mmol) in dry DMF (15 mL) is heated to 50 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (12 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 97/3 CH2C12/ACN to afford 0.109 g (20%) of the title compound.

'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C2oH2203 310, found 311 <BR> <BR> <BR> (M+1, 100%).<BR> <BR> <BR> <P> Step B Methanesulfonic acid 3- (3-phenyl-benzofuran-6-yloxy)-hexyl ester

A 0 °C solution of 3- (3-phenyl-benzofuran-6-yloxy)-hexan-1-ol (0.109 g, 0.351 mmol) and TEA (0.053 g, 0.524 mmol) in CH2C12 (8 mL) is treated with MsCl (0.049 g, 0.426 mmol), and the reaction is stirred for 2 hours at 0 °C under N2. The reaction is quenched with 1 N HC1 (10 mL) and diluted with more CH2C12 and extracted with water. The organic layer is dried (MgS04), and the solvent is removed in vacuo to afford 0.146 g (100%) of the title compound that is utilized without purification.'H NMR (400 MHz, CDC13).

Step C 2-Methyl-2-{4-[3-(3-phenyl-benzofuran-6-yloxy)-hexyloxy]-phe noxy}-propionic acid ethyl ester A mixture of (2- (4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (0.054 g, 0.241 mmol), methanesulfonic acid 3- (3-phenyl-benzofuran-6-yloxy)-hexyl

ester (0.093 g, 0.239 mmol) and Cs2CO3 (0.117 g, 0.359 mmol) in dry DMF (7 mL) is heated to 50 OC and stirred for 17 hours under N2. The reaction is cooled, quenched with 1 N HC1 (12 mL), diluted with Et20 and extracted with water. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford crude ester that is purified with column chromatography using 7/1 hexanes/acetone to afford 0.062 g (50%) of the title compound. Rf= 0.38 (2/1 hexanes/acetone).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C32H3606 516, found 517 (M + 1,100%). step D 2-Methyl-2- {4- [3- (3-phenyl-benzofuran-6-yloxy)-hexyloxy]-phenoxy}-propionic acid A solution of 2-methyl-2- {4- [3- (3-phenyl-benzofuran-6-yloxy)-hexyloxy]- phenoxy}-propionic acid ethyl ester (0.062 g, 0.120 mmol) in ethanol (6) is treated with 5 N NaOH (0.50 mL) and stirred at rt for 3 hours. The solvent is removed in vacuo to afford a residue that is acidified with 1 N HC1. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford 0.060 g (100%) of the title compound. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C3oH3206 488, found 489 (M + 1,100%).

Example 148 2-Methyl-2- {4- [3- (3-phenyl-7-propyl-benzo [d] isoxazol-6-yloxy)-hexyloxy]-phenoxy}- propionic acid Step A (2, 4-Dihydroxy-3-propyl-phenyl)-phenyl-methanone oxime

A mixture of (2,4-dihydroxy-3-propyl-phenyl)-phenyl-methanone (1.97 g, 7.69 mmol), hydroxylamine hydrochloride (3.52 g, 50.6 mmol) and sodium acetate (4.16 g, 50.6 mmol) in methanol (20 mL) is heated to reflux and stirred for 24 hours under N2.

The reaction is cooled and diluted with isopropylacetate and extracted with water and brine. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford 2.09 g (100%) of the title compound that is utilized without purification. Roi=0. 45 (1/1 hexanes/acetone).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for CHnOsN 271, found 272 (M + 1, 100%).

Step B 3-Phenyl-7-propyl-benzo [d] isoxazol-6-ol A solution of (2,4-dihydroxy-3-propyl-phenyl)-phenyl-methanone oxime (2.09 g, 7.69 mmol) in acetic anhydride (22 mL) is stirred at rt for 17 hours under N2.

The solvent is removed from the mixture in vacuo to afford a solid that is dissolved in isopropylacetate and extracted with water. The organic layer is dried (MgS04) and the solvent is removed in vacuo to afford 2.37 g of a residue that is dissolved in pyridine (24 mL) and heated to reflux and stirred for 8 hours under N2. The mixture is cooled to 0 °C

and quenched with 1 N HC1 (200 mL). The mixture is diluted with EtOAc and extracted with water and additional 1 N HC1 (200 mL). The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and column purified using 6/1 hexanes/acetone to afford 1.34 g (69%) of the title compound.

Rf= 0.25 (2/1 hexanes/acetone). IH NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C16HI502N 253, found 254 (M + 1,100%).

Step C 3- (3-Phenyl-7-propyl-benzo [d] isoxazol-6-yloxy)-hexan-1-ol

A mixture of 3-phenyl-7-propyl-benzo [d] isoxazol-6-ol (0.50 g, 1.97 mmol), 3-bromo-hexan-1-ol (0.790 g, 4.36 mmol) (Example 101, Step C) and Cs2CO3 (1.60 g, 4.91 mmol) in dry DMF (20 mL) is heated to 50 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (20 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude product that is purified by column chromatography using 98/2 CH2C12/ACN to afford 0.233 g (33%) of the title compound. Rf = 0.26 (98/2 CH2C12/ACN).'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C22H2703N 353, found 354 (M + 1,100%).

Step D Methanesulfonic acid 3- (3-phenyl-7-propyl-benzo [d] isoxazol-6-yloxy)-hexyl ester

A 0 °C solution of 3- (3-phenyl-7-propyl-benzo [d] isoxazol-6-yloxy)-hexan- 1-ol (0.240 g, 0.679 mmol) and TEA (0.103 g, 1.02 mmol) in CH2C12 (15 mL) is treated with MsCI (0.093 g, 0.814 mmol), and the reaction stirred for 1.5 hours at 0 °C under N2.

The reaction is quenched with 1 N HC1 (20 mL) and diluted with more CH2Cl2 and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 0.294 g (100%) of the title compound that is utilized without purification.

'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C23H2905SN 431, found 432 (M+1, 100%).

Step E 2-Methyl-2- {4- [3- (3-phenyl-7-propyl-benzo [d] isoxazol-6-yloxy)-heXyloxy]-phenoxy}- propionic acid ethyl ester

A mixture of (2- (4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (0.049 g, 0.219 mmol), methanesulfonic acid 3- (3-phenyl-7-propyl-benzo [d] isoxazol-6- yloxy)-hexyl ester (0.095 g, 0.220 mmol) and Cs2CO3 (0.086 g, 0.264 mmol) in dry DMF (7 mL) is heated to 50 °C and stirred for 17 hours under N2. The reaction is cooled, quenched with 1 N HC1 (15 mL), diluted with Et20 and extracted with water. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude ester that is purified with column chromatography using 7/1 hexanes/acetone to afford 0.064 g (52%) of the title compound. Rf= 0.39 (2/1 hexanes/acetone). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C34H4] O6N 559, found 560 (M + 1,100%).

Step F 2-Methyl-2- {4- [3- (3-phenyl-7-propyl-benzo [d] isoxazol-6-yloxy)-heXyloxy]-phenoxy}- propionic acid A solution of 2-methyl-2- {4- [3- (3-phenyl-7-propyl-benzo [d] isoxazol-6- yloxy)-hexyloxy]-phenoxy}-propionic acid ethyl ester (0.064 g, 0.114 mmol) in ethanol (6 mL) is treated with 5 N NaOH (0. 50 mL) and stirred at rt until saponification is completed. The solvent is removed in vacuo to afford a residue that is acidified with 1 N HC1. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford 0.048 g (79%) of the title

compound. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C32H3706N 531, found 532 (M + 1, 100%).

Example 149 {4- [3- (3-Phenyl-7-propyl-benzo [d] isoxazol-6-yloxy)-hexylsulfanyl]-phenoxy}-acetic acid

The title compound is prepared according to the procedure described in Example 148 by utilizing (4-mercapto-2-methyl-phenoxy) -acetic acid ethyl ester and methanesulfonic acid 3- (3-phenyl-7-propyl-benzo [d] isoxazol-6-yloxy) -hexyl ester to afford 0.080 g (64%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z exact mass calcd for C31H36O5NS 534.2314, found 534.2308.

Example 150 (2-Methyl-4-{1-[2-(3-phenyl-7-propyl-benzo [d] isoxazol-6-yloxy)-ethyl]-butylsulfanyl}- phenoxy) -acetic acid Step A {4- [1- (2-Hydroxy-ethyl)-butylsulfanyl]-phenoxy}-acetic acid ethyl ester A mixture of (4-mercapto-2-methyl-pllenoxy)-acetic acid ethyl ester (0.41 g, 1. 81 mmol), 3-bromo-hexan-l-ol (0.360 g, 1.99 mmol) (Example 101, Step C) and Cs2CO3 (0.89 g, 2.73 mmol) in dry DMF (12 mL) is purged with N2 and then heated to 50 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (20 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford crude product that is purified by column chromatography using 7/1 hexanes/acetone to afford 0. 387 g (66%) of the title compound. Rf= 0.19 (2/1 hexanes/acetone). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C17H26O4S 326, found 327 (M + 1, 100%)..

step B {4- [1- (2-Methanesulfonyloxy-ethyl)-butylsulfanyl]-phenoxy}-acetic acid ethyl ester A 0 °C solution of {4- [1- (2-hydroxy-ethyl)-butylsulfanyl]-phenoxy}-acetic acid ethyl ester (0. 387 g, 1.19 mmol) and TEA (0.180 g, 1.78 mmol) in CH2Cl2 (20 mL) is treated with MsCI (0.163 g, 1.42 mmol), and the mixture is stirred for 1.5 hours at 0 °C under N2. The mixture is quenched with 1 N HC1 (15 mL) and diluted with more CH2C12 and extracted with water. The organic layer is dried (Na2S04) and the solvent is removed in vacuo to afford 0. 500 g (100%) of the title compound that is utilized without purification.'H NMR (400 MHz, CDC13) ; MS (ES+) mlz mass calcd for CtsH2s06S2 404, found 405 (M + 1, 100%).

Step C (2-Methyl-4- {1- [2- (3-phenyl-7-propyl-benzo [d] isoxazol-6-yloxy)-ethyl]-butylsulfanyl}- phenoxy) -acetic acid ethyl ester A mixture of 3-phenyl-7-propyl-benzo [d] isoxazol-6-ol (0. 051 g, 0.201 mmol) (Example 147, Step B), {4-[1-(2-methanesulfonyloxy-ethyl)-butylsulfanyl]-

phenoxy}-acetic acid ethyl ester (0.081 g, 0.200 mmol) and Cs2CO3 (0. 078 g, 0.239 mmol) in dry DMF (6 mL) is heated to 50 °C and stirred for 17 hours under N2. The mixture is cooled, quenched with 1 N HC1 (15 mL), diluted with Et20 and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude ester that is purified with column chromatography using 7/1 hexanes/acetone to afford 0.063 g (56%) of the title compound. Rf= 0.21 (2/1 hexanes/acetone). IH NMR (400 MHz, CDC13); MS (ES+) m/z mass calcd for C33H3905SN 561, found 562 (M + 1, 100%).

Step D (2-Methyl-4- {1- [2- (3-phenyl-7-propyl-benzo [d] isoxazol-6-yloxy)-ethyl]-butylsulfanyl}- phenoxy) -acetic acid A solution of (2-methyl-4-11- [2- (3-phenyl-7-propyl-benzo [d] isoxazol-6- yloxy)-ethyl]-butylsulfanyl}-phenoxy)-acetic acid ethyl ester (0.063 g, 0.112 mmol) in ethanol (6 mL) is treated with 5 N NaOH (0.50 mL) and stirred at rt until saponification is completed. The solvent is removed in vacuo to afford a residue that is acidified with 1N HC1. The mixture is diluted with water and extracted with EtOAc. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford 0.059 g (99%) of the title compound. 1H NMR (400 MHz, CDC13); HRMS (ES+) m/z exact mass calcd for C3iH3s05SN 534.2314, found 534.2311.

Example 151 (R)-3-14- [3- (5-Chloro-pyridin-2-yloxy)-butoxy]-2-methyl-phenyll-propioni c acid The title compound is prepared by reacting the compound of (S)-3-[4-(3- methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester with 5-

chloro-pyridin-2-ol as in Exampled 107 to afford 0.044 g (37%).'H NMR (400 MHz, CDC13) ; HRMS (ES+) nilz mass calcd for C19H23NO4Cl 364.1316, found 364.1311.

Example 152 (R)- 3-{4-[3-(4-Chloro-phenoxy)-butoxy]-2-methyl-phenyl}-propioni c acid

The title compound is prepared by reacting the compound of (S)-3-[4-(3- methanesulfonyloxy-butoxy)-2-metliyl-phenyl]-propionic acid methyl ester with 4- chlorophenol as in Example 107 to afford 0.012 g (12%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C2oH2204Cl 361. 1207, found 361.1204.

Example 153 (R)- 3-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-methyl-phenyl }-propionic acid

Step A 4-Chloro-2-phenoxy-1-methoxy-b enzene

A mixture of 2-bromo-4-chloro-l-methoxy-benzene (8. 0 g, 36.1 mmol), phenol (6.80 g, 72.2 mmol), cesium carbonate (23.54 g, 72.2 mmol), copper (I) chloride (1.79 g, 18.1 mmol) and 2,2, 6,6-tetramethyl-3, 5-heptanedione (1.66 g, 9.00 mmol) in dry l-methyl-2-pyrrolidinone (80 mL) is heated to 120 °C for 20 hours under N2. The reaction is cooled, filtered and the filtrate quenched with 1 N HC1 (50 mL). The filtrate is diluted with Et20 and extracted with water. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 9/1 hexanes/EtOAc to afford 7.42 g (88%) of the title compound. Rf = 0. 37 (4/1 hexanes/EtOAc).

Step B 4-Chloro-2-phenoxy-phenol A-40 OC solution of 4-chloro-2-phenoxy-1-methoxy-benzene (7.16 g, 30.5 mmol) in dry CH2C12 (70 mL) is treated dropwise with borontribromide (22.9 g, 91.5 mmol) and then warmed to 0 °C and stirred for 3 h under N2. The reaction is diluted with Et20 and quenched with water. The organic layer is dried (Na2S04), and the solvent is removed in vacuo to afford 7.11 g (100%) of the title compound. Rf= 0.30 (4/1 hexanes/acetone).'H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for CI2H9O2CI 220, found 219 (M-1,100%).

Step C (R)-3-14- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-methyl-phenyll-propio nic acid (S)-3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester is reacted with 4-chloro-2-phenoxy-phenol as in Example 108 to afford 0.342 g (61%) of the title compound. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) nilz mass calcd for C26H31NO5Cl 472. 1891, found 472.1909 (M + NH4).

Example 154 (R)-3-{2-Mehtyl-4-[3-(2-phenoxy-4-trifluoromethyl-phenoxy)-b utoxy]-phenyl}-propionic acid Step A <BR> <BR> (R)-3-f{4- [3- (2-Bromo-4-trifluoromethyl-phenoxy)-butoxy]-2-methyl-phenyl} -propionic acid methyl ester A mixture of 2-bromo-4-trifluoromethyl-phenol (0.105 g, 0.436 mmol), (S)-3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester

(0.165 g, 0.479 mmol) and Cs2C03 (0. 184 g, 0.565 mmol) in dry DMF (7 mL) is heated to 60 °C and stirred for 17 hours under N2. The reaction is cooled and acidified with 1 N HC1 (20 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 8/1 hexanes/EtOAc to afford 0.157 g (74%) of the title compound. Rf= 0.27 (4/1 hexanes/ EtOAc).'H NMR (400 MHz, CDC13) ; MS (ES+) nzlz mass calcd for C22H2404F3Br 489, found 506 and 508 (M + 17 and M + 19,100%). <BR> <BR> <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> <BR> (R)-3- {2-Methyl-4- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butoxy]-phenyl}-propio nic acid A mixture of (R)-3-14- [3- (2-bromo-4-trifluoromethyl-phenoxy)-butoxy]-2- methyl-phenyl}-propionic acid methyl ester (0.157 g, 0.321 mmol), phenol (0.060 g, 0.638 mmol), cesium carbonate (0.209 g, 0.642 mmol), copper (I) chloride (0.032 g, 0.323 mmol) and 2,2, 6,6-tetramethyl-3, 5-heptanedione (0.059 g, 0.320 mmol) in dry 1- methyl-2-pyrrolidinone (7 mL) is heated to 130°C for 17 hours under N2. The reaction is cooled and then quenched with 1 N HC1 (10 mL). The mixture is diluted with Et20 and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed ill vacuo to afford crude product that is taken up in MeOH (5 mL) treated with 5 N NaOH (2 mL). After stirring at rt until saponification is completed, the solvent is removed in vacuo, and the residue is acidified with 1 N HC1. The mixture is extracted with EtOAc to give 0.420 g of crude acid that is purified by preparative HPLC to afford 0.065 g (41%) of the title compound.'H NMR (400 MHz, CDC13) ; HRMS (ES+) nalz mass calcd for C27H31NOsF3 506.2154, found 506.2168 (M + NH4).

Example 155 <BR> <BR> (R)-3- {2-Methyl-4- [3- (2-phenoxy-4-trifluoromethoxy-phenoxy)-butoxy]-phenyl}- propionic acid

The title compound is prepared by reacting the compound of (R) 3- {4- [3- (2-Bromo-4-trifluoromethoxy-phenoxy)-butoxy]-2-methyl-phenyl }-propionic acid methyl ester with phenol as in Example 154 to afford 0.030 g (11%).'H NMR (400 MHz, CDC13); HRMS (ES+) n/z mass calcd for C27H31NO6F3 522.2103, found 522. 2098 (M + NH4).

Example 156 (R)-3-{2-Mehtyl-4-[3-(4-methyl-2-phenoxy-phenoxy)-butoxy]-ph enyl}-propionic acid

The title compound is prepared by reacting compound of (R)-3- {4- [3- (2- bromo-4-methyl-phenoxy)-butoxy]-2-methyl-phenyl}-propionic acid methyl ester with phenol as in Example 154 to afford 0.031 g (19%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C27H31O5 435.2171, found 435.2181 (M + 1).

Example 157 (R)- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-methyl-phenylsulfanyl }-acetic acid

The title compound is prepared by reacting the compound of (S)- [4- (3- methanesulfonyloxy-butoxy)-2-methyl-phenylsulfanyl]-acetic acid ethyl ester with 4- chloro-2-phenoxy-phenol as in Example 108 to afford 0.056 g (55%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) nilz mass calcd for C25H29NO5SCl 490. 1455, found 490.1447 (M + NH4).

Example 158 3-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-propoxy]-2-methyl-pheny l}-propionic acid

The title compound is prepared by reacting the compound of 3- [4- (3- methanesulfonyloxy-propoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4- chloro-2-phenoxy-phenol as in Example 132 to afford 0.107 g (63%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) n/z mass calcd for C2sH29NO5CI 458.1734, found 458. 1735 (M + NH4).

Example 159 (R)-3-f 2-Methyl-4- [3- (1-phenoxy-naphthalen-2-yloxy)-butoxy]-phenyl}-propionic acid

The title compound is prepared by reacting the compound of (S)-3- [4- (3- methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester with 1- phenoxy-naphthalen-2-ol as in Example 108 to afford 0.075 g (59%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C30H34O5N 488.2437, found 488. 2431 (M+NH4).

Example 160 <BR> <BR> <BR> (R)-3- {4- [3- (2-Benzofuran-2-yl-4-chloro-phenoxy)-butoxy]-2-methyl-phenyl }-propionic acid Step A <BR> <BR> (R)-3- {4- [3- (2-Benzofuran-2-yl-4-chloro-phenoxy)-butoxy]-2-metliyl-pheny l}-propionic acid methyl ester

A mixture of benzo [B] furan-2-boronic acid (0.084 g, 0.519 mmol), (R)-3- {4- [3- (2-bromo-4-chloro-phenoxy)-butoxy]-2-methyl-phenyll-propioni c acid methyl ester (0. 118 g, 0.259 mmol) and CsF (0.098 g, 0.645 mmol) in dry 1,4-dioxane (6 mL) is purged with N2 and then 1, 1'-bis (diphenylphospino) ferrocene palladium (II) chloride complex with CH2C12 (0.028 g, 0.0383 mmol) is added. The mixture is heated to 80°C and stirred for 10 hours under N2. The reaction is cooled, and the crude product is absorbed on silica gel and purified by column chromatography using 9/1 hexanes/EtOAc to afford 0.029 g (23%) of the title compound. Rf= 0.21 (4/1 hexanes/EtOAc). IH NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C22H2404F3Br 489, found 506 and 508 (M+17 and M+19, 100%). <BR> <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> (R)-3- {4- [3- (2-Benzofuran-2-yl-4-chloro-phenoxy)-butoxy]-2-methyl-phenyl }-propionic acid A solution of (R)-3- {4- [3- (2-benzofuran-2-yl-4-chloro-phenoxy)-butoxy]- 2-methyl-phenyl}-propionic acid methyl ester (0.029, 0.0588 mmol) in methanol (6 mL) is treated with 5 N NaOH (1.5 mL). The mixture is heated to reflux and stirred until saponification is completed. The solvent is removed in vacuo to afford a residue that is acidified with 1 N HC1. The mixture is diluted with water and extracted with EtOAc.

The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford 0.017

g (61%) of the title compound. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z exact mass calcd for C28H28O5Cl 479. 1625, found 479. 1631 (M + 1,100%).

Example 161 (R)-3- {4- [3- (2-Benzo [b] thiophen-3-yl-4-chloro-phenoxy)-butoxy]-2-methyl-phenyl}- propionic acid The title compound is prepared by reacting the compound of (R)-3- {4- [3- (2-bromo-4-chloro-phenoxy)-butoxy]-2-methyl-phenyl}-propioni c acid methyl ester with benzothiophene-3-boronic acid as in Example 161 to afford 0.087 g (53%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) nilz mass calcd for C28H31O4NSCl 512. 1662, found 512.1674 (M+NH4).

Example 162 (R)-3- {4- [3- (4-Chloro-2-pyridin-3-yl-phenoxy)-butoxy]-2-methyl-phenyl}-p ropionic acid

The title compound is prepared by reacting the compound of ()-3- {4- [3- (2-bromo-4-chloro-phenoxy)-butoxy]-2-methyl-phenyl}-propioni c acid methyl ester with 3-pyridine boronic acid as in Example 160 to afford 0. 018 g (21%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C25H27O4NCl 440. 1629, found 440.1607 (M+NH4).

Example 163 (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-phenyl}-2, 2-difluoro-propionic acid

The title compound is prepared by reacting the compound of (R)- methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-butyl ester with 2, 2-difluoro-3- (4- hydroxy-phenyl)-propionic acid ethyl ester as in Example 63 to afford 0.058 g (42%) of the title compound. 'H NMR (400 MHz, CDC13) ; MS (ES-) mass calcd for C25H2305F2Cl 476, found 475 (M-1).

Example 164 ()-3- {3-Bromo-4- [3- (4-chloro-2-phenoxy-phenoxy)-butoxy]-phenyl}-propionic acid

step A 3- (3-Bromo-4-hydroxy-phenyl)-propionic acid methyl ester A 0 °C solution of 3- (4-hydroxy-phenyl)-propionic acid methyl ester (3.0 g, 16.6 mmol) in CH2C12 (15 mL) is treated with bromine (2.66 g, 16.7 mmol). The mixture is stirred at 0 OC for 20 minutes, warmed to rt and stirred under N2. The reaction is diluted with water and extracted with CH2C12. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 99/1 CH2C12/ACN to afford 3.58 g (83%) of the title compound. Rf= 0.37 (98/2 CH2C12/ACN).'H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C10H11O3Br 258, found 257 NS 259 (M-1 and M + 1).

Step B (R)-3-{3-Bromo-4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-phe nyl}-propionic acid The compound of (R)-methanesulfonic acid 3- (4-chloro-2-phenoxy- phenoxy) -butyl ester is reacted with 3- (3-bromo-4-hydroxy-phenyl)-propionic acid methyl ester as in Example 63 to afford 0.060 g (18%) of the title compound. IH NMR (400 MHz, CDC13); HRMS (ES+) m/z mass calcd for C25H2sNO5ClBr 536.0839, found 536.0830 (M + NH4).

Example 165 (R)-3-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-butoxy]-3-methyl-ph enyl}-propionic acid

The title compound is prepared by reacting the compound of (R)-3- {3- bromo-4- [3- (4-chloro-2-phenoxy-phenoxy)-butoxy]-phenyl}-propionic acid methyl ester with methyl boronic acid as in Example 160 to afford 0.150 g (90%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) fnlz mass calcd for C26H3lNO5CI 472. 1891, found 472. 1881 (M+NH4).

Example 166 (R)-3-f 4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-3, 5-dimethyl-phenyl}-propionic acid

The title compound is prepared by reacting the compound of (R)- methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-butyl ester with 3- (4-hydroxy-3, 5- dimethyl-phenyl)-propionic acid methyl ester as in Example 63 to afford 0.095 g (69%).

IH NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C27H33NO5Cl 486. 2047, found 486.2051 (M + NH4).

Example 167 (R)-f 3-Bromo-4- [3- (4-chloro-2-phenoxy-phenoxy)-butoxy]-phenyl}-acetic acid

The title compound is prepared by reacting the compound of (R)- methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-butyl ester with (3-bromo-4- hydroxy-phenyl) -acetic acid methyl ester as in Example 63 to afford 0.050 g (21%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C24H26NO5ClBr 522.0683, found 522.0653 (M + NH4).

Example 168 (R)-3-{2-Methyl-4-[3-(4-phenoxy-naphthalen-2-yloxy)-butoxy]- phenyl}-propionic acid

The title compound is prepared by reacting the compound of (S)-3- [4- (3- methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4- phenoxy-naphthalen-2-ol as in Example 108 to afford 0.076 g (64%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C30H31O5 471.2171, found 471.2166 (M+1).

Example 169 (R)-3-{4-[3-(4-Bromo-2-trifluoromethoxy-phenoxy)-butoxy]-2-m ethyl-phenyl}-propionic acid

The title compound is prepared by reacting the compound of (S)-3- [4- (3- methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4- bromo-2-trifluoromethoxy-phenol as in Example 108 to afford 0.033 g (23%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) nilz mass calcd for C2sH26NO5F3Br 508.0946, found 508. 0942 (M + 1).

Example 170 (R)-3-{4-[3-(4-Ethyl-2-trifluoromethoxy-phenoxy)-butoxy]-2-m ethyl-phenyl}-propionic acid

The title compound is prepared by reacting the compound of (R)-3- {4- [3- (4-bromo-2-trifluoromethoxy-phenoxy)-butoxy]-2-methyl-phenyl }-propionic acid methyl ester (Example 169) with ethyl boronic acid as in Example 160 to afford 0.073 g (60%)

after saponification. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C23H31NO5F3 458.2154, found 458. 2160 (M + 1).

Example 171 ()- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-3-methyl-phenyl}-acetic acid

The title compound is prepared by reacting the compound of (R)-{ 3- bromo-4- [3- (4-chloro-2-phenoxy-phenoxy)-butoxy]-phenyl}-acetic acid methyl ester with methyl boronic acid as in Example 160 to afford 0.086 g (53%). 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C25H29NO5Cl 458. 1734, found 458.1723 (M + NH4).

Example 172 (R)-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-butoxy]-phenyl}-aceti c acid

The title compound is prepared by reacting the compound of (R)- methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-butyl ester with (4-hydroxy-

phenyl) -acetic acid methyl ester as in Example 63 to afford 0.094 g (52%).'H NMR (400 MHz, CDC13) ; HRMS (ES+) 771/Z mass calcd for C24H2705NC1444. 1578, found 444. 1588.

Example 173 {4- [3- (4-Chloro-2-phenoxy-phenoxy)-propyl]-2-methyl-phenoxy}-aceti c acid Step A [4- (3-Hydroxy-propyl)-2-iodo-phenoxy]-acetic acid ethyl ester A mixture of [4- (3-hydroxy-propyl)-phenoxy]-acetic acid ethyl ester ethyl ester (0.50 g, 2.09 mrnol), silver sulfate (1.31 g, 4.20 mol) and iodine (1.07 g, 4.22 mmol) in ethanol (10 mL) is stirred at rt for 17 hours under N2. The mixture is filtered, and the solvent is removed in vacuo to afford crude product that is purified by column chromatography using 3/1 hexanes/acetone afford 0.24 g (31 %) of the title compound.

Rf=0. 21 (2/1 hexanes/acetone).

Step B [[4- (3-Hydroxy-propyl)-2-methyl-phenoxy]-acetic acid ethyl ester A mixture of [4- (3-hydroxy-propyl)-2-iodo-phenoxy]-acetic acid ethyl ester (0.23 g, 0.632 mmol), methylboronic acid (0.113 g, 1. 89 mol) and cesium fluoride (0.34 g, 2.24 mmol) in 1,4-dioxane (4 mL) is stinted at rt and purged with N2 for 3 minutes. The reaction is treated with 1, 1'-bis (diphenylphosphino) ferrocene palladium

(II) chloride, CH2Cl2 complex (0.040 g) and then stirred at 80 °C for 1 hour under N2.

The mixture is cooled, and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using 3/1 hexanes/acetone afford 0.086 g (54%) of the title compound. Rf= 0.37 (1/1 hexanes/acetone).

Step C {2-Methyl-4- [3- (toluene-4-sulfonyloxy)-propyl]-phenoxy}-acetic acid ethyl ester A solution of [4- (3-hydroxy-propyl)-2-methyl-phenoxy]-acetic acid ethyl ester (0.086 g, 0. 341 mmol), pyridine (0.108 g, 1.36 mmol) and N,N- dimethylaminopyridine (0.012 g, 0.098 mmol) in CH2C12 (8 mL) is treated with p- toluenesulfonic anhydride (0.222 g, 0.680 mmol). and the reaction is stirred at rt for an hour under N2. The reaction is quenched with 1 N HC1 (5 mL) and diluted with more CH2C12 and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is purified by column chromatography using 6/1 hexanes/acetone to afford 0.117 g (84%) of the title compound. Rf= 0.49 (1/1 hexanes/acetone).'H NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C21H26O6S 406, found 424 (M + NH4).

Step D {4- [3- (4-Chloro-2-phenoxy-phenoxy)-propyl]-2-methyl-phenoxy}-aceti c acid The compound of {2-methyl-4- [3- (toluene-4-sulfonyloxy)-propyl]- phenoxy}-acetic acid ethyl ester is reacted with 4-chloro-2-phenoxy-phenol as in Example 98 to afford 0.054 g (67%) of the title compound. 1H NMR (400 MHz, CDC) ; HRMS (ES+) y mass calcd for C24H2705NC1444. 1578, found 444.1583.

Example 174 <BR> <BR> (R)-2- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-methyl-phenyl}- cyclopropanecarboxylic acid Step A 2- (4-Benzyloxy-2-methyl-phenyl)-cyclopropanecarboxylic acid methyl ester A mixture of trimethylsulfoxonium iodide (0.88g, 4.00 mmol) in DMSO (5 mL) is treated with 1 N potassium tert-butoxide in THF (4 mL, 4.00 mmol), and the resultant mixture is stirred at rt for 20 minutes under N2. A solution of 3- (4-benzyloxy-2- methyl-phenyl) -acrylic acid methyl ester (0.75 g, 2.65 mmol) in dry THF (6 mL) is added dropwise, and the reaction is stirred 17 h at rt. The mixture is quenched with IN HC1 (10 mL), diluted with water and extracted with Et20. The organic layer is dried (Na2S04), and the solvent is removed i7s vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography 7/1 hexanes/EtOAc to afford 0.076 g (10%) of the title compound.'H NMR (400 MHz, CDC13).

Step B 2- (4-Hydroxy-2-methyl-phenyl)-cyclopropanecarboxylic acid methyl ester

A mixture 2- (4-benzyloxy-2-methyl-phenyl)-cyclopropanecarboxylic acid methyl ester (0.076g, 0.256 mmol) and 10% Pd/C (80 mg) in EtOAc (20 mL) is purged with N2 and then hydrogen. The mixture is stirred under a hydrogen balloon for 2 hours at rt. The mixture is filtered through hyflo to remove the catalyst, and the solvent is removed in vacuo from the filtrate to afford 0.056 g (100%) of the title compound. MS (ES-) n/z mass calcd for C12Hl4O3 206, found 205 (M-1).

Step C<BR> (R)-2- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-methyl-phenyl}- cyclopropanecarboxylic acid The compound of (R)-methanesulfonic acid 3- (4-chloro-2-phenoxy- phenoxy)-butyl ester is reacted with (2- (4-hydroxy-2-methyl-phenyl)- cyclopropanecarboxylic acid methyl ester as in Example 63 to afford 0. 086 g (68%) of the title compound. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C27H31O5NCl 484. 1891, found 484. 1883.

Example 175 (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-trifluoromethyl-pheny l}-propionic acid Step A 1-Benzyloxy-4-bromo-3-trifluoromethyl-benzene

A mixture of 4-bromo-3-trifluoromethyl-phenol (10.95 g, 45.4 mmol) and 325 mesh K2CO3 (7.54 g, 54.6 mmol) in DMF (80 mL) is treated with benzyl bromide (8.55 g, 50.0 mmol) and stirred at 55 °C hr for 3 h under N2. The mixture is filtered using Et20 to rinse the solids, and the filtrate is acidified with 1 N HC1. The filtrate is diluted with more Et20 and then extracted with twice with water and brine. The organic layer is dried (Na2SO4), and the solvent is removed i71 vacuo to afford crude product that is absorbed onto silica gel and column purified with 9/1 hexanes/EtOAc to afford 14.46 g (96%) of the title compound. Rf = 0.47 (4/1 hexanes/acetone).'H NMR (400 MHz, CDCl3).

Step B 4-Benzyloxy-2-trifluoromethyl-benzaldehyde A-78 °C solution of l-benzyloxy-4-bromo-3-trifluoromethyl-benzene (6.00 g, 18.1 mmol) in dry THF (60 mL) is treated dropwise with a 1.6 M solution of n- butyl lithium (17.0 mL, 27.1 mmol), and the reaction is stirred 10 minutes at-78 °C.

DMF (7.92 g, 0.108 mol) is added, and the mixture is warmed to rt and stirred. The reaction is quenched with 1 N HC1, diluted with Et20 and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed onto silica gel and column purified with 9/1 hexanes/EtOAc to afford 2.92 g (57%) of the title compound. Rf = 0.56 (2/1 hexanes/EtOAc).'H NMR (400 MHz, CDC13); MS (ES+) nilz mass calcd for C15H102F3 280, found 281 (M + 1, 100%).

Step C 3- (4-Benzyloxy-2-trifluoromethyl-phenyl)-acrylic acid ethyl ester

A mixture of 4-benzyloxy-2-trifluoromethyl-benzaldehyde (2.92 g, 10.4 mmol), triethyl phosphonoacetate (2.80 g, 12.5 mmol) and 325 mesh K2CO3 (4.32 g, 31.3 mmol) in ethanol (40 mL) is heated to reflux until starting material is gone by TLC (2/1 hexanes/EtOAc). The reaction is cooled, filtered, and the filtrate is quenched with 1 N HC1. The filtrate is diluted with water and extracted with EtOAc. The organic layer is dried (Na2SO4) and the solvent is removed in vacuo to afford crude product that is absorbed onto silica gel and column purified with 9/1 hexanes/EtOAc to afford 3.10 g (85%) of the title compound. Rf= 0.40 (2/1 hexanes/EtOAc). IH NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for ClgHz703F3 350, found 351 (M + 1, 100%).

Step D 3- (4-Hydroxy-2-trifluoromethyl-phenyl)-propionic acid ethyl ester A mixture of 3- (4-benzyloxy-2-trifluoromethyl-phenyl)-acrylic acid ethyl ester (3.10 g, 8.85 mmol) and 10% palladium on carbon (2.0 g) in EtOAc (100 mL) is purged with N2 then hydrogen, and then stirred under a hydrogen balloon for 4 h at rt.

The reaction is filtered through hyflo to remove the catalyst, and the organic layer is dried (Na2S04). The solvent is removed in vacuo to afford 2.46 g (100%) of the title

compound. Rf= 0.41 (2/1 hexanes/EtOAc). IH NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C12H13O3F3 262, found 261 (M-1, 100%).

Step E (R)-3-{4-[3-(4-CHloro-2-phenoxy-phenoxy)-butoxy]-2-trifluoro methyl-phenyl}-propionic acid The compound of (R)-methanesulfonic acid 3- (4-chloro-2-phenoxy- phenoxy) -butyl ester is reacted with 3- (4-hydroxy-2-trifluoromethyl-phenyl)-propionic acid ethyl ester as in Example 63 to afford 0.764 g (75%) of the title compound. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C26H2805F3C1N 526.1608, found 526.1597 (M + NH4).

Example 176 (R)- {4- [3- (4-chloro-2-phenoxy-phenoxy)-butylsulfanyl]-2-methyl-phenoxy }-acetic acid A solution of (4-mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (0.219 g, 0.968 mmol) and (R)-methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)- butyl ester (0.30 g, 0.809 mmol) in DMF (7 mL) is purged with N2, and then 325 mesh K2CO3 (0.145 g, 1. 05 mmol) is added. The mixture is stirred at rt for 17 hours under N2.

The reaction is acidified with 1 N HC1 (20 mL). The mixture is diluted with water and extracted with Et20. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by column chromatography using a gradient of 7/1 to 4/1 hexanes/EtOAc to afford 0.361 g (74%) of (R)- {4- [3- (4-chloro-2-phenoxy-phenoxy)-butylsulfanyl]-2-methyl-phenoxy }-acetic acid

ethyl ester [Rf= 0.29 (4/1 hexanes/EtOAc) ]. The ester then is saponified to afford 0.333 g (98%) of the title compound.'H NMR (400 MHz, CDC13) ; HRMS (ES+) m/Z mass calcd for C25H2505SC1 473. 1189, found 473.1172 (M + 1).

Example 177 ()-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butylsulfanyl]-2-methyl-phenyl} -propionic acid Step A 3- (4-Mercapto-2-methyl-phenyl)-propionic acid methyl ester The compound of 3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (5.0 g, 25.75 mmol) is dissolved into dry dioxane (100 mL) and combined with 4- dimethylamino pyridine (0.500 g, 2.6 mmol), TEA (7.0 mL, 51.5 mmol) and dimethylaminothiocarbomoyl chloride (4.5 g, 32.17 mmol). The mixture is heated to reflux under nitrogen. The reaction is monitored by TLC until phenol is completely consumed after 20hours. After cooling to rt, the reaction is diluted with EtOAc (200 mL).

Water (75 mL) is added and the two layers are separated. The organic layer is washed with brine (75mL) then dried over anhydrous sodium sulfate. The solvent is removed,

and the residue is dried under vacuum to give 3- (4-dimethylthiocarbamoyloxy-2-methyl- phenyl) -propionic acid methyl ester.

The 3- (4-dimethylthiocarbamoyloxy-2-methyl-phenyl)-propionic acid methyl ester, taken crude from the previous step, is diluted with 75 mL of tetradecane and heated to reflux under nitrogen. The reaction is monitored by TLC until all the conversion is completed after 20h. The reaction is cooled to rt, and tetradecane is decanted away from the resulting oil. The residue is rinsed several times with hexanes.

This oil is then purified using flash column chromatography to afford 5.01 g (69%) of 3- (4-dimethylcarbamoylsulfanyl-2-methyl-phenyl)-propionic acid methyl ester. This propionic acid methyl ester (5.01 g, 17.8 mmol) is diluted with methanol (30 mL) and sodium methoxide (1.7 mL of 4M in methanol, 7.23 mmol) is added. The reaction is heated to reflux under nitrogen and monitored by TLC. After complete conversion, the reaction is cooled to rt, and then neutralized with 1N HC1 (7.23 mL) and diluted with EtOAc (150 mL). The two phases are separated, and the organic layer is washed with water (75 mL) and brine (75 mL). The organic layer is dried over anhydrous sodium sulfate and concentrated to yield 4.43 g crude product, which is used without further purification. <BR> <BR> <BR> <BR> step B<BR> <BR> <BR> <BR> <BR> <BR> (R)-3-f{4- [3- (4-Chloro-2-phenoxy-phenoxy)-butylsulfanyl]-2-methyl-phenyl} -propionic acid The compound of (R)-methanesulfonic acid 3- (4-chloro-2-phenoxy- phenoxy)-butyl ester is reacted with 3- (4-mercapto-2-methyl-phenyl)-propionic acid methyl ester as in Example 176 to afford 0.329 g (86%) of the title compound. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) iiilz mass calcd for C26H3lO4SClN 487. 1346, found 487.1331 (M+NH4).

Example 178 Preparation of 2-Cyclopropylmethyl-4-trifluoromethyl-phenol

step A<BR> <BR> 1-Methoxy-4-trifluoromethyl-benzene The compound of 4-hydroxybenzotrifluoride (15.0 g, 93 mmol) is dissolved in acetone (400 ml), and K2CO3 (19.3 g, 140 mmol) and MeI (17.3 mL, 280 mmol) are added. The mixture is stirred at rt overnight. The precipitate is filtered and the filtrate is concentrated, which is dissolved in EtOAc, washed with brine, dried over Na2S04 and concentrated under reduced pressure. Purification by flash chromatography, eluting with EtOAc: hexane (1: 5) provides the title compound (11.5 g, 70 %). GC/MS: M-+ 176 ;'HNMR (400 MHz, CDC13) <BR> <BR> Step B<BR> <BR> 2-Cyclopropylmethyl-1-methoxy-4-trifluoromethyl-benzene N, N, N', N'-tetramethylethylenediamine (TMEDA, 6.00 mL, 40 mmol) is dissolved in THF (30 ml), and the solution is cooled to-78 °C. n-BuLi (1.6 M in hexane; 25.0 mL, 40 mmol) is added slowly, and the mixture is stirred for 15 min. The compound of l-methoxy-4-trifluoromethyl-benzene (3.48 g, 20 mmol) is added in THF (20 mL) at- 78 °C and is stirred at-20 °C to-30 °C for 2h. Cyclopropylmethylbromide (4.80 mL, 49 mmol) is added at-78 °C and stirred at-78 °C to rt overnight. The mixture is quenched with aqueous NH4C1, extacted with EtOAc, washed with brine, dried over Na2S04 and under reduced pressure. Purification by chromatography, eluting with 5% EtOAc in hexane then 10 % EtOAc in hexane provides the title compound (1.54g, 33 %). GC/MS: M-+ 230 ;'HNMR (400 MHz, CDC13)

Step C 2-Cyclopropylmethyl-4-trifluoromethyl-phenol The compound from Step B (1.54 g, 6.7 mmol) is dissolved in CH2C12 (15 mL), n-Bu4NI (4.95 g, 13.4 mmol) is added and the mixture is cooled to-78 °C. BC13 (1M in CH2C12, 13.4 mL, 13.4 mmol) is added slowly and mixture is stirred at 0 °C for about 0. 5h and rt for about 1. 5h. The mixture is quenched with ice/H20 at 0°C and stirred for 0.5h. The mixture is extracted with CH2C12, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography, eluting with 10% EtOAc in hexane and 15 % EtOAc in hexane provides the title compound (0. 91 g, 63 %). Mass (ES-) : 215 (M-H) ; 1HNMR (400 MHz, CDC13).

Example 179 Preparation of 2-Cyclohexylmethyl-4-trifluoromethyl-phenol Step A<BR> <BR> 2-Cyclohexylmethyl-1-methoxy-4-trifluoromethyl-benzene TMEDA (5.1 mL, 33.6 mmol) is dissolved in THF (30 ml), and the mixture is cooled to-78 °C. n-BuLi (1.6 M in hexane; 21.0 mL, 33.6 mmol) is added slowly and stirred for 15 min. The compound of l-methoxy-4-trifluoromethyl-benzene (2.96 g, 16.8 mmol) is added in THF (20 mL) at-78 °C, and the mixture is stirred at-10 °C to-30 °C for 4h. Cyclohexylmethyl bromide (5.2 mL, 37.0 mmol) is added at-78°C and stirred at-78 °C to rt overnight. The mixture is quenched with aqueous NH4Cl, extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography, eluting with 5% EtOAc in hexane then 10 % EtOAc in hexane provided the title compound (0.95 g, 21 %). GC/MS: M-+ 272; 1HNMR (400 MHz, CDC13).

Step B 2-Cyclohexylmethyl-4-trifluoromethyl-phenol The compound from Step A (0.95 g, 3.5 mmol) is dissolved in CH2C12 (30 mL), and n-Bu4NI (3.21 g, 8.7 mmol) is added. The mixture is cooled to-78 °C and BC13 (1 M in CH2C12, 8.7 mL, 8.7 mmol) is added slowly. The mixture is stirred at 0 °C for about 45 min and rt for about 1. 5h. The mixture is quenched with ice/H20 at 0°C, stirred for 0. 5h and extracted with CH2C12, which then washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue is triturated with EtOAc, the precipitate is filtered, and the filtrate is concentrated. Purification by chromatography, eluting with 10% EtOAc in hexane then 15 % EtOAc in hexane provides the title compound (0.74g, 82 %). MS: (ES-) : 257 (M-H+) ;'HNMR (400 MHz, CDC13).

Example 180 Preparation of 2, 7-Dimethyl-3-phenyl-benzofuran-6-ol Step A 6-Methoxy-2-methyl-3-phenyl-benzofuran The compound of 6-methoxy-3-phenyl-benzofuran (5.52 g, 24.6 mmol) is dissolved in THF (80 mL), and the mixture is cooled to-78 °C and n-BuLi (1.6M in hexane ; 16.6 mL, 26. 5 mmol) is added slowly. The mixture is warmed to-10 °C to-20 °C and stirred for 3h. MeI (1.65 mL, 26.5 mmol) is added and the mixture is stirred at- 78 °C to rt overnight. The mixture is quenched with aqueous NH4C1, extracted with EtOAc, washed with brine, dried over Na2S04 and concentrated. Purification by chromatography, eluting with EtOAc: hexane (1: 5) provides the title compound (5.19 g, 89 %). GC/MS: M-+ 238 ;'HNMR (400 MHz, CDC13).

Step B 6-Methoxy-2, 7-dimethyl-3-phenyl-benzofuran TMEDA (1.66 mL, 11 mmol) is dissolved in THF (10 mL), the mixture is cooled to-78 °C, and n-BuLi (1.6 M in hexane, 6.7 mL, 11 mmol) is added slowly. The mixture is stirred for 15 min and 6-methoxy-2-methyl-3-phenyl-benzofuran (1.16 g, 4.9 mmol) in THF (30 ml) is added at-78 °C and stirred at-68 °C for lh. MeI (0.76 mL, 12 mmol) is added at-78 °C, and the mixture is stirred at-78 °C to rt for lh. The mixture is quenched with aqueous NH4C1, extracted with EtOAc, washed with brine, dried over Na2S04 and concentrated under reduced pressure. Purification by chromatography, eluting with 10% CH2C12 in hexane provides the title compound (0.40 g, 33 %) along with a side-product, 6-methoxy-2-ethyl-3-phenyl-benzofuran (0.49 g). GC/MS: M-+ 252; 'HNMR (400 MHz, CDC13).

Step C 2, 7-Dimethyl-3-phenyl-benzofuran-6-ol The compounds of 6-methoxy-2, 7-dimethyl-3-phenyl-benzofuran (0.40 g, 1.59 mmol) and terabutylammonium iodide (1.47 g, 3.97 mmol) are dissolved in DCM (15 mL) and cool to-78 °C followed by a dropwise addition of boron trichloride solution (4.0 mL, 1.0 M in DCM, 3.97 mmol). The mixture is stirred for 0.5 hours at 0°C and then 1.5 hours at rt. The mixture is quenched with ice water and stirred for 0.5 hours and then diluted additional water and DCM. Organic layer is separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash chromatography, eluting with 10% EtOAc in hexane then 15 % EtOAc in hexane (linear gradient) provides the title compound (0.27 g, 76%). GC/MS: M-+ 238 ;'H NMR (400 MHz, CDC13).

Example 181 Preparation of 4-Methyl-3-phenyl-benzofuran-6-ol

Step A<BR> <BR> <BR> <BR> <BR> 2- (3-Methoxy-5-methyl-phenoxy)-l-phenyl-ethanone A mixture of 2-bromoacetophenone (7.20 g, 36 mmol), 3-methoxy-5- methylphenol (5.00 g, 36 mmol) and K2CO3 (7.45 g, 54 mmol) in methyl ethyl ketone (78 mL) is heated under reflux overnight. The precipitate is filtered, and the filtrate is concentrated and partitioned between EtOAc and aqueous NaCl. Organic layer is washed with brine and dried over Na2S04 and concentrated under reduced pressure. Purification by chromatography, eluting with EtOAc: hexane (1: 5) provides the title compound (8.78 g, 95 %). GC/MS: Mv 256 ; 1HNMR (400 MHz, CDC13).

Step B 6-Methoxy-4-methyl-3-phenyl-benzofuran Amberlyst 15 (8 g) under reflux in toluene (200 mL) is heated for 1h with a Dean and Stark separator to remove water. The compound from Step B (8.69 g, 34 mmol) is added after cool to rt, and the mixture is heated under reflux for 3h. The mixture is cooled to rt, the precipitate is filtered and the filtrate is concentrated.

Purification by chromatography, eluting with 10% CH2C12 in hexane and then 15% CH2C12 in hexane provides the title compound (4.83 g, 60 %). GC/MS: M + 238 ; 1HNMR (400 MHz, CDC13).

Step C 4-Methyl-3-phenyl-b enzofuran-6-ol The title compound is prepared according to the procedure used in Example 180, Step 3 using 6-methoxy-4-methyl-3-phenyl-benzofuran. Purification by flash chromatography, eluting with 10% EtOAc in hexane then 15 % EtOAc in hexane

(linear gradient) provides the title compound (0.31 g, 65%). GC/MS: M'+ 224 ; 1H NMR (400 MHz, CDC13).

Example 182 Preparation of 4-Methyl-3-phenyl-7-propyl-benzofuran-6-ol Step A (6-Methoxy-4-methyl-3-phenyl-benzofuran-2-yl)-trimethyl-sila ne The compound of 6-methoxy-4-methyl-3-phenyl-benzofuran (1.5 g, 6.3 mmol) is dissolved in THF (10 mL), and the mixture is cooled to-78 °C and then n-BuLi (1.6 M in hexane, 4.33 mL, 6.9 mmol) is added and stirred at-78 °C for lh. TMSC1 (1.2 mL, 9.5 mmol) is added and stirred at-78 °C for 1h, and then rt overnight. The mixture is quenched with aqueous NH4C1, extracted with EtOAc, washed with water and brine, and then dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography, eluting with 10% CH2C12 in hexane and then 15 % CH2C12 in hexane provides the title compound (0.64 g, 33 %) with a mixture of the title compound and the starting material (0.51 g). GC/MS: M-+ 310 ; 1HNMR (400 MHz, CDC13. <BR> <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> (6-Methoxy-4-methyl-3-phenyl-7-propyl-benzofuran-2-yl)-trime thyl-silane TMEDA (0.49 ml, 3. 28 mmol) is dissolved in THF (10 mL), and the mixture is cooled to-78 °C, and then n-BuLi (1.6 M in hexane, 2.1 mL, 3.28 mmol) is added slowly and stirred for 15 min. The compound from Step A (0.51 g, 1.64 mmol) is added in THF (15 ml) at-78 °C and warmed to-30 °C for 1.5h followed by the addition of 1-iodopropane (0.48 mL, 4.92 mmol) at-78 °C. The mixture is stirred at-78 °C to rt for 3h and then quenched with aqueous NH4C1, extracted with EtOAc, washed with brine,

dried over Na2S04 and concentrated under reduced pressure. Purification by chromatography, eluting with 10% CH2C12 in hexane and then 15 % CH2C12 in hexane provides the title compound (0.40 g, 69 %). GC/MS : M-+ 352 ;'HNMR (400 MHz, CDC13).<BR> <P> Step C<BR> 6-Methoxy-4-methyl-3-phenyl-7-propyl-benzofuran The compound obtained from Step B (0.40 g, 1.14 mmol) is dissolved in THF (10 mL) and n-Bu4NF (1M in THF, 1.70 mL, 1.70 mmol) is added. The mixture is stirred at rt overnight. The mixture is diluted with EtOAc, washed with brine, dried over Na2S04 and concentrated under reduced pressure. Purification by chromatography, eluting with 10% CH2C12 in hexane and then 15 % CH2C12 in hexane provides the title compound (0.29 g, 92 %). GC/MS : M-+ 280 ; 1HNMR (400 MHz, CDC13).

Step D 4-Methyl-3-phenyl-7-propyl-benzofuran-6-ol The title compound is prepared by following the procedure described in Example 180, Step 3 using 6-methoxy-4-methyl-3-phenyl-7-propyl-benzofuran.

Purification by chromatography, eluting with 10% EtOAc in hexane then 15 % EtOAc in hexane (linear gradient) provides the title compound (0.11 g, 38%). MS: (ES-) 265 (M- H) ; IH NMR (400 MHz, CDC13).

Example 183 Preparation of 2-Methyl-3-phenyl-7-propyl-benzofuran-6-ol

Step A 2-methyl-3-phenyl-benzofuran-6-ol A mixture of 6-methoxy-2-methyl-3-phenyl-benzofuran (Example 181, Step 1) (1.9 g, 7.97 mmol) and pyridine HC1 (11.0 g, 95.1 mmol) is heated neat 10 minutes at 210 °C. The mixture is cooled and acidified with 5N HC1, and then extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1.72 g, quantitative), which is utilized without purification. MS: (ES+) 224 (M+H) ; 1H NMR (400 MHz, CDC13). <BR> <BR> <P> Step B<BR> <BR> 6-Allyloxy-2-methyl-3-phenyl-benzofuran A mixture of 2-methyl-3-phenyl-benzofuran-6-ol (1.59 g, 7.09 mmol), allyl bromide (1.2 g, 9.93 mmol), and potassium carbonate (1.36 g, 9.93 mmol) in methyl ethyl ketone (50mL) are heated at reflux overnight under nitrogen atmosphere. The mixture is concentrated under reduced pressure followed by the addition of water. The mixture is extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by chromatography, eluting with EtOAc: hexane (4: 1) provides the title compound (1.62 g, 86%). GC/MS: M-+ 264 ; 1H NMR (400 MHz, CDC13).

Step C 7-Allyl-2-methyl-3-phenyl-benzofuran-6-ol The compound of Step B (1.62 g, 6.13 mmol) is dissolved in N, N- dimethylaniline and degassed with nitrogen, and then heated to reflux (192 °C) overnight.

The mixture is cooled, diluted with EtOAc and washed with IN HC1. Organic phase is washed with brine, dried over sodium sulfate, and concentrated under reduced pressure.

Purification by recrystallization (toluene/hexane) provides the title compound (0.46 g, 28%). GC/MS: M-+ 264 ; 1H NMR (400 MHz, CDC13). <BR> <BR> <P> Step D<BR> <BR> 2-Methyl-3-phenyl-7-propyl-benzofuran-6-ol The compound of Step C (260 mg, 0. 98 mmol) is added in 2B ethanol (50 mL) to flask containing 10% Pd/C (90 mg) and the mixture is stirred about 2 hours under hydrogen filled balloon at rt. Catalyst is removed by filtration and the filtrate is concentrated under reduced pressure to give a mixture of title compound and over

reduced material, 2-methyl-3-phenyl-7-propyl-2, 3-dihydro-benzofuran-6-ol (200 mg).

This mixture (200 mg) and 2,3 dichloro-5,6-dicyano l, 4benzoquinone (0. 085 g, 0. 37 mmol) is dissolved in dioxane (5 mL) and stirred overnight at rt. Water is added, and the mixture is extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by chromatography, eluting with EtOAc: hexane (2: 98) provides the title compound (0.040 g). MS: (ES-) 265 (M-H) ; 1H NMR (400 MHz, CDC13).

Example 184 Preparation of 4-Ethyl-2-phenylsulfanyl-phenol Step A 4-Ethyl-2-thiophenyl anisole 4-Ethyl anisole (3.5 g, 25. 7 mmol) and thiophenol (5.66 g, 51.4 mmol) are dissolved in 30 mL 1,1, 1,3, 3,3-hexafluoro-2-propanol. Bis (trifluoroacetoxy) iodo benzene (13.2 g 30.8 mmol) dissolved in 30 mL 1, 1, 1, 3,3, 3-hexafluoro-2-propanol is added dropwise to the solution while keeping the temperature near room temperature. The mixture is stirred for 30 minutes and then concentrated under reduced pressure.

Purification by chromatography, eluting with EtOAc: hexane (3: 97) provides the title compound (0.57 g, 15%). GC/MS: M-+ 244 ;'H NMR (400 MHz, CDC13).

Step B 4-Ethyl-2-phenylsulfanyl-phenol The compound of Step A (570 mg, 2.33 mmol) and tetrabutylammonium iodide (1.72 g, 4.67 mmol) in 25 mL is dissolved in DCM, and the mixture is cooled reaction to-78 °C. Boron trichloride solution (4.7 ml, 1.0 M in DCM) is added dropwise over 5-10 minutes and stirred for 3 hours at 0°C. The mixture is quenched with ice water and stirred for 0.5 hours. The mixture is diluted with additional water and DCM.

Organic layer is separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by chromatography, eluting with EtOAc: hexane (2.5 : 97.5) provides the title compound (0.41 g, 76%). GC/MS: M-+ 230; 'H NMR (400 MHz, CDC13).

Example 185 Procedure 1-General Procedures for Coupling and Hydrolysis Ru t) rv R R R3 ArOH Br H DMF O Y OH Ruz RI COOR6 R3 CH3SO2C1 I A", & R4 R5 'EtN 0 y o-\ 0 Cs2CO3, DMF R3 COOR6 LiOH H20 R3 I dioxane/H O ArOA/R4 Rs a R3 R3 RH RI R2, A1- COOH Ar///R4 RS O R4 A", 6

Example 186 Procedure 2-General Procedures for Coupling and Hydrolysis R3 A COOR6 ro O R R2 A1 COOR6 Cs2C03 ' DMF ArOH Ri e S \ /R4 RS O Y A2 0 0 y A2 R3 RI R2 A COOR6 LIOH H20 \ 1 _ R4 R5 dioxane/H20 R4 Rs a R3 R3 'cool Ar,, R4 R5 O ! R5 2 0 Y A Example 187 (R, S)-2-Methyl-2- (4-3- [4- (4-trifluoromethyl-phenoxy)-phenoxy]-hexyloxy}-phenoxy)- propionic acid Step A (R, S)-3- [4- (4-trifluoromethyl-phenoxy)-phenoxy]-hexan-l-ol A mixture of 4- [4- (trifluoromethyl) phenoxy] phenol (1.4 g, 5.52 mmol), (R, S)-3-bromo-hexan-1-ol (1.0 g, 5.52 mmol), tetrabutyl anunonium iodide (1.0 g, 2.76 mmol), and cesium carbonate (3.6 g, 11.0 mmol) in 60 mL of DMF is heated overnight at 50°C under nitrogen atmosphere. After cooling water is added, and the mixture is

extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by chromatography, eluting with EtOAc: hexane (1: 4) provides the title compound (0.73 g, 36%). MS: (ES+) 709 ; 1H NMR (400 MHz, <BR> <BR> <BR> <BR> CDC13).<BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Step B (R, S)-2-methyl-2- (4- {3- [4- (4-trifluoromethyl-phenoxy)-phenoxy]-hexyloxy}- phenoxy) -propionic acid ethyl ester The compound of 3- [4- (4-trifluoromethyl-phenoxy)-phenoxy]-hexan-l-ol (730 mg, 2.06 mmol) and TEA (0.34 mL, 2.47 mmol) are dissolved in 25 mL DCM, and the mixture is cooled to 0°C followed by dropwise addition of MsCl (0.19 mL, 2.47 mmol). The mixture is stirred under nitrogen for 1.5 hours at 0°C. Water is added, and the organic layer is separated, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give crude methanesulfonic acid 3- [4- (4- trifluoromethyl-phenoxy) -phenoxy] -hexyl ester (0.930 g) that is utilized without purification.

A mixture of methanesulfonic acid 3- [4- (4-trifluoromethyl-phenoxy)- phenoxy]-hexyl'ester (144 mg, 0.33 mmol), 2- (4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (LLY 1433362) (74 mg 0.33 mmol), and cesium carbonate (280 mg, 0.66 mmol) in dry DMF (4 mL) is heated at 60 °C for 16 hours under nitrogen. The mixture is cooled and quenched with water. The mixture is extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash chromatography, eluting with EtOAc: hexane (1: 99), provides the title compound (0.11 g, 55%). MS: (ES+) 578;'H NMR (400 MHz, CDC13).

Step C (R, S)-2-Methyl-2- (4- {3- [4- (4-triftuoromcthyl-phenoxy)-phenoxy]-hexyloxy}- phenoxy) -propionic acid Purified 2-methyl-2- (4- {3- [4- (4-trifluoromethyl-phenoxy)-phenoxy]- hexyloxy}-phenoxy)-propionic acid ethyl ester (110.0 mg, 0.196 mmol) (1 eq) is dissolved in 4 mL dioxane and lithium hydroxide hydrate (100.0 mg, 2. 39 mmol) (-12 eq) dissolved in 2 mL water is added. The mixture is stirred at rt overnight under nitrogen. The mixture is acidified with 5 N HC1, and water is added. The mixture is extracted into EtOAc, washed with brine, dried with sodium sulfate and concentrated

under reduced pressure to give the title compound (0. 101 g, 97%). Exact mass calcd for C29H25CF3NO6 (M+NH4+) : 550.2416, found 550. 2426. HNMR (400 MHz, CDC13).

Example 188 (R, S)-2-f 4- [3- (4-Ethyl-2-phenylsulfanyl-phenoxy)-butoxy]-phenoxy}-2-methyl - propionic acid Step A (R, S)-2- {4- [3- (4-ethyl-2-phenylsulfanyl-phenoxy)-butoxy]-phenoxy}-2-methyl - propionic acid ethyl ester A mixture of 4-ethyl-2-phenylsulfanyl-phenol (Example 185) (98.4 mg, 0.43 mmol), (R, S)-2- [4- (3-methanesulfonyloxy-butoxy)-phenoxy]-2-methyl-propionic acid ethyl ester (160.0 mg 0.43 mmol), and cesium carbonate (347 mg, 1.07 mmol) in dry DMF (5 mL) is heated at 60 °C for 16 hours under nitrogen. The mixture is cooled and quenched with water. The mixture is extracted with EtOAc, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by flash chromatography, eluting with 7% EtOAc in hexane then 12% EtOAc in hexane (linear gradient), provides the title compound (0.067 g, 31%). MS: (ES+) 526 (M+NH4+) ; IH NMR (400 MHz, CDC13).

Step B (R, S)-2- {4- [3- (4-ethyl-2-phenylsulfanyl-phenoxy)-butoxy]-phenoxy}-2-methyl - propionic acid Purified compound of Step A (67.0 mg, 0.13 mmol) (1 eq) is dissolved in 2mL dioxane and lithium hydroxide hydrate (27.0 mg, 0.66 mmol) (-5 eq) dissolved in I mL water is added. The mixture is stirred at rt overnight under nitrogen. The mixture is acidified with 5 N HC1, and water is added. The mixture is extracted into EtOAc, washed

with brine, dried with sodium sulfate and concentrated under reduced pressure to give the title compound (24.0 mg, 74%). Mass (ES+) : 481 (M+H+) ;'H NMR (400 MHz, CDC13).

Example 189 2- {4- [3- (R, S-2-Benzenesulfinyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenyl sulfanyl}-2- methyl-propionic acid (enantiomer 1 and enantiomer 2) Step A (R, S)-3-Bromo-butan-l-ol A solution of ethyl beta-bromobutyrate (10.0 g, 51.3 mmol) in dry THF (100 mL) is cooled to-78 °C and treated dropwise with a 1M diisobutylaluminum hydride in toluene (107 mL, 107.7 mmol). The mixture is stirred for 15 minutes at-78 °C and then warmed to 0 °C and stirred for additional 45 minutes under nitrogen. The mixture is quenched slowly with 1 N HC1 (200 mL) and then diluted with water, extracted with ether, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure with bath at rt to give the title compound (6.1 g, 78%) that is utilized without purification.'H NMR (400 MHz, CDC13) : õ = 1.755 (d, 3H), 8 = 2.021 (m, 2H), 8 = 2.204 (s, 1H), 8 = 3. 802 (t, 2H), 8 = 4. 311 (m, 1H) Step B (R, S)-2-Benzenesulfinyl-4-ethyl-phenol The compound of 4-ethyl-2-phenylsulfanyl-phenol (480 mg 2.08 mmol) is dissolved in 5 mL chloroform, and the mixture is cooled to 0°C and solid meta- chloroperoxybenzoic acid (77%) (465 mg 2.08 mg) is added. The mixture is stirred about 10 minutes, and then quenched with water followed by the addition of ECM. The mixture is washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (0.51 g,

quantitative). No purification is carried out. MS: (ES+) 247 (M+H+) ; 1H NMR (400 MHz, CDC13.

Step C (R, S)-3-(2-Benzenesulfinyl-4-ethyl-phenoxy)-butan-1-ol The title compound is prepared according to the procedure described in Example 187, Step A by using 3-bromo-butan-1-ol and 2-benzenesulfinyl-4-ethyl-phenol.

Purification by flash chromatography, eluting with 50% EtOAc in hexane then to 70% EtOAc in hexane (linear gradient) provides the title compound (0.21 g, 30% yield). MS: (ES+) 319 (M+H+) ; 1H NMR (400 MHz, CDC13).

Step D (R, S)-Methanesulfonic acid 3- (2-benzenesulfinyl-4-ethyl-phenoxy)-butyl ester The title compound (0.25 g, 95%) is prepared according to the procedure described in Example 187, Step B by using 3- (2-benzenesulfinyl-4-ethyl-phenoxy)-butan- 1-ol. MS: (ES+) 397 (M+H+) ; IH NMR (400 MHz, CDCl3).

Step E (R, S) 2-f4- [3- ( (R, S) 2-Benzenesulfinyl-4-ethyl-phenoxy)-butoxy]-2-methyl- phenylsulfanyl}-2-methyl-propionic acid ethyl ester The title compound is prepared according to the procedure described in Example 187, Step B by using methanesulfonic acid 3- (2-benzenesulfinyl-4-ethyl- phenoxy) -butyl ester and 2- (4-hydroxy-2-methyl-phenylsulfanyl)-2-methyl-propionic acid ethyl ester. Purification by flash chromatography, eluting with 20% EtOAc in hexane and then to 50% EtOAc in hexane (linear gradient) provides the title compound (0.055 g, 65%). MS: (ES+) 555 (M+H+) ;'H NMR (400 MHz, CDC13).

Step F 2-f4- [3- ( (R, S) 2-Benzenesulfinyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenylsu lfanyl}-2- methyl-propionic acid (enantiomer pair 1 and enantiomer pair 2) The compound obtained in Step F (55.0 mg, 0.099 mmol) (1 eq) is dissolved in 3 mL dioxane followed by the addition of lithium hydroxide hydrate (83.0 mg, 1. 98 mmol) (-20 eq) dissolved in 1.5 mL water. The mixture is stirred at rt overnight under nitrogen. The mixture is acidified with 5 N HC1 and water is added, which then is extracted into EtOAc, washed with brine, dried with sodium sulfate and concentrated under reduced pressure. Purification by HPLC provides the title compounds (0. 0107g of

enantiomer 1 and 0.0063g of enamtiomer 2). Exact mass calcd for C29H35O5S2 (M+H+) : 527.1926, found 527. 1912. 1HNMR (400 MHz, CDC13) ; Exact mass calcd for C29H3505S2 (M+H+) : 527.1926, found 527. 1916. 1H NMR (400 MHz, CDC13).

Examples 190 to 210 are prepared according to Procedure 1 (Example 185) or Procedure 2 (Example 186) and for the coupling and hydrolysis as exemplified in Examples 187-189.

Example 190 (R, S)-3- {4- [3- (4'-Methoxy-biphenyl-4-yloxy)-hexyloxy]-2-methyl-phenyl}-pro pionic acid The title compound is prepared according to Procedure (Example 185).

Exact mass calcd for C29H38NO5 (M+NH4+) : 480.2750, found 480.2769 ;'HNMR (400 MHz, CDC13).

Example 191 (R, S)- {4- [3- (4'-Methoxy-biphenyl-4-yloxy)-hexylsulfanyl]-2-methyl-phenox yl-acetic acid The title compound is prepared according to Procedure 1 (Example 185).

MS (ES-) : 479.15 (M-H) ;'HNMR (400 MHz, CDCl3).

Example 192 (R, S)-2-{4-[3-(4'-Methoxy-biphenyl-4-yloxy)-hexyloxy]-phenoxy}- 2-methyl-propionic acid The title compound is prepared according to Procedure 1 (Example 185).

Exact mass calcd for C29H38NO6 (M+NH4+) : 496.2699, found 496.2697 ; IHNMR (400 MHz, CDC13).

Example 193 (R, S)-2- {4- [3- (2-Cyclohexylmethyl-4-trifluoromethyl-phenoxy)-butoxy]-pheno xy}-2- methyl-propionic acid The title compound is prepared according to Procedure 2 (Example 186).

Exact mass calcd for C28H39NO5F3 (M+NH4+) : 526.2780, found 526.2771 ; 1HNMR (400 MHz, CDC13).

Example 194 (R, S)-2-f 4- [3- (2-Cyclopropylmethyl-4-trifluoromethyl-phenoxy)-butoxy]-phen oxy}-2- methyl-propionic acid The title compound is prepared according to Procedure (Example 186).

Exact mass calcd for C25H33N05F3 (M+NH4+) : 484.2311, found 484.2321 ; 1HNMR (400 MHz, CDC13).

Example 195 {6- [R, S-3- (R, S-2-Benzenesulfinyl-4-ethyl-phenoxy)-butoxy]-1-propyl-1H-ind ol-3-yll- acetic acid The title compound is prepared according to Procedure 1 (Example 185).

MS (ES+) : 534.4 (M+H+) ;'HNMR (400 MHz, CDCl3).

Example 196 (R, S)-2-f 4- [3- (2, 7-Dimethyl-3-phenyl-benzofuran-6-yloxy)-butoxy]-phenoxy}-2- methyl-propionic acid The title compound is prepared according to Procedure 2 (Example 186).

Exact mass calcd for C3oH3306 (M+H): 489.2277, found 489.2273 ; 1H NMR (400 MHz, CDCl3).

Example 197 (R, S)-2-Methyl-2-{4-[3-(2-methyl-3-phenyl-7-propyl-benzofuran-6 -yloxy)- butoxy]-phenoxy}-propionic acid The title compound is prepared according to Procedure 2 (Example 186).

Exact mass calcd for C32H3706 (M+H): 517.2590, found 517.2587 ;'H NMR (400 MHz, CDC13).

Example 198 (R, S)-2-Methyl-2-14- [3- (4-methyl-3-phenyl-7-propyl-benzofuran-6-yloxy)- butoxy]-phenoxy}-propionic acid The title compound is prepared according to Procedure 2 (Example 186).

Exact mass calcd for C32H3706 (M+H): 517.2590, found 517.2587 ; IH NMR (400 MHz, CDCl3).

Example 199 (R, S)-2-Methyl-2-{4-[3-(4-methyl-3-phenyl-benzofuran-6-yloxy)-b utoxy]-phenoxy}- propionic acid The title compound is prepared according to Procedure 2 (Example 186).

Exact mass calcd for C29H31O6 (M+H): 475. 2121, found 475. 2132 ; 1H NMR (400 MHz, CDCl3).

Example 200 (R, S)-2-Methyl-2- (4- {3- [4- (4-trifluoromethyl-phenoxy)-phenoxy]-butoxy}-phenoxy)- propionic acid The title compound is prepared according to Procedure 2 (Example 186).

Exact mass calcd for C27H3lF3NO6 (M+NH4+) : 522.2103 found 522.2127 ; 1H NMR (400 MHz, CDCl3).

Example 201 2-Methyl-2- (4- {2-methyl-3- [4- (4-trifluoromethyl-phenoxy)-phenoxy]-propoxy}- phenoxy) -propionic acid The title compound is prepared according to Procedure 2 (Example 186).

Exact mass calcd for C27H3lF3NO6 (M+NH4+) : 522.2103 found 522.2125 ; 1H NMR (400 MHz, CDC13).

Example 202 (R, S)-3-(2-Methyl-4-{3-[4-(4-trifluoromethyl-phenoxy)-phenoxy]- hexyloxy}-phenyl)- propionic acid The title compound is prepared according to Procedure 1 (Example 185).

MS (ES-): 515 (M-H) ;'H NMR (400 MHz, CDCl3).

Example 203 (R, S)- (2-Methyl-4- {3- [4- (4-trifluoromethyl-phenoxy)-phenoxy]-hexylsulfanyl}- phenoxy) -acetic acid The title compound is prepared according to Procedure 1 (Example 185).

MS (ES-): 533 (M-H) ;'H NMR (400 MHz, CDCl3).

Example 204 (R, S)-2-{4-[3-(2-Cyclopropylmethyl-4-trifluoomethyl-phenoxy)-bu toxy]-2-methyl- phenoxy}-2-methyl-propionic acid The title compound is prepared according to Procedure 1 (Example 185).

Exact mass calcd for C26H35F3NO5 (M+NH4+) : 498.2467, found 498.2487 ; IH NMR (400 MHz, CDC13).

Example 205 (R, S)-3-f4- [3- (2-Cyclopropylmethyl-4-trifluoromethyl-phenoxy)-butoxy]-2-me thyl- phenyl}-propionic acid The title compound is prepared according to Procedure 1 (Example 185).

Exact mass calcd for C2sH33F3NO4 (M+NH4+) : 468.2362, found 468.2376 ; 1H NMR (400 MHz, CDC13).

Example 206 3-[R-4-[3-(R, S-2-Benzenesulfinyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenyl }- propionic acid The title compound is prepared according to Procedure 2 (Example 186).

Exact mass calcd for C28H3305S (M+H): 481.2049, found 481.2032 ; 1H NMR (400 MHz, CDCl3).

Example 207 3- {4- [3- (4-Ethyl-2-phenylsulfanyl-phenoxy)-butoxy]-2-methyl-phenyl}- propionic acid isomer 1 isomer 1 The title compound is prepared according to Procedure 2 (Example 186).

Exact mass calcd for C2sH36NO4S (M+NH4+) : 482.2365, found 482.2358 ; 1H NMR (400 MHz, CDC13).

Example 208 3- {4- [3- (4-Ethyl-2-phenylsulfanyl-phenoxy)-butoxy]-2-methyl-phenyl}- propionic acid isomer 2 isomer 2 The title compound is prepared according to Procedure 2 (Example 186).

Exact mass calcd for C28H36NO4S (M+NH4+) : 482. 2365, found 482.2375 ; 1H NMR (400 MHz, CDC13).

Example 209 (R, S)-3-{4-[3-(4-Ethyl-2-phenylsulfanyl-phenoxy)-butoxy]-2-meth yl-phenyl}-propionic acid The title compound is prepared according to Procedure 2 (Example 186).

Exact mass calcd for C28H36NO4S (M+H+) : 465.2117, found 465.2117 ; 1H NMR (400 MHz, CDC13).

Example 210 (R, S)-2-14- [3- (4-Ethyl-2-phenylsulfanyl-phenoxy)-butoxy]-phenoxyl-2-methyl - propionic acid

The title compound is prepared according to Procedure 2 (Example 186).

Partial oxidation to the sulfoxide may occur under certain conditions. LC/MS: (linear gradient: 90% water/5% ACN/5% formic acid to 0% water/95% ACN/5% formic acid) single peak tR=2. 24 minutes, ES+ 495 (M+H) ; IH NMR (400 MHz, CDC13).

Example 211 (R, S)-3- {4- [3- (R, S-2-Benzenesulfinyl 4-ethyl-phenoxy)-butoxy]-2-methyl-phenyl}- propionic acid Pure (R, S)-3-f4- [3- (4-ethyl-2-phenylsulfanyl-phenoxy)-butoxy]-2- methyl-phenyl}-propionic acid (47. 9 mg, 0.103 mmol, 1 equivalent) is dissolved in 5mL chloroform, and the mixture is cooled to 0°C and then solid 77% meta- chloroperoxybenzoic acid (22 mg, 0.098 mmol, 0.95 eq) is added. The mixture is stirred for about 10 minutes and quenched with water. DCM is added to the mixture. The mixture is washed with saturated sodium bicarbonate and brine, and then dried with sodium sulfate, and concentrated under reduced pressure to give the title compound (46.4 mg, 94%). Exact mass calcd for C28H3305S (M+H): 481.2049, found 481.2041 ; IH NMR (400 MHz, CDC13).

Example 212 (R, S)-2-14- [3- (R, S-2-Benzenesulfinyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenox yl-2- methyl-propionic acid'

Pure (R, S)-2- {4- [3- (4-ethyl-2-phenylsulfanyl-phenoxy)-butoxy]- phenoxy}-2-methyl-propionic acid (Example 210) (54.4 mg, 0.110 mmol, 1 equivalent) is dissolved in 5mL chloroform, and the mixture is cooled to 0°C, and solid 77% meta- chloroperoxybenzoic acid (23.4 mg, 0.104 mmol, 0.95 equivalent) is added. The mixture is stirred for about 10 minutes, quenched with water, and DCM is added. The mixture is washed with saturated sodium bicarbonate and brine, and then dried with sodium sulfate, and concentrated under reduced pressure to give the title compound (44.6 mg, 80%).

Exact mass calcdforC29H3506S (M+H): 511.2154, found 511. 2168 ; 1H NMR (400 MHz, CDC13).

Example 213 (R, S)-3- {4- [3- (2-Benzenesulfonyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenyl} - propionic acid Step A (R, S)-3-{4-[3-(2-Benzenesulfinyl-4-ethyl-phenoxy)-butoxy]-2-met hyl-phenyl}-propionic acid methyl ester The compound of (R, S)-3-14- [3- (2-Benzenesulfonyl-4-ethyl-phenoxy)- butoxy]-2-methyl-phenyl}-propionic acid methyl ester (prepared by procedure 2) (60.0 mg, 0.125 mmol, 1 eq) is dissolved in 10 mL chloroform at rt and then solid 77% meta-

chloroperoxybenzoic acid (70.0 mg, 0.312 mmol, 2.5 equivalents) is added. The mixture is stirred for an hour, quenched with water and DCM is added. The mixture is washed with 10% solution of sodium bisulfite, saturated sodium bicarbonate and brine, and then dried with sodium sulfate, and concentrated under reduced pressure. Purification by chromatography, eluting with 10% EtOAc in hexane to 20% EtOAc in hexane provides the title compound (41.7 mg, 65%). Ms: (ES+) 511 (M+H). step B (R, S)-3- {4- [3- (2-Benzenesulfonyl-4-ethyl-phenoxy)-butoxy]-2-methyl-phenyl} - propionic acid The title compound is prepared by using the compound obtained from Step A according to the procedure described in Example 187, Step C. Exact mass calcd for C28H3206SNa (M+Na) 519.1817, found 519.1830 ;'H NMR (400 MHz, CDC13).

Example 214 3- {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-2-methyl-phen yl}-propionic acid Step A <BR> <BR> 3- {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-2-methyl-phen yl}-propionic acid methyl ester A mixture of (2-hydroxy-5-trifluoromethoxy-phenyl)-phenyl-methanone (0.94g, 3.33 mmol), 3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic

acid methyl ester (1.38 g, 4.0 mmol) and Cs2CO3 (2.61 g, 8.0 mmol) in DMF (25 mL) is heated to 55°C for 17 hr under N2. The mixture is cooled to r. t. and diluted with Et20 and filtered through a pad of celite. Organic layer is washed with IN HC1, H20 and brine, and then dried over Na2S04, filtered and concentrated. Crude material is purified by chromatography (hexanes/acetone = 10: 1) to afford the title compound as colorless oil in 79% yield. Rf= 0.4 (2/1 hexanes/acetone). IH NMR (400 MHz, CDC13). <BR> <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> <BR> 3- {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-2-methyl-phen yl}-propionic acid A mixture of 3- {4- [3- (2-benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-2- methyl-phenyl}-propionic acid methyl ester (1.17 g, 2.19 mmol) and 4.4 mL of 5N NaOH (21.95 mmol) in 25 mL of EtOH is heated to reflux for 3 h. The mixture is cooled to r. t. and EtOH is removed under the vacuum. The residue is then dissolved in Et20 and IN HC1. Organic layer is washed with IN HC1, H20 and brine, and then dried over Na2S04, filtered and concentrated. Crude material is submitted to chiral chromatography separation. Two enantiomers are separated using Chiralpak AD (4.6 X 250 mm) with 4: 1 heptane/isopropanol with 0.1% TFA as the eluent (1 mL/min, UV280 nm). Isomer A : 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z exact mass calcd for C28H27F306 516, found 517 (M + 1,100%). Isomer B: 1 H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z exact mass calcd for C28H27F306 516, found 517 (M + 1,100%).

Example 215 3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-l-methyl-propoxy]-2-methyl-pheny l}-propionic acid

Step A [5-Ethyl-2- (3-hydroxy-butoxy)-phenyl]-phenyl-methanone

The mixture of (5-ethyl-2-hydroxy-phenyl) -phenyl-methanone (1.05 g, 4.6 mmol), toluene-4-sulfonic acid 3-hydroxy-butyl @ 1.25 g, 5. 1 mmol) and Cs2C03 (1. 8 g, 5.6 mmol) in 25 mL of dry DMF is i sland at 50°C for overnight. The mixture is then cooled to r. t. und diluted with Et20 and filtered through a pad of celite..

Organic layer is washed with 1N HC1, H20 and brine, and then dried over Na2SO4, filtered and concentrated. Crude material is purified by chromatography (hexanes/ EtOAc = 8: 1) to afford the title compound as a colorless oil in 89% yield. Rf= 0.29 (8/1 hexanes/EtOAc).'H NMR (400 MHz, CDCl3).

Step B Methanesulfonic acid 3-(2-benzoyl-4-ethyl-phenoxy)-1-methyl-propyl ester

A mixture of [5-ethyl-2- (3-hydroxy-butoxy)-phenyl]-phenyl-methanone (0.85 g, 2.85 mmol), MsCI (0.33 mL, 4. 27 mmol) and Et3N (1.0 mL, 7.12 mmol) in 25 mL of dry CH2C12 is allowed to stand at 0°C for lh and wanned up to r. t. for 2h. The resulting mixture is washed with IN HC1, H20 and brine, and then dried over Na2SO4, filtered and concentrated. The crude material is used for next step without further purification. Rf= 0.32 (8/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3). <BR> <BR> <BR> <BR> <P> Step C<BR> <BR> <BR> <BR> <BR> <BR> 3- {4- [3-(2-Benzoyl-4-ethyl-phenoxy)-1-methyl-propoxy]-2-methyl-ph enyl}-propionic acid methyl ester A mixture of methanesulfonic acid 3-(2-benzoyl-4-ethyl-phenoxy)-1- methyl-propyl ester (1.09 g, 2.90 mmol), 3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (469 mg, 2.41 mmol) and Cs2C03 (1. 18 g, 3.62 mmol) in 25 mL of dry DMF is allowed to stand at 55°C for overnight. The mixture is cooled to r. t. and diluted with Et20 and filtered through a pad of celite. Organic layer is washed with IN HC1, H20 and brine, and then dried over Na2SO4, filtered and concentrated. Crude material is purified by chromatography (hexanes/acetone = 10: 1) to afford the title compound as a colorless oil in 62% yield. Rf= 0.26 (10/1 hexanes/acetone).'H NMR (400 MHz, CDC13).

Step D<BR> <BR> <BR> <BR> <BR> <BR> 3-f{4- [3- (2-Benzoyl-4-ethyl-phenoxy)-1-metliyl-propoxy]-2-methyl-phen yl}-propionic acid A solution of 3-{4-[3-(2-benzoyl-4-ethyl-phenoxy)-1-methyl-propoxy]-2-meth yl- phenyl}-propionic acid methyl ester (isomer 1 from chiral chromatography, 250 mg, 0.52 mmol) and 0.5 mL of 5N NaOH (2.63 mmol) in 10 mL of MeOH is allowed to stand at r. t. for 4 h. The organic solvent is removed under the vacuum. The residue is then dissolved in Et20 and IN HC1. Organic layer is washed with IN HC1, H20, brine and dried over Na2S04, filtered and concentrated to give the title compound in a colorless oil in 98% yield.'H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z exact mass calcd for C29H3205 460, found 461 (M + 1,100%).

Step E <BR> <BR> <BR> <BR> 3-f{4- [3- (2-Benzoyl-4-ethyl-phenoxy)-1-methyl-propoxy]-2-metliyl-phen yl}-propionic acid A solution of 3-{4-[3-(2-benzoyl-4-ethyl-phenoxy)-1-mthyl-propoxy]-2- methyl-phenyl}-propionic acid methyl ester (isomer 2 from chiral chromatography, 241 mg, 0.50 mmol) and 0.5 mL of 5N NaOH (2.50 mmol) in 10 mL of MeOH is allowed to stand at r. t. for 4 h. The organic solvent is removed under the vacuum. The residue is then dissolved in Et20 and IN HC1. Organic layer is washed with IN HC1, H20, brine, and then dried over Na2SO4, filtered and concentrated to give the title compound in a colorless oil in 98% yield.'H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z exact mass calcd for C29H3205 460, found 461 (M + 1,100%).

Example 215A 3- {2-Ethyl-4- [3- (4-ethyl-2-pyridin-2-yl-phenoxy)-butoxy]-phenyl}-propionic acid Cesium carbonate (0.091 g, 0.28 mmol) is added to 4-ethyl-2-pyridin-2-yl- phenol (0.04 g, 0.20 mmol) and 3- [2-ethyl-4- (3-methanesulfonyloxy-butoxy)-phenyl]-

propionic acid ethyl ester (0.09 g, 0.28 mmol) in DMF (5 mL), and the mixture is stirred under N2 at 55 °C. After 16 h, mixture is cooled to ambient temperature and filtered. The solid is washed with ethyl acetate. Filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: ethyl acetate (8 : 2) gives 3-12-ethyl-4- [3- (4-ethyl-2-pyridin-2-yl-phenoxy)-butoxy]-phenyll-propionic acid ethyl ester (0.045 g, 0.096 mmol, 48%): ES+ (m/e) 476.3 (M+H) +.

A 5 M aqueous solution of sodium hydroxide (0.30 mL, 1.50 mmol) is added to the above propionic acid ethyl ester (0.045 g, 0.10 mmol) in ethanol (3 mL), and the mixture is stirred at ambient temperature for 4 h. The mixture is acidified to pH = 7 with a 1 M HC1 and extracted with ethyl acetate. Organic layers were combined and washed with saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated at reduced pressure to obtain title compound (0.035g, 0.078 mmol, 82%): ES+ (m/e) : 448.3 (M+H) +.

Example 216 <BR> <BR> <BR> 3- {2-Methyl-4- [3- (2-pyridin-2-yl-4-trifluoromethyl-phenoxy)-butoxy]-phenyl}-p ropionic acid Step A 2-methoxy-5-(trifluoromethyl) phenylboronic acid

n-BuLi (1.6 M in hexane) (44.45 mL, 71.13 mmol) is added a solution of 2-bromo-1-methoxy-4-trifluoromethyl-benzene (18.14 g, 71.13 mmol) in diethylether (71 mL) at-78 °C and the mixture is stirred for an hour while maintaining the internal temperature below-75 °C. The mixture is stirred at r. t. for 30 minutes, cooled to-78°C and added over a solution of triisopropylborate (19.70 mL, 85.35 mmol) in diethylether (239 mL). The temperature is maintained below-75 °C for 1 h and stirred at r. t. for 30 minutes and concentrated HCI (200 mL) is added. The mixture is extracted with diethylether. Organic layers are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (quantitative).

Step B<BR> <BR> 2-(2-Methoxy-5-trifluoromethyl-phenyl)-pyridine A mixture of 2-methoxy-5- (trifluoromethyl)-phenylboronic acid (15.64 g, 71. 10 mmol), 2-bromopyridine (5.65 mL, 59.25 mmol), palladium tetrakis- (triphenylphosphine) (2.74 g, 2.37 mmol) and sodium carbonate (2 M in water) (83 mL, 165.9 mmol) in dimethoxyethane (118 mL) is stirred overnight under reflux. The mixture is cooled to rt and the layers are separated. The aqueous layer is extracted with ethylacetate and the organic layers are combined, dried, filtered and concentrated.

Purification by flash chromatography, eluting with hexane: EtOAc 5: 1 provides the title compound (11.68 g, 78 %).

Step C 2-Pyridin-2-yl-4-trifluoromethyl-phenol

Boron tribromide (1.0 M in dichloromethane) (92.25 mL, 92.25 mmol) is added to a solution of 2- (2-methoxy-5-trifluoromethyl-phenyl)-pyridine (11.68 g, 46.12 mmol) in DCM (230 mL) at-78 °C. The mixture is stirred at that temperature forl O minutes, and the bath is removed and stirred at rt for 1 h. Water is added slowly and stirred for 1 h. The mixture is extracted with DCM and the organic layers are combined which is then dried over sodium sulfate, filtered and concentrated under reduced pressure.

Purification by flash chromatography, eluting with hexane: EtOAc 5: 1 provides the title compound (6.00 g, 54 %). <BR> <BR> <P> Step D<BR> <BR> 3- {2-Methyl-4- [3- (2-pyridin-2-yl-4-trifluoromethyl-phenoxy)-butoxy]-phenyl}-p ropionic acid Cesium carbonate (0.091 g, 0.28 mmol) is added to 2-pyridin-2-yl-4- trifluoromethyl-phenol (0.045 g, 0.20 mmol) and 3- [4- (3-methanesulfonyloxy-butoxy)-2- methyl-phenyl] -propionic acid methyl ester (0.083 g, 0.24 mmol) in DMF (3 mL), and the mixture is stirred under N2 at 55 °C. After 16 h, the mixture is cooled to ambient temperature, filtered and washed solid with EtOAc. The filtrate is washed with water and saturated aqueous sodium chloride, and then dried over magnesium sulfate, filtered and concentrated under reduce pressure. Purification by flash chromatography, silica, hexanes: EtOAc (8: 2) provides 3- {2-methyl-4- [3- (2-pyridin-2-yl-4-trifluoromethyl- phenoxy)-butoxy]-phenyll-propionic acid methyl ester (0.045 g, 0.092 mmol, 46%): ES+ (m/e) 488.2 (M+H) +.

Aqueous solution of sodium hydroxide (5M, 0.25 mL, 1.2 mmol) is added to the above propionic acid methyl ester (0.041 g, 0.08 mmol) in methanol (3 mL), and the mixture is stirred at ambient temperature for 4 h. The mixture is acidified to pH = 7 with a 1 M HC1 and extracted with EtOAc. Organic layers are combined and washed with saturated aqueous sodium chloride dry over magnesium sulfate, filtrated and concentrated at reduced pressure to obtain title compound (0.040g, 0.085 mmol, 100%): ES+ (m/e): 474.2 (M+H) +.

Example 217 3- {2-Methyl-4- [3- (2-pyridin-4-yl-4-trifluoromethyl-phenoxy)-butoxy]-phenyl}-p ropionic acid Step A 4-(2-Methoxy-5-trifluoromethyl-phenyl)-pyridine Na2CO3 2M in H20 (2.8 mmol) and Pd (PPh3) 4 (4 %) are added to a solution of the bromide (1 mmol) and boronic acid (1.4 mmol) in DME (2 mL/mmol).

The mixture is stirred at 85 °C overnight. The crude is quenched with H20 and extracted with AcOEt. The combined organic layers are dried over Na2S04, filtered, evaporated and purified by column chromatography using the appropriate eluent.

Bromide: 4-Bromo-pyridine hydrochloride (1.76 g, 9.09 mmol). Boronic acid: 2- methoxy-5- (trifluoromethyl)-phenylboronic acid (2.00 g, 9.09 mmol) Eluent: Hexane: AcOEt 1 : 1.

Step B<BR> <BR> 2-Pyridin-4-yl-4-trifluoromethyl-phenol To a solution of the methoxyderivative (1 mmol) in CH2C12 (5 mL/mmol) at-78 °C under N2, BBr3 1. OM (CH2C12) is added (2 mmol). After 10 min, the bath is removed, and the mixture is stirred at rt. After 1-2 h, water is added. The crude is extracted with CH2C12. The organic layer is dried over Na2S04, filtered, evaporated and purified by flash chromatography using the eluent. Methoxyderivative: 4- (2-Methoxy-5- trifluoromethyl-phenyl) -pyridine (0.77 g, 3.04 mmol). Eluent: Hexane: AcOEt 1: 2. 1H NMR (CDC13,300 MHz): 8 7.10 (d, 1 H, J= 8. 48 Hz), 7.51 (dd, 1 H, J= 2.02, 8.48 Hz), 7.62 (s, 1 H), 7.74 (d, 2 H, J= 6.05 Hz), 8.62 (d, 1 H, J= 6. 05 Hz).

MS [M+H] 239.9. <BR> <BR> <BR> <BR> step C<BR> <BR> <BR> <BR> <BR> 3- {2-Methyl-4- [3- (2-pyridin-4-yl-4-trifluoromethyl-phenoxy)-butoxy]-phenyl}-p ropionic acid The title compound is prepared according to the procedure described in Example 216 by using 3- {2-methyl-4- [3- (2-pyridin-4-yl-4-trifluoromethyl-phenoxy)- butoxy]-phenyl}-propionic acid methyl ester. MS: ES+ (m/e) 474.2 (M+).

Example 218 <BR> <BR> 3- {2-Ethyl-4- [3- (2-pyridin-2-yl-4-trifluoromethyl-phenoxy)-butoxy]-phenyl}-p ropionic acid The title compound is prepared according to the procedure described in Example 215A by using 3- {2-ethyl-4- [3- (2-pyridin-2-yl-4-trifluoromethyl-phenoxy)- butoxy]-phenyl}-propionic acid ethyl ester. MS: ES+ (m/e): 488. 2 (M+).

Example 219 3-{2-Ethyl-4-[3-(2-pyridin-4-yl-4-trifluoromthyl-phenoxy)-bu toxy]-phenyl}-propionic acid The title compound is prepared according to the procedure described in Example 215A by using 3- 2-ethyl-4- [3- (2-pyridin-4-yl-4-trifluoromethyl-phenoxy)- butoxy]-phenyl}-propionic acid ethyl ester. MS: ES+ (m/e): 488.2 (M+).

Example 220 <BR> <BR> 3- {4- [3- (2-Benzo [d] isoxazol-3-yl-4-cMoro-phenoxy)-butoxy]-2-methyl-phenyl}- propionic acid Step A (5-Chloro-2-methoxy-phenyl)- (2-fluoro-phenyl)-methanone To a solution of the anisole (1 mmol) in CH2Cl2 (1 mL/mmol), under N2 at 0 °C, A1C13 (1.2 mmol) is d in several portions. After stirring for 10 min, acyl chloride (1. 1 mmol) is added. The mixture is stirred for 2-3 h and is poured into an ice: water: HCl mixture. The organic layer is washed with saturated NaHCO3 and water, dried over Na2SO4, filtered, evaporated and purified by flash chromatography using the eluent.

Anisole : l-Chloro-4-methoxy-benzene (2.00 g, 14.03 mmol). Acylchloride: 2-Fluoro- benzoyl chloride (2.45 g, 15.45 mmol). Eluent: Hexane: AcOEt 10: 1.

Step B<BR> <BR> (5-Chloro-2-methoxy-phenyl)-(2-fluoro-phenyl)-methanone oxime A solution of (5-chloro-2-methoxy-phenyl)-(2-fluoro-phenyl)-methanone (1.73 g, 6.52 mmol) in warm ethanol (26.0 mL) is treated with NH2OH. HC1 (2.18 g, 31.32 mmol) and refluxed for 6 h. The mixture is poured into water and cooled in an ice: water bath. The oxime is filtered off and dried in vacuo. step C 3- (5-Chloro-2-methoxy-phenyl)-benzo [d] isoxazole To a solution of (5-chloro-2-methoxy-phenyl)- (2-fluoro-phenyl)- methanone oxime (1.64 g, 5.86 mmol) in 1-methyl-pyrrolidin-2-one (26.0 mL), potassium t-butoxide (0.72 g, 6.45 mmol) is added. The mixture is heated at 100 °C for 3 h. The crude is diluted with water and extracted with AcOEt. The organic layer is washed with water and brine, and then dried over Na2S04, filtered, evaporated, purified by flash chromatography using hexane: AcOEt 5: 1 as eluent. step D 2-Benzo [d] isoxazol-3-yl-4-chloro-phenol

To a solution of the methoxy derivative (1 mmol) in CH2C12 (5 mL/mmol) at-78 °C under N2, BBr3 1. tOM (CH2C12) is added (2 mmol). After 10 min the bath is removed and the mixture is stirred at rt. After 1-2 h, water is added and the crude is extracted with CH2C12. The organic layer is dried over Na2SO4, filtered and evaporated.

The crude product is purified by flash chromatography using the eluent.

Methoxyderivative: 3- (5-Chloro-2-methoxy-phenyl)-benzo [d] isoxazole (0.57 g, 2.20 mmol). Eluent: Hexane: AcOEt 5: 1. 1H NMR (CDC13, 300 MHz): 7.05 (d, 1 H, J= 8. 88 Hz), 7.30 (dd, 1 H, J= 2. 42,8. 88 Hz), 7.38-7. 43 (m, 1 H), 7.62 (m, 2 H), 7.85 (d, 1 H, J= 2.43 Hz), 7.99 (d, 1 H, J= 8. 28 Hz). MS [M+H] 246.1.

Step E 3- 4- [3- (2-Benzo [d] isoxazol-3-yl-4-chloro-phenoxy)-butoxy]-2-methyl-phenyl}- propionic acid The title compound is prepared according to the procedure described in Example 216 by using 3-{4-[3-(2-benzo [d] isoxazol-3-yl-4-chloro-phenoxy)-butoxy]-2- methyl-phenyl}-propionic acid methyl ester gives the title compound. MS: ES+ (m/e) 480.2 (M+).

Example 221 3-f 4- [3- (4-Chloro-2-pyridin-4-yl-phenoxy)-butoxy]-2-methyl-phenyl}-p ropionic acid Step A 3-Chloro-6-methoxy-benzene boronic acid To a solution of the bromide (1 mmol) in THF (ImL/mmol) at-78 °C under N2, n-BuLi (1.2 mmol) is added and then B (OPr') 3 (2 mmol) is added after 15-30 min. The mixture is stirred for 3 h at rt. The crude is quenched with HCl. The aqueous layer is extracted with AcOEt, and the organic layers are combined, dried over Na2S04, filtered and evaporated. The boronic acids are used without further purification in the next step. Bromide: 2-Bromo-4-chloro-1-methoxy-benzene (0.50 g, 2.26 mmol); nBuLi (1.6 M, Hex): 1.69 mL, 2.71 mmol; Triisopropylborate: 1.04 mL, 4.52 mmol.'H NMR (300 MHz, CDC13) : 3.80 (s, 3 H), 6.73 (d, 1 H, J= 8. 9 Hz), 7.16 (d, 1 H, J= 8. 9 Hz), 7.70 (s, 1 H). Rf=0. 4 (hex: AcOEt 5: 1).

Step B<BR> <BR> 4- (5-Chloro-2-methoxy-phenyl)-pyridine

To a solution of the bromide (1 mmol) and boronic acid (1.4 mmol) in DME (2 mL/mmol), Na2CO3 2M in H20 (2.8 mmol) and Pd (PPh3) 4 (4 %) are added. The mixture is stirred at 85 °C overnight. The crude is quenched with H20 and extracted with AcOEt. The combined organic layers are dried over Na2SO4, filtered and evaporated.

The crude product is purified by column chromatography using the appropriate eluent.

Bromide: 4-bromo-pyridine hydrochloride (3.50 g, 17.88 mmol) ; Boronic acid: 3-Chloro- 6-methoxy-benzene boronic acid (4.00 g, 21.46 mmol); Eluent: Hexane: AcOEt 1: 1.

Step C 4-Chloro-2-pyridin-4-yl-phenol To a solution of the methoxy derivative (1 mmol) in CH2C12 (5 mL/mmol) at-78 °C underN2, BBr3 l. OM (CH2Cl2) is added (2 mmol). After 10 min. , the bath is removed and the mixture is stirred at rt. After 1 to 2 h, water is added, and the crude is extracted with CH2C12. The organic layer is dried over Na2SO4, filtered and evaporated.

The crude product is purified by flash chromatography using the eluent indicated in each case. Methoxyderivative : 4- (5-Chloro-2-methoxy-phenyl)-pyridine (1.10 g, 5.00 mmol) ; Eluent: AcOEt. 1H NMR (CDCl3, 300 MHz): 6.99 (d, 1 H, J= 8. 67 Hz), 7.21 (d, 1 H, J= 8.67 Hz) ; 7.33 (s, 1 H), 7.71 (d, 2 H, J= 5.05 Hz), 8.60 (d, 1 H, J= 4. 64 Hz). MS [M+H] 206.1.

Step D 3- {4- [3- (4-Chloro-2-pyridin-4-yl-phenoxy)-butoxy]-2-methyl-phenyl}-p ropionic acid The title compound is prepared according to the procedure described in Example 216 by using 3-{4-[3-(3-chloro-2-pyridin-4-yl-pheoxy)-butyoxy]-2-methyl- phenyl}-propionic acid methyl ester. MS: ES+ (m/e) 440.1 (M+).

Example 222 {4- [3- (2-Benzo [d] isoxazol-3-yl-4-chloro-phenoxy)-butoxy]-2-methyl-phenylsulfa nyl}- acetic acid The title compound is prepared according to the procedure described in Example 215A by using {4- [3- (2-benzo [d] isoxazol-3-yl-4-chloro-phenoxy)-butoxy]-2- methyl-phenylsulfanyl}-acetic acid ethyl ester. MS : ES+(m/e) : 498.0 (M+).

Example 223 3- {2-Ethyl-4- [3- (2-pyridin-3-yl-4-trifluoromethyl-phenoxy)-butoxy]-phenyl}-p ropionic acid Step A 2-Pyridin-3-yl-4-trifluoromethyl-phenol

To a solution of the bromide (1 mmol) and boronic acid (1.4 mmol) in DME (2 mL/mmol), Na2CO3 2M in H20 (2.8 mmol) and Pd (PPh3) 4 (4 %) are added. The mixture is stirred at 85°C overnight. The crude is quenched with H20 and extracted with AcOEt. The combined organic layers are dried over Na2SO4, filtered and evaporated.

The crude product is purified by column chromatography using the appropriate eluent in each case. Bromide: 2-Bromo-4-trifluormethyl-phenol (4.70 g, 19.52 mmol); Boronic acid: 3-pyridine boronic acid (2.40 g, 19.52 mmol); Eluent: Hexane: AcOEt 1: 2. 1H NMR (DMSO, 300 MHz): 6.96 (d, 1 H, J= 8. 5 Hz), 7.34 (dd, 1 H, J=4. 8,7. 7 Hz), 7.60 (d, 1 H, J= 8. 1 Hz), 7.76 (dd, 1 H, J= 2. 4, 8. 5 Hz), 7.85 (m, 1 H), 7. 98 (d, 1 H, J= 2. 4 Hz), 8. 45 (dd, 1 H, J= 1. 6,6. 4 Hz), 8.64 (d, 1 H,. J= 2.0 Hz).

MS [M+H] 239.8. <BR> <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> 3- {2-Ethyl-4- [3- (2-pyridin-3-yl-4-trifluoromethyl-phenoxy)-butoxy]-phenyl}-p ropionic acid The title compound is prepared according to the procedure described in Example 215A by using 3- {2-ethyl-4- [3- (2-pyridin-3-yl-4-trifluoromethyl-phenoxy)- butoxy]-phenyl}-propionic acid ethyl ester. MS: ES+ (m/e): 488.2 (M+).

Example 224 2-Methyl-2-14- [3- (7-phenyl-naphthalen-2-yloxy)-butoxy]-phenoxyl-propionic acid

Step A 4-Methyl- [1, 3,2] dioxathiane 2-oxide Thionyl chloride (15. 9mL, 217mmol) is added drop wise over lh to a 0°C solution of 1,3-butanediol (15mL, 167mmol) in methylene chloride (80mL) and vented to a sodium hydroxide scrubber. The resulting solution, while still vented to the scrubber, is refluxed for 1h and cooled to ambient temperature. The solution is washed thoroughly with water, saturated aqueous sodium bicarbonate, and more water. The organic layer is dried over MgS04 and concentrated in vacuo over a cool water bath to provide 17. 5g (77%) of the title compound.

Step B 4-Methyl- [1, 3,2] dioxathiane 2,2-dioxide Ruthenium (III) chloride (0.365g, 1. 76mmol) is added to a biphasic solution of 4-methyl- [1, 3,2] dioxathiane 2-oxide) (10. 9g, 80. lmmol) and sodium periodate (34.3g, 160. 1mmol) in carbon tetrachloride (150mL), water (230mL) and ACN (150mL). The reaction suspension is stirred at ambient temperature for 2h, and then extracted from the aqueous layer with methylene chloride. The organic layer is filtered through a pad of celite, dried over MgS04, and concentrated i71 vacuo to provide 12. 0g

(99%) of the title compound. 1H NMR (400 MHz, CDC13) 8 5.04-4. 98 (m, 1H), 4.73 (tt, 1H, J= 10.9 Hz, 2.7 Hz), 4.56-4. 52 (m, 1H), 2.15-2. 03 (m, 1H), 1.87 (dt, 1H, J= 14.0 Hz, 1.9 Hz), 1.44 (dd, 3H, J= 6.3 Hz, 2.8 Hz).

Step C 2- [4- (3-Hydroxy-butoxy)-phenoxy]-2-methyl-propionic acid ethyl ester A 0°C solution of 4-methyl- [1, 3,2] dioxathiane 2, 2-dioxide (8.1g, 53.2mmol) in ACN (300mL) is treated with cesium carbonate (29. 5g, 79. 8mmol) and 2- (4- hydroxy-phenoxy) -2-methyl-propionic acid ethyl ester (29. 5g, 90. 5mmol). The mixture is stirred at ambient temperature for 10h and concentrated in vacuo. The reaction residue, which is partitioned between diethyl ether and concentrated HC1, is stirred rapidly for 1 Oh at ambient temperature. The organic layer is washed with water, saturated aqueous sodium bicarbonate and brine, and then dried over Na2SO4 and concentrated in vacuum.

The crude material is purified by flash chromatography to provide 10. 2g (65%) of the title compound. step D 2- [4- (3-Methanesulfonyloxy-butoxy)-phenoxy]-2-methyl-propionic acid ethyl ester Methanesulphonyl chloride (3.2mL, 41. 3mmol) is added to a 0°C solution of 2- [4- (3-hydroxy-butoxy)-phenoxy]-2-methyl-propionic acid ethyl ester (10.2g, 34. 4mmol) and TEA (7.2mL, 51. 6mmol) in methylene chloride (300mL). The resulting solution is stirred at 0°C for 2h, and then quenched with IN HC1. The organic layer is washed with IN HCl, dried over Na2SO4, and concentrated in vacuo. The crude material is purified by flash chromatography, using 25% acetone in hexanes as eluent, to provide 11.12g (86%) of the title compound. IH NMR (400 MHz, CDC13) õ 7. 15 (d, 2H, J=9. 1 Hz), 6.85 (d, 2H, J= 9. 1 Hz), 4.22 (q, 2H, J= 7.1 Hz), 3.09 (s, 3H), 2.92 (s, 1H), 1.58 (s, 6H), 1.52 (s, 1H), 1.50 (d, 1H, J= 6.4 Hz), 1.26 (t, 2H, J= 7.1 Hz), 1.24 (t, 2H, J= 7.4 Hz). MS [EI+] 392 (M+NH4) +. RrO. 18 in 33% acetone in hexanes.

Step E 2-Methoxy-7-phenyl-naphthalene

A flame-dried reaction vessel is charged with trifluoro-methanesulfonic acid 7-methoxy-naphthalen-2-yl ester (l. lOg, 3.59mmol), phenyl boronic acid (1. 31g, 10. 8mmol), tricyclohexyphosphine (0. 151g, 0. 54mmol), palladium (II) acetate (0. 081g, 0. 36mmol), and cesium fluoride (4. 91g, 32.3mmol). ACN (35mL) is added to the reaction vessel, and the reaction suspension is heated at 90°C for 6 minutes, and then cooled to ambient temperature and filtered through celite. The filtrate is diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, dried over MgS04, and concentrated in vacuo. The crude material is purified by flash chromatography, using 5% acetone in hexanes as eluent, to provide 0.65g (77%) of the title compound.'H NMR (400 MHz, CDC13) 8 7.97 (d, 1H, J = 1.7 Hz), 7. 85 (d, 1H, J = 9.2 Hz), 7.78 (d, 1H, J = 8.8 Hz), 7.74 (dd, 2H, J = 8.4 Hz, 1.3 Hz), 7.62 (dd, 1H, J = 8.4 Hz, 1.7 Hz), 7.50 (t, 2H, J = 7.9 Hz), 7.41 (t, 1H, J = 7.9 Hz), 7.22 (d, 1H, J = 2.5 Hz), 7.17 (dd, 1H, J = 9.2 Hz, 2.5 Hz). MS [EI+] 235 (M+H) +. Rif=0. 52 in 33% acetone in hexanes.

Step F 7-Phenyl-naphthalen-2-ol A mixture of 2-methoxy-7-phenyl-naphthalene (0.65g, 2.77mmol) and pyridine HC1 (6.41g, 55. 5mmol) is melted at 205°C for 45minutes. The reaction mixture is cooled to ambient temperature, diluted with CH2Cl2, and washed with IN HC1. The

organic layer is dried over Na2S04, and concentrated in vacuo. The crude material is purified by flash chromatography, using 17% acetone in hexanes as eluent, to provide 0. 61g (100%) of the title compound. 1H NMR (400 MHz, CDC13) 6 7. 88 (s, 1H), 7.84 (d, 1H, J= 8.2 Hz), 7. 78 (d, 1H, J-8. 7 Hz), 7.71 (d, 2H, J = 8.2 Hz), 7.60 (dd, 1H, J= 8.2 Hz, 1.4 Hz), 7.48 (t, 2H, J= 8.2 Hz), 7. 38 (t, 1H, J= 8.2 Hz), 7. 20 (d, 1H, J= 2.4 Hz), 7.10 (dd, 1H, J= 8.7 Hz, 2.4 Hz). MS [EI-] 219 (M-H)+. Rf=0. 30 in 33% acetone in hexanes. <BR> <BR> <BR> <BR> <P> Step G<BR> <BR> <BR> <BR> <BR> 2-Methyl-2- {4- [3- (7-phenyl-naphthalen-2-yloxy)-butoxy]-phenoxy}-propionic acid A solution of 7-phenyl-naphthalen-2-ol (Step F (0.033g, 0. 15mmol) and 2- [4- (3-methanesulfonyloxy-butoxy)-phenoxy]-2-methyl-propionic acid ethyl ester (Step D) (0.056g, 0. 15mmol) in DMF (3mL) is treated with cesium carbonate (0.58g, 0. 18mmol) and heated to 50°C under N2. After 10h, the mixture is cooled to ambient temperature and diluted with diethyl ether. The organic layer is washed with IN HCI, water and brine, and then dried over Na2S04, and concentrated in vacuo. The crude material is purified by flash chromatography using 17% acetone in hexanes as eluent, to provide a quantitative yield of the ester. Rf=0. 38 in 33% acetone in hexanes.

A solution of 2-methyl-2- {4- [3- (7-phenyl-naplithalen-2-yloxy)-butoxy]- phenoxy}-propionic acid ethyl ester and 5N NaOH (0. 5mL) in ethanol (5mL) is refluxed under N2 for 30 minutes, and then cooled to ambient temperature and concentrated in vacuo. The reaction residue is dissolved in DCM, washed with IN HCI, dried over Na2S04, and concentrated in vacuo to provide the title compound. 1H NMR (400 MHz, CDC13) 57. 85 (d, 1H, J= 1.2 Hz), 7.81 (d, 1H, J= 9.4 Hz), 7.74 (d, 1H, J= 9.4 Hz), 7.70 (dd, 2H, J= 8.8 Hz, 1.2 Hz), 7. 59 (dd, 1H, J= 8. 8 Hz, 1.8 Hz), 7. 48 (t, 2H, J= 8.2 Hz), 7.37 (t, 1H, J= 8. 2 Hz), 7.24 (d, 1H, J= 1.8 Hz), 7.13 (dd, 1H, J= 8.8 Hz, 2.4 Hz), 6.89 (d, 2H, J= 9.4 Hz), 6.82 (d, 2H, J= 9.4 Hz), 4. 87-4. 82 (m, 1H), 4.18-4. 09 (m, 2H), 2.29- 2.22 (m, 1H), 2.18-2. 11 (m, 1H), 1.50 (s, 6H), 1.46 (d, 3H, J= 6.1 Hz). HRMS (ES+) m/z exact mass calcd for C30H3105 471.2171, found 471.2187.

Example 225 2-Methyl-2-{4-[2-methyl-3-(7-phenylpaphthalen-2-yloxy)-propo xy}-phenoxy}-propionic acid Step A Methanesulfonic acid 3-methanesulfonyloxy-2-methyl-propyl ester Methanesulphonyl chloride (5.2mL, 66.6mmol) is added to a 0°C solution of 2-methyl-1, 3-propanediol (5mL, 55. 5mmol) and TEA (11. 6mL, 83. 2mmol) in methylene chloride (200mL). The resulting solution is stirred at 0°C for 2h and quenched with IN HC1. The organic layer is washed with IN HC1, dried over Na2S04, and concentrated i7i vacuo to provide 8.8g (65%) of the title compound. 1H NMR (400 MHz, CDC13) 8 4.19 (d, 1H, J= 4.8 Hz), 4.17 (d, 1H, J= 4.8 Hz), 4.12 (d, 1H, J= 6.3 Hz), 4.10 (d, 1H, J= 6.3 Hz), 2.99 (s, 6H), 2.34-2. 27 (m, 1H), 1.04 (d, 3H, J= 6.3 Hz). MS [EI+] 264 (M+NH4) +. Rf=0. 08 in 33% acetone in hexanes.

Step B 2- [4- (3-Methanesulfonyloxy-2-methyl-propoxy)-phenoxy]-2-methyl-pr opionic acid ethyl ester A solution of methanesulfonic acid 3-methanesulfonyloxy-2-methyl- propyl ester (8.8g, 35. 7mmol) and 2- (4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (1. 09g, 35. 73mmol) in DMF (20mL) is treated with cesium carbonate (3. 5g,

10. 7mmol) and heated to 50°C under N2. After lOh, the mixture is cooled to ambient temperature and diluted with EtOAc. The organic layer is washed with IN HC1, water and brine, and then dried over MgS04, and concentrated in vacuo. The crude material is purified by flash chromatography, using 20% acetone in hexanes as eluent to provide 1.62g (60%) of the title compound. 1H NMR (400 MHz, CDC13) 8 7.81 (d, 2H, J= 9.2 Hz), 7.74 (d, 2H, J= 9.2 Hz), 4.27, 4.26 (ABq, 2H, J= 5.3 Hz, 3.8 Hz), 4.88 (d, 1H, J= 5.0 Hz, isomer 1), 4.85 (d, 1H, J= 5.0 Hz, isomer 2), 4.82 (d, 1H, J= 6.1 Hz, isomer 1), 4.79 (d, 1H, J= 6.1 Hz, isomer 2), 2.95 (s, 3H), 2.38-2. 31 (m, 1H), 1.51 (s, 6H), 1.26 (t, 3H, J= 7. 3 HzO, 1. 10 d, 3H, J= 6. 9 Hz). MS [EI+] 392 (M+NH4) +. Rf=0. 12 in 33% acetone in hexanes. <BR> <BR> <BR> <BR> <BR> <P> Step C<BR> <BR> <BR> <BR> <BR> <BR> 2-Methyl-2- {4-[2-methyl-3-(7-phenyl-naphthalen-2-yloxy)-propoxy]-phenox y}-propionic acid A solution of 7-phenyl-naphthalen-2-ol (0.036g, 0. 16mmol) and 2- [4- (3- methanesulfonyloxy-2-methyl-propoxy)-phenoxy]-2-methyl-propi onic acid ethyl ester (0. 065g, 0. 16mmol) in DMF (3mL) is treated with cesium carbonate (0.62g, 0. 20mmol) and heated to 50°C under N2. After 1 Oh, the mixture is cooled to ambient temperature and diluted with diethyl ether. The organic layer is washed with IN HC1, water and brine, and then dried over Na2SO4, and concentrated in vacuo. The crude material is purified by flash chromatography using 17% acetone in hexanes as eluent to provide the ester. Rf=0. 35 in 33% acetone in hexanes.

A solution of 2-methyl-2- {4- [2-methyl-3- (7-phenyl-naphthalen-2-yloxy)- propoxy]-phenoxy}-propionic acid and 5N NaOH (0. 5mL) in ethanol (5mL) is refluxed under N2 for 30 minutes, and then cooled to ambient temperature and concentrated in vacuo. The reaction residue is dissolved in DCM, washed with IN HC1, dried over Na2SO4, and concentrated in vacuo to provide the title compound.'H NMR (400 MHz, CDC13) 8 7.85 (d, 1H, J 1. 7 Hz), 7.81 (d, 1H, J= 8.9 Hz), 7.74 (d, 1H, J= 8. 9 Hz), 7.70 (d, 2H, J= 7.3 HzO, 7.60 (dd, 1H, J= 8.9 Hz, 2.2 Hz), 7.48 (t, 2H, J= 7. 8 Hz), 7.38 (d, 1H, J = 7.8 Hz), 7.24 (d, 1H, J= 2.2 Hz), 7.13 (dd, 1H, J= 8. 9 Hz, 2.2 Hz), 6. 89 (d, 2H, J = 9.5 Hz), 6. 82 (d, 2H, J= 9.5 Hz), 4.84 (q, 1H, J= 6.1 Hz), 4.18-4. 09 (m, 2H), 2. 30-2. 22 (m, 1H), 2.18-2. 11 (m, 1H), 1.50 (s, 6H), 1.46 (d, 3H, J= 6. 1 Hz). HRMS (ES+) m/z exact mass calcd for C30H31N05 471.2171, found 471. 2187.

Example 226 <BR> <BR> 2-f{4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-phenoxy}-2-me thyl-propionic acid

step A (2-Methoxy-5-trifluoromethoxy-phenyl)-phenyl-methanone n-Butyl lithium (32. 5mL, 52mmol) is added drop wise to-10°C TMEDA (7.85mL, 52mmol) in a flame-dried reaction vessel over 30 minutes. The compound of 4- (trifluoromethoxy) anisole (3.94mL, 26mmol) is added drop wise to the resulting yellow mixture. This resulting brown solution is stirred at-10°C for thirty minutes and treated with N-methoxy-N-methylbenzamide (7.92mL, 52mmol). The mixture is stirred at 10°C for 40 minutes, and then quenched with IN HC1 and diluted with diethyl ether. The organic layer is washed with IN HC1, water and brine, and then dried over Na2SO4, and concentrated in vacuo. The crude material is purified by flash chromatography using 11% acetone in hexanes as eluent to provide 5. 38g (70%) of the title compound.'H NMR (400 MHz, CDC13) 8 7.80 (dd, 2H, J=8. 4 Hz, 1.3 Hz), 7.58 (tt, 1H, J= 8.0 Hz, 1.3 Hz), 7.45 (t, 2H, J = 8. 0 Hz), 7. 33 (dd, 1H, J= 8. 4 Hz, 3. 0 Hz), 7.24 (d, 1H, J= 3. 0 Hz), 6.99 (d, 1H, J= 9.3 Hz), 3.73 (s, 3H). Rf=0. 42 in 33% acetone in hexanes. step B (2-Hydroxy-5-trifluoromethoxy-phenyl)-phenyl-methanone

A mixture of (2-methoxy-5-trifluoromethoxy-phenyl)-phenyl-methanone (5. 38g, 18. 6mmol) and pyridine HC1 (42g, 36. 3mmol) is melted at 205°C for 3. 5h. The mixture is cooled to ambient temperature, diluted with CH2Cl2, and washed with IN HC1.

The organic layer is dried over Na2SO4 and concentrated in vacuo. The crude material is purified by flash chromatography using 17% acetone in hexanes as eluent to provide 2. 71g (71%) of the title compound. 1H NMR (400 MHz, CDC13) 8 11.93 (s, 1H), 7.69 (dd, 2H, J= 8.4 Hz, 1.5 Hz), 7.64 (tt, 1H, J= 7.5 Hz, 2.1 Hz), 7.55 (d, 2H, J= 8.1 Hz), 7.47 (d, 1H, J= 2.7 Hz), 7.40 (dd, 1H, J= 8.7 Hz, 2.7 Hz), 7.10 (d, 1H, J= 9.3 Hz). MS [EI-] 281 (M-H) +. Rf=0. 56 in 33% acetone in hexanes. <BR> <BR> <BR> <P> Step C<BR> <BR> <BR> <BR> 2-14- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-phenoxyl-2-me thyl-propionic acid A solution of (2-hydroxy-5-trifluoromethoxy-phenyl)-phenyl-methanone (0.044g, 0. 16mmol) and 2- [4- (3-methanesulfonyloxy-butoxy)-phenoxy]-2-methyl- propionic acid ethyl ester (0. 058g, 0. 16mmol) in DMF (2.9mL) is treated with cesium carbonate (0. 066g, 0.20mmol) and heated to 50°C under N2. After 1 Oh, the mixture is cooled to ambient temperature and diluted with diethyl ether. The organic layer is washed with IN HC1, water and brine, and then dried over Na2S04, and concentrated in vacuo. The crude material is purified by flash chromatography using 17% acetone in hexanes as eluent to provide the ester. Rif=0. 33 in 33% acetone in hexanes.

A solution of 2- {4- [3- (2-benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]- phenoxy}-2-methyl-propionic acid ethyl ester and 5N NaOH (0.3mL) in ethanol (3mL) is refluxed under N2 for 30 minutes, and then cooled to ambient temperature and concentrated in vacuo. The reaction residue is dissolved in DCM, washed with IN HC1,

dried over Na2S04, and concentrated i7l vacuo to provide 0. 021g of the title compound.

1H NMR (400 MHz, CDC13) 8 7.78, 7.74 (ABq, 2H, J= 7.6 Hz), 7.53 (t, 1H, J= 7.6 Hz), 7.40 (t, 2H, J= 7.6 Hz), 7.26 (d, 2H, J= 1. 9 Hz), 6.98 (d, 1H, J= 8.9 Hz), 6.87 (d, 2H, J = 8. 9 Hz), 6.66 (d, 2H, J= 8.9 Hz), 4.62 (q, 1H, J= 6.4 Hz), 3.73-3. 68 (m, 2H), 1. 86-1.82 (m, 2H), 1.54 (s, 6H), 1.20 (d, 3H, J= 6.4 Hz). MS [EI+] 533 (M+H) +.

Example 227 2- {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-2-methyl-propoxy]-phe noxy}-2- methyl-propionic acid A solution of (2-hydroxy-5-trifluoromethoxy-phenyl)-phenyl-methanone (0.061g, 0.22mmol) and 2- [4- (3-methanesulfonyloxy-2-methyl-propoxy)-phenoxy]-2- methyl-propionic acid ethyl ester (0. 081g, 0.22mmol) in DMF (2.9mL) is treated with cesium carbonate (0.092g, 0.28mmol) and heated to 50°C under N2. After lOh, the mixture is cooled to ambient temperature and diluted with diethyl ether. The organic layer is washed with IN HC1, water and brine, and then dried over Na2SO4 and concentrated in vacuo. The crude material is purified by flash chromatography using 17% acetone in hexanes as eluent to provide the ester. Rf=0.33 in 33% acetone in hexanes.

A solution of 2-f 4- [3- (2-benzoyl-4-trifluoromethoxy-phenoxy)-2-methyl- propoxy]-phenoxy3-2-methyl-propionic acid ethyl ester and 5N NaOH (0.3mL) in ethanol (3mL) is refluxed under N2 for 30 minutes, then cooled to ambient temperature and concentrated in vacuo. The reaction residue is dissolved in DCM, washed with IN HC1, dried over Na2SO4, and concentrated in vacuo to provide 0.054g of the title compound.'H NMR (400 MHz, CDC13) 8 7.77, 7.73 (ABq, 2H, J= 7. 3 Hz), 7.49 (t, 1H, J= 7.3 Hz), 7. 36 (t, 2H, J = 7.3 Hz), 7.27 (d, 2H, J= 3.0 Hz), 6.97 (d, 1H, J= 9.1 Hz),

6.87 (d, 2H, J= 9. 1 Hz), 6.62 (d, 2H, J= 9. 1 Hz), 3.93 (t, 2H, J= 5. 5 Hz), 3.45 (q, 2H, J = 2.4 Hz), 2.14-2. 06 (m, 1H), 1.55 (s, 6H), 0.80 (d, 3H, J= 6.7 Hz). MS [EI+] 533 (M+H) +.

Example 228 2-f 4- [3- (3-Benzoyl-naphthalen-2-yloxy)-butoxy]-phenoxy}-2-methyl-pro pionic acid Step A (3-Hydroxy-naphthalen-2-yl)-phenyl-methanone Phenyllithium (95mL, 1.8M in 70/30 cyclohexane/ether) is added drop wise to a-78°C solution of 3-hydroxy-2-naphthoic acid (4. 0g, 21. 3mmol) in THF. The mixture is warmed to ambient temperature for 3h, and then cooled to 0°C and quenched with water. Then resulting bright yellow solution is stirred vigorously while 1 N HC1 is added. The organic layer is washed with water and brine, and then dried over MgS04 and adsorbed onto silica gel. The crude material is purified by flash chromatography, using 20% acetone in hexanes as eluent, to provide the title compound. 1H NMR (400 MHz, CDC13) 8 11.15 (s, 1H), 8.17 (s, 1H), 7.78 (d, 2H, J= 7.4 Hz), 7.73 (d, 1H J= 5.0 Hz), 7.71 (d, 1H, J= 5.0 Hz), 7.66 (tt, 1H, J= 8.1 Hz), 7.55-7. 52 (m, 3H), 7.39 (s, 1H), 7.32 (t, 2H, J= 8. 1 Hz). HRMS (ES+) m/z exact mass calcd for C28H29N06S2C1 574. 1125, found 574.1122. Rf=0. 44 in 33% acetone in hexanes.

Step B 2- {4- [3- (3-Benzoyl-naphthalen-2-yloxy)-butoxy]-phenoxy}-2-methyl-pro pionic acid A solution of (3-hydroxy-naphthalen-2-yl) -phenyl-methanone (0.042g, 0.17mmol) and 2- [4- (3-methanesulfonyloxy-butoxy)-phenoxy]-2-methyl-propionic acid ethyl ester (0.064g, 0. 17mmol) in DMF (3mL) is treated with cesium carbonate (0.072g,

0. 22mmol) and heated to 50°C under N2. After l Oh, the mixture is cooled to ambient temperature and diluted with EtOAc. The organic layer is washed with IN HC1 and water, dried through a Varian ChemElut cartridge, and concentrated in vacuo. The crude material is purified by flash chromatography, using 20% acetone in hexanes as eluent, to provide the ester. Rf=0. 26 in 33% acetone in hexanes.

A solution of 2-f4- [3- (3-benzoyl-naphthalen-2-yloxy)-butoxy]-phenoxyl- 2-methyl-propionic acid ethyl ester and 5N NaOH (0.3mL) in ethanol (3. 5mL) is refluxed under N2, then cooled to ambient temperature and concentrated in vacuo. The reaction residue is dissolved in DCM, washed with IN HC1, dried through a Varian ChemElut cartridge, and concentrated in vacuo to provide 0.034g of the title compound. 1H NMR (400 MHz, CDC13) 8 7.89 (s, 1H), 7. 82-7. 75 (m, 4H), 7.53-7. 46 (m, 2H), 7.39 (td, 1H, J= 8.2 Hz, 1.5 Hz), 7.34 (t, 2H, J= 8. 2 Hz), 7.23 (s, 1H), 6.87 (d, 2H, J= 8. 9 Hz), 6.63 (d, 2H, J= 8.9 Hz), 3.78 (q, 1H, J= 5.7 Hz), 3.73 (td, 2H, J= 5.7 Hz, 1.9 Hz), 2.17 (s, 1H), 1.89 (q, 2H, J= 6.2 Hz), 1.51 (s, 6H), 1.27 (d, 3H, J= 6.2 Hz). MS [EI+] 499 (M+H) +.

Example 229 2- {4- [3- (3-Benzoyl-naphthalen-2-yloxy)-2-methyl-propoxy]-phenoxy}-2- methyl- propionic acid A solution of (3-hydroxy-naphthalen-2-yl) -phenyl-methanone (0.042g, 0. 17mmol) and 2- [4- (3-methanesulfonyloxy-2-methyl-propoxy)-phenoxy]-2-methyl- propionic acid ethyl ester (0.063g, 0.17mmol) in DMF (3mL) is treated with cesium carbonate (0. 071 g, 0. 22mmol) and heated to 50°C under N2. After 1 Oh, the mixture is cooled to ambient temperature and diluted with EtOAc. The organic layer is washed with IN HC1 and water, dried through a Varian ChemElut cartridge, and concentrated in vacuo. The crude material is purified by flash chromatography, using 20% acetone in hexanes as eluent, to provide the ester. Rif=0. 24 in 33% acetone in hexanes.

A solution of 2-{4-[3-(3-benzoyl-naphthalen-2-yloxy)-2-methyl-propoxy]- phenoxy}-2-methyl-0ropionic acid ethyl ester and 5N NaOH (0.3mL) in ethanol (3.5mL) is refluxed under N2, then cooled to ambient temperature and concentrated in vacuo. The residue is dissolved in DCM, washed with 1N HC1, dried through a Varian ChemElut cartridge, and concentrated in vacuo. The material is lost while purifying by flash chromatography. 1H NMR (400 MHz, CDC13) 8 7.89 (s, 1H), 7.79 (q, 4H, J= 9.1 Hz), 7.53-7. 46 (m, 2H), 7.39 (td, 1H, J= 7.0 Hz, 0.7 Hz), 7.34 (t, 2H, J= 7.7 Hz), 7.22 (s, 1H), 6.87 (d, 2H, J = 9.1 Hz), 6.64 (d, 2H, J = 9.1 Hz), 4.04 (p, 2H, J = 5.9 Hz), 3.50 (d, 2H, J= 6.8 Hz), 2. 18 (p, 2H, J= 5.9 Hz), 1. 53 (s, 6H), 0. 85 (d, 3H, J= 6.8 Hz). MS [EI+] 499 (M+H) +.

Example 230 <BR> <BR> <BR> <BR> 3- {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-2-methyl-phen yl}-propionic acid step A Toluene-4-sulfonic acid 3-hydroxy-butyl ester A solution of 1,3-butanediol (2mL, 22. 3mmol), TEA (3. 1 lmL, 22.3mmol), and p-toluene sulphonyl chloride (4.25g, 22.3mmol) in methylene chloride (45mL) is treated with dibutyltin oxide (0. 111 g, 0.45mmol) and stirred under N2 for 1 Oh. The reaction suspension is filtered through a pad of celite and concentrated in vacuo. The crude material is purified by flash chromatography, using 20% acetone in hexanes as eluent, to provide 3.44g (63%) of the title compound. MS [EI+] 245 (M+H) +. Rf=0. 18 in 33% acetone in hexanes. step B 3- [4- (3-Hydroxy-butoxy)-phenyl]-propionic acid methyl ester

A solution of (toluene-4-sulfonic acid 3-hydroxy-butyl ester (3. 5g, 14. 3mmol) and (2.3g, 11. 9mmol) in DMF (40mL) is treated with cesium carbonate (5.8g, 17.8mmol) and heated to 50°C under N2. After lOh, the mixture is cooled to ambient temperature and diluted with diethyl ether. The organic layer is washed with IN HC1 and water, dried over Na2S04, and concentrated in vacuo. The crude material is purified by flash chromatography, using 17% acetone in hexanes as eluent, to provide 1. 51g (48%) of the title compound. 1H NMR (400 MHz, CDC13) 8 7.03 (d, 1H, J= 8.2 Hz), 6.71 (d, 1H, J= 2.5 Hz), 6.67 (dd, 1H, J= 8.2 Hz, 2.5 Hz), 4.15-4. 02 (m, 3H), 3.67 (s, 3H), 2.87 (t, 2H, J= 7.5 Hz), 2.54 (t, 2H, J= 7.5 Hz), 2.35 (d, 1H, J= 4. 1 Hz), 2.28 (s, 3H), 1.89 (q, 2H, J= 6.3 Hz), 1.25 (d, 3H, J= 6.3 Hz). Rif=0. 31 in 33% acetone in hexanes.

Step C 3- [4- (3-Metlianesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester Methanesulphonyl chloride (0.53mL, 6. 8mmol) is added to a 0°C solution of 3- [4- (3-Hydroxy-butoxy)-phenyl]-propionic acidmethyl ester (1. 51g, 5. 67mmol) and TEA (1. 2mL, 8. 5mmol) in methylene chloride (60mL). The resulting solution is stirred at 0°C for lOh and quenched with 1N HC1. The organic layer is washed with 1N HC1, dried over Na2SO4, and concentrated ira vacua to provide 1.9g (100%) of the title compound.

'H NMR (400 MHz, CDC13) 6 7.03 (d, 1H, J= 8. 3 Hz), 6.69 (d, 1H, J= 2.4 Hz), 6.65 (dd, 1H, J= 8.3 Hz, 2.4 Hz), 5.04 (q, 1H, J= 6.3 Hz), 4.03 (t, 2H, J= 5.0 Hz), 3.67 (s, 3H), 2.93 (s, 3H), 2.87 (t, 2H, J= 7.5 Hz), 2.54 (t, 2H, J= 7.5 Hz), 2. 28 (s, 3H), 2.10 (qd, 2H, J= 6. 3 Hz, 2.3 Hz), 1.51 (d, 3H, J= 6. 3 Hz). MS [EI+] 362 (M+H) +. Rf=0. 18 in 33% acetone in hexanes.

step D 3- {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-2-methyl-phen yl}-propionic acid A solution of (2-hydroxy-5-trifluoromethoxy-phenyl)-phenyl-methanone (0.14g, 0. 47mmol) and 3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]-propionic acid methyl ester (O. 24g, 0. 71mmol) in DMF (5mL) is treated with cesium carbonate (0.262g, O. 80mmol) and heated to 50°C under N2. After 10h, the reaction mixture is cooled to ambient temperature and diluted with EtOAc. The organic layer is washed with IN HC1, water and brine, and then dried over Na2S04, and concentrated in vacuo. The crude material is purified by flash chromatography, using 17% acetone in hexanes as eluent, to provide the ester. Rf=0. 28 in 33% acetone in hexanes.

A solution of 3- {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-2- methyl-phenyl}-propionic acid methyl ester and 5N NaOH (0.4mL) in ethanol (4mL) is refluxed under N2, then cooled to ambient temperature and concentrated in vacuo. The reaction residue is dissolved in DCM, washed with IN HC1, dried over Na2S04, and concentrated in vacuo to provide 0. 115g of the title compound. IH NMR (400 MHz, CDC13) 8 7.74 (d, 2H, J= 7.0 Hz), 7.52 (t, 1H, J= 7.0 Hz), 7.38 (t, 2H, J= 7.8 Hz), 7.25 (d, 2H, J= 7.8 Hz), 6.96 (d, 2H, J= 8.7 Hz), 6.55 (d, 1H, J= 2.6 Hz), 6.49 (dd, 1H, J= 8. 7 Hz, 2.6 Hz), 4.59 (q, 1H, J= 6.0 Hz), 3.67 (t, 2H, J= 6.0 Hz), 2.81 (t, 2H, J= 8.3 Hz), 2.51 (t, 2H, J = 8.3 Hz), 2.22 (s, 3H), 1.79 (q, 2H, J = 6.0 Hz), 1.16 (d, 3H, J = 6.0 Hz). MS [EI+] 517 (M+H) +. Rj=0. 54 in 10% methanol in methylene chloride.

Example 231 3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-1-methyl-propoxy]-2-methyl-pheny l}-propionic acid

Step A [5-Ethyl-2- (3-hydroxy-butoxy)-phenyl]-phenyl-methanone A 0°C solution of 4-methyl- [1, 3,2] dioxathiane 2,2-dioxide (0.19g, 1.25mmol) in ACN (lOmL) is treated with cesium carbonate (0.69g, 2. 12mmol) and (5- ethyl-2-hydroxy-phenyl) -phenyl-methanone (0.42g, 1. 87mmol). The mixture is stirred at ambient temperature for l Oh and concentrated in vacuo. The residue, partitioned between diethyl ether and concentrated HC1, is stirred rapidly for lOh at ambient temperature. The resulting mixture is diluted with EtOAc, washed with water, saturated aqueous sodium bicarbonate and brine, and then dried over Na2SO4, and concentrated in vacuo. The crude material is purified by flash chromatography to provide 10. 2g (65%) of the title compound.'H NMR (400 MHz, CDC13) 6 7.79 (d, 2H, J= 7.9 Hz), 7.54 (d, 1H, J= 7.9 Hz), 7.43 (t, 2H, J= 7.9 Hz), 7.29 (dd, 1H, J= 8.6 Hz, 2.0 Hz), 7.23 (d, 1H, J= 2. 0 Hz), 6.92 (d, 1H, J= 8.6 Hz), 4.12-4. 06 (m, 1H, isomer 1), 4.03-3. 98 (m, 1H, isomer 2), 6.34 (q, 1H, J= 6.0 Hz), 2.62 (q, 2H, J= 7.8 Hz), 2.04 (s, 2H), 1.64 (q, 2H, J= 6.0 Hz), 1. 48 (d, 1H, J= 6.0 Hz), 1.22 (t, 3H, J= 7. 8 Hz), 1.06 (d, 3H, J= 7.8 Hz). MS [EI+] 299 (M+H) +.

Step B Methanesulfonic acid 3- (2-benzoyl-4-ethyl-phenoxy)-l-methyl-propyl ester

Methanesulphonyl chloride (O. lmL, 0. 60mmol) is added to a 0°C solution of [5-ethyl-2- (3-hydroxy-butoxy)-phenyl]-phenyl-methanone (0. 15g, 0. 50mmol) and TEA (0. 11mL, 0. 75mmol) in methylene chloride (5mL). The resulting solution is stirred at 0°C for 2h and quenched with IN HC1. The organic layer is washed with IN HC1, dried over Na2SO4, and concentrated in vacuo. The crude material is purified by flash chromatography, using 20% acetone in hexanes as eluent, to provide 0.12g (63%) of the title compound. 1H NMR (400 MHz, CDC13) 8 7. 78 (d, 2H, J= 7.3 Hz), 7.56 (t, 1H, J= 7.3 Hz), 7.44 (t, 2H, J= 7.3 Hz), 7. 28 (dd, 1H, J= 8.4 Hz, 2.1 Hz), 7.24 (d, 1H, J= 2.1 Hz), 6. 88 (d, 1H, J= 8.4 Hz), 4.50-4. 44 (m, 1H), 4.06-3. 97 (m, 1H), 3.95-3. 90 (m, 1H), 2.84 (s, 3H), 2.63 (q, 2H, J= 7.4 Hz), 1. 87-1. 79 (m, 1H), 1.72-1. 64 (m, 1H), 1.21 (d, 3H, J= 7.4 Hz), 1.23 (t, 3H, J= 5.9 Hz). MS [EI+] 377 (M+H)+. Rf=0. 25 in 33% acetone in hexanes. <BR> <BR> <BR> <P> Step C<BR> <BR> <BR> 3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-1-methyl-propoxy]-2-methyl-pheny l}-propionic acid methyl ester A solution of (3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.03g, 0. 15mmol) andmethanesulfonic acid3-(2-benzoyl-4-ethyl-phenoxy)-1-methyl- propyl ester (0.057g, 0. 151mmol) in DMF (5mL) is treated with cesium carbonate (0.064g, 0. 197mmol) and heated to 50°C under N2. After lOh, the reaction mixture is

cooled to ambient temperature and diluted with EtOAc. The organic layer is washed with IN HC1, water and brine, and then dried over Na2S04, and concentrated in vacuo. The crude material is purified by flash chromatography, using 17% acetone in hexanes as eluent, to provide the ester NMR (400 MHz, CDC13) 8 7.79 (d, 2H, J= 7.3 Hz), 7.54 (t, 1H, J= 7.3 Hz), 7.41 (t, 2H, J= 7.3 Hz), 7.25 (d, 2H, J= 7 : 3 Hz), 6.95 (d, 1H, J= 8.1 Hz), 6.85 (d, 1H, J= 8.1 Hz), 6. 55 (d, 1H, J=2. 4 Hz), 6.45 (dd, 1H, J= 8.1 Hz, 2.4 Hz), 4.08-4. 01 (m, 2H), 3.96-3. 91 (m, 1H), 3.68 (s, 3H), 2.85 (t, 2H, J= 7.7 Hz), 2.62 (q, 2H, J = 7. 4 Hz), 2.54 (t, 2H, J= 7.4 Hz), 2.24 (s, 3H), 1.90-1. 78 (m, 1H), 1.65-1. 57 (m, 1H), 1.22 (t, 3H, J= 7.7 Hz), 1.07 (d, 3H, J= 6.1 Hz). MS [EI+] 475 (M+H) +. Rf=0. 38 in 30% acetone in hexanes. <BR> <BR> <BR> <BR> <P> Step D<BR> <BR> <BR> <BR> <BR> 3-f{4- [3- (2-Benzoyl-4-ethyl-phenoxy)-1-methyl-propoxy]-2-metliyl-phen yl}-propionic acid A solution of 3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-l-methyl-propoxy]- 2-methyl-phenyl}-propionic acid methyl ester (0. 30g, 063mmol) and 5N NaOH (0.3mL) in ethanol (3mL) is refluxed under N2, then cooled to ambient temperature and concentrated in vacuo. The residue is dissolved in DCM, washed with IN HC1, dried through a Varian ChemElut cartridge, and concentrated in vacuo to provide the title compound. HRMS (ES+) m/z exact mass calcd for C29H3305 461.2328, found 461.2333.

Example 232 3-f 4- [3- (2-Benzoyl-4-ethyl-phenoxy)-pentyloxy]-2-methyl-phenyl}-prop ionic acid step A Toluene-4-sulfonic acid 3-hydroxy-pentyl ester

Dibutyltin oxide (0.30g, 1.20mmol) and TEA (10.9mL, 78mmol) are added to a 0°C solution of pentane-1, 3-diol (6.24g, 59. 9mmol) in methylene chloride (100mL). The resulting solution is treated with p-toluenesulphonic anhydride (1.14g, 59. 9mmol) in two portions over 10 minutes. The mixture is stirred under N2 for lOh while gradually wanning to ambient temperature. The reaction is quenched with IN HC1.

The organic layer is washed with IN HC1, dried over Na2S04, and concentrated in vacuo.

The crude material is purified by flash chromatography, using 17% acetone in hexanes as eluent, to provide 1.03g (7%) of the title compound.'H NMR (400 MHz, CDC13) 8 7.78 (d, 2H, J = 8.2 Hz), 7. 33 (d, 2H, J= 8.2 Hz), 4. 27-4. 21 (m, 1H), 4.14-4. 09 (m, 1H), 3.66- 3.61 (m, 1H), 2.43 (s, 3H), 1. 88-1. 80 (m, 2H), 1.67-1. 59 (m, 1H), 1.47-1. 39 (m, 2H), 0.90 (t, 3H, J=7. 8Hz). Rf=0. 15 in 33% acetone in hexanes.

Step B 3- [4- (3-Hydroxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester A solution of toluene-4-sulfonic acid 3-hydroxy-pentyl ester (1.03g, 3. 99mmol) and 3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.52g, 2.7mmol) in DMF (25mL) is treated with cesium carbonate (1.47g, 4. 52mmol) and heated to 50°C under N2. After 1 Oh, the reaction mixture is cooled to ambient temperature and diluted with diethyl ether and IN HC1. The organic layer is washed with IN HC1 and brine, dried over Na2SO4, and concentrated in vacuo. The crude material is purified by flash chromatography, using 20% acetone in hexanes as eluent, to provide 0.29 (39%) of the title compound. 1H NMR (400 MHz, CDC13) 8 7.02 (d, 1H, J= 8.4 Hz), 6.71 (d, 1H,

J-2.4 Hz), 6.67 (dd, 1H, J=8. 4Hz, 2. 4 Hz), 4.16-4. 10 (m, 1H, isomer 1), 4.09-4. 03 (m, 1H, isomer 2), 3.81-3. 76 (m, 1H), 3.66 (s, 3H), 2.86 (t, 2H, J= 8.6 Hz), 2.53 (t, 2H, J= 8.2 Hz), 2.36 (d, 1H, J= 4.3 Hz) 2.27 (s, 3H), 1.97-1. 90 (m, 1H, isomer 1), 1.88-1. 80 (m, 1H, isomer 2), 1.53 (p, 2H, J= 7.5 Hz), 0.96 (t, 3H, J= 7.5 Hz). Rf=0. 31 in 33% acetone in hexanes. step C 3- [4- (3-Methanesulfonyloxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester Methanesulphonyl chloride (O. lmL, l. 3mmol) is added to a 0°C solution of 3- [4- (3-hydroxy-pentyloxy)-2-methyl-phenyl]-propionic acid methyl ester (0.29g, l. Ommol) and TEA (0.2mL, 1. 6mmol) in methylene chloride (lOmL). The resulting solution is stirred under N2 for 2h while gradually warming to ambient temperature, which then quenched with IN HCl. The organic layer is washed with IN HC1, dried over Na2SO4, and concentrated in vacuo to provide 0.37g (100%) of the title compound. 1H NMR (400 MHz, CDC13) 8 7.03 (d, 1H, J= 8.4 Hz), 6.70 (d, 1H, J= 2.7 Hz), 6.66 (dd, 1H, J=8. 4 Hz, 2.7 Hz), 4.91 (p, 1H, J= 5. 8 Hz), 4.04 (t, 2H, J=5. 8 Hz), 3.67 (s, 3H), 2.95 (s, 3H), 2.87 (t, 2H, J= 7.4 Hz), 2.54 (t, 2H, J= 7.4 Hz), 2.28 (s, 3H), 2.15-2. 10 (m, 2H), 1.90-1. 79 (m, 2H), 1.02 (t, 3H, J= 7.4 Hz). MS [EI+] 376 (M+NH4) +. Rf=0. 30 in 33% acetone in hexanes.

Step D 3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-pentyloxy]-2-methyl-phenyl}-prop ionic acid A solution of 3- [4- (3-methanesulfonyloxy-pentyloxy)-2-methyl-phenyl]- propionic acid methyl ester (0. 1 g, 0. 30mmol) and (5-ethyl-2-hydroxy-phenyl)-phenyl- methanone (0.045g, 0. 20mmol) in DMF (5mL) is treated with cesium carbonate (0. 1 lg, 0. 34mmol) and heated to 50°C under N2. After 10h, the mixture is cooled to ambient temperature and diluted with diethyl ether. The organic layer is washed with IN HC1, water and brine, and then dried over Na2S04, and concentrated in vacuo. The crude

material is purified by flash chromatography, using 17% acetone in hexanes as eluent, to provide the ester. Rf=0. 38 in 33% acetone in hexanes.

A solution of 3-f4- [3- (2-benzoyl-4-ethyl-phenoxy)-pentyloxy]-2-methyl- phenyl}-propionic acid methyl ester and 5N NaOH (0.3mL) in ethanol (3mL) is refluxed under N2, then cooled to ambient temperature and concentrated in vacuo. The residue is dissolved in DCM, washed with 1N HC1, dried through a Varian ChemElut cartridge, and concentrated in vacuo to provide the title compound.'H NMR (400 MHz, CDC13) 8 7. 78 (d, 2H, J= 7.0 Hz), 7.51 (t, 1H, J= 7.0 Hz), 7.40 (t, 2H, J= 7.0 Hz), 7.23 (d, 2H, J= 8. 4 Hz), 7.01 (dd, 1H, J= 8.4 Hz, 3.5 Hz), 6.90 (d, 1H, J= 8.4 Hz), 6.61 (d, 1H, J= 2.8 Hz), 6. 55 (dd, 1H, J= 8.4 Hz, 2.8 Hz), 4.42 (p, 1H, J= 5.4 Hz), 3.76-3. 71 (m, 2H), 2.90-2. 85 (m 2H), 2.61 (q, 4H, J= 7.6 Hz), 2.28 (s, 3H), 1.89-1. 77 (m, 2H), 1.56-1. 49 (m, 2H), 1.27-1. 20 (m 4H), 0.75 (t, 3H, J= 7.5 Hz). MS [EI+] 475 (M+H)+.

Example 233 3- {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-pcntyloxy]-2-methyl-p henyl}- propionic acid A solution of 3- [4- (3-methanesulfonyloxy-pentyloxy)-2-methyl-phenyl]- propionic acid methyl ester (O. llg, 0. 30mmol) and (2-hydroxy-5 trifluoromethoxy- phenyl)-phenyl-methanone (0.045g, 0. 20mmol) in DMF (5mL) is treated with cesium carbonate (0. 11 g, 0. 34mmol) and heated to 50°C under N2. After lOh, the mixture is cooled to ambient temperature and diluted with diethyl ether. The organic layer is washed with 1N HC1, water and brine, and then dried over Na2S04 and concentrated in vacuo. The crude material is purified by flash chromatography, using 17% acetone in hexanes as eluent, to provide the ester. Rf=0. 38 in 33% acetone in hexanes.

A solution of 3-14- [3- (2-b enzoyl-4-trifluoromethoxy-phenoxy) - pentyloxy]-2-methyl-phenyl}-propionic acid methyl ester and 5N NaOH (0.3mL) in ethanol (3mL) is refluxed under N2, and then cooled to ambient temperature and concentrated in vacuo. The residue is dissolved in DCM, washed with 1N HC1, dried

through a Varian ChemElut cartridge, and concentrated in vacuo to provide the title compound. 1H NMR (400 MHz, CDC13) 8 7.77 (d, 2H J= 7.0 Hz), 7.55 (t, 1H, J= 7.0 Hz, 1.6 Hz), 7.41 (t, 2H, J= 7.8 Hz), 7. 25 (d, 2H, J= 2.3 Hz), 7.24 (s, 1H), 7.01 (td, 2H, J= 7.0 Hz, 2.3 Hz), 6.61 (d, 1H, J= 2.3), 6. 56 (dd, 1H, J= 7.8 Hz, 2.3 Hz), 4.47 (p, 1H, J = 5. 6 Hz), 3.78-3. 72 (m, 2H), 2.90-2. 85 (m, 2H), 2.61 (t, 1H, J= 7.5 Hz), 2.28 (s, 3H), 2.17 (s, 1H), 1.92-1. 80 (m, 2H), 1.55 (p, 2H, J= 5.6 Hz), 1.25 (t, 1H, J= 7.5 Hz), 0.76 (t, 3H, J= 7.5 Hz). MS [EI+] 531 (M+H) +.

Example 234 3-f 4- [3- (3-Benzoyl-naphthalen-2-yloxy)-butoxy]-2-methyl-phenyl}-prop ionic acid Step A Acetic acid 3-hydroxy-butyl ester DIPEA (39. 0mL, 223mmol) is added to a-60°C solution of 1,3-butanediol (10. OmL, 112mmol) in dry methylene chloride (80mL). Acetyl chloride (9. 5mL, 134mmol) is added slowly via syringe to the resulting solution. The mixture is stirred at 0°C under N2 until all 1,3-butanediol is consumed and quenched with IN HC1. The organic layer is washed with IN HC1, dried over Na2SO4, and concentrated in vacuo. The crude material is purified by flash chromatography, using 20% acetone in hexanes as eluent, to provide 10.35g (72%) of the title compound.'H NMR (400 MHz, CDCl3) õ 4.28-4. 21 (m, 1H), 4.11-4. 05 (m, 1H), 3.86-3. 81 (m, 1H), 2.44 (s, 1H), 2.00 (s, 3H), 1.76- 1.62 (m, 2H), 1.17 (d, 3H, J= 6.2 Hz). RrO. 19 in 33% acetone in hexanes.

Step B Acetic acid 3- (toluene-4-sulfonyloxy)-butyl ester

A 0°C solution of acetic acid 3-hydroxy-butyl ester (10.4g, 78. 3mmol), DMAP (2.87g, 23.5mmol), and pyridine (l9. OmL, 235mmol) in methylene chloride (500mL) is treated with p-toluenesulphonic anhydride (38.3g, 117. 5mmol) and stirred at 0°C under N2 for 30 minutes. The mixture is warmed to ambient temperature to continue stirring until the acetic acid 3-hydroxy-butyl ester is consumed. The reaction is quenched with IN HC1. The organic layer is washed with IN HC1, dried over Na2SO4, and concentrated in vacuo. The crude material is purified by flash chromatography, using 17% acetone in hexanes as eluent,. to provide 20. 12g (90%) yield of the title compound.

IH NMR (400 MHz, CDC13) 8 7.79 (d, 2H, J= 7.87 Hz), 7. 33 (d, 2H, J= 7. 8 Hz), 4.76- 4.71 (m, 1H), 4.05-3. 99 (m, 1H), 3.93-3. 87 (m, 1H), 2.44 (s, 3H), 1.96 (s, 3H), 1.94-1. 80 (m, 2H), 1.34 (d, 3H, J= 6.5 Hz). Rif=0. 31 in 33% acetone in hexanes. step C Acetic acid 3- (3-benzoyl-naphthalen-2-yloxy)-butyl ester A solution of acetic acid 3- (toluene-4-sulfonyloxy)-butyl ester (2. 13g, 7.43mmol) and (3-hydroxy-naphthalen-2-yl) -phenyl-methanone (1.23g, 4. 95mmol) in DMF (20mL) is treated with cesium carbonate (4.12g, 12. 6mmol) and heated to 50°C under N2. After lOh, the mixture is cooled to ambient temperature and diluted with diethyl ether. The organic layer is washed with IN HC1, water and brine, and then dried over Na2S04 and concentrated in vacuo. The crude material is purified by flash chromatography, using 14% acetone in hexanes as eluent, to provide 1.25g (70%) of the title compound. 1H NMR (400 MHz, CDC13) 8 7.89 (s, 1H), 7.80 (dd, 3H, J= 8.3 Hz, 3.2

Hz), 7.75 (d, 1H, J= 7.75 Hz), 7.53 (p, 2H, J= 8.3 Hz), 7.44-7. 36 (m, 3H), 7.20 (s, 1H), 4.62 (q, 1H, J= 5.7 Hz), 3.93 (p, 1H, J= 5.7 Hz), 3.86-3. 80 (m, 1H), 2.01 (s, 3H), 1.75 (q, 2H, J= 5.7 Hz), 1.23 (d, 3H, J= 5.7 Hz). HRMS (ES+) m/z exact mass calcd for C24H2504S 409.1474, found 409.1486. MS [EI+] 363 (M+H) +. Rr0. 39 in 33% acetone in hexanes.

Step D [3- (3-Hydroxy-1-methyl-propoxy)-naphthalen-2-yl]-phenyl-methano ne A solution of acetic acid 3- (3-benzoyl-naphthalen-2-yloxy)-butyl ester in methanol (30mL) is treated with DIPEA (6mL, 0.34mmol) and stirred under N2 for 20h, then concentrated in vacuo. The residue is dissolved in methanol, treated with potassium carbonate (2.25g, 0.16mmol), and stirred at ambient temperature under N2 for 2h. The mixture is quenched with IN HC1 and diluted with methylene chloride. The organic layer is washed with IN HC1, dried over Na2S04, and concentrated in vacuo. The crude material is purified by flash chromatography, using 17% acetone in hexanes as eluent, to provide 0.873g (79%) of the title compound. MS [EI+] 321 (M+H) +. Rf= 0.27 in 33% acetone in hexanes.

Step E Methanesulfonic acid 3- (3-benzoyl-naphthalen-2-yloxy)-butyl ester Methanesulphonyl chloride (0.3mL, 3. 3mmol) is added to a 0°C solution of [3- (3-hydroxy-1-methyl-propoxy)-naphthalen-2-yl]-phenyl-methano ne (0. 873g, 2.72mmol) and TEA (0.6mL, 4. lmmol) in methylene chloride (l OmL). The resulting is stirred under N2 for 2h while gradually warming to ambient temperature, which then quenched with IN HC1. The organic layer is washed with IN HC1, dried over Na2S04,

and concentrated in vacuo to provide l. lg (100%) of the title compound. 1H NMR (400 MHz, CDC13) 8 7.85 (s, 1H), 7.83-7. 76 (m, 4H), 7.57 (tt, 1H, J= 7.0 Hz, 2.1 Hz), 7.52 (td, 1H, J= 7.0 Hz, 1.2 Hz), 7.44 (t, 2H, J= 7.8 Hz), 7.23 (s, 1H), 4.75-4. 68 (m, 1H), 4.10, 4.08 (ABq, 2H, J= 6.1 Hz), 2.86 (s, 3H), 1.99-1. 91 (m, 1H), 1.85-1. 77 (m 1H), 1.29 (d, 3H, J= 6.1 Hz). MS [EI+] 399 (M+H) +.

Step F 3-{4-[3-(3-Benzoyl-naphthalen-2-yloxy)-butyoxy]-2-methyl-phe nyl}-propionic acid A solution of methanesulfonic acid 3- (3-benzoyl-naphthalen-2-yloxy)- butyl ester (0.057g, 0. 14mmol) and 3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0. 036g, 0. 19mmol) in DMF (3mL) is treated with cesium carbonate (0.070g, 0. 21mmol) and heated to 50°C under N2. After lOh, the mixture is treated with 5N NaOH (lmL), heated at 50°C for 20 minutes, and cooled to ambient temperature over 2h. The mixture is diluted with diethyl ether, washed with IN HC1, dried through a Varian ChemElut cartridge, and concentrated in vacuo. The crude material is purified by LCMS to provide the title compound.'H NMR (400 MHz, CDC13) 8 7.86 (s, 1H), 7.79 (dd, 3H, J= 8.4 Hz, 1.5 Hz), 7.69 (d, 1H, J= 7.7 Hz), 7.55-7. 47 (m, 2H), 7.40-7. 35 (m, 3H), 7.21 (s, 1H), 7.01 (d, 1H, J= 8.4 Hz), 6.61 (d, 1H, J= 2.3 Hz), 6.55 (dd, 1H, J= 7.7 Hz, 2.3 Hz), 4.78 (q, 1H, J= 6. 0 Hz), 3.74 (t, 2H, J= 6. 0 Hz), 2. 87 (t, 2H, J=8. 4 Hz), 2. 59 (t, 2H, J= 8.4 Hz), 2.26 (s, 3H), 1. 88 (q, 2H, J= 6.0 Hz), 1.26 (d, 3H, J= 6.0 Hz).

HRMS (ES+) m/z exact mass calcd for C3lH3105 483.2171, found 483.2184.

Example 235 3- {4- [3- (3-Benzoyl-naphthalen-2-yloxy)-butylsulfanyl]-2-methyl-pheny l}-propionic acid A solution of methanesulfonic acid 3- (3-benzoyl-naphthalen-2-yloxy)- butyl ester (0.057g, 0.14mmol) and 3- (4-mercapto-2-methyl-phenyl)-propionic acid methyl ester (0.039g, 0. 1 9mmol) in DMF (3mL) is treated with cesium carbonate (0.070g, 0. 21mmol) and heated to 50°C under N2. After lOh, the mixture is treated with

5N NaOH (lmL), heated at 50°C for 20 minutes and cooled to ambient temperature over 2h. The mixture is diluted with diethyl ether, washed with IN HC1, dried through a Varian ChemElut cartridge, and concentrated in vacuo. The crude material is purified by LCMS to provide the title compound. 1H NMR (400 MHz, CDC13) 8 7.87 (s, 1H), 7.81- 7.76 (m, 3H), 7.71 (d, 1H, J= 7. 5 Hz), 7.52 (q, 2H, J=7. 5 Hz), 7.41-7. 36 (m, 3H), 7.13 (s, 1H), 7.04 (s, 1H), 6.99, 6.97 (ABq, 2H, J= 8.0 Hz), 4.70-4. 64 (m, 1H), 2.82 (t, 2H, J= 7.4 Hz), 2.73-2. 59 (m, 2H), 2.56 (t, 2H, J= 7.4 Hz), 2.21 (s, 3H), 1.80-1. 69 (m, 2H), 1.20 (d, 3H, J= 7.4 Hz). HRMS (ES+) m/z exact mass calcd for C3lH3104S 499.1943, found 499.1954.

Example 236 {4- [3- (3-Benzoyl-naphthalen-2-yloxy)-butoxy]-2-methyl-phenylsulfan yl}-acetic acid The title compound is prepared according to the procedure described in Example 235 by using methanesulfonic acid 3- (3-benzoyl-naphthalen-2-yloxy)-butyl ester (0.060g, 0. 1 5mmol) and (4-hydroxy-2-methyl-phenylsulfanyl) -acetic acid ethyl ester (0.044g, 0. 19mmol). 1H NMR (400 MHz, CDC13) 8 7.85 (s, 1H), 7.79 (d, 3H, J= 7.5 Hz), 7.70 (d, 3H, J= 8.3 Hz), 7.51 (q, 2H, J= 7.5 Hz), 7. 39 (m, 5H), 7.21 (s, 1H), 6.66 (d, 1H, J= 2.5 Hz), 6.56 (dd, 1H J= 8.3 Hz, 2.5 Hz), 4.77 (p, 1H, J= 5.9 Hz), 3.77- 3. 68 (m, 2H), 3.47 (s, 3H), 2.41 (s, 3H), 1.91-1. 86 (m, 2H), 1.27 (d, 3H, J= 5.9 Hz).

HRMS (ES+) m/z exact mass calcd for C3pH2905S 501. 1736, found 501.1755.

Example 237 {4- [3- (3-Benzoyl-naphthalen-2-yloxy)-butylsulfanyl]-2-methyl-pheno xy}-acetic acid

The title compound is prepared according to the procedure described in Example 235 by using methanesulfonic acid 3- (3-benzoyl-naphthalen-2-yloxy)-butyl ester (0.059g, 0. 15mmol) and (4-mercapto-2-methyl-phenoxy) -acetic acid ethyl ester (0.044g, 0. 19mmol).'H NMR (400 MHz, CDC13) 8 7.86 (s, 1H), 7.79 (t, 3H, J= 8.6 Hz), 7.71 (d, 1H, J= 8.6 Hz), 7.51 (qd, 2H, J= 8.6 Hz, 1.7 Hz), 7.41-7. 36 (m, 3H), 7.11 (d, 2H, J= 1. 7 Hz), 7.05 (dd, 1H, J= 8.6 Hz, 1.7 Hz), 6.53 (d, 1H, J=, 8.6 Hz), 4.67-4. 60 (m, 1H), 4.54 (s, 2H), 2.68-2. 54 (m, 2H), 2.18 (s, 3H), 1.78-1. 64 (m, 2H), 1.19 (d, 3H, J= 6.0 Hz). HRMS (ES+) m/z exact mass calcd for C3oH290sS 501.1736, found 501.1754.

Example 238 3- {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-2-methyl-phen yl}-propionic acid step A Acetic acid 3- (2-benzoyl-4-trifluoromethoxy-phenoxy)-butyl ester A solution of acetic acid 3- (toluene-4-sulfonyloxy)-butyl ester (1.57g, 5. 47mmol) and (2-hydroxy-5-trifluoromethoxy-phenyl)-phenyl-methanone (1. 03g,

3.65mmol) in DMF (15mL) is treated with cesium carbonate (2.02g, 6.21mmol) and heated to 50°C under N2. After lOh, the mixture is cooled to ambient temperature and diluted with diethyl ether. The organic layer is washed with IN HC1, water and brine, and then dried over Na2S04, and concentrated in vacuo. The crude material is purified by flash chromatography, using 17% acetone in hexanes as eluent, to provide 1. 31g (90%) of the title compound.'H NMR (400 MHz, CDC13) 8 7.75 (dd, 2H, J= 8.5 Hz, 1.4 Hz), 7. 55 (tt, 1H, J= 7.5 Hz, 1.4 Hz), 7.41 (t, 2H, J= 8.5 Hz), 7.27 (dd, 1H, J= 8.5 Hz, 2.9 Hz), 7.23 (d, 1 H, J = 2.9 Hz), 6. 95 (d, 1H, J= 8.5 Hz), 4.44 (q, 1H, J= 6.4 Hz), 3.92-3. 86 (m, 1H), 3.82-3. 76 (m, 1H), 1.97 (s, 3H), 1.67 (qd, 2H, J= 6.4 Hz, 1.3 Hz), 1.14 (d, 3H, J = 6. 4 Hz). MS [EI+] 397 (M+H) +. Rr0. 39 in 33% acetone in hexanes. <BR> <BR> <P> Step B<BR> <BR> <BR> [2- (3-Hydroxy-l-methyl-propoxy)-5-trifluoromethoxy-phenyl]-phen yl-methanone A solution of acetic acid 3- (2-benzoyl-4-trifluoromethoxy-phenoxy)-butyl ester (1.31g, 3. 31mmol) in methanol (15mL) is treated with potassium carbonate (2.15g, 6.61mmol). The mixture is stirred at ambient temperature under N2 for 2h, quenched with IN HC1, and diluted with methylene chloride. The organic layer is washed with IN HC1, dried over Na2S04, and concentrated i7z vacuo. The crude material is purified by flash chromatography, using 25% acetone in hexanes as eluent, to provide 1. 05g (90%) of the title compound. 1H NMR (400 MHz, CDC13) 8 7.75 (d, 2H, J= 8.7 Hz), 7.55 (td, 1H, J= 7.7 Hz, 1.0 Hz), 7.41 (t, 2H, J= 7.7 Hz), 7.27 (dd, 1H, J= 8.7 Hz, 2.9 Hz), 7.23 (d, 1H, J= 2.9 Hz), 7.02 (d, 1H, J= 8. 7 Hz), 4.60-4. 52 (m, 1H), 3.49 (td, 2H, J= 5.6 Hz, 1.9 Hz), 2.51 (s, 1H), 1.64 (q, 2H, J= 5.6 Hz), 1.15 (d, 3H, J= 5.6 Hz). MS [EI+] 355 (M+H) +. Rf=0. 24 in 33% acetone in hexanes.

Step C Methanesulfonic acid 3- (2-benzoyl-4-trifluoromethoxy-phenoxy)-butyl ester

Methanesulphonyl chloride (0.28mL, 3. 6mmol) is added to a 0°C solution of [2- (3-hydroxy-1-methyl-propoxy)-5-trifluoromethoxy-phenyl]-phen yl-methanone (1. 05g, 3. 3mmol) and TEA (0.6mL, 4. 5mmol) in methylene chloride (lOmL). The resulting solution is stirred under N2 for 2h while gradually warming to ambient temperature, which then quenched with IN HC1. The organic layer is washed with IN HC1, dried over Na2SO4, and concentrated in vacuo to provide 1.3g (100%) of the title compound.'H NMR (400 MHz, CDC13) 8 7.76 (dd, 2H, J= 7. 3 Hz, 1. 3 Hz), 7.57 (tt, 1H, J= 7.3 Hz, 1.3 Hz), 7.44 (t, 2H, J= 8.6 Hz), 7. 30 (dd, 1H, J= 8.6 Hz, 0.9 Hz), 7.24 (d, 1H J= 3.0 Hz, 0.9 Hz), 6.98 (d, 1H, J= 8.6 Hz), 4.57-4. 49 (m, 1H), 4.04 (d, 1H, J= 5.2 Hz), 4.02 (dd, 1H, J= 5.2 Hz, 1.7 Hz), 2.88 (s, 3H), 1.92-1. 84 (m, 1H), 1. 77-1. 69 (m, 1H), 1.19 (d, 3H, J= 5.6 Hz). MS [EI+] 433 (M+H) +. Rr0. 20 in 33% acetone in hexanes. <BR> <BR> <BR> <BR> <BR> <BR> <P> Step D<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 3- {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-2-methyl-phen yl}-propionic acid A solution of methanesulfonic acid 3- (2-benzoyl-4-trifluoromethoxy- phenoxy) -butyl ester (0. 050g, 0.12mmol) and (3- (4-Hydroxy-2-metliyl-phenyl)- propionic acid methyl ester (0.029g, 0. 15mmol) in DMF (3mL) is treated with cesium carbonate (0.056g, 0. 17mmol) and heated to 50°C under N2. After lOh, the reaction mixture is treated with 5N NaOH (ImL), heated at 50°C for 20 minutes, then cooled to ambient temperature over 2h. The reaction mixture is diluted with diethyl ether, washed with IN HC1, dried through a Varian ChemElut cartridge, and concentrated in vacuo.

The crude material is purified by LCMS to provide the title compound. 1H NMR (400 MHz, CDC13) 5 7.76 (d, 2H J= 7.5 Hz, 7.55 (t, 1H, J= 7.5 Hz), 7.40 (t, 2H, J= 8.3 Hz),

7.28-7. 25 (m, 2H), 7.02 (d, 1H, J= 8. 3 Hz), 6.98 (d, 1H, J= 8. 3 Hz), 6.59 (d, 1H J= 3.0 Hz), 6.54 (dd, 1H, J= 8.3 Hz, 3.0 Hz), 4.66-4. 59 (m, 1H), 3.71 (t, 2H, J= 6. 0 Hz), 2.88 (t, 2H, J= 7.6 Hz), 2.60 (t, 2H, J= 7.6 Hz), 2.27 (s, 3H), 1.82 (qd, 2H, J= 6.0 Hz, 2.2 Hz), 1. 58 (d, 3H, J= 6.0 Hz). HRMS (ES+) m/z exact mass calcd for C28H2gF306 517. 1838, found 517. 1818.

Example 239 3- {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butylsulfanyl]-2-meth yl-phenyl}- propionic acid A solution of methanesulfonic acid 3- (2-benzoyl-4-trifluoromethoxy- phenoxy) -butyl ester (0. 051g, 0. 12mmol) and 3- (4-mercapto-2-methyl-phenyl)-propionic acid methyl ester (0.032g, 0. 15mmol) in DMF (3mL) is treated with cesium carbonate (0.0588g, 0. 18mmol) and heated to 50°C under N2. After 1 Oh, the mixture is treated with 5N NaOH (lmL), heated at 50°C for 20 minutes, and cooled to ambient temperature over 2h. The mixture is diluted with diethyl ether, washed with IN HC1, dried through a Varian ChemElut cartridge, and concentrated in vacuo. The crude material is purified by LCMS to provide the title compound. IH NMR (400 MHz, CDC13) 8 7. 76 (d, 2H, J=8. 1 Hz), 7.54 (tt, 1H, J= 7.6 Hz), 7.41 (t, 2H, J= 7.6 Hz), 7.28-7. 26 (m, 2H), 7.02 (d, 2H, J= 8.1 Hz), 6.98 (dd, 1H, J= 8.1 Hz, 1.6 Hz), 6.91 (d, 1H, J= 9.2 Hz), 4.55-4. 47 (m, 1H), 2. 89 (t, 2H, J= 8.2 Hz), 2.71-2. 53 (m, 4H), 2.25 (s, 3H), 1.75-1. 61 (m, 2H), 1.13 (d, 3H, J = 5.5 Hz). HRMS (ES+) m/z exact mass calcd for C28H27F305NaS 555.1429, found 555.1411.

Example 240 <BR> <BR> {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butoxy]-2-methyl-phen ylsulfanyl}-acetic acid

The title compound is prepared according to the procedure described in Example 239 by using methanesulfonic acid 3- (2-benzoyl-4-trifluoromethoxy-phenoxy)- butyl ester (0.054g, 0.12mmol) and (4-hydroxy-2-methyl-phenylsulfanyl)-acetic acid ethyl ester (0.037g, 0. 16mmol).'H NMR (400 MHz, CDC13) b 7. 75 (d, 2H, J= 7. 6 Hz), 7. 55 (tt, 1H, J= 7.6 Hz), 7.41 (t, 2H, J= 7.6 Hz), 7.29-7. 24 (m, 2H), 6.97 (d, 1H, J= 8.3 Hz), 6.64 (d, 1H, J= 2. 8 Hz), 6.54 (dd, 1H, J= 8.3 Hz, 2.8 Hz), 4.64-4. 57 (m, 1H), 3.75- 3.66 (m, 2H), 3. 48 (s, 2H), 2.42 (s, 3H), 1.83 (p, 2H, J= 6.2 Hz), 1.21 (d, 3H, J= 6.2 Hz).

HRMS (ES+) m/z exact mass calcd for C27H26F306S 535.1402, found 535.1400.

HRMS (ES+) m/z exact mass calcd for C27H25F306NaS 557.1222, found 557.1222.

Example 241 {4- [3- (2-Benzoyl-4-trifluoromethoxy-phenoxy)-butylsulfanyl]-2-meth yl-phenoxy}-acetic acid The title compound is prepared according to the procedure described in Example 239 by using methanesulfonic acid 3- (2-benzoyl-4-trifluoromethoxy-phenoxy)- butyl ester (0.064g, 0. 15mmol) and (4-mercapto-2-methyl-phenoxy) -acetic acid ethyl ester (0.044g, 0. 19mmol).'HNMR (400 MHz, CDC13) 8 7. 74 (d, 2H, J= 7.9 Hz), 7.54 (t, lH, J=7. 2Hz), 7.41 (t, 2H, J=7. 2Hz), 7.28-7. 26 (m, 2H), 7.10 (s, lH), 7.04 (d, 1H, J= 7.9 Hz), 6.90 (d, 1H, J= 8.6 Hz), 6.60 (d, 1H, J= 8.6 Hz), 4.66 (s, 2H), 4.52-4. 47 (m,

1H), 2.65-2. 58 (m, 1H), 2.55-2. 48 (m, 1H), 2.22 (s, 3H), 1.71-1. 57 (m, 2H), 1.11 (d, 3H, J = 5.8 Hz). MS [EI+] 535 (M+H) +.

Example 242 3-{4-[3-(2-Benzoyl-4-ethyl-pheoxy)-1-ethyl-propxoy]-2-methyl -phenyl}-propionic acid Step A <BR> <BR> [5-Ethyl-2- (3-hydroxy-pentyloxy)-phenyl]-phenyl-methanone A solution of acetic acid toluene-4-sulfonic acid 3-hydroxy-pentyl ester (0.77g, 3. 0mmol) and (5-ethyl-2-hydroxy-phenyl)-phenyl-methanone (0. 45g, 2. 0mmol) in DMF (20mL) is treated with cesium carbonate (1. 1 lg, 3. 4mmol) and heated to 50°C under N2. After 10h, the mixture is cooled to ambient temperature and diluted with diethyl ether. The organic layer is washed with IN HC1, water and brine, and then dried over Na2SO4, and concentrated in vacuo. The crude material is purified by flash chromatography, using 14% acetone in hexanes as eluent, to provide 0.32g (51 %) of the title compound. 1H NMR (400 MHz, CDC13) 8 7.79 (dd, 2H, J= 8.7 Hz, 1.6 Hz), 7.54 (tt, 1H, J= 7.6 Hz, 1.6 Hz), 7.42 (t, 2H, J= 7.6 Hz), 7. 28 (tt, 1H, J= 8.7 Hz, 2.2 Hz), 7.23 (d, 1H, J= 2. 2 Hz), 6.91 (d, 1H, J=8. 2 Hz), 4.11-4. 06 (m, 1H), 4.03-3. 98 (m, 1H), 3.32- 3.26 (m, 1H), 2.61 (s, 1H), 1.68-1. 51 (m, 2H), 1. 38 (m, 2H), 1.21 (t, 3H, J= 7.9 Hz), 0.80 (t, 3H, J= 7.9 Hz). Rf=0. 25 in 33% acetone in hexanes.

Step B Methanesulfonic acid 3- (2-benzoyl-4-ethyl-phenoxy)-l-ethyl-propyl ester

Methanesulphonyl chloride (0.14mL, 1. 8mmol) is added to a 0°C solution of [5-ethyl-2- (3-hydroxy-pentyloxy)-phenyl]-phenyl-methanone) (0.32g, 1. 5mmol) and TEA (0.3mL, l. 8mmol) in methylene chloride (lOmL). The resulting solution is stirred under N2 for 2h while gradually warming to ambient temperature, which then quenched with IN HC1. The organic layer is washed with IN HC1, dried over Na2S04, and concentrated in vacuo to provide 0.44g (75%) of the title compound.'H NMR (400 MHz, CDC13) 8 7.80 (dd, 2H, J= 7. 8 Hz, 1.7 Hz), 7.55 (tt, 1H, J= 7.8 Hz, 1.7 Hz), 7.43 (t, 2H, J= 7.8 Hz), 7. 28 (dd, 1H, J= 8.4 Hz, 2.2 Hz), 7.24 (d, 1H, J= 2.2 Hz), 6. 88 (d, 1H, J= 8. 4 Hz), 4.40-4. 34 (m, 1H), 4.04-3. 99 (m, 1H), 3.96-3. 91 (m, 1H), 2.86 (s, 3H), 2.62 (q, 2H, J= 7. 3 Hz), 1.88-1. 69 (m, 2H), 1.54 (p, 2H, J= 7.3 Hz), 1.22 (t, 3H, J= 7.3 Hz), 0.77 (t, 3H, J= 7.3 Hz). MS [EI+] 391 (M+H) +. Rf= 0.24 in 33% acetone in hexanes.

Step C 3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-l-ethyl-propoxy]-2-methyl-phenyl }-propionic acid methyl ester A solution of methanesulfonic acid 3- (2-benzoyl-4-ethyl-phenoxy)-l- ethyl-propyl ester (0.44g, l. lmmol) and 3- (4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.17g, 0. 8mmol) in DMF (lOmL) is treated with cesium carbonate (0.46g, 1. 4mmol) and heated to 50°C under N2. After 1 Oh, the mixture is cooled to ambient

temperature and diluted with diethyl ether. The organic layer is washed with IN HC1, water and brine, and then dried over Na2S04, and concentrated in vacuo. The crude material is purified by flash chromatography to provide 0.044g (10%) of the title compound. 1H NMR (400 MHz, CDC13) 8 7.80 (d, 2H, J= 7.9 Hz), 7.54 (t, 1H, J= 7.9 Hz), 7.42 (q, 2H, J= 8.7 Hz), 7.25 (d, 2H, J= 8.7 Hz), 6.94 (d, 1H, J= 8.7 Hz), 6.84 (d, 1H, J= 8.7 Hz), 6.57 (d, 1H, J= 2.4 Hz), 4.46 (dd, 1H, J= 7.9 Hz, 2.4 Hz), 4.03-3. 97 (m, 1H), 3.96-3. 87 (m, 2H), 3.68 (s, 3H), 2.85 (t, 2H, J= 8. 5 Hz), 2.62 (q, 2H, J= 7.7 Hz), 2.53 (t, 2H, J= 8. 5 Hz), 2.23 (s, 3H), 1.83-1. 73 (m, 1H), 1.71-1. 61 (m, 1H), 1. 51-1. 36 (m, 2H), 1.23 (t, 3H, J= 7.7 Hz), 0.73 (t, 3H, J= 7.7 Hz). MS [EI+] 489 (M+H) +. Rf= 0.03 in 33% acetone in hexanes.

Step D <BR> <BR> <BR> 3- {4- [3- (2-Benzoyl-4-ethyl-phenoxy)-l-ethyl-propoxy]-2-methyl-phenyl }-propionicacid A solution of 3-f4- [3- (2-benzoyl-4-ethyl-phenoxy)-l-ethyl-propoxy]-2- methyl-phenyl}-propionic acid methyl ester (0.044g, 0. 09mmol) and 5N NaOH (0.4mL) in ethanol (2mL) is refluxed under N2, and then cooled to ambient temperature and concentrated in vacuo. The reaction residue is dissolved in DCM, washed with IN HC1, dried through a Varian ChemElut cartridge, and concentrated in vacuo to provide O. Olg (24%) of the title compound.'H NMR (400 MHz, CDC13) 8 7.80 (d, 2H, J= 7.9 Hz), 7.54 (t, 1H, J=7. 9 Hz, 1. 6 Hz), 7.42 (q, 2H, J= 7. 9 Hz), 7.25 (d, 2H, J=7. 9 Hz), 6.95 (d, 1H, J= 8.7 Hz), 6. 83 (d, 1H, J= 8.7 Hz), 6. 57 (d, 1H, J= 2.4 Hz), 6.47 (dd, 1H, J= 7.9 Hz, 2.4 Hz), 4.04-3. 98 (m, 1H), 3.96-3. 88 (m, 2H), 2.86 (t, 2H, J= 7.7 Hz), 2.62 (q, 2H, J= 7.7 Hz), 2.58 (t, 2H, J= 7.7 Hz), 2.23 (s, 3H), 1.83-1. 74 (m, 1H), 1.70-1. 62 (m, 1H), 1.49-1. 38 (m, 2H), 1.22 (t, 3H, J= 7.7 Hz), 0.74 (t, 3H, J= 7.7 Hz). MS [EI+] 475 (M+H) +.

Example 243 Preparation of 2-phenoxy 4- (trifluoromethyl)-phenol

Step A 4-trifluorormethyl-2-phenoxybenzaldehyde A mixture of 4-triflurormethyl-2-fluorobenzaldehyde (5 g, 26.04 mmol), phenol (2.5 g, 26.60 mmol) and K2CO3 (3.5 g, 26.04 mmol) in anhydrous DMF (50 mL) is warmed to 135°C, and the mixture is stirred at that temperature for 3 h. It is allowed to reach r. t. and poured into brine. The organic layer is diluted with EtOAc, washed with brine and water, and then dried, filtered and concentrated. The resulting crude residue is flash chromatographed on Si02 (2% EtOAc/hexanes) to afford 6.62 g of the substitution compound (96%, pale yellow solid). <BR> <BR> <BR> <BR> step B<BR> <BR> <BR> <BR> <BR> <BR> 4-trifluorormethyl-2-phenoxyphenol MCPBA (7 g, 70%, 28. 39 mmol) is added to a solution of compound obtained in Step A (6.6 g, 24.81 mmol) in MeOH (80 mL, HPLC grade). The mixture is warmed to reflux and stirred overnight. It is allowed to reach r. t. , diluted with CHC13 and washed with NaHSO3 and NaHCO3. The organic layer is dried, filtered and concentrated, affording 5. 8 g of a white solid that is submitted to the next reaction without further purification. This compound is dissolved in MeOH (40 mL, HPLC grade), and HC1 (2 mL, 36% solution in water) is added. The mixture is refluxed overnight, allowed to reach r. t. and poured into brine. It is extracted with EtOAc and washed with water. The organic layer is dried, filtered and concentrated to give a crude residue that is flash

chromatographed on Si02 (3% EtOAc/hexanes) to afford 4 g of the final compound (64% for the two steps, white solid).

Example 244 Preparation of 4-hydroxy-2-ethyl-phenylsulfanyl-acetic acid ethyl ester Step A 3-ethylbenzyloxyphenol Benzyl bromide (4.92 mL, 41.36 mmol) is added to a suspension of 3- ethylphenol (5.055 g, 41.36 mmol) and K2C03 (8.5 g, 61.5 mmol) in CH3CN (50 mL, HPLC grade), and the mixture is stirred at r. t. for 5 h. The mixture is acidified with diluted HC1 (1M) and partitioned between EtOAc and H20. The organic layer is dried, filtered and concentrated, and the product is purified by flash chromatography on Si02 (3% EtOAc/hexanes) to afford 8.3 g of 3-ethylbenzyloxyphenol (94%, colorless oil).

Step B 4-bromo-3-ethylbenzyloxyphenol NBS (1.68 g, 9.438 mmol) is added to a solution of 3-ethylbenzyl- oxyphenol (2 g, 9.433 mmol) in CH3CN (30 mL, HPLC grade). The mixture is stirred at r. t. overnight (c. a. 14 h) and extracted with EtOAc and H20. The organic layer is dried, filtered and concentrated, and the resulting crude residue is flash chromatographed on Si02 (2% EtOAc/hexanes) to afford 2.3 g of the bromide (84%, colorless oil).

Step C 4-benzyloxy-2-ethyl-phenylsulfanyl-acetic acid ethyl ester

Tert-BuLi (5.25 mL, 1.7 M solution, 8.94 mmol) is added to a-78°C cooled solution of 4-bromo-3-ethylbenzyloxyphenol (1.3 g, 4.467 mmol) in THF (20 mL). The mixture is stirred at low temperature for 30 min and allowed to reach r. t.

Sulfur (150 mg, 4. 68 mmol) is added in one portion, and the reaction is stirred at r. t. for 5 min. Ethylbromoacetate (2.5 mL, 22.33 mmol) is added, and the mixture is stirred at r. t. overnight (c. a. 14h). It is quenched with NH4Cl (sat) and extracted with EtOAc/H20. The organic layer is dried, filtered and concentrated, and the crude residue is flash chromatographed on Si02 (2-4% EtOAc/hexanes) to afford 490 mg of the title compound (33%, colorless oil). step D 4-hydroxy-2-ethyl-phenylsulfanyl-acetic acid ethyl ester TiCl4 (1.3 mL, 1 M solution in CH2C12, 1.3 mmol) is added to a-78°C cooled solution of the benzyloxyphenol (400 mg, 1.21 mmol) in CH2C12 (12 mL), and the mixture is allowed to reach 0°C, and then r. t. and stirred for 4 h. The reaction is quenched with H20 and diluted with CH2Cl2. The organic layer is washed with brine, dried, filtered and concentrated. The crude residue is flash chromatographed on Si02 (5-10-15% EtOAc/hexanes) to afford 160 mg of the title compound (55%, colorless oil).

Example 245 Preparation of 4-hydroxy-2, 6 dimethyl-dihydro-ethyl cinnamate

Step A 3,5-dimethyl-4-bromobenzyloxyphenol Benzyl bromide (1.53 mL, 12.86 mmol) is added to a suspension of 3,5- dimethyl-4-bromophenol (2.6 g, 12.93 mmol) and K2CO3 (2.2 g, 14.47 mmol) in CH3CN (30 mL, HPLC grade). The mixture is stirred at r. t. for 16 h. It is acidified with diluted HC1 (1M) and partitioned between EtOAc and H20. The organic layer is dried, filtered and concentrated, and the product is purified by flash chromatography on Si02 (5% EtOAc/hexanes) to afford 3.66 g of the benzyloxyphenol (97%, white solid).

Step B 3,5-dimethyl-4-ethylacrylate-benzyloxyphenol Ethyl acrylate (6 mL, 66.6 mmol) is added to a solution of 3, 5-dimethyl-4- bromobenzyloxyphenol (3.6 g, 12.37 mmol), Pd (OAc) 2 (280 mg, 1.247 mmol), P (o-tol) 3 (750 mg, 2. 464 mmol) and DIPEA (6 mL, 34.4 mmol) in EtCN (50 mL, HPLC grade). The mixture is warmed to 95°C and stirred at that temperature for 36 h. It is allowed to reach r. t. , filtered trough Celite and partitioned between EtOAc and H20. The organic layer is dried, filtered and concentrated, and the resulting crude is flash

chromatographed on Si02 (2% EtOAc/hexanes) to afford 2.59 g of the Heck product (68%, white solid).

Step C Preparation of 4-hydroxy-2, 6 dimethyl-dihydro-ethyl cinnamate Palladium (1 g, 10% on activated carbon, 0.94 mmol) is added to a solution of the benzyloxyphenol obtained in Step B (2.5 g, 8.012 mmol), and the mixture is stirred under H2 atmosphere (H2 balloon) overnight. The mixture is filtered trough Celite, and the solvent is removed. The crude residue is flash chromatographed on Si02 (10% EtOAc/hexanes) to afford 1.4 g of the title compound (79%, white solid).

Example 246 Preparation of (2-hydroxy-4,5 dichloro-phenyl) -phenyl-methanone Step A 3, 4-dichloromethoxyphenol Methyl iodide (2 mL, 32.12 mmol) is added to a suspension of 3,4- dichlorophenol (2.5 g, 15.33 mmol) and K2CO3 (2.2 g, 15.92 mmol) in CH3CN (40 mL, HPLC grade), and the mixture is stirred at r. t. overnight (c. a. 14 h). The mixture is poured into water, acidified with HC1 (1M), and extracted with EtOAc. The organic layer is dried, filtered and concentrated, and the resulting crude residue is flash chromatographed on Si02 (3-5% EtOAc/hexanes) to afford 2.01 g of the methoxyphenol (74%, colorless oil).

Step B (2-Methoxy-4,5 dichloro-phenyl)-phenyl-methanone

PhCOCI (1.45 mL, 12.43 mmol) is added to a 0°C cooled solution of the methoxyphenol from Step A (2 g, 11.3 mmol) and AlCl3 (1.81 g, 13.56 mmol) in 1,2- dichloroethane (30 mL). The mixture is stirred at that temperature for 90 min, and then at r. t. for 1 h. It is quenched with HC1 (1M) and partitioned between CH2C12 and H20. The organic layer is dried, filtered and concentrated, and the crude residue flash chromatographed on Si02 (2% EtOAc/hexanes) to afford 3.15 g of the diaryl ketone (1: 13 mixture of product and unreacted starting material, 11%, colorless oil).

Step C Preparation of (2-hydroxy-4,5 dichloro-phenyl) -phenyl-methanone BBr3 (15 mL, 1 M in CH2C12 solution) is added to a-78°C cooled solution of the methoxy compound from Step B (3.15 g of the previously described mixture) in CH2C12 (40 mL), and the mixture is allowed to reach r. t. overnight. The reaction is poured into brine and extracted with CH, The organic layer is dried, filtered and concentrated, and the crude residue purified by flash chromatography on Si02 (2-3-10% EtOAc/hexanes) to afford 90 mg of the title compound (27%, white solid).

Example 247 Preparation of 4-hydroxy-2-fluoro-dihydro-ethyl cinnamate

Step A<BR> <BR> 3-fluorobenzyloxyphenol Benzyl bromide (2.9 mL, 24.08 mmol) is added to a suspension of 3- fluorophenol (3.0 g, 26.76 mmol) and K2CO3 (4.0 g, 28.94 mmol) in DMF (30 mL), and the mixture is stirred at r. t. for 5 h. It is acidified with diluted HC1 (1M) and partitioned between EtOAc and H20. The organic layer is dried, filtered and concentrated, and the product is purified by flash chromatography on Si02 (3% EtOAc/hexanes) to afford 4.7 g of the title compound (87%, colorless oil).

Step B 4-bromo-3-fluorobenzyloxyphenol NBS (2.11 g, 11. 88 mmol) is added to a solution of 3-fluorobenzyl- oxyphenol (2.4 g, 11.88 mmol) in CH3CN (50 mL, HPLC grade). The mixture is stirred at r. t. overnight (c. a. 14 h) and extracted with EtOAc and H20. The organic layer is dried, filtered and concentrated, and the resulting crude residue is flash chromatographed on Si02 (5% EtOAc/hexanes) to afford 3.3 g of title compound (99%, white solid). step C 3-fluoro-4-ethylacrylate-benzyloxyphenol

Ethyl acrylate (6.73 mL, 74.73 mmol) is added to a solution of 4-bromo-3- fluorobenzyloxyphenol (3.5 g, 12.455 mmol), Pd (OAc) 2 (280 mg, 1.245 mmol), P (o-tol) 3 (758 mg, 2.49 mmol) and DIPEA (6.5 mL, 37.37 mmol) in EtCN (80 mL, HPLC grade).

The mixture is warmed to 95°C and stirred at that temperature for 1 h. It is allowed to reach r. t. , filtered trough Celite and partitioned between EtOAc and H20. The organic layer is dried, filtered and concentrated, and the resulting crude is flash chromatographed on Si02 (2-3% EtOAc/hexanes) to afford 2.05 g of the Heck product (55%, white solid). step D Preparation of 4-hydroxy-2-fluoro-dihydro-ethyl cinnamate Palladium (120 mg, 10% on activated carbon, 0.112 mmol) is added to a solution of the fluorobenzyloxy compound of Step C (1.2 g, 4.0 mmol), and the mixture is stirred under H2 atmosphere (H2 balloon) overnight (c. a. 14 h). The mixture is filtered trough Celite, and the solvent is removed in a rotatory evaporator. The crude residue is flash chromatographed on Si02 (10-20% EtOAc/hexanes) to afford 510 mg of the title compound (60%, colorless oil).

Example 248 Preparatio, n of 4-hydroxy-2-chloro-dihydro-ethyl cinnamate Step A 4-bromo-3-chlorobenzyloxyphenol Benzyl bromide (0. 83 mL, 6.95 mmol) is added to a suspension of 3- chloro-4-bromophenol (1.0 g, 4.82 mmol) and K2CO3 (960 mg, 6.95 mmol) in DMF (25 mL), and the mixture is stirred at r. t. for 3 h. It is acidified with diluted HC1 (1M) and partitioned between Et20 and H20. The organic layer is dried, filtered and concentrated, and the product is purified by flash chromatography on Si02 (1-2% EtOAc/hexanes) to afford 1.39 g of the title compound (97%, white solid).

Step B 3-chloro-4-ethylacrylate-benzyloxyphenol Ethyl acrylate (5.0 mL, 55.5 mmol) is added to a solution of 4-bromo-3- chlorobenzyloxyphenol (2.7 g, 9.08 mmol), palladium acetate (215 mg, 0.96 mmol), P (o- tol) 3 (550 mg, 1.8 mmol) and Et3N (3 mL, 21.5 mmol) in EtCN (100 mL, HPLC grade).

The mixture is warmed to 95°C and stirred at that temperature overnight (c. a. 16 h). It is allowed to reach r. t. , filtered trough Celite and partitioned between EtOAc and H20. The organic layer is dried, filtered and concentrated, and the resulting crude is flash chromatographed on Si02 (5% EtOAc/hexanes) to afford 1.79 g of the Heck product (62%, white solid). step C 4-hydroxy-2-chloro-dihydro-ethyl cinnamate

Palladium (121 mg, 10% on activated carbon, 0.113 mmol) is added to a solution of the chlorobenzyloxyphenol (1.2 g, 3.79 mmol), and the mixture is stirred under H2 atmosphere (H2 balloon) overnight (c. a. 14 h). The mixture is filtered trough Celite, and the solvent is removed in a rotatory evaporator. The crude residue is flash chromatographed on Si02 (5-10% EtOAc/hexanes), and repurified by HPLC (normal phase) to afford 515 mg of the title compound (93%, colorless oil).

Example 249 Preparation of 2- (2'-pyridyl)-4- (trifluoromethyl) phenol step A 2-methoxy-5- (trifluoromethyl) phenylboronic acid n-BuLi (1.6 M in hexane) (44.45 mL, 71.13 mmol) is added to a solution of 2-bromo-4- (trifluoromethyl) anisole (18.14 g, 71.13 mmol) in diethylether (71 mL) at- 78 °C, and the mixture is stirred for an hour while maintaining the internal temperature

below-75 °C. The mixture is stirred at r. t. for 30 minutes, cooled to-78 °C and then a solution of triisopropylborate (19.70 mL, 85.35 mmol) in diethylether (239 mL) is added.

The temperature is maintained below-75 °C for an hour and then the mixture is stir at r. t. for 30 minutes. Concentrated HC1 (200 mL) is added and the mixture is extracted with diethylether. The organic layers are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (quantitative).

Step B 2- (2'-pyridyl)-4- (trifluorometliyl) anisole A mixture of 2-methoxy-5- (trifluoromethyl)-phenylboronic acid (15.64 g, 71.10 mmol), 2-bromopyridine (5.65 mL, 59.25 mmol), palladium tetrakis- (triphenylphosphine) (2.74 g, 2.37 mmol) and sodium carbonate (2 M in water) (83 mL, 165.9 mmol) in dimethoxyethane (118 mL) is stirred overnight under reflux. The mixture is cooled to r. t. , and the layers are separated and the aqueous layer is extracted with ethylacetate. The organic layers are combined, dried, filtered and concentrated.

Purification by flash chromatography, eluting with hexane: EtOAc 5: 1 provides the title compound (11.68 g, 78 %).

Step C 2- (2'-pyridyl)-4- (trifluoromethyl) phenol Boron tribromide (1.0 M in DCM) (92.25 mL, 92.25 mmol) is added to a solution of 2- (2'-pyridyl)-4- (trifluoromethyl)-anisole (11.68 g, 46.12 mmol) in DCM (230 mL) at-78 °C, and the mixture is stirred for 10 minutes at that temperature. The bath is removed and stirred at r. t. for 1 h. Water is added slowly and stirred for 1 h, and the mixture is extracted with DCM. The organic layers are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, eluting with hexane: EtOAc 5: 1 provides the title compound (6.00 g, 54 %).

Example 250 Preparation of 4-hydroxy-2-ethyl-dihydro-ethyl cinnamate

Step A 3-iodobenzyloxybenzene Sodium hydride (mineral dispersion 60 %) (1.36 g, 34.10 mmol) is added slowly to a solution of 3-iodophenol (5.0 g, 22.73 mmol) and TABI (0. 84 g, 2.27 mmol) in THF (113 mL), and the mixture is stirred overnight. The crude is treated with water and extracted with EtOAc. The organic layers are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, eluting with hexane: EtOAc 10: 1 provides the title compound (7.00 g, 99 %). Rf=0. 77 (hexane: EtOAc 5: 1).'H NMR (200 MHz, CDC13) : 5.03 (s, 2 H), 6.93 (m, 1 H), 7.02 (d, 1 H, J= 8. 3 Hz), 7.27-7. 34 (m, 7 H).

Step B 3-ethylbenzyloxybenzene Copper (I) chloride (0. 016 g, 0.17 mmol), ethyl iodide (0.40 mL, 5.03 mmol) and diethyl zinc (1.0 M, THF) (4.61 mL, 4.61 mmol) are added successively to a solution of manganese bromide (0.054 g, 0.25 mmol) in 1, 3-dimetbyl-3, 4,5, 6-tetrahydro- 2 (1H) pyrimidinone (4.20 mL), and the mixture is stirred at for 4 h. A solution of 3- iodobenzyloxybenzene (1.3 g, 4.19 mmol) and dichloro (diphenylphosphinoferrocene)-

Pd (II) (DCM complex) (0.14 g, 0.17 mmol) in THF (21 mL) is added, and the mixture is stirred under reflux for 2.5 h. The mixture is cooled to r. t. and HC1 1N is added. The mixture is extracted with EtOAc. The organic layers are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, eluting with hexane : EtOAc 20: 1 provides the title compound (0.81 g, 91 %). Rf=0. 82 (hexane: EtOAc 5: 1).'H NMR (200 MHz, CDC13) : 1.30 (t, 3 H, J= 7.8 Hz), 2.70 (q, 2 H, J= 7.5 Hz), 5.11 (s, 2 H), 6.86-6. 91 (m, 3 H), 7.23-7. 53 (m, 6 H).

Step C 4-bromo-3-ethylbenzyloxybenzene N-bromosuccinimide (0.75 g, 4.20 mmol) is added to a solution of 3- ethylbenzyloxybenzene (0.81 g, 3.82 mmol) in ACN (19 mL) and the mixture is stirred for an hour. The solvent is evaporated in vacuo and the resultant is purified by flash chromatography, eluting with hexane : EtOAc 20: 1 to give the title compound (1.09 g, 98 %). Rf=0. 74 (hexane: EtOAc 5 : 1).'H NMR (200 MHz, CDC13) : 1.22 (t, 3 H, J=7. 5 Hz), 2.72 (q, 2 H, J= 7.5 Hz), 5.04 (s, 2 H), 6.69 (dd, 1 H, J= 3.0, 8.6 Hz), 6. 88 (d, 2 H, J= 3. 0 Hz), 7.32-7. 45 (m, 6 H).

Step D 4-benzyloxy-2-ethyl-ethyl trans-cinnamate A mixture of 4-bromo-3-ethylbenzyloxybenzene (0.95 g, 3.27 mmol), palladium acetate (0.073 g, 0.33 mmol), tri-o-tolylphosphine (0.20 g, 0.65 mmol), DIPEA (1.14 mL, 6.53 mmol) and ethyl acrylate (1.42 mL, 13.06 mmol) in propionitrile (49 mL) is stirred at 90 °C under nitrogen overnight. The solution is filtered through Celite and washed with EtOAc. The mixture is concentrated under reduced pressure. Purification by flash chromatography, eluting with hexane: EtOAc 10: 1 provides the title compound

(0.43 g, 43 %). Rf=0. 22 (hexane : EtOAc 20: 1). 1H NMR (300 MHz, CDC13) : 1.25 (t, 3 H, J= 7. 7 Hz), 1.37 (t, 3 H, J= 7. 1 Hz), 2.80 (q, 2 H,. J= 7.7 Hz), 4.30 (q, 2 H, J= 7. 3 Hz), 5.09 (s, 2 H), 6.32 (d, 1 H, J= 15. 7 Hz), 6.83-6. 87 (m, 2 H), 7.35-7. 47 (m, 5 H), 7.56 (d, 1 H, J= 8. 5 Hz), 8. 01 (d, 1 H, J= 15. 9 Hz).

Step E Preparation of 4-hydroxy-2-ethyl-dihydro-ethyl cinnamate A solution of 4-benzyloxy-2-ehtyl-ethyl trans-cinnamate (0.43 g, 1.39 mmol) and pd/C (10 %) (0.074 g, 0.07 mmol) in methanol (14 mL) is stirred under 1 atm of hydrogen. After 4 h, the mixture is filtered through Celite and washed with metanol and concentrated under reduced pressure. Purification by flash chromatography, eluting with hexane: EtOAc 5: 1 provides the title compound (0.29 g, 63 %).

Rf : 0. 17 (hexane: EtOAc 5: 1). 1H NMR (300 MHz, CDC13) : 1.19 (t, 3 H, J= 7. 5 Hz), 1.26 (t, 3 H, J= 7. 3 Hz), 2.54-2. 63 (m, 4 H), 2.87-2. 92 (m, 2 H), 4.16 (q, 2 H, J= 7. 1 Hz), 5.94 (s, 1 H), 6.62 (dd, 1 H, J= 2.6, 8.3 Hz), 6.70 (d, 1 H, J= 2. 6 Hz), 6.99 (d, 1 H,. J= 8.3 Hz).

Example 251 Preparation of 4-hydroxy-2-propyl-dihydro-ethyl cinnamate Step A 3-propylbenzyloxybenzene

Copper (I) chloride (0.016 g, 0.17 mmol), propyl iodide (0.49 mL, 5.03 mmol) and diethyl zinc (1.0 M, THF) (4.61 mL, 4.61 mmol) is added successively to a solution of manganese bromide (0.054 g, 0.25 mmol) in 1, 3-dimethyl-3,4, 5,6-tetrahydro- 2 (1H) pyrimidinone (4.20 mL), and the mixture is stirred at r. t. for 4 h. A solution of 3- iodobenzyloxybenzene (Example 250, step A) (1.3 g, 4.19 mmol) and dichloro- (diphenylphosphinoferrocene) palladium (II) (DCM complex) (0.14 g, 0.17 mmol) in THF (21 mL) is added, and the mixture is stirred under reflux for 2.5 h. The mixture is cooled to r. t. and 1N HC1 is added. The mixture is extracted with EtOAc, and the organic layers are combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography, eluting with hexane: EtOAc 20: 1 provides the title compound together with 25 % of 3-ethylbenzyloxybenzene (0.85 g, 81 % overall). Rf=0. 82 (hexane: EtOAc 5 : 1).'H NMR (200 MHz, CDC13) : 1.13-1. 20 (m, 3 H), 1.81-1. 92 (m, 2 H), 2.74-2. 85 (m, 2 H), 5.22 (s, 2 H), 7.00-7. 03 (m, 3 H), 7.37-7. 61 (m, 6 H).

Step B 4-bromo-3-propylbenzyloxybenzene N-bromosuccinimide (0.66 g, 3.74 mmol) is added to a solution of 3- propylbenzyloxybenzene (0. 85 g, 3.40 mmol) in ACN (17 mL), and the mixture is stirred for an hour. The solvent is evaporated in vacuo and purified by flash chromatography by

eluting with hexane: EtOAc 20: 1 to give the title compound together with 25 % of 4- bromo-3-ethylbenzyl-oxybenzene (1.03 g, 99 % overall). Rf=0. 74 (hexane: EtOAc 5: 1). tH NMR (200 MHz, CDC13) : 1.00 (t, 3 H, J= 7. 2 Hz), 1.65 (sext, 2 H, J= 7. 2 Hz), 2.71 (q, 2 H, J= 7. 5 Hz), 5.05 (s, 2 H), 6.71 (dd, 1 H, J= 3. 0,8. 6 Hz), 6.91 (d, 2 H, J= 3. 0 Hz), 7.32-7. 47 (m, 6 H).

Step C 4-benzyloxy-propylbenzaldehyde n-BuLi (1.6 M in hexane) (7.03 mL, 11.25 mmol) is added to a solution of 4-bromo-3-propylbenzyloxybenzene (2.29 g, 7.50 mmol) in THF (30 mL) under nitrogen at-78 °C, and the mixture is stirred for 30 minutes. N-Formylpiperidine (1.25 mL, 11.25 mmol) is added and stirred for 4 h. The mixture is allowed to gradually warm up to-40 °C, and then water is added and extracted with EtOAc. The organic layers are combined, dried and filtered, and then the solvent is evaporated in vacuo. Purification by flash chromatography by eluting with hexane: EtOAc 10: 1 provides the title compound together with 25 % of 4-bromo-3-ethylbenzyloxybenzene (1.00 g, 52 % overall). Rf=0. 63 (hexane: EtOAc 5 : 1).'H NMR (300 MHz, CDC13) : 1.26 (t, 3 H, J= 7. 7 Hz), 1.65 (sext, 2 H,. J= 7.2 Hz), 2.99 (q, 2 H, J= 7. 7 Hz), 5.13 (s, 2 H), 6.84-6. 94 (m, 2 H), 7.33-7. 46 (m, 5 H), 7.79 (d, 1 H, J= 8. 2 Hz), 10.12 (s, 1 H).

Step D 4-benzyloxy-2-propyl-ethyl trans-cinnamate Method 1: A mixture of 4-bromo-3-ethylbenzyl-oxybenzene (0.56 g, 1.85 mmol), palladium acetate (0.042 g, 0. 18 mmol), tri-o-tolylphosphine (0.11 g, 0.37 mmol),

DIPEA (0.64 mL, 3.70 mmol) and ethyl acrylate (0.80 mL, 7.42 mmol) in propionitrile (28 mL) is stirred at 90 °C a under nitrogen overnight. The mixture is filtered through Celite, washed with EtOAc and concentrated under reduced pressure. Purification by flash chromatography by eluting with hexane: EtOAc 10: 1 provides the title compound with a 25 % of 4-benzyloxy-2-ethyl-ethyl trans-cinnamate (0.22 g, 37 % overall).

Method 2: Triethylphosphono acetate (0.15 mL, 0.74 mmol) is added to a solution of 4-benzyloxy-proylbenzaldehyde (5lep C mmol) and potassium carbonate (0.26 g, 1.86 nunol) in ethanol (2.10 mL), and the mixture is stirred under reflux for 2.5 h. The mixture is cooled to r. t. and water is added. The mixture is extracted with EtOAc, and the organic layers are combined, dried and filtered. The solvent is evaporated in vacuo. Purification by flash chromatography by eluting with hexane: EtOAc 5: 1 provides the title compound together with 25 % of 4-benzyloxy-2- ethyl-ethyl trans-cinnamate (0.17 g, 86 % overall). Rf=0. 22 (hexane: EtOAc 20: 1). 1H NMR (300 MHz, CDC13) : 0.99 (t, 3 H, J= 7. 3 Hz), 1.25 (t, 3 H, J= 7. 5 Hz), 1.58-1. 69 (m, 2 H), 2.75 (q, 2 H, J= 7.1 Hz), 4.29 (q, 2 H, J= 7.3 Hz), 5.10 (s, 2 H), 6.31 (d, 1 H, J= 15.7 Hz), 6. 85 (d, 2 H, J= 7. 3 Hz), 7. 35-7. 47 (m, 5 H), 7. 56 (d, 1 H, J= 7. 9 Hz), 8.00 (d, 1 H, J= 15. 7 Hz).

Step E 4-hydroxy-2-propyl-dihydro-ethyl cinnamate A solution of 4-benzyloxy-2-propyl-ethyl trans-cinnamate (0.44 g, 1.35 mmol) and pd/C (10 %) (0.14 g, 0.14 mmol) in methanol (13 mL) is stirred under 1 atm of hydrogen. After 4 h, the mixture is filtered through Celite, washed with metanol, and concentrated under reduced pressure. Purification by flash chromatography by eluting with hexane: EtOAc 5: 1 provides the title compound (0.17 g, 54 %) with a 25 % of 4- hydroxy-2-ethyl-dihydro-ethyl cinnamate. The mixture is separated by HPLC (reverse phase purification) under acidic conditions (ACN: TFA=99.95 : 0.05). Rf=0. 17 (hexane: EtOAc 5: 1). 1H NMR (300 MHz, CDC13) : 0.97 (t, 3 H, J= 7. 5 Hz), 1.26 (t, 3 H, J= 7. 1 Hz), 1.59 (sext, 2 H, J= 7. 5 Hz), 2.55 (q, 4 H, J= 8. 9 Hz), 2.89 (t, 2 H, J= 7. 5 Hz), 4.16 (q, 2 H, J= 7. 13 Hz), 5.72 (s, 1 H), 6.71 (dd, 1 H, J= 3. 0,8. 1 Hz), 6.67 (d, 1 H, J= 2. 6 Hz), 6.99 (d, 1 H, J= 8. 3 Hz).

Example 252 Preparation of 4- (4-hydroxy-2-methylphenyl)-butyric acid ethyl ester

Step A 4-benzyloxy-2-methyl bromobenzene To a solution of 15 g (80.2 mmol) of 4-bromo-3-methyl-phenol and 1.5 g (10% in weight) oftetrebutylammonium iodide in THF (100 ml) is added 60% NaH (2. 88 gr, 120 mmol) at 0°C. After the mixture is stirred at 0°C for 30 min, benzyl bromide (14.3 ml 120 mmol) is added drop wise. The reaction is stirred at r. t. overnight under argon atmosphere. Then the reaction is poured into ice-water and extracted with EtOAc (3x100 ml). The organic extracts are dried over MgS04 and concentrated. The title compound (16. 5g, 66%) is isolated by precipitation in hexane. <BR> <BR> <P> Step B<BR> <BR> <BR> 4- (4-benzyloxy-2-methyl-phenyl)-4-oxo-butyric acid A solution of 4-benzyloxy-2-methyl bromobenzene (4 g, 14.4 mmol) in THF (25 ml) is added drop wise over a mixture of Mg (414 mg, 17.3 mmol), 1,2- dibromoethane (a few drops) and I2 (a crystal) at 70°C under argon atmosphere. After the addition is completed, the mixture is stirred at 70°C for 3 hours. Grignard reagent is added over a solution of succinic anhydride (1.73 gr, 17.3 mmol) and Fe (acac) 3 (254mg, 0.7 mmol) in 25 ml of THF over argon atmosphere and is stirred overnight at r. t. The reaction is quenched with sat NH4Cl and extracted with EtOAc (3x50 ml). The organic

phase is basified with 2N NaOH, and the aqueous phase is washed with EtOAc (3x50 ml). The aqueous phase is acidified with 2N HC1 and then extracted with EtOAc (3x50 ml), dried over MgS04 and concentrated to give 3.4 g (40%) of the title compound. The crude is used for the next step without further purification.

Step C 4- (4-benzyloxy-2-methylphenyl)-4-oxo-butyric acid ethyl ester A solution of 4- (4-benzyloxy-2-methyl-phenyl)-4-oxo-butyric acid (1.6 g, 5.6 mmol) and H2SO4 (1 ml) in EtOH (50 ml) is stirred at 80°C overnight. The solvent is evaporated, and water (100 ml) and sat. NaHCO3 is added up to pH=9. The aqueous phase is extracted with EtOAc (3x50 ml) and the organic are dried over MgS04 and concentrated to give about 1.3 g (71 %) of the title compound, which is used for the next step without further purification. step D 4- (4-hydroxy-2-methylphenyl)-butyric acid ethyl ester A mixture of 4- (4-benzyloxy-2-methylphenyl)-4-oxo-butyric acid ethyl ester (1.2 g, 3.4 mmol), Pd/C (120 mg) 10% in 10 ml of AcOH is hydrogenated at 60psi overnight. The mixture is filtered over celite, washed with EtOH and evaporated. Water (50 ml) and saturated NaHCO3 are added until neutral pH is achieved. The aqueous phase is extracted with AcOEt (3x50 ml), and the organic phase is dried over MgS04 and concentrated. The crude is purificated using silica gel chromatography (hexane/EtOAc 6: 1) to afford 700 mg (92%) of the title compound.

Example 253 Preparation of 1,3-butanediol

Methanol (320 ml) is added to a refluxing mixture of methyl 3- oxopentanoate (50 g, 0.38 mol) and sodium borohydride (37. 8 g, 1 mol) in 800 ml of tert- butanol over a period of two hours. The mixture is to cooled to r. t. and HC1 (200 ml, 6N) is added drop wise followed by K2C03 (120 g) in several portions until pH is reached to 10. The solvents are evaporated in vacuo and the residue is extracted with EtOAc (2 x 200 ml). The mixture is filtered, and the filtrate is dried over magnesium sulfate. The solvent is evaporated in vacuo to afford 31 g of the crude product (78%). Further purification by distillation under high vacuum (b. p. = 89°C/ltorr) provides about 17 g (43%) of pure 1,3-butanediol (98% HPLC-MS).

Example 254 (R)-3- {6- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-4-methyl-pyridin-3-yl}- propionic acid step A 2-benzyloxy-4-methylpyridine Silver carbonate (6.32 g, 22.91 mmol) and benzylbromide (6.00 mL, 50.40 mmol) are added to a solution of 2-hydroxy-4-methylpyridine (5.0 g, 45.82 mmol) in benzene (200 mL), and the mixture is stirred at 50 °C overnight. The mixture is cooled to

r. t. and filtered through Celite, and the solvent is evaporated in vacuo. Purification by flash chromatography by eluting with hexane: ethyl acetate 10: 1 affords the title compound (9.00 g, 98 %). Rf = 0.87 (hexane: ethyl acetate 1: 1).'H NMR (300 MHz, CDC13) : 2.30 (s, 3 H), 5.37 (s, 2 H), 6.64 (s, 1 H), 6.72 (d, 1 H, J= 5.2 Hz), 7.28-7. 48 (m, 5 H), 8. 04 (d, 1 H, J= 5. 2 Hz).

Step B 2-benzyloxy-5-bromo-4-methylpyridine N-bromosuccinimide (5.43 g, 30.51 mmol) is added to a solution of 2- benzyloxy-4-methylpyridine (6.08 g, 30. 51 mmol) in ACN (152 mL), and the mixture is stirred overnight at r. t. The solvent is evaporated in vacuo and purification by flash chromatography by eluting with hexane: ethyl acetate 10: 1 affords the title compound (7.38 g, 87 %). Rf= 0.62 (hexane: ethyl acetate 5: 1). 1H NMR (300 MHz, CDC13) : 2.34 (s, 3 H), 5.34 (s, 2 H), 6.72 (s, 1 H), 7.26-7. 46 (m, 5 H), 8.20 (s, 1 H).

Step C 3- (6-Benzyloxy-4-methyl-pyridin-3-yl)-acrylic acid ethyl ester A mixture of 2-benzyloxy-5-bromo-4-methylpyridine (7.38 g, 26.53 mmol), palladium acetate (0.30 g, 1.33 mmol), tri-o-tolylphosphine (0.81 g, 2.65 mmol), diisopropylethylamine (13.9 mL, 79. 59 mmol) and ethyl acrylate (11.5 mL, 106.13 mmol) in propionitrile (106 mL) is stirred 90 °C under nitrogen overnight. The mixture is filtered off through Celite, washed with ethyl acetate, and concentrated under reduced pressure. Purification by flash chromatography by eluting with hexane: ethyl acetate 10: 1 affords the title compound (4.04 g, 51 %) together with starting material (2.87 g, 39 %).

Rf= 0.27 (hexane: ethyl acetate 5: 1). 1H NMR (300 MHz, CDC13) : 1.35 (t, 3H, J=7. 3 Hz), 2.38 (s, 3 H), 4.28 (q, 2 H, J= 7. 3 Hz), 5.40 (s, 2 H), 6.33 (d, 1 H, J= 16. 1 Hz), 6.65 (s, 1 H), 7.29-7. 46 (m, 5 H), 7.82 (d, 1 H, J= 16. 0 Hz), 8.34 (s, 1 H). (m, 5 H), 7.56 (d, 1 H, J= 7. 9 Hz), 8.00 (d, 1 H, J= 15.7 Hz).

Step D 3- (6-Hydroxy-4-methyl-pyridin-3-yl)-propionic acid ethyl ester

A solution of 3- (6-benzyloxy-4-methyl-pyridin-3-yl)-acrylic acid ethyl ester (5.91 g, 19. 87 mmol) and palladium is stirred under 1 atm H2 under carbon (10 %) (2.11 g, 1.99 mmol) in ethanol (50 mL) and acetic acid (10 mL). After stirring overnight, the mixture is filtered through Celite, washed with methanol, and concentrated under reduced pressure. The crude product is dissolved in ethyl acetate and washed with 10% HC1. The aqueous layer is neutralized with 10 % NaOH, and the title compound is precipitated from this aqueous layer, which is filtered and dried. The remaining aqueous layer is extracted with DCM, and then dried with Na2S04 and filtered. The solvent is evaporated in vacuo giving a second batch of the title compound. Total amount: 2.60 g (62 %). Rf= 0.05 (hexane: ethyl acetate 5: 1). 1H NMR (300 MHz, CDC13) : 1.24 (t, 3 H, J= 7. 3 Hz), 2.21 (s, 3 H), 2.49 (t, 2 H, J= 8. 0 Hz), 2.71 (t, 2 H, J= 7.7 Hz), 4.16 (q, 2 H, J= 7.3 Hz), 6.39 (s, 1 H), 7.11 (s, 1 H). <BR> <BR> step E<BR> <BR> (R)-3- {6- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-4-methyl-pyridin-3-yl}- propionic acid A solution of (S)-methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)- butyl ester (0.177 g, 0.48 mmol) and 3- (6-hydroxy-4-methyl-pyridin-3-yl)-propionic acid ethyl ester (0.1 g, 0.48 mmol) in DMF (5 mL) is treated with cesium carbonate (171 mg, 0.53 mmol). The mixture is heated to 50 °C and stirred overnight. The mixture is then treated with aqueous 5N NaOH (0.4 mL, 2.2 mmol) and stirred for 2 additional hours at 50 °C. The mixture is cooled and quenched with IN HC1 to give pH=4. The mixture is extracted with Et20. The organic layer is washed with brine, dried over sodium sulfate and filtered. The solvent is removed, and the crude product is purified by prep HPLC to

afford 72 mg (33%) of the title product. 1H NMR (400 MHz, CDC13) ; MS (ES+) 7H/z mass calcd for C25H26C1N05 455, found 456 (M + 1, 100%).

Example 255 (R)-3- {6- [3- (4-Ethyl-2-phenoxy-phenoxy)-butoxy]-4-methyl-pyridin-3-yl}-p ropionic acid A solution of (S) -methanesulfonic acid 3- (4-ethyl-2-phenoxy-phenoxy)- butyl ester (0.174 g, 0.48 mmol) and 3- (6-hydroxy-4-methyl-pyridin-3-yl)-propionic acid ethyl ester (0.1 g, 0.48 mmol) in DMF (5 mL) is treated with cesium carbonate (171 mg, 0.53 mmol). The mixture is heated to 50 °C and stirred overnight. The mixture is treated with aqueous 5N NaOH (0.4 mL, 2.2 mmol) and stirred for 2 additional hours at 50 °C.

The mixture is cooled and quenched with IN HC1 to give pH=4. The mixture is extracted with Et20, and the organic layer is washed with brine, dried over sodium sulfate and filtered. The solvent is removed, and the crude product is purified by prep HPLC to afford 77 mg (36%) of the desired product. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C27H31NO5 449, found 450 (M + 1,100%).

Example 256 <BR> <BR> (R)-3- 4-Methyl-6- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butoxy]-pyridin-3-yl}- propionic acid

A solution of (S)-Methanesulfonic acid 3- (2-phenoxy-4-trifluoromethyl- phenoxy) -butyl ester (0.193 g, 0.48 mmol) and 3- (6-Hydroxy-4-methyl-pyridin-3-yl)- propionic acid ethyl ester (0.1 g, 0. 48 mmol) in DMF (5 mL) is treated with cesium carbonate (171 mg, 0.53 mmol). The mixture is heated to 50 °C and stirred overnight.

The mixture is treated with aqueous 5N NaOH (0.4 mL, 2.2 mmol) and stirred for 2 additional hours at 50 °C. The mixture is cooled and quenched with 1N HC1 to give pH=4. The mixture is extracted with Et20, and the organic layer is washed with brine, dried over sodium sulfate and filtered. The solvent is removed, and the crude product is purified by prep HPLC to afford 96 mg (41 %) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C26H26F3NO5 489, found 490 (M + 1,100%).

Example 257 (R)-3- {6- [3- (2-Benzoyl-4-ethyl-phenoxy)-butoxy]-4-methyl-pyridin-3-yl}-p ropionic acid A solution of (S)-methanesulfonic acid 3- (2-benzoyl-4-ethyl-phenoxy)- butyl ester (0.18 g, 0.48 mmol) and 3- (6-hydroxy-4-methyl-pyridin-3-yl)-propionic acid ethyl ester (0.1 g, 0. 48 mmol) in DMF (5 mL) is treated with cesium carbonate (171 mg, 0.53 mmol). The mixture is heated to 50 °C and stirred overnight. The mixture is treated

with aqueous 5N NaOH (0.4 mL, 2.2 mmol) and stirred for 2 additional hours at 50 °C.

The mixture is cooled and quenched with 1N HC1 to give pH=4. The mixture is extracted with Et20, and the organic layer is washed with brine, dried over sodium sulfate and filtered. The solvent is removed, and the crude product is purified by prep HPLC to afford 64 mg (29%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C28H31NO5 461, found 462 (M+1,100%).

Example 258 (R)-f 4- [3- (4-Ethyl-2-pyridin-2-yl-phenoxy)-butoxy]-3-methyl-phenyl}-ac etic acid [4- (3-Methanesulfonyloxy-butoxy)-3-methyl-phenyl]-acetic acid methyl ester is reacted with 4-ethyl-2-pyridin-2-yl-phenol as in Example 11 to afford 0.115 g (43%) of (R)- {4- [3- (4-Ethyl-2-pyridin-2-yl-phenoxy)-butoxy]-3-methyl-phenyl}-ac etic acid. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C26H29NO4 420.2175, found 420.2201 (M + 1).

Example 259 <BR> <BR> (R)- {3-Metliyl-4- [3- (2-pyridin-2-yl-4-trifluoromethyl-phenoxy)-butoxy]-phenyl}-a cetic acid [4- (3-Methanesulfonyloxy-butoxy)-3-methyl-phenyl]-acetic acid methyl ester is reacted with 2-pyridin-2-yl-4-trifluoromethyl-phenol as in Example 11 to afford 0. 118 g (61%) of (R)- 3-methyl-4- [3- (2-pyridin-2-yl-4-trifluoromethyl-phenoxy)- butoxy]-phenyl}-acetic acid. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C25H24NF304 460.1736, found 460.1733 (M + 1).

Example 260 (R)- {3-Methyl-4- [3- (2-pyrimidin-2-yl-4-trifluoromethyl-phenoxy)-butoxy]-phenyl} - acetic acid [4- (3-Methanesulfonyloxy-butoxy)-3-methyl-phenyl]-acetic acid methyl ester is reacted with 2-pyrimidin-2-yl-4-trifluoromethyl-phenol as in Example 11 to afford 0.084 g (71%) of (R)- {3-metliyl-4- [3- (2-pyrimidin-2-yl-4-trifluorometliyl-

phenoxy)-butoxy]-phenyl}-acetic acid.'H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C24H23N2F304 461.1688, found 461.1716 (M + 1).

Example 261 (R)- (4-{3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-butoxy}-3-meth yl-phenyl)-acetic acid [4- (3-Methanesulfonyloxy-butoxy)-3-methyl-phenyl]-acetic acid methyl ester is reacted with 4-chloro-2- (4-fluoro-phenoxy)-phenol as in Example 11 to afford 0.172 g (56%) of (R)-(4-{3-[4-chloro-2-(4-fluoro-phenoxy)-phenoxy]-butyxo}-3- methyl- phenyl) -acetic acid.'H NMR (400 MHz, CDC13) ; MS (ES-) 77l/Z mass calcd for C25H24C1F05 458, found 457 and 459 (M-1 and M + 1).

Example 262 <BR> <BR> (R)- {3-Methyl-4- [3- (2-o-tolyloxy-4-trifluoromethyl-phenoxy)-butoxy]-phenyl}-ace tic acid [4- (3-Methanesulfonyloxy-butoxy)-3-methyl-phenyl]-acetic acid methyl ester is reacted with 2-o-tolyloxy-4-trifluoromethyl-phenol as in Example 11 to afford 0.124 g (65%) of (R)-f3-methyl-4- [3- (2-o-tolyloxy-4-trifluoromethyl-phenoxy)-butoxy]- phenyl}-acetic acids NMR (400 MHz, CDC13) ; MS (ES-) nilz mass calcd for C27H27F305 488, found 487 (M-1).

Example 263 (R)-{3-Methyl-4-[3-2-phenoxy-4-trifluoromethyl-phenoxy)-buto xy]-phenyl}-acetic acid [4- (3-Methanesulfonyloxy-butoxy)-3-methyl-phenyl]-acetic acid methyl ester is reacted with 4-chloro-2- (4-fluoro-phenoxy)-phenol as in Example 11 to afford 0.230 g (58%) of (R)-{3-methyl-4-[3-(2-phenoxy-4-trifluoromethyl-phenoxy)-but oxy]-

phenyl}-acetic acid. 1H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C26H25F305 474, found 473 (M-1).

Example 264 (R)- {4- [3- (2-Phenoxy-4-trifluoromethyl-phenoxy)-butoxy]-phenyl}-acetic acid Methanesulfonic acid 3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butyl ester is reacted with methyl-4-hydroxyphenylacetate as in Example 11 to afford 0.154 g (54%) of (R)-{4-[3-(2-phenoxy-4-trifluoromethyl-phenoxy)-butoxy]-phen yl}-acetic acid.

1H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C25H23F305 460, found 459 (M-1).

Example 265 <BR> <BR> (R)- {2-Methyl-4- [3- (2-o-tolyloxy-4-trifluoromethyl-phenoxy)-butoxy]-phenylsulfa nyl}- acetic acid

[4- (3-Methanesulfonyloxy-butoxy)-2-methyl-phenylsulfanyl]-aceti c acid ethyl ester is reacted with 2-o-tolyloxy-4-trifluoromethyl-phenol as in Example 11 to afford 0. 124 g (58%) of (R)-{2-methyl-4-[3-(2-o-tolyloxy-4-trifluoromethyl-phenoxy)- butoxy]-phenylsulfanyl}-acetic acid. 1H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C27H27F305S 520, found 519 (M-1).

Example 266 (R)- {2-Methyl-4- [3- (2-o-tolyloxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phen oxy}- acetic acid

[4- (3-Methanesulfonyloxy-butylsulfanyl)-2-methyl-phenoxy]-aceti c acid ethyl ester is reacted with 2-o-tolyloxy-4-trifluoromethyl-phenol as in Example 11 to afford 0.156 g (73%) of (R)-12-methyl-4- [3- (2-o-tolyloxy-4-trifluorometliyl-phenoxy)- butylsulfanyl]-phenoxy}-acetic acid. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C27H27F305S 521.1609, found 521.1599 (M + 1).

Example 267 (R)- {2-Methyl-4- [3- (2-pyrimidin-2-yl-4-trifluoromethyl-phenoxy)-butylsulfanyl]- phenoxy}-acetic acid

[4- (3-Methanesulfonyloxy-butylsulfanyl)-2-methyl-phenoxy]-aceti c acid ethyl ester is reacted with 2-pyrimidin-2-yl-4-trifluoromethyl-phenol as in Example 11 to afford 0.050 g (51%) of (R)- {2-methyl-4- [3- (2-pyrimidin-2-yl-4-trifluoromethyl- phenoxy)-butylsulfanyl]-phenoxy}-acetic acid. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C24H23N204F3S 493.1409, found 493.1407 (M + 1).

Example 268 (R)- (4-{3-[2-(4-Fluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butyl sulfanyl}-2-methyl- phenoxy) -acetic acid

[4- (3-Methanesulfonyloxy-butylsulfanyl)-2-methyl-phenoxy]-aceti c acid ethyl ester is reacted with 2- (4-fluoro-phenoxy)-4-trifluoromethyl-phenol as in Example 11 to afford 0.035 g (29%) of (R)-(4-{3-[2-(4-fluoro-phenoxy)-4-trifluoromethyl- phenoxy]-butylsulfanyl}-2-methyl-phenoxy)-acetic acid. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C26H2405F4S 525.1359, found 525.1351 (M + 1).

Example 269 (R)-(4-{3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-butylsulfa nyl}-2-methyl-phenoxy)- acetic acid

[4- (3-Methanesulfonyloxy-butylsulfanyl)-2-metliyl-phenoxy]-acet ic acid ethyl ester is reacted with 4-chloro-2- (4-fluoro-phenoxy)-phenol as in Example 11 to afford 0.012 g (11%) of (R)-(4-{3-[4-chloro-2-(4-fluoro-phenoxy)-phenoxy]- butylsulfanyl}-2-methyl-phenoxy)-acetic acid.'H NMR (400 MHz, CDC13) ; HRMS (ES+) nilz mass calcd for C25H240sFCIS 491.1095, found 491.1106 (M + 1).

Example 270 <BR> <BR> 3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-2-methyl-propoxy]-2-methyl-phen yl}-propionic acid

3- [2-methyl-4- (3-methanesulfonyloxy-2-methyl-propoxy)-phenyl]- propionic acid ethyl ester is reacted with 4-chloro-2-phenoxy-phenol as in Example 11 to afford 0.055 g (98%) of 3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-2-methyl-propoxy]-2- methyl-phenyl}-propionic acid. 1H NMR (400 MHz, CDC13) ; Il (ES-) m/z mass calcd for C26H2705C1454, found 453 and 455 (M-1 and M + 1).

Example 271 3-{4-[3-(4-Chloro-2-phenoxy-phneoxy)-2-methyl-propoxy]-2-eth yl-phenyl}-propionic acid 3- [2-ethyl-4- (3-methanesulfonyloxy-2-methyl-propoxy)-phenyl]-propionic acid ethyl ester is reacted with 4-chloro-2-phenoxy-phenol as in Example 11 to afford 0.250 g (56%) of 3-f4- [3- (4-chloro-2-phenoxy-phenoxy)-2-methyl-propoxy]-2-ethyl- phenyl}-propionic acid. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) filz mass calcd for C27H2905C1469. 1782, found 469.1804 (M + 1).

Example 272 <BR> <BR> <BR> <BR> 3- {2-Methyl-4-[2-methyl-3-(2-phenoxy-4-trifluoromethyl-phenoxy )-propoxy]-phenyl}- propionic acid 3- [2-methyl-4- (3-methanesulfonyloxy-2-methyl-propoxy)-phenyl]- propionic acid ethyl ester is reacted with 2-phenoxy-4-trifluoromethyl-phenol as in

Example 11 to afford 0.052 g (96%) of3- {2-methyl-4- [2-methyl-3- (2-phenoxy-4- trifluoromethyl-phenoxy)-propoxy]-phenyl}-propionic acid. 1H NMR (400 MHz, CDC13) ; MS (ES-) walz mass calcd for C27H27O5F3 488, found 487 (M-1).

Example 273 3-{2-Ethyl-4-[2-methyl-3-(2-phenoxy-4-trifluoromethyl-phenox y)-propoxy]-phenyl}- propionic acid

3- [2-Ethyl-4- (3-methanesulfonyloxy-2-methyl-propoxy)-phenyl]- propionic acid ethyl ester is reacted with 2-phenoxy-4-trifluoromethyl-phenol as in Example 11 to afford 0.048 g (60%) of 3-{2-ethyl-4-[2-methyl-3-(2-phenoxy-4- trifluoromethyl-phenoxy)-propoxy]-phenyl}-propionic acid. 1H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C2gH29O5F3 502, found 501 (M-1).

Example 274 2-Methyl-2-{4-[2-methyl-3-(2-phenoxy-4-trifluoromethyl-pheno xy)-propoxy]-phenoxy}- propionic acid methanesulfonic acid 2-methyl-3-(2-phenoxy-4-trifluoromethyl-phenoxy)- propyl ester is reacted with 2- (4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester as in Example 1 to afford 0.270 g (37%) of 2-methyl-2-{4-[2-methyl-3-(2-phenoxy-4- trifluoromethyl-phenoxy)-propoxy]-phenoxy}-propionic acid. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C27H2706F3 503.1682, found 503.1664 (M + 1).

Example 275 <BR> <BR> <BR> <BR> 2-Methyl-2- {2-methyl-4-[2-methyl-3-(2-phenoxy-4-trifluoromethyl-phenoxy )-propoxy]- phenoxy}-propionic acid Methanesulfonic acid 2-methyl-3-(2-phenoxy-4-trifluoromethyl-phenoxy)- propyl ester is reacted with 2- (4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid

ethyl ester as in Example 1 to afford 0.165 g (60%) of 2-methyl-2-{2-methyl-4-[2- methyl-3-(2-phenoxy-4-trifluormethyl-phenoxy)-propoxy]-pheno xy}-propionic acid. 1H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C28H29O6F3 518, found 517 (M- 1).

Example 276 {2-Methyl-4-[2-methyl-3-(2-phenoxy-4-trifluoromethyl-phenoxy )-propoxy]-phenoxy}- acetic acid Methanesulfonic acid 2-methyl-3- (2-phenoxy-4-trifluoromethyl-phenoxy)- propyl ester is reacted with 2- (4-hydroxy-2-methyl-phenoxy)-propionic acid methyl ester as in Example 1 to afford 0.047 g (32%) of {2-methyl-4-[2-methyl-3-(2-phenoxy-4- trifluoromethyl-phenoxy)-propoxy]-phenoxy}-acetic acid. 1H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C26H2506F3 490, found 489 (M-1).

Example 277 2-{4-[3-(2-Benzoyl-4-trifluoromethyl-phenoxy)-2-methyl-propo xy]-phenoxy}-2-methyl- propionic acid

2- [4- (3-Methanesulfonyloxy-2-methyl-propoxy)-phenoxy]-2-methyl- propionic acid ethyl ester is reacted with (2-hydroxy-5-trifluoromethyl-phenyl)-phenyl- methanone as in Example 1 to afford 1.05 g (74%) of 2- {4- [3- (2-benzoyl-4- trifluoromethyl-phenoxy)-2-methyl-propoxy]-phenoxy}-2-methyl -propionic acid. 1 H NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C28H2706F3 532, found 531 (M- 1).

Example 278 <BR> <BR> 2-Methyl-2- {4- [2-methyl-3- (2-phenoxy-5-trifluoromethyl-phenoxy)-propoxy]-phenoxy}- propionic acid

2- [4- (3-Methanesulfonyloxy-2-methyl-propoxy)-phenoxy]-2-methyl- propionic acid ethyl ester is reacted with 2-phenoxy-5-trifluoromethyl-phenol as in Example 1 to afford 0.46 g (93%) of 2-methyl-2-{4-[2-methyl-3-(2-phenoxy-5- trifluoromethyl-phenoxy)-propoxy]-phenoxy}-propionic acid. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C27H2706F3 505.1838, found 505.1856 (M + 1).

Example 279 2-Methyl-2-{4-[2-methyl-3-(2-phenoxy-3-trifluormethyl-phenox y)-propoxy]-phenoxy}- propionic acid

2- [4- (3-Methanesulfonyloxy-2-methyl-propoxy)-phenoxy]-2-metliyl- propionic acid ethyl ester is reacted with 2-phenoxy-3-trifluoromethyl-phenol as in Example 11 to afford 0.229 g (77%) of 2-methyl-2-{4-[2-methyl-3-(2-phenoxy-3- trifluuoromethyl-phenoxy)-propoxy]-phenoxy}-propionic acid. 1H NMR (400 MHz, CDC13); MS (ES-) m/z mass calcd for C27H2706F3 504, found 503 (M-1).

Example 280 (R)-3-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-1-methyl-propylsulf anyl]-2-methyl-phenyl}- propionic acid

(S)-Methanesulfonic acid 3-(4-chloro-2-phenoxy-phenoxy)-1-methyl- propyl ester is reacted with 3- (4-mercapto-2-methyl-phenyl)-propionic acid methyl ester as in Example 1 to afford 0.130 g (42%) of 3- [3- (4-chloro-2-phenoxy-phenoxy)-l- methyl-propylsulfanyl]-2-methyl-phenyl}-propionic acid. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C26H27O4SCl 471. 1397, found 471.1391 (M + 1).

Example 281 (R)-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-1-methyl-propylsulfan yl]-2-methyl-phenoxy}- acetic acid

($-Methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-l-methyl- propyl ester is reacted with (4-mercapto-2-methyl-phenoxy) -acetic acid ethyl ester as in Example 1 to afford 0.156 g (45%) of {4- [3- (4-chloro-2-phenoxy-phenoxy)-l-methyl- propylsulfanyl]-2-methyl-phenoxy}-acetic acid. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) 7nlz mass calcd for C25H2505SCI 473. 1189, found 473.1190 (M + 1).

Example 282 <BR> <BR> (R)-3-f{4- [3- (4-Chloro-2-phenoxy-phenoxy)-1-methyl-propoxy]-2-methyl-phen yl}- propionic acid

(2-Methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-1-methyl- propyl ester is reacted with 3- (4-hydroxy-2-metliyl-phenyl)-propionic acid methyl ester as in Example 1 to afford 0.114 g (42%) of 3- {4- [3- (4-chloro-2-phenoxy-phenoxy)-l- methyl-propoxy]-2-methyl-phenyl}-propionic acid. 1H NMR (400 MHz, CDC13) ; HRMS (ES+) walz mass calcd for C26H27O5Cl 472. 1891, found 472.1894 (M + NH4).

Example 283 <BR> <BR> (R)- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-1-methyl-propoxy]-2-methyl-phen ylsulfanyl}- acetic acid (2-Methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-1-methyl- propyl ester is reacted with (4-hydroxy-2-methyl-phenylsulfanyl)-acetic acid ethyl ester as in to afford 0.092 g (36%) of {4- [3- (4-chloro-2-phenoxy-phenoxy)-l-methyl-propoxy]- 2-methyl-phenylsulfanyl}-acetic acid.'H NMR (400 MHz, CDC13) ; HRMS (ES+) m/z mass calcd for C25H2505SC1490. 1455, found 490.1440 (M + NH4).

Example 284 (S)-3-{2-Ethyl-4-[3-(2-phenoxy-4-trifluoromethyl-phenoxy)-bu tylsulfanyl]-phenyl}- propionic acid Step A (R)-3- [2-Ethyl-4- (3-hydroxy-butylsulfanyl)-phenyl]-propionic acid ethyl ester

A solution of (R)-toluene-4-sulfonic acid 3-hydroxy-butyl ester (1.1 g, 4.6 mmol) and 3- (2-Ethyl-4-mercapto-phenyl)-propionic acid ethyl ester (1.0 g, 4.2 mmol) is combined in DMF (20 mL) and purged with nitrogen. The solution is treated with potassium carbonate (0.87 g, 6.3 mmol) and stirred overnight at room temperature. The reaction is then quenched with l. ON aqueous HC1 to pH=6 and extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent removed. The crude is purified by silica gel column chromatography using 9: 1 hexanes: ethyl acetate to elute the pure product. The solvent is removed to afford 1.13 g (87%) of product NMR (400 MHz, CDC13) ; MS (ES+) salz mass calcd for Cl7H2603S 310, found 311 (M + 1, 100%).

Step B (R)-3- [2-Ethyl-4- (3-methanesulfonyloxy-butylsulfanyl)-phenyl]-propionic acid ethyl ester (R)-3- [2-Ethyl-4- (3-hydroxy-butylsulfanyl)-phenyl]-propionic acid ethyl ester (1.13 g, 3.6 mmol) in dichloromethane (20 mL) is cooled to 0°C in an ice bath. The reaction is then treated with triethylamine (0.44 g, 4.4 mmol) and methanesulfonyl chloride (0.46 g, 4.0 mmol). The reaction is allowed to warm to room temperature and stirred for 2 hr. The reaction is then quenched with 1. ON aqueous HC1 to pH=6, and the aqueous is extracted with dichloromethane. The organic is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford 1. 28 g (91%) of product.

'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C18H28O5S2 388, found 406 <BR> <BR> <BR> <BR> (M + NH4, 100%).<BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Step C<BR> <BR> <BR> <BR> <BR> <BR> <BR> (S)-3- {2-Ethyl-4- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phenyl} - propionic acid A solution of (R)-3- [2-ethyl-4- (3-methanesulfonyloxy-butylsulfanyl)- phenyl] -propionic acid ethyl ester (0.15 g, 0. 39 mmol) and 2-Phenoxy-4-trifluoromethyl- phenol (0.098 g, 0.39 mmol) in DMF (3 mL) is treated with cesium carbonate (0. 151 g, 0.46 mmol). The reaction is heated to 60 °C and stirred overnight. The reaction is then treated with 5N aqueous sodium hydroxide (0.4 mL) and stirred for an additional 2 hr.

The reaction is cooled and quenched with IN aqueous hydrochloric acid to pH=4. The aqueous solution is extracted with diethyl ether. The organic is washed with brine and dried over sodium sulfate. The organic is filtered, and the solvent is removed to afford the crude product. The crude is purified by reverse phase HPLC. The solvent is removed to afford 0.081 g (40%) of the desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C28H29F304S 518, found 536 (M + NH4,100%) ; MS (ES-) found 517 (M-1,100%).

Example 285 (S)- {3- [3- (2-Phenoxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phenyl} -acetic acid Step A (R)- [3- (3-Hydroxy-butylsulfanyl)-phenyl]-acetic acid methyl ester

The procedure from Example 284, Step A is utilized with (3-mercapto- phenyl) -acetic acid methyl ester. The reaction affords 1. 1 g (79%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for Cl7H2603S 254, found 255 (M + 1, 100%).

Step B (R)- [3- (3-Methanesulfonyloxy-butylsulfanyl)-phenyl]-acetic acid methyl ester The procedure from Example 284, Step B is utilized with (R)- [3- (3- hydroxy-butylsulfanyl) -phenyl] -acetic acid methyl ester. The reaction affords 1.37 g (95%) of product. 1H NMR (400 MHz, CDC13) ; MS (ES+) n/z mass calcd for C14H2005S2 332, found 350 (M + NH4, 100%). step C (S)- {3- [3- (2-Phenoxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phenyl} -acetic acid The procedure from Example 284, Step C is utilized with (R)- [3- (3- methanesulfonyloxy-butylsulfanyl)-phenyl]-acetic acid methyl ester. The reaction affords 0.053 g (37%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C25H23F304S 476, found 494 (M + NH4,100%) ; MS (ES-) found 475 (M-1, 100%).

Example 286 (S)-3- [3- (4-Chloro-2-phenoxy-phenoxy)-butylsulfanyl]-phenyl}-acetic acid The procedure from Example 284, Step C is utilized with (R)- [3- (3- methanesulfonyloxy-butylsulfanyl)-phenyl]-acetic acid methyl ester and 4-chloro-2- phenoxy-phenol. The reaction affords 0.053 g (40%) of product. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C24H23C104S 442, found 460 (M + NH4, 100%); MS (ES-) found 441 (M-1,100%).

Example 287 (S)-{3-[3-(2-Benzoyl-4-ethyl-phenoxy)-butysulfanyl]-phenyl}- acetic acid The procedure from Example 284, Step C is utilized with (R)- [3- (3- methanesulfonyloxy-butylsulfanyl)-phenyl]-acetic acid methyl ester and (5-ethyl-2- hydroxy-phenyl)-phenyl-methanone. The reaction affords 0.051 g (40%) of product. 1H NMR (400 MHz, CDC13) ; MS (ES+) nilz mass calcd for C27H2804S 448, found 449 (M + 1,100%) ; MS (ES-) found 447 (M-1,100%).

Example 288 (S)- {3- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-phenyl}-acetic acid The procedure from Example 284, Step C is utilized with (S)- methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-butyl ester and (3-hydroxy- phenyl) -acetic acid methyl ester. The reaction affords 0.1 g (58%) of product. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C24H23C105 426, found 444 (M + NH4, 100%); MS (ES-) found 425 (M-1,100%).

Example 289 (S)-3-13- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-phenyll-propionic acid The procedure from Example 284, Step C is utilized with (S)- methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-butyl ester and 3- (3-hydroxy- phenyl) -propionic acid methyl ester. The reaction affords 0.12 g (67%) of product. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C25H25CIO5 440, found 458 (M + NH4,100%) ; MS (ES-) found 439 (M-1,100%).

Example 290 <BR> <BR> (S)-3- {2-Ethyl-4- [3- (2-phenoxy-4-trifluorometlioxy-phenoxy)-butylsulfanyl]-pheny l}- propionic acid

Step A<BR> <BR> (S)-3- {4- [3- (2-Bromo-4-trifluoromethoxy-phenoxy)-butylsulfanyl]-2-ethyl- phenyl}- propionic acid ethyl ester A solution of (R)-3- [2-ethyl-4- (3-methanesulfonyloxy-butylsulfanyl)- phenyl] -propionic acid ethyl ester (0.15 g, 0.39 mmol) and 2-Bromo-4-trifluoromethoxy- phenol (0.099 g, 0.39 mmol) in DMF (3 mL) is treated with cesium carbonate (0.151 g, 0.46 mmol). The reaction is heated to 60 °C and stirred overnight. The reaction is cooled and. quenched with IN aqueous hydrochloric acid to pH=6. The aqueous solution is extracted with diethyl ether. The organic is washed with brine and dried over sodium sulfate. The organic is filtered, and the solvent is removed to afford the crude product.

The crude is purified by silica gel column chromatography using 4: 1 hexanes: ethylacetate to elute the pure product. The solvent is removed to afford 0.185 g (87%) of product. 1H NMR (400 MHz, CDC13) ; MS (ES+) walz mass calcd for C24H2$BrF304 548, found 566 (M +NH4, 100%).

Step B (S) -3- {2-Ethyl-4- [3- (2-phenoxy-4-trifluoromethoxy-phenoxy)-butylsulfanyl]-phenyl - propionic acid A solution of (S)-3- {4- [3- (2-bromo-4-trifluoromethoxy-phenoxy)- butylsulfanyl]-2-ethyl-phenyl}-propionic acid ethyl ester (0.185 g, 0.34 mmol), phenol (0.095 g, 1.01 mmol), copper (I) chloride (17 mg, 0.17 mmol), cesium carbonate (0.329 g, 1.01 mmol) and 2,2, 6,6-tetramethyl-3, 5-heptanedione (0.02 mL, 0.08 mmol) in NMP (5 mL) is purged with nitrogen. The reaction is heated to 120 °C and stirred overnight. The reaction is cooled to 60 °C and treated with 5N aqueous NaOH. The reaction is stirred an additional 2 hr, and then cooled and quenched with IN aqueous hydrochloric acid to pH=4. The aqueous solution is extracted with diethyl ether. The organic is washed with brine and dried over sodium sulfate. The organic is filtered, and the solvent is removed to afford the crude product. The crude is purified by reverse phase HPLC to afford 0.107 g (59%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C28H29F305S 534, found 532 (M + NH4,100%) ; MS (ES-) found 533 (M-1,100%).

Example 291 <BR> (S)-3- {4- [3- (5-Chloro-2'-fluoro-biphenyl-2-yloxy)-butoxy]-2-methyl-pheny l}-propionic acid Step A (S)-3-(2-Bromo-4-chloro-phenoxy)-butan-1-ol

A solution of (R) -acetic acid 3- (toluene-4-sulfonyloxy)-butyl ester (4.0 g, 14 mmol), 2-bromo-4-chlorophenol (2.9 g, 14 mmol), and cesium carbonate (5.45 g, 16.8 mmol) is combined in DMF (100 mL). The solution is heated to 60 °C and stirred overnight. The reaction is cooled and quenched with IN aqueous HC1 to pH=6. The aqueous is extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The residue is taken up in MeOH (50 mL) and treated with potassium carbonate (5.8 g, 42 mmol). The reaction is stirred at room temperature for 3 hr. The reaction is filtered and the filtrate is concentrated. The crude is purified by silica gel column chromatography using 4: 1 hexanes: ethylacetate to elute the pure product. The solvent is removed to afford 3.29 g (84%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for CIOHI2BrCI02 278, found 301 (M +Na, 100%).

Step B (S)-Methanesulfonic acid 3- (2-bromo-4-chloro-phenoxy)-butyl ester The procedure from Example 284, Step B is utilized with (S)-3- (2-bromo- 4-chloro-phenoxy)-butan-1-ol. The reaction affords 4.14 g (99%) of product NMR (400 MHz, CDC13) ; MS (ES+) nilz mass calcd for C11H14BrClO4S 356, found 374 (M + NH4, 100%).

Step C (S)-3-f4- [3- (2-Bromo-4-chloro-phenoxy)-butoxy]-2-methyl-phenyl}-propioni c acid methyl ester

The procedure from Example 290, Step A is utilized with (S)- methanesulfonic acid 3- (2-bromo-4-chloro-phenoxy)-butyl ester and 3- (4-hydroxy-2- methyl-phenyl) -propionic acid methyl ester. The reaction affords 3.59 g (68%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C2IH24BrC104 454, found 472 (M + NH4, 100%); MS (ES-) found 471 (M-1,100%).

Step D (S)-3- {4- [3- (5-Chloro-2'-fluoro-biphenyl-2-yloxy)-butoxy]-2-methyl-pheny l}-propionic acid methyl ester A solution of (S)-3- {4- [3- (2-bromo-4-chloro-phenoxy)-butoxy]-2-methyl- phenyl}-propionic acid methyl ester (0.1 g, 0.22 mmol), 2-fluorophenylboronic acid (0.092 g, 0.66 mmol), cesium fluoride (0.117 g, 0.77 mmol), and 1,1'- bis (diphenylphosphino) ferrocene palladium (II) chloride complex with dichloromethane (0.032 g, 0.04 mmol) in acetonitrile (10 mL) is purged with nitrogen. The reaction is heated to reflux and stirred for 3 hr. The reaction is quenched with IN aqueous hydrochloric acid to pH=6. The aqueous is extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered, and solvent is removed. The crude is purified using silica gel column chromatography with 9: 1 hexanes: ethyl acetate to elute

the pure product. The solvent is removed to afford 0.026g (25%). 1H NMR (400 MHz, CDC13) ; MS (ES+) nilz mass calcd for C27H28ClF04 470, found 488 (M + NH4, 100%).

Step E (S)-3-{4-[3-(5-Chloro-2'-fluoro-biphenyl-2-yloxy)-butoxy]-2- methyl-phenyl}-propionic acid A solution of (S)-3- {4- [3- (5-chloro-2'-fluoro-biphenyl-2-yloxy)-butoxy]- 2-methyl-phenyl}-propionic acid methyl ester (0.026 g, 0.05 mmol) in methanol (5 mL) is treated with 5N aqueous sodium hydroxide (0.1 mL). The reaction is heated to reflux and stirred for 3hr. The reaction is cooled to room temperature and the pH is adjusted to pH=4 with IN aqueous hydrochloric acid. The aqueous is extracted with diethyl ether.

The organic is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford 0.023 g (92%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C26H26C1F04 456, found 474 (M + NH4,100%) ; MS (ES-) found 455 (M- 1,100%).

Example 292 (S)-3-f 4- [3- (5-Chloro-2'-methoxy-biphenyl-2-yloxy)-butoxy]-2-methyl-phen yl}- propionic acid step A <BR> <BR> (S)-3- {4- [3- (5-Chloro-2'-methoxy-biphenyl-2-yloxy)-butoxy]-2-methyl-phen yl}- propionic acid methyl ester

The procedure from Example 291, Step D is utilized with 2- methoxyphenyl boronic acid. The reaction affords 0.076 g (75%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C28H31ClO5 482, found 500 (M + NH4, 100%).

Step B (S)-3-{4-[3-(5-Chloro-2'-methoxy-biphenyl-2-yloxy)-butoxy]-2 -methyl-phenyl}- propionic acid The procedure from Example 291, Step E is utilized with (S)-3-{4-[3-(5- chloro-2'-methoxy-biphenyl-2-yloxy)-butoxy]-2-methyl-phenyl} -propionic acid methyl ester. The reaction affords 0.063 g (85%) of product. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C27H29C105 468, found 486 (M + NH4,100%) ; MS (ES-) found 467 (M-1, 100%).

Example 293 <BR> <BR> (S)-3- (4-f3- [4-Chloro-2- (2-fluoro-phenoxy)-phenoxy]-butoxyl-2-methyl-phenyl)- propionic acid Step A 4-Chloro-2- (2-fluoro-phenoxy)-benzaldehyde A solution of 4-chloro-2-fluorobenzaldehyde (1.0 g, 6.3 mmol) and 2- fluorophenol (0.78 g, 6.9 mmol) in DMSO (10 mL) is treated with potassium carbonate (1.04 g, 7.6 mmol). The reaction is heated to 100 °C and stirred overnight. The reaction is cooled to room temperature and quenched with 1N aqueous hydrochloric acid to pH=6.

The aqueous is extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The crude is purified by silica gel column chromatography using 4: 1 hexanes: acetone to elute the pure product. The solvent is removed to afford 0.8 g (51%) of product.'H NMR (400 MHz, CDC13), TLC (1 : 1 Hexanes: EtOAc) Rf=0. 8.

Step B<BR> <BR> 4-Chloro-2- (2-fluoro-phenoxy)-phenol

A solution of 4-chloro-2- (2-fluoro-phenoxy)-benzaldehyde (0.8 g, 3.2 mmol) in chloroform (10 mL) is treated with m-CPBA (2.75 g, 16 mmol). The reaction is heated to reflux and stirred for 2 hr. The reaction is cooled to room temperature and quenched with 10% aqueous NaHS04. The aqueous is extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, and the solvent is removed. The crude is diluted in methanol (20 mL) and treated with potassium carbonate (1.32 g, 9.6 mmol). The reaction is stirred for 30 minutes at room temperature. The reaction is filtered and the solvent removed. The crude is purified by silica gel column chromatography using 4: 1 hexanes: acetone to elute the pure product. The solvent is removed to afford 0.64 g (84%) of product NMR (400 MHz, CDC13). MS (ES-) nilz mass calcd for C12H8ClFO2 238, found 237 (M-1, 100%).

Step C (S)-3- (4-{3-[4-Chloro-2-(2-fluoro-phenoxy)-phenoxy]-butoxy}-2-meth yl-phenyl)- propionic acid methyl ester The procedure from Example 290, Step A is utilized with 4-chloro-2- (2- <BR> <BR> <BR> fluoro-phenoxy)-phenol and 3- [4- (3-Methanesulfonyloxy-butoxy)-2-methyl-phenyl]- propionic acid methyl ester. The reaction affords 0.195 g (92%) of product NMR

(400 MHz, CDCl3). MS (ES+) m/z mass calcd for C27H28C1F05 486, found 504 (M + NH4,100%).

Step D (S)-3-(4-{3-[4-Chloro-2-(2-fluoro-phenoxy)-phenoxy]-butoxy}- 2-methyl-phenyl)- propionic acid The procedure from Example 291, Step E is utilized with (S)-3- (4- f 3- [4- chloro-2-(2-fluoro-phenoxy)-phenoxy]-butoxy}-2-methyl-phenyl )-propionic acid methyl ester. The reaction affords 0.166 g (88%) of product. 1H NMR (400 MHz, CDCl3). MS (ES+) nilz mass calcd for C26H26ClFO5 472, found 490 (M + NH4, 100%); MS (ES-) <BR> <BR> <BR> <BR> found 47 1.<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Example 294 (S)-3- (4-{3-[4-Chloro-2-(2-fluoro-phenoxy)-phenoxy]-butoxy}-2-ethy l-phenyl)- propionic acid Step A <BR> <BR> (S)-3- (4- {3- [4-Chloro-2- (2-fluoro-phenoxy)-phenoxy]-butoxy}-2-ethyl-phenyl)-propioni c acid ethyl ester The procedure from Example 290, Step A is utilized with 4-chloro-2- (2- fluoro-phenoxy)-phenol and 3- (2-ethyl-4-hydroxy-phenyl)-propionic acid ethyl ester.

The reaction affords 0.135 g (65%) of product NMR (400 MHz, CDC13). MS (ES+) nilz mass calcd for C29H32C1F05 514, found 532 (M + NH4, 100%).

Step B (S)-3- (4-{3-[4-Chloro-2-(2-fluoro-phenoxy)-phenoxy]-butoxy}-2-ethy l-phenyl)-propionic acid A solution of (S)-3-(4-{3-[4-chloro-2-(2-fluoro-phenoxy)-phenoxy]- butoxy}-2-ethyl-phenyl)-propionic acid ethyl ester (0. 135 g, 0.26 mmol) in ethanol (10 mL) is treated with 5N aqueous sodium hydroxide (0.5 mL, 2.6 mmol). The reaction is heated to reflux and stirred for 3 hr. The reaction is cooled to room temperature and quenched with IN aqueous hydrochloric acid to pH=4. The aqueous is extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, and filtered.

The solvent is removed to afford 0.108 g (85%) of product NMR (400 MHz, CDC13).

MS (ES+) m/z mass calcd for C27H28ClF05 486, found 504 (M + NH4, 100%); MS (ES-) found 485.

Example 295 <BR> <BR> <BR> <BR> (S)-3- {2-Methyl-4- [3- (2-phenoxy-4-trifluoromethoxy-phenoxy)-butylsulfanyl]-phenyl }- propionic acid Step A <BR> <BR> (S)-3- {4- [3- (2-Bromo-4-trifluorometlioxy-phenoxy)-butylsulfanyl]-2-methy l-phenyl}- propionic acid methyl ester

The procedure from Example 290, Step A is utilized with (R)-3- [4- (3- methanesulfonyloxy-butylsulfanyl)-2-melthyl-phenyl]-propioni c acid methyl ester to afford 0.13 g (90%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C22H24BrF304S 520, found 538 (M + NH4, 100%). <BR> <BR> <P> Step B<BR> (S)-3- {2-Methyl-4- [3- (2-phenoxy-4-trifluoromethoxy-phenoxy)-butylsulfanyl]-phenyl }- propionic acid The procedure from Example 290, Step B is utilized with (S)-3-14- [3- (2- bromo-4-trifluoromethoxy-phenoxy)-butylsulfanyl]-2-methyl-ph enyl}-propionic acid methyl ester to afford 0.009 g (9%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C27H27F305S 520, found 538 (M + NH4,100%) ; MS (ES-) found 519 (M-1,100%).

Example 296 (S)- {2-Methyl-4- [3-(2-phenoxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phen oxy}- acetic acid

Step A (S)-3-(2-Phenoxy-4-trifluoromelthyl-phenoxy)-butan-1-ol The procedure from Example 291, Step A is utilized 2-phenoxy-4- trifluoromethyl-phenol to afford 3.29 g (85%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for Cl7Hl7F303 326, found 327 (M + 1,60%) ; 344 (M + NH4, 100%); MS (ES-) found 385 (M + CH3COO-, 100%).

Step B (S) -Methanesulfonic acid 3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butyl ester The procedure from Example 284, Step B is utilized with (S)-3- (2- phenoxy-4-trifluoromelthyl-phenoxy)-butan-1-ol afford 3.8 g (95%) of product. IH NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C18H19F3O5S 404, found 422 (M + NH4,100%). <BR> <BR> <BR> <BR> step C<BR> <BR> <BR> <BR> <BR> <BR> (S)- {2-Methyl-4- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phenoxy }- acetic acid ethyl ester

The procedure from Example 290, Step A is utilized with (S)- methanesulfonic acid 3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butyl ester and (4- Mercapto-2-methyl-phenoxy) -acetic acid ethyl ester to afford 0.082 g (62%) of product.

'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C28H29F305S 534, found 535 (M + 1, 20%), found 552 (M + NH4, 100%); MS (ES-) found 593 (M + CH3C00, 100%).

Step D (S)- {2-Methyl-4- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phenoxy }- acetic acid The procedure from Example 294, Step B is utilized with (S)- {2-methyl-4- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phenoxy }-acetic acid ethyl ester to afford 0.072 g (92%) of product. 1H NMR (400 MHz, CDC13) ; MS (ES+) inlz mass calcd for C26H25F305S 506, found 524 (M + NH4,100%) ; MS (ES-) found 505 (M- 1,100%).

Example 297 (S)- {2-Ethyl-4- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phenoxy }- acetic acid Step A <BR> <BR> (S)- {2-Ethyl-4- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phenoxy }- acetic acid ethyl ester

The procedure from Example 290, Step A is utilized with (S)- methanesulfonic acid 3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butyl ester and (4- mercapto-2-ethyl-phenoxy) -acetic acid ethyl ester to afford 0.115 g (85%) of product. IH NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C29H31F3O5S 548, found 549 (M + 1, 20%), found 566 (M + NH4, 100%); MS (ES-) found 607 (M + CH3C00-, 100%).

Step B<BR> (S)- {2-Ethyl-4- ['- (2-phenoxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phenoxy }- acetic acid The procedure from Example 294, Step B is utilized with (S) - {2-ethyl-4- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phenoxy }-acetic acid ethyl ester to afford 0.072 g (92%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C27H27F305S 520, found 538 (M + NH4,100%) ; MS (ES-) found 519 (M- 1,100%).

Example 298 (S)-3- (4-{3-[4-Chloro-2-(3-fluoro-phenoxy)-phenoxy]-butoxy}-2-meth yl-phenyl)- propionic acid

Step A 4-Chloro-2- (3-fluoro-phenoxy)-benzaldehyde The procedure from Example 293, Step A is utilized with 3-fluorophenol to afford 1.4 g (89%) of product NMR (400 MHz, CDC13), TLC (1: 1 hexanes: EtOAc) Rf=0. 8. <BR> <BR> <P> Step B,<BR> <BR> <BR> <BR> <BR> <BR> <BR> 4-Chloro-2- (3-fluoro-phenoxy)-phenol The procedure from Example 293, Step B is utilized with 4-chloro-2- (3- fluoro-phenoxy) -benzaldehyde to afford 0.914 g (69%) of product NMR (400 MHz, CDC13). MS (ES-) nilz mass calcd for Ci2HsClF02 238, found 237 (M-1,100%).

Step C (S)-3- (4-{3-[4-Chloro-2-(3-fluoro-phenoxy)-phenoxy]-butoxy}-2-meth yl-phenyl)- propionic acid methyl ester The procedure from Example 290, Step A is utilized with 4-chloro-2- (3- fluoro-phenoxy)-phenol and 3- [4- (3-methanesulfonyloxy-butoxy)-2-methyl-phenyl]- propionic acid methyl ester. The reaction affords 0.09 g (64%) of product NMR (400

MHz, CDCl3). MS (ES+) m/z mass calcd for C27H28ClFO5 486, found 504 (M + NH4, 100%).

Step D (S)-3- (4-{3-[4-Chloro-2-(3-fluoro-phenoxy)-phenoxy]-butoxy}-2-meth yl-phenyl)- propionic acid The procedure from Example 291, Step E is utilized with (S)-3- (4- {3- [4- chloro-2- (3-fluoro-phenoxy)-phenoxy]-butoxy}-2-methyl-phenyl)-propion ic acid methyl ester. The reaction affords 0.06 g (91%) of product. 1H NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C26H26C1F05 472, found 490 (M + NH4, 100%); MS (ES-) found 471.

Example 299 (S)-3- (4-{3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-butoxy}-2-meth yl-phenyl)- propionic acid Step A<BR> <BR> 4-Chloro-2- (4-fluoro-phenoxy)-benzaldehyde The procedure from Example 293, Step A is utilized with 3-fluorophenol to afford 1.2 g (76%) of product NMR (400 MHz, CDC13), TLC (1: 1 hexanes: EtOAc) RO. 8.

Step B<BR> <BR> 4-Chloro-2- (4-fluoro-phenoxy)-phenol

The procedure from Example 293, Step B is utilized with 4-chloro-2- (4- fluoro-phenoxy) -benzaldehyde to afford 0.994 g (87%) of product NMR (400 MHz, CDC13). MS (ES-) m/z mass calcd for C12H8ClFO2 238, found 237 (M-1,100%). <BR> <BR> <BR> <BR> step C<BR> <BR> <BR> <BR> <BR> <BR> <BR> (S)-3- (4-f3- [4-Chloro-2- (4-fluoro-phenoxy)-phenoxy]-butoxyl-2-methyl-phenyl)- propionic acid methyl ester The procedure from Example 290, Step A is utilized with 4-chloro-2- (4- fluoro-phenoxy) -phenol and 3- [4- (3-Methanesulfonyloxy-butoxy)-2-methyl-phenyl]- propionic acid methyl ester. The reaction affords 0.09 g (64%) of product NMR (400 MHz, CDCl3). MS (ES+) nilz mass calcd for C27H28ClFO5 486, found 504 (M + NH4, 100%).

Step D (S)-3- (4-{3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-butoxy}-2-meth yl-phenyl)-n propionic acid The procedure from Example 291, Step E is utilized with (S)-3-(4-{3-[4- chloro-2- (3-fluoro-phenoxy)-phenoxy]-butoxy}-2-methyl-phenyl)-propion ic acid methyl ester. The reaction affords 0.06 g (91 %) of product NMR (400 MHz, CDC13). MS

(ES+) m/z mass calcd for C26H26C1FO5 472, found 490 (M + NH4, 100%); MS (ES-) found 471.

Example 300 (S)- {2-Ethyl-4- [3- (2-phenoxy-4-trifluoromcthyl-phenoxy)-butoxy]-phenylsulfanyl }- acetic acid The procedure from Example 284, Step C is utilized with (S)- methanesulfonic acid 3-(2-phenoxy-4-trifluoromethyl-phenoxy)-butyl ester and (2-ethyl- 4-hydroxy-phenylsulfanyl)-acetic acid ethyl ester to afford 0.068 g (53%) of product NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C27H27F305S 520, found 538 (M + NH4,100%) ; MS (ES-) found 519.

Example 301 (S)-3- {4- [3- (2'-fluoro-5-Trifluoromethyl-biphenyl-2-yloxy)-butoxy]-2-met hyl-phenyl}- propionic acid Step A (S)-3-(2-Bromo-4-trifluoromethyl-phenoxy)-butan-1-ol

The procedure from Example 291, Step A is utilized with 2-bromo-4- trifluoromethylphenol to afford 0.45 g (51 %) of product NMR (400 MHz, CDCl3) ; MS (ES+) m/z mass calcd for C11H12BrF3O2 312, found 335 (M + Na, 100%).

Step B (S)-Methanesulfonic acid 3- (2-bromo-4-trifluoromethyl-phenoxy)-butyl ester The procedure from Example 284, Step B is utilized with (S)-3- (2-bromo- 4-trifluoromethyl-phenoxy)-butan-1-ol. The reaction affords 0.56 g (100%) of product.

IH NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C12Hl4BrClF304S 390, found 408 (M + NH4, 100%).

Step C <BR> <BR> <BR> <BR> (S)-3- {4- [3- (2-Bromo-4-triftuoromethyl-phenoxy)-butoxy]-2-methyl-phenyl} -propionic acid methyl ester The procedure from Example 290, Step A is utilized with (S)- methanesulfonic acid 3- (2-bromo-4-trifluoromethyl-phenoxy)-butyl ester and 3- (4- hydroxy-2-methyl-phenyl) -propionic acid methyl ester. The reaction affords 0.43 g (61%) of product.'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C22H24BrF304 488, found 508 (M + NH4, 100%). step D<BR> <BR> (S)-3- {4- [3- (2'-Fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-2-met hyl-phenyl}- propionic acid methyl ester

The procedure from Example 291, Step D is utilized with (S)-3- {4- [3- (2- bromo-4-trifluoromethyl-phenoxy)-butoxy]-2-methyl-phenyl}-pr opionic acid methyl ester to afford 0.148g (72%). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C2sH2sF404 504, found 522 (M + NH4,100%).

Step E <BR> <BR> <BR> <BR> (S)-3-f{4- [3- (2'-fluoro-5-Trifluoromethyl-biphenyl-2-yloxy)-butoxy]-2-met liyl-phenyl}- propionic acid The procedure from Example 291, Step E is utilized with (S)-3- {4- [3- (2'- fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-2-methyl- phenyl}-propionic acid methyl ester to afford 0.135 g (94%) of product NMR (400 MHz, CDC13) ; MS (ES+) nilz mass calcd for C27H26F404 490, found 508 (M + NH4,100%) ; MS (ES-) found 489 (M-1,100%).

Example 302 (S)-3- {4- [3- (2'-Methoxy-5-Trifluoromethyl-biphenyl-2-yloxy)-butoxy]-2-me thyl- phenyl}-propionic acid Step A <BR> <BR> (S)-3- {4- [3- (2'-Methoxy-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-2-me thyl-phenyl}- propionic acid methyl ester

The procedure from Example 291, Step D is utilized with (S)-3- {4- [3- (2- bromo-4-trifluoromethyl-phenoxy)-butoxy]-2-methyl-phenyl}-pr opionic acid methyl ester and 2-methoxyphenyl boronic acid to afford 0.068g (64%). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C29H31F3O5 516, found 534 (M + NH4, 100%).

Step B (S)-3-{4-[3-(2'-Methoxy-5-Trifluoromethyl-biphenyl-2-yloxy)- butoxy]-2-methyl- phenyl}-propionic acid The procedure from Example 291, Step E is utilized with (S)-3- {4- [3- (2'- methoxy-5-trif acid methyl ester to afford 0.06 g (91%) of product. 1 H NMR (400 MHz, CDC13) ; MS (ES+) 7n/z mass calcd for C2gH29F305 502, found 520 (M + NH4, 100%); MS (ES-) found 501 (M-1,100%).

Example 303 (S)-3- {2-Ethyl-4- [3- (2'-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-pheny l}- propionic acid Step A <BR> <BR> (S)-3- {4- [3- (2-Bromo-4-trifluoromethyl-phenoxy)-butoxy]-2-methyl-phenyl} -propionic acid methyl ester

The procedure from Example 290, Step A is utilized with (R)-3- [2-ethyl- 4- (3-methanesulfonyloxy-butoxy)-phenyl]-propionic acid ethyl ester and 2-bromo-4- trifluoromethyl-phenol to afford 0.5 g (69%) of product NMR (400 MHz, CDC13) ; MS (ES+) walz mass calcd for C24H28BrF304 516, found 534 (M + NH4, 100%). <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> (S)-3- {2-Ethyl-4- [3- (2'-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-pheny l}- propionic acid ethyl ester The procedure from Example 291, Step D is utilized with (S)-3-14- [3- (2- bromo-4-trifluoromethyl-phenoxy)-butoxy]-2-methyl-phenyl}-pr opionic acid methyl ester to afford 0. 104g (68%). 1H NMR (400 MHz, CDC13) ; MS (ES+) walz mass calcd for C3oH32F404 532, found 550 (M + NH4, 100%). <BR> <BR> step C<BR> <BR> (S)-3- {2-Ethyl-4- [3- (2'-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-pheny l}- propionic acid The procedure from Example 291, Step E is utilized with (S)-3- {2-ethyl-4- [3-(2'-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-ph enyl}-propionic acid ethyl ester to afford 0.096 g (97%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C28H28F404 504, found 522 (M + NH4,100%) ; MS (ES-) found 503 (M- 1,100%).

Example 304 (S)-3-{2-Ethyl-4-[3-(3'-fluoro-5-trifluoromelthyl-biphenyl-2 -yloxy)-butoxy]-phenyl}- propionic acid

Step A <BR> <BR> (S)-3- {2-Ethyl-4- [3- (3'-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-pheny l}- propionic acid ethyl ester The procedure from Example 291, Step D is utilized with (S)-3-4- [3- (2- bromo-4-trifluoromethyl-phenoxy)-butoxy]-2-methyl-phenyl}-pr opionic acid methyl ester and 3-Fluorophenylboronic acid to afford 0. 115g (75%). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C3oH32F404 532, found 550 (M + NH4,100%). <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> (S)-3- {2-Ethyl-4- [3- (3'-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-pheny l}- propionic acid The procedure from Example 291, Step E is utilized with (S)-3- {2-ethyl-4- [3- (3'-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-pheny l}-propionic acid ethyl ester to afford 0.104 g (95%) of product.'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C28H28F404 504, found 522 (M + NH4,100%) ; MS (ES-) found 503 (M- 1,100%).

Example 305 <BR> <BR> <BR> (S)-3- {2-Ethyl-4- [3- (4'-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-pheny l}- propionic acid

Step A <BR> <BR> (S)-3- {2-Ethyl-4- [3- (4'-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-pheny l}- propionic acid ethyl ester The procedure from Example 291, Step D is utilized with (S)-3- {4- [3- (2- bromo-4-trifluoromethyl-phenoxy)-butoxy]-2-methyl-phenyl}-pr opionic acid methyl ester and 4-fluorophenylboronic acid to afford 0. 131 g (85%).'H NMR (400 MHz, CDC13) ; MS (ES+) nzlz mass calcd for C3oH32F404 532, found 550 (M + NH4, 100%). <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> (S)-3- {2-Ethyl-4- [3- (4'-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-pheny l}- propionic acid The procedure from Example 291, Step E is utilized with (S)-3-{2-ethyl-4- [3- (4'-fluoro-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-pheny l}-propionic acid ethyl ester to afford 0.113 g (91%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C28H28F404 504, found 522 (M + NH4,100%) ; MS (ES-) found 503 (M- 1,100%).

Example 306 (S)-3-{ {2-Ethyl-4- [3- (5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-phenyl}-propion ic acid

Step A (S)-3-{2-Ethyl-4-[3-(5-trifluoromethyl-biphenyl-2-yloxy)-but oxy]-phenyl}-propionic acid ethyl ester The procedure from Example 291, Step D is utilized with (S)-3- {4- [3- (2- bromo-4-trifluoromethyl-phenoxy)-butoxy]-2-methyl-phenyl}-pr opionic acid methyl ester and Phenylboronic acid to afford 0.068g (68%). 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C3oH33F304 514, found 532 (M + NH4, 100%). <BR> <BR> <P> Step B<BR> <BR> (S)-3- {2-Ethyl-4- [3- (5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-phenyl}-propion ic acid The procedure from Example 291, Step E is utilized with (S)-3- {2-ethyl-4- [3- (5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-phenyl}-propion ic acid ethyl ester to afford 0.059 g (92%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C28H29F304 486, found 504 (M + NH4,100%) ; MS (ES-) found 485 (M-1,100%).

Example 307 <BR> <BR> (S)-3- {2-Ethyl-4- [3- (3'-methoxy-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-phen yl}- propionic acid

A solution of (S)-3- {4- [3- (2-bromo-4-trifluoromethyl-phenoxy)-butoxy]- 2-methyl-phenyl}-propionic acid methyl ester (0.1 g, 0.19 mmol), 3-methoxyphenyl- boronic acid (0.088 g, 0. 58 mmol), cesium fluoride (0.103 g, 0.68 mmol), and 1,1'- bis (diphenylphosphino) ferrocene palladium (II) chloride complex with dichloromethane (0.028 g, 0.04 mmol) in acetonitrile (3 mL) is purged with nitrogen. The reaction is heated to reflux and stirred overnight. The reaction is then treated with 5N aqueous sodium hydroxide (0.5 mL) and stirred for an additional 2 hr. The reaction is cooled and quenched with IN aqueous hydrochloric acid to pH=4. The aqueous solution is extracted with diethyl ether. The organic is washed with brine and dried over sodium sulfate. The organic is filtered and the solvent is removed to afford the crude product. The crude is purified by reverse phase HPLC. The solvent is removed to afford 0.027 g (27%) of product NMR (400 MHz, CDC13) ; MS (ES-)/ mass calcd for C2gH31F3O5 516, found 515 (M-1,100%).

Example 308 <BR> <BR> (S)-3- {2-Ethyl-4- [3- (4'-methoxy-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-phen yl}- propionic acid The procedure from Example 307 is utilized with 4- methoxyphenylboronic acid to afford 0.034 g (34%) of product NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C29H31F305 516, found 515 (M-1,100%).

Example 309 (S)-3- (4-f3- [2- (2, 3-Dihydro-benzo [1, 4] dioxin-6-yl)-4-trifluoromethyl-phenoxy]-butoxy}- 2-ethyl-phenyl) -propionic acid The procedure from Example 307 is utilized with 1, 4-benzodioxane-6- boronic acid to afford 0.059 g (56%) of product NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C30H31F3O6 544, found 543 (M-1,100%).

Example 310<BR> <BR> (S)-3- {4- [3- (2'-Chloro-5-trinuoromethyl-biphenyl-2-yloxy)-butoxy]-2-cthy l-phenyl}- propionic acid The procedure from Example 307 is utilized with 2-chlorophenylboronic acid to afford 0.042 g (41%) of product. IH NMR (400 MHz, CDC13) ; MS (ES-) mlz mass calcd for C28H28ClF304 520, found 519 (M-1,100%).

Example 311 (S)-3-{4-[3-(3'-Chloro-5-trifluoromelthyl-biphenyl-2-yloxy)- butoxy]-2-ethyl-phenyl}- propionic acid The procedure from Example 307 is utilized with 3-chlorophenylboronic acid to afford 0.035 g (35%) of product NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C28H28ClF304 520, found 519 (M-1,100%).

Example 312.

(S) -3- {4-[3-(4'-Chloro-5-trifluoromelthyl-biphenyl-2-yloxy)-butoxy ]-2-ethyl-phenyl}- propionic acid The procedure from Example 307 is utilized with 4-chlorophenylboronic acid to afford 0.052 g (52%) of product NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C28H28ClF304 520, found 519 (M-1,100%).

Example 313 (S)-3- {4- [3- (4'-Dimethylamino-5-trifluoromethyl-biphenyl-2-yloxy)-butoxy ]-2-ethyl- phenyl}-propionic acid The procedure from Example 307 is utilized with 4-Dimethylaminophenyl boronic acid to afford 0.046 g (46%) of product NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C30H34F3NO4 529, found 528 (M-1,100%).

Example 314 (S)-3-{4-[3-(5,2'-Bis-trifluoromethyl-biphenyl-2-yloxy)-buto xy]-2-ethyl-phenyl}- propionic acid The procedure from Example 307 is utilized with 2-trifluoromethyl- phenylboronic acid to afford 0.02 g (19%) of product NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C29H28F604 554, found 553 (M-1,100%).

Example 315 (S)-3- {4- [3- (5, 3'-Bis-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-2-ethyl-phe nyl}- propionic acid The procedure from Example 307 is utilized with 3-trifluoromethyl- phenylboronic acid to afford 0.049 g (45%) of product NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C29H28F604 554, found 553 (M-1, 100%).

Example 316 <BR> <BR> (S)-3-f{4- [3- (5, 4'-Bis-trifluoromethyl-biphenyl-2-yloxy)-butoxy]-2-etliyl-ph enyl}- propionic acid The procedure from Example 307 is utilized with 4-trifluoromethyl- phenylboronic acid to afford 0.07 g (65%) of product NMR (400 MHz, CDC13) ; MS (ES-) m/z mass calcd for C29H28F604 554, found 553 (M-1,100%).

Example 317 (S)-3-{2-Ethyl-4-[3-(4'-methanesulfonyl-5-trifluoromethyl-bi phenyl-2-yloxy)-butoxy]- phenyl}-propionic acid The procedure from Example 307 is utilized with (4- methylsulfonylphenyl) boronic acid to afford 0.021 g (19%) of product. 1H NMR (400 MHz, CDCl3); MS (ES-) m/z mass calcd for C29H3lF306S 564, found 563 (M-1, 100%).

Example 318 <BR> <BR> (S)-3- {6- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-4-methyl-pyridin-3-yl}- propionic acid

A solution of (S)-3-methanesulfonic acid 3- (4-chloro-2-phenoxy- phenoxy)-butyl ester (0.177 g, 0.48 mmol) and 3- (6-hydroxy-4-methyl-pyridin-3-yl)- propionic acid ethyl ester (0.1 g, 0. 48 mmol) in DMF (5 mL) is treated with cesium carbonate (0.171 g, 0.53 mmol). The reaction is heated to 60 °C and stirred overnight.

The reaction is then treated with 5N aqueous sodium hydroxide (0.4 mL) and stirred for an additional 2 hr. The reaction is cooled and quenched with 1N aqueous hydrochloric acid to pH=7. The aqueous solution is extracted with diethyl ether. The organic is washed with brine and dried over sodium sulfate. The organic is filtered and the solvent is removed to afford the crude product. The crude is purified by reverse phase HPLC.

The solvent is removed to afford 0.072 g (33%) of product NMR (400 MHz, CDC13) ; MS (ES+) snlz mass calcd for C25H26ClNO5 455, found 456 (M + 1,100%) ; MS (ES-) found 454 (M-l, 100%).

Example 319 (S)-3- {6- [3- (4-Ethyl-2-phenoxy-phenoxy)-butoxy]-4-methyl-pyridin-3-yl}-p ropionic acid The procedure from Example 318 is utilized with (S) -methanesulfonic acid 3- (4-ethyl-2-phenoxy-phenoxy)-butyl ester to afford 0.077 g (36%) of desired product.

'H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C27H31NO5 449, found 450 (M + 1,100%) ; MS (ES-) found 448 (M-1, 100%).

Example 320 (S)-3- {4-Methyl-6- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butoxy]-pyndin-3-yl}- propionic acid The procedure from Example 318 is utilized with (S)-methanesulfonic acid 3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butyl ester to afford 0.096 g (41%) of desired product NMR (400 MHz, CDC13) ; MS (ES+) nilz mass calcd for C26H26F3NO5 489, found 490 (M + 1,100%) ; MS (ES-) found 488 (M-1,100%).

Example 321 (S)-3- {6- [3- (2-Benzoyl-4-ethyl-phenoxy)-butoxy]-4-methyl-pyridin-3-yl}-p ropionic acid The procedure from Example 318 is utilized with (S)-methanesulfonic acid 3- (2-benzoyl-4-ethyl-phenoxy)-butyl ester to afford 0.064 g (29%) of desired product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C28H31NO5 461, found 462 (M + 1,100%) ; MS (ES-) found 460 (M-1,100%).

Example 322 (S)- {3- [3- (2-Phenoxy-4-trifluorometliyl-phenoxy)-butoxy]-phenyl}-aceti c acid The procedure from Example 284, Step C is utilized with (S)- methanesulfonic acid 3-(2-phenoxy-4-trifluoromethyl-phenoxy)-butyl ester and (3- hydroxy-phenyl)-acetic acid methyl ester to afford 0.072 g (63%) of desired product. IH NMR (400 MHz, CDC13) ; MS (ES+) 7n/z mass calcd for C25H23F305 460, found 478 (M + NH4,100%) ; MS (ES-) found 459 (M-1,100%).

Example 323 (S)-3-{3-[3-(2-Phenoxy-4-trifluoromelthyl-phenoxy)-butoxy]-p henyl}-propionic acid The procedure from Example 284, Step C is utilized with (S)- methanesulfonic acid 3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butyl ester and 3- (3- hydroxy-phenyl) -propionic acid methyl ester to afford 0.076 g (65%) of desired product.

IH NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C26H25F305 474, found 492 (M + NH4,100%) ; MS (ES-) found 473 (M-1, 100%).

Example 324 (S)-3-f4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-isopropyl-phenyl}-pro pionic acid

Step A (S)-3-{4-[3-(4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-isopropyl -phenyl}-propionic acid ethyl ester The procedure from Example 290, Step A is utilized with (S)- methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-butyl ester and 3- (4-hydroxy-2- isopropyl-phenyl) -propionic acid ethyl ester to afford 0.122 g (54%) of product NMR (400 MHz, CDC13) ; MS (ES+) walz mass calcd for C30H35ClO5 510, found 528 (M + NH4,100%).

Step B (S)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-2-isopropyl-phenyl}-pro pionic acid The procedure from Example 294, Step B is utilized with (S)-3- {4- [3- (4- chloro-2-phenoxy-phenoxy)-butoxy]-2-isopropyl-phenyl}-propio nic acid ethyl ester to afford 0.109 g (95%) of product. 1H NMR (400 MHz, CDC13) ; MS (ES+) nzlz mass calcd for C28H31C105 482, found 500 (M + NH4,100%) ; MS (ES-) found 481 (M-1, 100%).

Example 325 (S)- 3-{5-[3-(4-Chloro-2-phenoxy-phenoxy)-butoxy]-3-methyl-pyridi n-2-yl}-propionic acid

Step A <BR> <BR> (S)-3- {5- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-3-methyl-pyridin-2-yl}- propionic acid ethyl ester The procedure from Example 290, Step A is utilized with (S)- methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-butyl ester and 3- (5-Hydroxy-3- methyl-pyridin-2-yl) -propionic acid ethyl ester to afford 0.062 g (31%) of product. IH NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C27H30ClNO5 483, found 484 (M+1, 100%).

Step B (S)-3- {5- [3- (4-Chloro-2-phenoxy-phenoxy)-butoxy]-3-methyl-pyridin-2-yl}- propionic acid The procedure from Example 294, Step B is utilized with (S)-3- {5- [3- (4- chloro-2-phenoxy-phenoxy)-butoxy]-3-methyl-pyridin-2-yl}-pro pionic acid ethyl ester to afford 0.022 g (38%) of product NMR (400 MHz, CDC13) ; MS (ES+) i7ilz mass calcd for C25H26ClNO5 455, found 456 (M + 1, 100%); MS (ES-) found 454 (M-1,20%).

Example 326 <BR> <BR> (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-1-methyl-propoxy]-2-ethyl-pheny l}- propionic acid Step A (R)-4- (4-Chloro-2-phenoxy-phenoxy)-butan-2-ol The procedure from Example 284, Step A is utilized with (R)-toluene-4- sulfonic acid 3-hydroxy-butyl ester and 4-Chloro-2-phenoxy-phenol to afford 0.73 g (61%) of product. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for Cj6Hi7C103 292, found 293 (M + 1, 70%), 310 (M + NH4, 100%).

Step B (R) -Methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-1-methyl-propyl ester The procedure from Example 284, Step B is utilized with (R)-4- (4-chloro- 2-phenoxy-phenoxy) -butan-2-ol to afford 0.84 g (92%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C17H19ClO5S 370, found 388 (M + NH4,100%). step C<BR> <BR> (R)-3-f4- [3- (4-Chloro-2-phenoxy-phenoxy)-1-methyl-propoxy]-2-ethyl-pheny l}- propionic acid ethyl ester

The procedure from Example 290, Step A is utilized with (R)- methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-l-methyl-propyl ester and 3- (2- ethyl-4-hydroxy-phenyl) -propionic acid ethyl ester to afford 0.074 g (55%) of product.

'H NMR (400 MHz, CDC13) ; MS (ES+) walz mass calcd for C29H33C105 496, found 514 (M + NH4, 100%).

Step D (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-1-methyl-propoxy]-2-ethyl-pheny l}- propionic acid The procedure from Example 294, Step B is utilized with (R)-3-4- [3- (4- chloro-2-phenoxy-phenoxy)-1-methyl-propoxy]-2-ethyl-phenyl}- propionic acid ethyl ester to afford 0.074 g (100%) of product. 1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C27H29C1O5 468, found 586 (M + NH4,100%) ; MS (ES-) found 467 (M- H, 100%).

Example 327 (R)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-l-methyl-propoxy]-2-ethyl-pheny l}- propionic acid

Step A <BR> <BR> (S)-4- (4-Chloro-2-phenoxy-phenoxy)-butan-2-ol The procedure from Example 284, Step A is utilized with (S)-toluene-4- sulfonic acid 3-hydroxy-butyl ester and 4-chloro-2-phenoxy-phenol to afford 0.78 g (65%) of product. IH NMR (400 MHz, CDC13) ; MS (ES+) nilz mass calcd for C16H17ClO3 292, found 293 (M + 1, 70%), 310 (M + NH4, 100%).

Step B (S)-Methanesulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-l-methyl-propyl ester

The procedure from Example 284, Step B is utilized with (S)-4- (4-chloro- 2-phenoxy-phenoxy) -butan-2-ol to afford 0.86 g (87%) of product NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C17Hl9CI05S 370, found 388 (M + NH4,100%). <BR> <BR> <BR> <BR> <P> Step C<BR> <BR> <BR> <BR> <BR> <BR> (R)-3-f{4- [3- (4-Chloro-2-phenoxy-phenoxy)-1-methyl-propoxy]-2-ethyl-pheny l}- propionic acid ethyl ester The procedure from Example 290, Step A is utilized with (S)- methanes. ulfonic acid 3- (4-chloro-2-phenoxy-phenoxy)-l-methyl-propyl ester and 3- (2- ethyl-4-hydroxy-phenyl) -propionic acid ethyl ester to afford 0.056 g (42%) of product.

1H NMR (400 MHz, CDC13) ; MS (ES+) m/z mass calcd for C29H33C105 496, found 514 (M + NH4, 100%).

Step D (R) -3- {4-[3-(4-Chloro-2-phenoxy-phenoxy)-1-melthyl-propoxy]-2-ethy l-phenyl}- propionic acid The procedure from Example 294, Step B is utilized with (R)-3-{4-[3-(4- chloro-2-phenoxy-phenoxy)-1-methyl-propoxy]-2-ethyl-phenyl}- propionic acid ethyl ester to afford 0.05 g (94%) of product. 'H NMR (400 MHz, CDC13) ; MS (ES+) nilz

mass calcd for C27H29C105 468, found 586 (M + NH4,100%) ; MS (ES-) found 467 (M- H, 100%).

Example 328 (S)-3- (4-{3-[4-Chloro-2-(3-fluoro-phenoxy)-phenoxy]-butoxy}-2-ethy l-phenyl)- propionic acid step A (S)-3- (4-{3-[4-Chloro-2-(3-fluoro-phenoxy)-phenoxy]-butoxy}-2-ethy l-phenyl)-propionic acid ethyl ester The procedure from Example 290, Step A is utilized with 4-chloro-2- (3- fluoro-phenoxy) -phenol and 3- [4- (3-methanesulfonyloxy-butoxy)-2-ethyl-phenyl]- propionic acid ethyl ester to afford 0.095 g (69%) of product NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C29H32C1F05 514, found 532 (M + NH4, 100%). step B (S)-3- (4-{3-[4-Chloro-2-(3-fluoro-phenoxy)-phenoxy]-butoxy}-2-ethy l-phenyl)-propionic acid The procedure from Example 291, Step E is utilized with (S)-3- (4- {3- [4- chloro-2- (3-fluoro-phenoxy)-phenoxy]-butoxy}-2-ethyl-phenyl)-propioni c acid ethyl ester. The reaction affords 0.074 g (82%) of product NMR (400 MHz, CDC13). MS

(ES+) inlz mass calcd for C27H28ClFO5 486, found 504 (M + NH4, 100%); MS (ES-) found 485.

Example 329 (S)-3- (4-{3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-butoxy}-2-ethy l-phenyl)-propionic acid Step A <BR> <BR> (S)-3- (4- {3- [4-Chloro-2- (4-fluoro-phenoxy)-phenoxy]-butoxy}-2-ethyl-phenyl)-propioni c acid ethyl ester The procedure from Example 290, Step A is utilized with 4-chloro-2- (4- fluoro-phenoxy) -phenol and 3- [4- (3-methanesulfonyloxy-butoxy)-2-ethyl-phenyl]- propionic acid ethyl ester to afford 0.174 g (63%) of product. 1H NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C29H32C1FO5 514, found 532 (M + NH4,100%). step B (S)-3- (4-{3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-butoxy}-2-ethy l-phenyl)-propionic acid The procedure from Example 291, Step E is utilized with (S)-3- (4-3- [4- chloro-2- (4-fluoro-phenoxy)-phenoxy]-butoxy}-2-ethyl-phenyl)-propioni c acid ethyl ester. The reaction affords 0.147 g (90%) of product. 1H NMR (400 MHz, CDCl3). MS

(ES+) m/z mass calcd for C27H28ClFO5 486, found 504 (M + NH4,100%) ; MS (ES-) found 485.

Example 330 (S)-3- {3-Methyl-5- [3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butoxy]-pyridin-2-yl}- propionic acid The procedure from Example 284, Step C is utilized with (S)- methanesulfonic acid 3- (2-phenoxy-4-trifluoromethyl-phenoxy)-butyl ester and 3- (5- hydroxy-3-methyl-pyridin-2-yl)-propionic acid ethyl ester to afford 0.092 g (51%) of product. 1H NMR (400 MHz, CDC13) ; MS (ES+) nzlz mass calcd for C26H26F3NO5 489, found 490 (M + 1, 100%); MS (ES-) found 488 (M-1,20%).

Example 331 (S)-3- {4- [3- (4-Chloro-2-o-tolyloxy-phenoxy)-butoxy]-2-ethyl-phenyl}-prop ionicacid Step A 4-Chloro-2-o-tolyloxy-benzaldehyde

The procedure from Example 293, Step A is utilized with o-cresol to afford 1.09 g (70%) of product NMR (400 MHz, CDCl3), MS (ES+) m/z mass calcd for C14H11ClO2 246, found 247 (M + 1,100%).

Step B 4-Chloro-2-o-tolyloxy-phenol The procedure from Example 293, Step B is utilized with 4-chloro-2-o- tolyloxy-benzaldehyde to afford 0.539 g (52%) of product NMR (400 MHz, CDCl3).

MS (ES-) nilz mass calcd for C13H11ClO2 234, found 233 (M-1,100%).

Step C (S)-3-{4-[3-(4-Chloro-2-o-tolyloxy-phenoxy)-butoxy]-2-ethyl- phenyl}-propionic acid The procedure from Example 284, Step C is utilized with (R)-3- [2-ethyl-4- (3-methanesulfonyloxy-butoxy)-phenyl]-propionic acid ethyl ester and 4-chloro-2-o- tolyloxy-phenol to afford 0.068 g (53%) of product NMR (400 MHz, CDC13). MS (ES+) m/z mass calcd for C28H31ClO5 482, found 500 (M + NH4,100%), MS (ES-) found 481 (M-1, 100%).

Example 332 (S)-3-{4-[3-(4-Chloro-2-m-tolyloxy-phenoxy)-butoxy]-2-ethyl- phenyl}-propionic acid

Step A 4-Chloro-2-m-tolyloxy-benzaldehyde The procedure from Example 293, Step A is utilized with m-cresol to afford 1.18 g (76%) of product NMR (400 MHz, CDCl3), MS (ES+) m/z mass calcd for C14H11ClO2 246, found 247 (M + 1, 100%). <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> 4-Chloro-2-m-tolyloxy-phenol The procedure from Example 293, Step B is utilized with 4-chloro-2-nz- tolyloxy-benzaldehyde to afford 0. 581 g (52%) of product NMR (400 MHz, CDC13).

MS (ES-)/ mass calcd for C13H11ClO2 234, found 233 (M-1, 100 Step C (S)-3-{4-[3-(4-Chloro-2-m-tolyloxy-phenoxy)-butoxy]-2-ethyl- phenyl}-propionic acid The procedure from Example 284, Step C is utilized with (R)-3- [2-ethyl-4- (3-methanesulfonyloxy-butoxy)-phenyl]-propionic acid ethyl ester and 4-chloro-2-m-

tolyloxy-phenol to afford 0.079 g (61%) of product NMR (400 MHz, CDC13). MS (ES+) m/z mass calcd for C28H3lClO5 482, found 500 (M + NH4, 100%), MS (ES-) found 481 (M-1, 100%).

Example 333 (S)-3-{4-[3-(4-Chloro-2-p-tolyloxy-phenoxy)-butoxy]-2-ethyl- phenyl}-propionic acid Step A 4-Chloro-2-p-tolyloxy-benzaldehyde The procedure from Example 293, Step A is utilized withp-cresol to afford 1.02 g (65%) of product NMR (400 MHz, CDC13), MS (ES+) m/z mass calcd for C14H11ClO2 246, found 247 (M + 1,100%). <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> <BR> <BR> <BR> 4-Chloro-2-p-tolyloxy-phenol The procedure from Example 293, Step B is utilized with 4-chloro-2-p- tolyloxy-benzaldehyde to afford 0.408 g (42%) of product NMR (400 MHz, CDCl3).

MS (ES-) m/z mass calcd for C13H11ClO2 234, found 233 (M-1,100%).

Step C (S)-3-f4- [3- (4-Chloro-2-p-tolyloxy-phenoxy)-butoxy]-2-ethyl-phenyl}-prop ionic acid The procedure from Example 284, Step C is utilized with (R)-3- [2-ethyl-4- (3-methanesulfonyloxy-butoxy) -phenyl] -propionic acid ethyl ester and 4-chloro-2-p- tolyloxy-phenol to afford 0.078 g (60%) of product NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C28H3, C105 482, found 500 (M + NH4, 100%), MS (ES-) found 481 (M-1,100%).

Example 334 (S)-3- (4- {3- [4-Chloro-2- (2, 4-difluoro-phenoxy)-phenoxy]-butoxy}-2-ethyl-phenyl)- propionic acid Step A 4-Chloro-2- (2, 4-difluoro-phenoxy) -benzaldehyde The procedure from Example 293, Step A is utilized with 2,4- difluorophenol to afford 1.69 g (100%) of product NMR (400 MHz, CDC13), MS (ES+) m/z mass calcd for C13H7ClF2O2 268, found 269 (M + 1,30%).

Step B 4-Chloro-2- (2, 4-difluoro-phenoxy)-phenol

The procedure from Example 293, Step B is utilized with 4-chloro-2- (2, 4- difluoro-phenoxy)-benzaldehyde to afford 0. 739 g (46%) of product NMR (400 MHz, CDCl3). MS (ES-) 7pilz mass calcd for C12H7ClF2O2 256, found 255 (M-1,100%). <BR> <BR> <BR> <BR> step C<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> (S)-3- (4- {3- [4-Chloro-2- (2, 4-difluoro-phenoxy)-phenoxy]-butoxy}-2-ethyl-phenyl)- propionic acid ethyl ester The procedure from Example 290, Step A is utilized with (R)-3- [2-ethyl-4- (3-methanesulfonyloxy-butoxy)-phenyl]-propionic acid ethyl ester and 4-chloro-2- (2, 4- difluoro-phenoxy) -phenol to afford 0.044 g (15%) of product NMR (400 MHz, CDCl3). MS (ES+) 7nlz mass calcd for C29H31ClFz05 532, found 550 (M + NH4, 100%).

Step D (S)-3-(4-{3-[4-Chloro-2-(2,4-difluoro-phenoxy)-phenoxy]-buto xy}-2-ethyl-phenyl)- propionic acid The procedure from Example 291, Step E is utilized with (S)-3- (4- {3- [4- chloro-2-(2,4-difluoro-phenoxy)-phenoxy]-butoxy}-2-ethyl-phe nyl)-propionic acid ethyl ester to afford 0.033 g (79%) of product NMR (400 MHz, CDCl3). MS (ES+) 7nlz mass calcd for C27H27CIF205 504, found 522 (M +NH4, 100%), MS (ES-) found 503 (M - 1, 100%).

Example 335 <BR> <BR> (S)-3- (4- {3- [4-Chloro-2- (2, 4-difluoro-phenoxy)-phenoxy]-butoxy}-2-ethyl-phenyl)- propionic acid

Step A 4-Chloro-2- (4-fluoro-2-methyl-phenoxy)-benzaldehyde The procedure from Example 293, Step A is utilized with 4-fluoro-2- methylphenol to afford 1.68 g (100%) of product NMR (400 MHz, CDCl3), MS (ES+) mass calcd for Ci4HioClF02 264, found 265 (M + 1,30%). <BR> <BR> step B<BR> <BR> <BR> <BR> <BR> <BR> <BR> 4-Chloro-2- (4-fluoro-2-methyl-phenoxy)-phenol The procedure from Example 293, Step B is utilized with 4-chloro-2- (4- fluoro-2-methyl-phenoxy)-benzaldehyde to afford 1.07 g (66%) of product NMR (400 MHz, CDCl3). MS (ES-) m/z mass calcd for C13H10ClFO2 252, found 251 (M-1, 100%).

Step C (S)-3- (4-{3-[4-Chloro-2-(4-fluoro-2-methyl-phenoxy)-phenoxy]-butox y}-2-ethyl- phenyl) -propionic acid ethyl ester

The procedure from Example 290, Step A is utilized with (R)-3- [2-ethyl-4- (3-methanesulfonyloxy-butoxy) -phenyl] -propionic acid ethyl ester and 4-chloro-2- (4- fluoro-2-methyl-phenoxy)-phenol to afford 0.208 g (73%) of product NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C3oH34ClF05 528, found 546 (M + NH4, 100%). <BR> <BR> <BR> <BR> step D<BR> <BR> <BR> <BR> <BR> <BR> <BR> (S)-3- (4- {3- [4-Chloro-2- (2, 4-difluoro-phenoxy)-phenoxy]-butoxy}-2-ethyl-phenyl)- propionic acid The procedure from Example 291, Step E is utilized with (S)-3-(4-{3-[4- <BR> <BR> <BR> <BR> chloro-2- (4-fluoro-2-methyl-phenoxy)-phenoxy]-butoxy}-2-ethyl-phenyl) -propionic acid ethyl ester to afford 0.190 g (96%) of product NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C28H3oClF05 500, found 518 (M + NH4, 100%), MS (ES-) found 499 (M-1,100%).

Example 336 <BR> <BR> (S)-f{3- [3- (2-Pyrimidin-2-yl-4-trifluoromethyl-phenoxy)-butylsulfanyl]- phenyl}-acetic acid

Step A <BR> <BR> (S)- {3- [3- (2-Pyrimidin-2-yl-4-trifluoromethyl-phenoxy)-butylsulfanyl]- phenyl}-acetic acid methyl ester The procedure from Example 290, Step A is utilized with (R)- [3- (3- methanesulfonyloxy-butylsulfanyl)-phenyl]-acetic acid methyl ester and 2-pyrimidin-2- yl-4-trifluoromethyl-phenol to afford 0.114 g (79%) of product. 1H NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C24H23F3N203S 476, found 477 (M + 1, 100%), MS (ES-) found 475 (M-1,100%). <BR> <BR> <BR> <P> Step B<BR> <BR> <BR> <BR> (S)- {3- [3- (2-Pyrimidin-2-yl-4-trifluoromethyl-phenoxy)-butylsulfanyl]- phenyl}-acetic acid The procedure from Example 291, Step E is utilized with (S)- {3- [3- (2- pyrimidin-2-yl-4-trifluoromethyl-phenoxy)-butylSulfanyl]-phe nyl}-acetic acid methyl ester to afford 0.1 g (91 %) of product. IH NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C23H2iF3N203S 462, found 463 (M + 1,100%), MS (ES-) found 461 (M-1, 100%).

Example 337 (S)- (3-{3-[2-(4-Fluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butyl sulfanyl}-phenyl)- acetic acid

Step A 2- (4-Fluoro-phenoxy)-4-trifluoromethyl-benzaldehyde The procedure from Example 293, Step A is utilized with 2-fluoro-4- trifluoromethyl-benzaldehyde and 4-fluorophenol to afford 1.46 g (99%) of product. IH NMR (400 MHz, CDCl3), MS (ES-)/ mass calcd for C14H8F4O2 284, found 343 (M + CH3COO-, 80%).

Step B<BR> <BR> 2- (4-Fluoro-phenoxy)-4-trifluoromethyl-phenol The procedure from Example 293, Step B is utilized with 2- (4-fluoro- phenoxy)-4-trifluoromethyl-benzaldehyde to afford 0.839 g (60%) of product NMR

(400 MHz, CDCl3). MS (ES-) m/z mass calcd for C13H8F402 272, found 271 (M-1, 100%).

Step C (S)- (3-{3-[2-(4-Fluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butyl sulfanyl}-phenyl)- acetic acid methyl ester The procedure from Example 290, Step A is utilized with (R)- [3- (3- methanesulfonyloxy-butylsulfanyl)-phenyl]-acetic acid methyl ester and 2- (4-fluoro- phenoxy) -4-trifluoromethyl-phenol to afford 0.114 g (75%) of product. 1H NMR (400 MHz, CDC13). MS (ES+) m/z mass calcd for C26H24F404S 508, found 526 (M + NH4, 100%), MS (ES-) found 507 (M-1, 100%). <BR> <BR> <BR> <BR> <P> Step D<BR> <BR> <BR> <BR> <BR> <BR> (S)- (3- {3- [2- (4-Fluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butylsulfanyl} -phenyl)- acetic acid The procedure from Example 291, Step E is utilized with (S)- (3- {3- [2- (4- fluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butylsulfanyl}-ph enyl)-acetic acid methyl ester to afford 0.091 g (82%) of product NMR (400 MHz, CDC13). MS (ES+) m/z mass calcd for C25H22F404S 494, found 512 (M + NH4,100%), MS (ES-) found 493 (M - 1, 100%).

Example 338 <BR> <BR> (S)- {3-[2-(2, 4-Difluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butylSulfanyl }-phenyl)- acetic acid Step A 2- (2, 4-Difluoro-phenoxy)-4-trifluoromethyl-benzaldehyde The procedure from Example 293, Step A is utilized with 2-fluoro-4- trifluoromethyl-benzaldehyde and 2,4-Difluorophenol to afford 1.25 g (80%) of product.

'H NMR (400 MHz, CDC13), MS (ES-) m/z mass calcd for Ci4H7P502 302, found 361 (M + CH3COO-, 80%).

Step B 2-(2,4-Difluoro-phenoxy)-4-trifluoromethyl-phenol The procedure from Example 293, Step B is utilized with 2- (2, 4-difluoro- phenoxy) -4-trifluoromethyl-benzaldehyde to afford 0.696 g (58%) of product NMR

(400 MHz, CDCl3). MS (ES-) mlz mass calcd for C13H7F502 290, found 289 (M-1, 100%). <BR> <BR> <P> Step C<BR> <BR> (S)- {3-[2-(2, 4-Difluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butylSulfanyl }-phenyl)- acetic acid methyl ester The procedure from Example 290, Step A is utilized with (R)- [3- (3- methanesulfonyloxy-butylsulfanyl)-phenyl]-acetic acid methyl ester and 2- (2, 4-difluoro- phenoxy) -4-trifluoromethyl-phenol to afford 0.047 g (30%) of product NMR (400 MHz, CDC13). MS (ES+) m/z mass calcd for C26H23F504S 526, found 544 (M + NH4, 100%), MS (ES-) found 525 (M-1,100%).

Step D (S)- (3-{3-[2-(2,4-Difluoro-phenoxy)-4-trifluoromethyl-phenoxy]-b utylsulfanyl}-phenyl)- acetic acid The procedure from Example 291, Step E is utilized with (S)-(3-{3-[2- (2, 4-difluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butylsulfanyl }-phenyl)-acetic acid methyl ester to afford 0.018 g (39%) of product NMR (400 MHz, CDC13). MS (ES+) inlz mass calcd for C25H2lFs04S 512, found 530 (M + NH4,100%), MS (ES-) found 511 (M-1,100%).

Example 339 <BR> <BR> (S)-3- {2-Methyl-4- [3- (2-pyrimidin-2-yl-4-trifluoromethyl-phenoxy)-butylsulfanyl]- phenyl}-propionic acid

The procedure from Example 284, Step C is utilized with (R)-3- [4- (3- methanesulfonyloxy-butylsulfanyl)-2-methyl-phenyl]-propionic acid ethyl ester and 2- pyrimidin-2-yl-4-trifluoromethyl-phenol to afford 0.076 g (56%) of product NMR (400 MHz, CDC13). MS (ES+) m/z mass calcd for C25H25F3N203S 490, found 491 (M + 1,100%), MS (ES-) found 489 (M-1,100%).

Example 340 <BR> <BR> <BR> (S)-3- {3-[2-(4-Fluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butylSul fanyl}-2-methyl- phenyl) -propionic acid The procedure from Example 284, Step C is utilized with (R)-3- [4- (3- methanesulfonyloxy-butylsulfanyl) -2-methyl-phenyl] -propionic acid ethyl ester and 2- (4- fluoro-phenoxy)-4-trifluoromethyl-phenol to afford 0. 078 g (54%) of product NMR (400 MHz, CDCl3). MS (ES+) nilz mass calcd for C27H26F404S 522, found 540 (M + NH4,100%), MS (ES-) found 521 (M-1,100%).

Example 341 <BR> <BR> (S)-3- {3-[2-(2, 4-Difluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butylSulfanyl }-2- methyl-phenyl)-propionic acid

The procedure from Example 284, Step C is utilized with (R)-3- [4- (3- methanesulfonyloxy-butylsulfanyl)-2-methyl-phenyl]-propionic acid ethyl ester and 2- (2, 4-difluoro-phenoxy)-4-trifluoromethyl-phenol to afford 0.045 g (30%) of product NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C27H25F504S 540, found 558 (M + NH4, 100%), MS (ES-) found 539 (M-1, 100%).

Example 342 (S)-3- {2-Ethyl-4- [3- (2-pyrimidin-2-yl-4-trifluoromethyl-phenoxy)-butylsulfanyl]- phenyl}-propionic acid The procedure from Example 284, Step C is utilized with (R)-3- [4- (3- methanesulfonyloxy-butylsulfanyl)-2-ethyl-phenyl]-propionic acid ethyl ester and 2- pyrimidin-2-yl-4-trifluoromethyl-phenol to afford 0.004 g (3%) of product NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C26H27F3N203S 504, found 505 (M + 1,100%), MS (ES-) found 503 (M-1,100%).

Example 343 <BR> <BR> (S)-3- {2-Ethyl-4- [3- (4-ethyl-2-pyridin-2-yl-phenoxy)-butylsulfanyl]-phenyl}-prop ionic acid

The procedure from Example 284, Step C is utilized with (R)-3- [4- (3- methanesulfonyloxy-butylsulfanyl)-2-ethyl-phenyl]-propionic acid ethyl ester and 4- ethyl-2-pyridin-2-yl-phenol to afford 0.014 g (12%) of product. 1H NMR (400 MHz, CDC13). MS (ES+) m/z mass calcd for C28H33NO3S 463, found 464 (M + 1,100%), MS (ES-) found 462 (M-1,100%).

Example 344 (S)-3- {3-[2-(4-Fluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butylSul fanyl}-2-ethyl- phenyl) -propionic acid The procedure from Example 284, Step C is utilized with (R)-3- [4- (3- methanesulfonyloxy-butylsulfanyl)-2-ethyl-phenyl]-propionic acid ethyl ester and 2- (4- fluoro-phenoxy)-4-trifluoromethyl-phenol to afford 0.09 g (65%) of product NMR (400 MHz, CECl3). MS (ES+) m/z mass calcd for C28H28F404S 536, found 554 (M + NH4,100%), MS (ES-) found 535 (M-1,100%).

Example 345 <BR> <BR> (S)-3- {3-[2-(2, 4-Difluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butylSulfanyl }-2- ethyl-phenyl)-propionic acid

The procedure from Example 284, Step C is utilized with (R)-3- [4- (3- methanesulfonyloxy-butylsulfanyl)-2-ethyl-phenyl]-propionic acid ethyl ester and 2- (2, 4- difluoro-phenoxy) -4-trifluoromethyl-phenol to afford 0.085 g (59%) of product NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C28H27F504S 554, found 572 (M + NH4,100%), MS (ES-) found 553 (M-1,100%).

Example 346 (S)- {3- [3- (4-Ethyl-2-pyridin-2-yl-phenoxy)-butylsulfanyl]-phenyl}-acet ic acid The procedure from Example 284, Step C is utilized with (R)- [3- (3- methanesulfonyloxy-butylsulfanyl)-phenyl]-acetic acid methyl ester and 4-ethyl-2- pyridin-2-yl-phenol to afford 0.005 g (3%) of product NMR (400 MHz, CDCl3). MS (ES+) nalz mass calcd for C25H27NO3S 421, found 422 (M + 1,100%), MS (ES-) found 420 (M-1,100%).

Example 347 (S)-3- {2-Ethyl-4- [3- (4-ethyl-2-o-tolyloxy-phenoxy)-butoxy]-phenyl}-propionic acid Step A 4-Ethyl-1-methoxy-2-o-tolyloxy-benzene The procedure from Example 290, Step B is utilized with 2-bromo-4- ethyl-l-methoxy-benzene and o-cresol to afford 1.13 g (67%) of product NMR (400 MHz, CDC13), MS (ES+)/ mass calcd for C16H, 802 242, found 260 (M + NH4,100%).

Step B 4-Ethyl-2-o-tolyloxy-phenol A solution of 4-ethyl-1-methoxy-2-o-tolyloxy-benzene (1.13 g, 4.66 mmol) in dichloromethane (10 mL) is cooled to-78 °C. The solution is then treated with 1M boron tribromide in dichloromethane (23 mL, 23 mmol). The reaction is warmed to room temperature and stirred for 2 hr. The reaction is then quenched with water followed by IN aqueous HC1 to pH=7. The aqueous is extracted with dichloromethane. The

organic is washed with brine, dried over sodium sulfate, filtered, and the solvent is removed. The crude is purified by silica gel column chromatography using 4: 1 hexanes: ethyl acetate to elute the pure product. The solvent is removed to afford 0.567 g (53%) of product NMR (400 MHz, CDCl3). MS (ES-) rfalz mass calcd for C15HI602 228, found 227 (M-1,100%).

Step C (S)-3- {2-Ethyl-4- [3- (4-ethyl-2-o-tolyloxy-phenoxy)-butoxy]-phenyl}-propionic acid ethyl ester The procedure from Example 290, Step A is utilized with (R)-3- [2-ethyl-4- (3-methanesulfonyloxy-butoxy)-phenyl]-propionic acid ethyl ester and 4-ethyl-2-o- tolyloxy-phenol to afford 0.322 g (48%) of product. 1H NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C32H40O5 504, found 522 (3k + NH4,100%).

Step D (S)-3- {2-Ethyl-4- [3- (4-ethyl-2-o-tolyloxy-phenoxy)-butoxy]-phenyl}-propionic acid The procedure from Example 294, Step B is utilized with (S)-3-{2-ethyl-4- [3- (4-ethyl-2-o-tolyloxy-phenoxy)-butoxy]-phenyl}-propionic acid ethyl ester to afford 0.23 g (76%) of product NMR (400 MHz, CDC13). MS (ES+) m/z mass calcd for C3oH3605 476, found 494 (M + NH4,20%), MS (ES-) found 475 (M-1,100%).

Example 348 (S)-3- (4-{3-[4-Chloro-2-(4-fluoro-phenoxy)-phenoxy]-butylsulfanyl} -2-ethyl-phenyl)- propionic acid

The procedure from Example 284, Step C is utilized with (R)-3- [2-ethyl-4- (3-methanesulfonyloxy-butylsulfanyl)-phenyl]-propionic acid ethyl ester and 4-chloro-2- (4-fluoro-phenoxy) -phenol to afford 0.106 g (81%) of product. 1H NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C27H28ClF04S 502, found 520 (M + NH4,100%), MS (ES-) found 501 (M - 1, 100%).

Example 349 (S)- (3- {3- [4-Chloro-2- (4-fluoro-phenoxy)-phenoxy]-butylsulfanyl}-phenyl)-acetic acid The procedure from Example 284, Step C is utilized with (R)- [3- (3- methanesulfonyloxy-butylsulfanyl)-phenyl]-acetic acid methyl ester and 4-chloro-2- (4- fluoro-phenoxy)-phenol to afford 0.073 g (53%) of product NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C24H22C1F04S 460, found 478 (M + NH4,100%), MS (ES-) found 459 (M-1, 100%).

Example 350 <BR> <BR> (S)-3- {2-Ethyl-4- [3- (2-o-tolyloxy-4-trifluoromethoxy-phenoxy)-butoxy]-phenyl}- propionic acid Step A 1-Methoxy-2-o-tolyloxy-4-trifluoromethoxy-benzene The procedure from Example 290, Step B is utilized with 2-brom-1- methoxy-4-trifluoromethoxy-benzene and o-cresol to afford 5.8 g (59%) of product NMR (400 MHz, CDCl3), MS (ES+) m/z mass calcd for C15H13F3O3 298, found 316 (M + NH4,100%).

Step B 2-o-Tolyloxy-4-trifluoromethoxy-phenol

The procedure from Example 314, Step B is utilized with 1-methoxy-2-o- tolyloxy-4-trifluoromethoxy-benzene to afford 5.11 g (93%) of product NMR (400 MHz, CDC13). MS (ES-) m/z mass calcd for C14H11F3O3 284, found 283 (M-1,100%).

Step C (S)-3- {2-Ethyl-4- [3- (2-o-tolyloxy-4-trifluoromethoxy-phenoxy)-butoxy]-phenyl}- propionic acid ethyl ester The procedure from Example 290, Step A is utilized with (R)-3- [2-ethyl- 4- (3-methanesulfonyloxy-butoxy)-phenyl]-propionic acid ethyl ester and 2-o-tolyloxy-4- trifluoromethoxy-phenol to afford 0.176 g (78%) of product NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C3lH35F306 560, found 578 (M + NH4,100%). <BR> <BR> <P> Step D<BR> <BR> (S)-3- {2-Ethyl-4- [3- (2-o-tolyloxy-4-trifluoromethoxy-phenoxy)-butoxy]-phenyl}- propionic acid The procedure from Example 294, Step B is utilized with (S)-3- {2-ethyl-4- [3-(2-o-tolyloxy-4-trifluoromethoxy-phenoxy)-butoxy]-phenyl} -propionic acid ethyl ester to afford 0.152 g (91 %) of product.'H NMR (400 MHz, CDC13). MS (ES+) m/z mass calcd for C29H31F306 532, found 550 (M + NH4,20%), MS (ES-) found 531 (M-1, 100%).

Example 351 <BR> <BR> (S)-3- {2-Ethyl-4- [3- (2-o-tolyloxy-4-trifluoromethyl-phenoxy)-butoxy]-phenyl}- propionic acid

The procedure from Example 290, Step B is utilized with 3-14- [3- (2- bromo-4-trifluoromethyl-phenoxy)-butoxy]-2-ethyl-phenyl}-pro pionic acid ethyl ester and o-cresol to afford 0.007 g (5%) of product NMR (400 MHz, CDCl3). MS (ES+) nilz mass calcd for C29H31F3O5 516, found 534 (M + NH4,100%), MS (ES-) found 515 (M-1, 100%).

Example 352 (S)- {3-[2-(2-Fluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butoxy}- 3-methyl-phenyl)- acetic acid The procedure from Example 284, Step C is utilized with (R)- [4- (3- methanesulfonyloxy-butoxy)-3-methyl-phenyl]-acetic acid methyl ester and 2- (2-fluoro- phenoxy)-4-trifluoromethyl-phenol to afford 0. 089 g (60%) of product NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C26H24F405 492, found 510 (M + NH4, 100%), MS (ES-) found 491 (M-1, 100%).

Example 353 <BR> <BR> (S)- {3-[2-(2-Fluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butoxy}- 2-methyl- phenylsulfanyl)-acetic acid

The procedure from Example 284, Step C is utilized with (R)- [4- (3- metlianesulfonyloxy-butoxy)-2-methyl-phenylsulfanyl]-acetic acid ethyl ester and 2- (2- fluoro-phenoxy) -4-trifluoromethyl-phenol to afford 0.079 g (57%) of product NMR (400 MHz, CDC13). MS (ES+) m/z mass calcd for C26H24F405S 524, found 542 (M + NH4,100%), MS (ES-) found 523 (M-1,100%).

Example 354 <BR> <BR> <BR> (S)- {3-[2-(2-Fluoro-phenoxy)-4-trifluoromethyl-phenoxy]-butylSul fanyl}-2-methyl- phenoxy) -acetic acid The procedure from Example 284, Step C is utilized with (R)- [4- (3- methanesulfonyloxy-butylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester and 2- (2- fluoro-phenoxy)-4-trifluoromethyl-phenol to afford 0.096 g (69%) of product NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C26H24F405S 524, found 542 (M + NH4,100%), MS (ES-) found 523 (M-1,100%).

Example 355 <BR> <BR> (S)-3- {4- [3- (4-Chloro-2-phenoxy-phenoxy)-butylsulfanyl]-2-ethyl-phenyl}- propionic acid The procedure from Example 284, Step C is utilized with (R)-3- [2-ethyl-4- (3-methanesulfonyloxy-butylsulfanyl)-phenyl]-propionic acid ethyl ester and 4-chloro-2- phenoxy-phenol to afford 0.068 g (54%) of product NMR (400 MHz, CDC13). MS (ES+) m/z mass calcd for C27H29C104S 484, found 502 (M + NH4,100%), MS (ES-) found 483 (M-1,100%).

Example 356' (S)-3- {2-Ethyl-4- [3- (2-o-tolyloxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phen yl}- propionic acid Step A 2-o-Tolyloxy-4-trifluoromethyl-benzaldehyde

The procedure from Example 293, Step A is utilized with 2-fluoro-4- trifluoromethyl-benzaldehyde and o-cresol to afford 3.7 g (84%) of product NMR (400 MHz, CDC13), MS (ES-) m/z mass calcd for C15H11F3O2 280, found 339 (M + CH3COO-, 100%). step B 2-o-Tolyloxy-4-trifluoromethyl-phenol: The procedure from Example 293, Step B is utilized with 2-o-tolyloxy-4- trifluoromethyl-benzaldehyde to afford 2.08 g (59%) of product NMR (400 MHz, CDCl3). MS (ES-) m/z mass calcd for Ci4HnF302 268, found 267 (M-1,100%). <BR> <BR> <BR> <BR> <P> Step C<BR> <BR> <BR> <BR> <BR> (S)-3- {2-Ethyl-4- [3- (2-o-tolyloxy-4-trifluoromethyl-phenoxy)-butylsulfanyl]-phen yl}- propionic acid The procedure from Example 284, Step C is utilized with (R)-3- [2-ethyl-4- (3-methanesulfonyloxy-butylsulfanyl)-phenyl]-propionic acid ethyl ester and 2-o- tolyloxy-4-trifluoromethyl-phenol to afford 0.084 g (61%) of product.'H NMR (400 MHz, CDCl3). MS (ES+) m/z mass calcd for C29H31F304S 532, found 550 (M + NH4, 100%), MS (ES-) found 531 (M-1,100%).

Example 357 (S)-3-(2-Ethyl-4-{3-[2-(2-fluoro-phenoxy)-4-trifluoromethyl- phenoxy]-butylsulfanyl}- phenyl) -propionic acid The procedure from Example 284, Step C is utilized with (R)-3-[2-ethyl-4- -methanesulfonyloxy-butylsulfanyl)-phenyl]-propionic acid ethyl ester and 2- (2-fluoro- enoxy)-4-trifluoromethyl-phenol to afford 0.092 g (67%) of product. 1H NMR (400 Hz, CDCl3). MS (ES+) m/z mass calcd for C28H2sF404S 536, found 554 (M + NH4, 0%), MS (ES-) found 535 (M - 1, 100%).

Example 358 S)-3-(2-Ethyl-4-{3-[2-(2-fluoro-phenoxy)-4-trifluoromethyl-p henoxy]-butoxy}-phenyl)- propionic acid The procedure from Example 284, Step C is utilized with (R)-3- [2-ethyl- zthanesulfonyloxy-butoxy)-phenyl]-propionic acid ethyl ester and 2- (2-fluoro- 7)-4-trifluoromethyl-phenol to afford 0.065 g (46%) of product NMR (400 Duc13). MS (ES+) m/z mass calcd for C28H28F405 520, found 538 (M + NH4, tS (ES-) found 519 (M-1,100%).