AU2006318527A1 - Thrombopoietin activity modulating compounds and methods - Google Patents

Thrombopoietin activity modulating compounds and methods Download PDF

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Publication number
AU2006318527A1
AU2006318527A1 AU2006318527A AU2006318527A AU2006318527A1 AU 2006318527 A1 AU2006318527 A1 AU 2006318527A1 AU 2006318527 A AU2006318527 A AU 2006318527A AU 2006318527 A AU2006318527 A AU 2006318527A AU 2006318527 A1 AU2006318527 A1 AU 2006318527A1
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compound
oxo
optionally substituted
dihydro
hydroxy
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AU2006318527A
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Jyun-Hung Chen
Catalina Cuervo
Jackline E. Dalgard
Robert Higuchi
Yongkai Li
Oliver Long
Matthew H. Mcneill
Richard J. Penuliar
Dean P. Phillips
Cornelis Arjan Van Oeveren
Lin Zhi
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Ligand Pharmaceuticals Inc
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Ligand Pharmaceuticals Inc
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    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
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    • A61K31/415—1,2-Diazoles
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    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
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    • C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
    • C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
    • C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
    • C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Description

WO 2007/062078 PCT/US2006/045129 THROMBOPOIETIN ACTIVITY MODULATING COMPOUNDS AND METHODS FIELD OF THE INVENTION 10001] The present invention relates to compounds and methods in the fields of chemistry and medicine. More specifically, the present invention relates to compounds that modulate one or more thrombopoietin activity and/or bind to thrombopoietin receptors, and to methods for making and using such compound. BACKGROUND [0002] Thrombopoietin (TPO), also referred to as c-Mpl ligand, mpl ligand, megapoietin, and megakaryocyte growth and development factor, is a glycoprotein that has been shown to be involved in production of platelets. See e.g., Wendling, F., et. al., Biotherapy 10(4):269-77 (1998); Kuter D.J. et al., The Oncologist, 1:98-106(1996); Metcalf, Nature 369: 519-520 (1994), all of which are incorporated herein by reference in their entirety. TPO has been cloned and its amino acid sequence and the cDNA sequence encoding it have been described. See e.g., U.S. 5,766,581; Kuter, D.J. et al., Proc. Natl. Acad. Sci., 91:11104-11108 (1994); de Sauvage F.V., et al., Nature, 369: 533-538 (1994); Lok, S. et al., Nature 369:565-568 (1994); Wending, F. et al., Nature, 369: 571-574 (1994), all of which are incorporated herein by reference in their entirety. [00031 In certain instances, TPO activity results from binding of TPO to the TPO receptor (also called MPL). The TPO receptor has been cloned and its amino acid sequence has been described. See e.g., Vigon et al., Proc. Natl. Acad. Sci., 89:5640-5644 (1992), which is incorporated herein by reference in its entirety. 10004] In certain instances, TPO modulators may be useful in treating a variety of hematopoietic conditions, including, but not limited to, thrombocytopenia. See e.g., Baser et al. Blood 89:3118-3128 (1997); Fanucchi et al. New Engl. J. Med. 336:404 409 (1997), both of which are incorporated herein by reference in their entirety. For example, patients undergoing certain chemotherapies, including but not limited to chemotherapy and/or radiation therapy for the treatment of cancer, may have reduced platelet levels. In certain instances, treating such patients with a selective TPO modulator increases platelet levels. In certain instances, selective TPO modulators stimulate production of glial cells, which may result in repair of damaged nerve cells. -1- WO 2007/062078 PCT/US2006/045129 SUMMARY OF THE INVENTION [0005] In certain embodiments, the present invention provides a compound of Formula I, II, III, IV, V, or VI: R R 2 R9 Q m R Z-b ,Rio R N O R ---- Z-L Df
R
8 / - I 1 R 8
R"
' 1 0.; = R3,N R XW Y, o 0o w N N RiOE-R / / I
R
6
R
6
R
6 (I) (II) (III) R (R2) R 8 12 RQ Rm R ZL R o R /Z--R \R N R 9
R
9 D 13( 0 O U R R O RR 3'-5 N Rx 0 R 12
R
12 W RO1NRNR233
R
°
i
-E
o - R R R I
RR
6
R
6 R (IV) (V) (VI) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: R' is selected from hydrogen, halogen, OR' 14 , NO 2 , CN, NRI 4
R
is , an optionally substituted CI-C 6 alkyl, an optionally substituted C 1
-C
6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, CO 2
R'
4 , CONR' 4 R' is , SO 3
R
4 ,
SO
2
NRI
4
R
15 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, OR 14 , NRI 4
R'
s 5 , an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl;
R
3 and R 4 are independently selected from hydrogen, an optionally substituted C,-C 6 alkyl, an optionally substituted C,-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl;
R
5 is selected from hydrogen, halogen, OR' 4 , C,-C 6 alkyl, C 1
-C
6 haloalkyl,
CI
1
-C
6 heteroalkyl, and C 1
-C
6 haloheteroalkyl;
R
6 is selected from an optionally substituted C,-Clo alkyl, an optionally substituted C,-Clo haloalkyl, and an optionally substituted CI-C 1 o heteroalkyl, -2- WO 2007/062078 PCT/US2006/045129 each optionally fused with a substituted aiyl or a substituted heteroaryl, or R 6 is selected from (CH 2 )mR' 8 , C(O)NHR" 8 , C=CR 8 , CR=CR 4
R
1 ", and CR 3
=R
8 ; R is selected from CO 2 R 4 , CONRI 4
R
5 , SO 3
RI
4 , SO 2
NR
4
R"
5 and a carboxylic acid bioisostere; each R 8 and each R 9 is independently selected from hydrogen, OR 16 , NR 6R 17 , an optionally substituted C,-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted C,-C 6 heteroalkyl, (CH 2 )mR' 1 8 , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -Cs ring; 10 1 17 16
R
1 o is selected from hydrogen, halogen, oxo, ORI 6 , NR 6 R , SR 6 , an optionally substituted C 1
-C
6 alkyl, an optionally substituted C,-C 6 haloalkyl, and an optionally substituted Cl-C 6 heteroalkyl; R" is selected from hydrogen, halogen, OR 14 , NRI 4 Ri 5 , and SR14; or R" and R 4 are linked to form a optionally substituted heterocycle;
R
12 is selected from hydrogen, halogen, C-C 6 alkyl, CI-C 6 haloalkyl, Ci
C
6 heteroalkyl, and C,-C 6 haloheteroalkyl;
R
13 is selected from hydrogen, halogen, CN, NO 2 , CO 2
R
14 , S(O)mR I4 , CI
C
4 alkyl, CI-C 4 haloalkyl, CI-C 4 heteroalkyl, and C 1
-C
4 haloheteroalkyl;
R
14 is selected from hydrogen, CI-C 6 alkyl, CI-C 6 haloalkyl, Ci-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl; R1 5 is selected from hydrogen, SO2R 19 , C I-C 6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI -C 6 heterohaloalkyl;
R
16 and R 17 are each independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted C,-C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, and (CH 2 )mR1 8 ; or one of R 16 and R 17 is an optionally substituted C 2
-C
6 alkyl and the other of R 16 and R 17 is null; or R' 6 and
R
17 are linked to form an optionally substituted C 3
-C
8 ring;
R
1 8 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R' 8 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system; -3- WO 2007/062078 PCT/US2006/045129 R1 9 is selected from hydrogen, CI-C 3 alkyl, CI-C 3 haloalkyl, and an optionally substituted aryl; D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; L is NH or null; Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; U is selected from O, NR 4 , CR 3
R
4 , CO, and null; W is selected from O, NR 4 , CR 3
R
4 , CO, and null; X is N or CR 5 ; Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted C 1
-C
6 alkyl, an optionally substituted C 1
-C
6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl; Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6
-C
1 0 aryl and an optionally substituted Ci-C 8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 heteroalkyl, and an optionally substituted CI-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -Co 10 aryl; m is 0, 1, 2, or 3; and n is 0 or 1; each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, -4- WO 2007/062078 PCT/US2006/045129 isocyanato, thiocyanato, isothiocyanato, nitro, sily), trihalomethanesulfonyl, =0, =S, amino, and protected derivatives of amino groups; *-N provided that if Y is 'R 12 oriented in compounds of Formulas I or 11 to form a dihydropyrazolylene, then: (i) D is not naphthyl if X is N and W is NH, (ii) D is not phenyl if X is CH, W is NH, Z is phenyl, and R1o or R" is -(CHz) 0 6 OH, I RII-D RIo (iii) is not pyrazolyl or optionally substituted 5 hydroxypyrazolyl, and (iv) U is not NH; provided further that if X is N and W is NH, then D is not phenyl; and provided further that if X is N and W is NH in compounds of Formulas III or VI, then R 6 , R 1 0 , and R" 1 do not contain a carboxylic, amrnido, ester, or sulfurate functionality or a carboxylic acid bioisostere. (00061 In certain embodiments, the present invention provides a compound of Formula I, II, or III as described above: R R2) R 9 m R7 Z-L- 1 R1 o
R
8 N I R8 R 1 Y O 0 Ix 00 w / / I NN R'o-E R11 R
R
6
R
6 (1) (II) (III) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R
1 is selected from hydrogen, halogen, OR 4 , NO 2 , CN, NR" 4
R
5 , an optionally substituted Ci-C 6 alkyl, an optionally substituted C 1
-C
6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, CO 2 R1 4 , CONRI 4
R"
5 , S0 3
R
4 ,
SO
2
NR
14
R
1 5 and a carboxylic acid bioisostere; -5- WO 2007/062078 PCT/US2006/045129 each R 2 is independently selected from hydrogen, halogen, ORI 4 , NRI 4
R
5 , an optionally substituted Cl-C 6 alkyl, an optionally substituted Cl-C 6 haloalkyl, and an optionally substituted C,-C 6 heteroalkyl;
R
3 and R 4 are independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl;
R
s is selected from hydrogen, halogen, OR 14 , C1-C 6 alkyl, Ci-C 6 haloalkyl,
CI-C
6 heteroalkyl, and Cl -C 6 haloheteroalkyl;
R
6 is selected from an optionally substituted C,-Cto alkyl, an optionally substituted CI-Clo haloalkyl, an optionally substituted CI-Clo heteroalkyl,
(CH
2 )mR , C(O)NHR s , C-CR s , CR =CR 4 R", and CR 3 =R'1 8 ;
R
7 is selected from CO 2
R
1 4 , CONRI 4 R", SO 3
R
14 , SO 2
NRI
4
R
5 and a carboxylic acid bioisostere; each R 8 and each R 9 is independently selected from hydrogen, OR 6 NR6 R 17 , an optionally substituted C,-C 6 alkyl, an optionally substituted C,-C 6 haloalkyl, an optionally substituted C,-C 6 heteroalkyl, (CH 2 )mR1 8 , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R8 and R 9 are linked to form an optionally substituted C 3
-C
8 ring;
R
i 0 is selected from hydrogen, halogen, oxo, OR 6 , NR 6
R
7 , SR 6 , an optionally substituted Ci-C 6 alkyl, an optionally substituted C,-C 6 haloalkyl, and an optionally substituted C,-C 6 heteroalkyl; R" is selected from hydrogen, halogen, OR 14 , NRI 4
R"
5 , and SRI 4 ; or R" and R 4 are linked to form a optionally substituted heterocycle;
R
1 2 is selected from hydrogen, halogen, CI-C 6 alkyl, CI-C 6 haloalkyl, C,
C
6 heteroalkyl, and CI-C 6 haloheteroalkyl;
R
14 is selected from hydrogen, C 1
-C
6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and Cl-C 6 heterohaloalkyl; R1 5 is selected from hydrogen, SO 2
R'
9 , CI-C 6 alkyl, Ci-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI -C 6 heterohaloalkyl;
R
16 and R 1 7 are each independently selected from hydrogen, an optionally substituted C,-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted C,-C 6 heteroalkyl, and (CH 2 )mR 8 ; or one of R 16 and R 1 7 is an optionally substituted C 2
-C
6 alkyl and the other of R' 16 and R 17 is null; or R 1 6 and
R
17 are linked to form an optionally substituted C 3
-C
8 ring; -6- WO 2007/062078 PCT/US2006/045129
R
18 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R' 18 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system;
R'
9 is selected from hydrogen, CI-C 3 alkyl, CI-C 3 haloalkyl, and an optionally substituted aryl; D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; L is NH or null; Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; U is selected from O, NR 4 , CR 3
R
4 , CO, and null; W is selected from O, NR 4 , CR 3
R
4 , CO, and null; X is N or CR 5 ; Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted CI-C 6 alkyl, an optionally substituted Ci-C 6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl; Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6
-C
0 lo aryl and an optionally substituted CI-C 8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 heteroalkyl, and an optionally substituted C]-C 6 haloalkyl, each optionally fused with an optionally substituted C 6
-C
1 0 aryl; .m is 0, 1, 2, or 3; and nis 0 or 1; -7- WO 2007/062078 PCT/US2006/045129 each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, =0, =S, amino, and protected derivatives of amino groups; IN provided that if Y is R"12 oriented in compounds of Formulas I or II to form a dihydropyrazolylene, then: (i) D is not naphthyl if X is N and W is NH, (ii) D is not phenyl if X is CH, W is NH, Z is phenyl, and Rio or R" is -(CH 2 )o-60H,
R
11 -D-Rio (iii) I is not pyrazolyl or optionally substituted 5 hydroxypyrazolyl, and (iv) U is not NH; provided further that if X is N and W is NH, then D is not phenyl; and provided further that if X is N and W is NH in compound of Formula III, then R 6 , R 1 o , and R" do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere. [0007] In certain embodiments, the present invention provides a compound of Formula I, II, or III as described above; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: R' is selected from a halogen, OR 1 4 , NO 2 , CN, NR1 4 R 5 , CI-C 4 alkyl, C 1 C 4 haloalkyl, an optionally substituted CI-C 4 heteroalkyl, CO 2
R
14 , CONRI 4
R
5 ,
SO
3
RI
4 , SO 2 NR' 4
R
5 and a carboxylic acid bioisostere selected from tetrazole,
NHSO
2
R'
9 , OC(S)NRI 4 R , SC(0)NR 4 R", and B AC wherein A, B, and C are each independently selected from 0, S, and NR 20 ; -8- WO 2007/062078 PCT/US2006/045129 each R 2 is independently selected from hydrogen, halogen, OR 4,
NR
4 R1 5 ,
CI-C
4 alkyl, C -C 4 haloalkyl, Ci-C 4 heteroalkyl, and CI-C 4 heterohaloalkyl;
R
3 and R 4 are independently selected from hydrogen, CI-C 4 alkyl, CI-C 4 haloalkyl, and an optionally substituted C,-C 4 heteroalkyl;
R
5 is selected from hydrogen, OR 14 , CI-C 4 alkyl, CI-C 4 haloalkyl, C,-C 4 heteroalkyl, and CI-C 4 haloheteroalkyl;
R
6 is selected from CI-Clo alkyl, CI-Clo haloalkyl, an optionally substituted CI-Clo heteroalkyl, (CH 2 )mR s
'
8 , C(O)NHR' 8 , C-CR" 8 , CR 3
=CR
4 R", and CR 3 =R";
R
7 is selected from CO 2
R
14 , CONRI 4
R'
5 , SO 3
R
1 4 , SO 2
NRI
4 Ri 5 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2
R'
9 , OC(S)NR1 4 Ri,
SC(O)NRI
4
R
5 , and B AC wherein A, B, and C are each independently selected from O, S, and N; each R 8 and each R 9 is independently selected from hydrogen, OR 1 6 , NRi R 17 , Cl-C 4 alkyl, CI-C 4 haloalkyl, an optionally substituted CI-C 4 heteroalkyl, (CH 2 )mR' 1 8 , and null; or R8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3
-C
8 ring; R1 0 is selected from hydrogen, halogen, oxo, CI-C 4 alkyl, CI-C 4 haloalkyl, and an optionally substituted C1-C 4 heteroalkyl; R" is selected from hydrogen, halogen, OR 14 , NR' 4
R
15 , and SRI 4 ; or R" and R 4 are linked to form a optionally substituted heterocycle;
R
1 2 is selected from hydrogen, halogen, C 1
-C
4 alkyl, CI-C 4 haloalkyl, Ci
C
4 heteroalkyl, and CI-C 4 haloheteroalkyl;
R'
3 is selected from hydrogen, halogen, CN, NO 2 , CO 2
R
1 4 , S(O)mR 1 4 , C 1
C
4 alkyl, CI-C 4 haloalkyl, CI-C 4 heteroalkyl, and CI-C 4 haloheteroalkyl;
R
14 is selected from hydrogen, CI-C 4 alkyl, CI-C 4 haloalkyl, CI-C 4 heteroalkyl, and C I-C 4 heterohaloalkyl;
R
is is selected from hydrogen, SO 2
R'
9 , Cl-C 4 alkyl, CI-C 4 haloalkyl, and
CI-C
4 heteroalkyl; -9- WO 2007/062078 PCT/US2006/045129
R
16 and R 17 are each independently selected from hydrogen, Cl-C 4 alkyl,
CI-C
4 haloalkyl, an optionally substituted CI-C 4 heteroalkyl, and (CH 2 )mR' 8 ; or one of R 1 6 and R 17 is C 2
-C
6 alkyl and the other of R1 6 and R1 7 is null; or R1 6 and
R
17 are linked to form an optionally substituted C 4
-C
7 ring;
R
19 is selected from hydrogen, CI-C 3 alkyl, CI-C 3 haloalkyl, and aryl; D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; G is selected from O, S, and NR 14 ; J is selected from O, S, NRI 4 , and CRI 4
R'
5 ; K is O or S; Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; U is selected from O, NR 4 , CR 3
R
4 , CO, and null; W is selected from O, NR 4 , CR 3
R
4 , CO, and null; X is N or CR 5 ; Y is selected from:
R
12 R12 -R 13
-R
13 , R 2 , and K AR , F 1 2 , andk Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6 -Co 10 aryl and an optionally substituted C 1
-C
8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted C 1
-C
6 alkyl, an optionally substituted CI-C 6 heteroalkyl, and an optionally substituted CI-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -Cl0 aryl; m is 0, 1, 2, or 3; and n is 0 or 1; -10- WO 2007/062078 PCT/US2006/045129 N provided that if Y is R 1 2 oriented in compounds of Formulas I or II to form a dihydropyrazolylene, then: (i) D is not naphthyl if X is N and W is NH, (ii) D is not phenyl if X is CH, W is NH, Z is phenyl, and R' 0 or R" is -(CH 2
)
0 -60H, R"i-D-Rio (iii) I is not pyrazolyl or optionally substituted 5 hydroxypyrazolyl, and (iv) U is not NH; provided further that if X is N and W is NH, then D is not phenyl; and provided further that if X is N and W is NH in compound of Formula III, then R 6 , R'o, and R" do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere. [00081 In certain embodiments, the present invention provides a compound of Formula IV, V, or VI as described above:
R
2 R XR 8 R9 .RQ -1 m2, R8 Z-L \ R 1° R12 /Z__8n R7 ORU D 1-"1 N R 9 IR 3 0 -' R3N R6 X.- W R RO R12 W N NR13 N --- 13 Rio-E-R" / I/
R
6
R
6 R (IV) (V) (VI) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: R' is selected from hydrogen, halogen, OR 1 4 , NO 2 , CN, NRI 4
R'
s , an optionally substituted C,-C 6 alkyl, an optionally substituted C,-C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, CO 2
R'
4 , CONR 4
R"
5 , SO 3
R
4 ,
SO
2
NR'
4 Ri 5 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 4
R'
s 5 , an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; -11 - WO 2007/062078 PCT/US2006/045129 R and R 4 are independently selected from hydrogen, an optionally substituted C 1
-C
6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted Cz-C 6 heteroalkyl;
R
5 is selected from hydrogen, halogen, OR 4 , CI-C 6 alkyl, CI-C 6 haloalkyl,
CI-C
6 heteroalkyl, and CI-C 6 haloheteroalkyl;
R
6 is selected from an optionally substituted CI-Co 10 alkyl, an optionally substituted C1-Clo haloalkyl, an optionally substituted Ci-Clo heteroalkyl, (CH2)mR 8 ", C(O)NHR" 8 , CCR", CR 3
=CR
4
R
8 , and CR=R" 8 ;
R
7 is selected from CO 2
R
14 , CONR'1 4
R'
5 , SO 3
R'
4 , SO 2 NR1 4 R " and a carboxylic acid bioisostere; 8 16 each R 8 and each R 9 is independently selected from hydrogen, OR , NR1 6
R
17 , an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted C 1 -Cs heteroalkyl, (CH 2 )mRl 8 , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -Cs ring;
R
1 0 is selected from hydrogen, halogen, oxo, OR" 6 , NR 6
R"
7 , SR' 6 , an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R" is selected from hydrogen, halogen, ORI 4 , NRI 4
R
5 , and SRI4; or R and R 4 are linked to form a optionally substituted heterocycle; R1 2 is selected from hydrogen, halogen, C 1
-C
6 alkyl, CI-C 6 haloalkyl, Ci
C
6 heteroalkyl, and C 1
-C
6 haloheteroalkyl;
R'
13 is selected from hydrogen, halogen, CN, NO 2 , CO 2
R
I4 , S(O)mR 14 , C1
C
4 alkyl, C I-C 4 haloalkyl, C -C 4 heteroalkyl, and CI-C 4 haloheteroalkyl;
R
14 is selected from hydrogen, CI-C 6 alkyl, C,-C 6 haloalkyl, C,-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl; R1 5 is selected from hydrogen, SO 2
R'
9 , CI-C 6 alkyl, C 1
-C
6 haloalkyl, C,-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl;
R
16 and R1 7 are each independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted C 1
-C
6 heteroalkyl, and (CH 2 )mR1 8 ; or one of R1 6 and R 7 is an optionally substituted C 2
-C
6 alkyl and the other of R' 16 and R 1 7 is null; or R 1 6 and
R
17 are linked to form an optionally substituted C 3
-C
8 ring; - 12- WO 2007/062078 PCT/US2006/045129
R
1 8 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R 8 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system; R1 9 is selected from hydrogen, CI-C 3 alkyl, CI-C 3 haloalkyl, and an optionally substituted aryl; D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; L is NH or null; Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; U is selected from O, NR 4 , CR 3
R
4 , CO, and null; W is selected from O, NR 4 , CR 3
R
4 , CO, and null; X is N or CR 5 ; Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6 -CIo aryl and an optionally substituted CI-Cg heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 heteroalkyl, and an optionally substituted C,-C 6 haloalkyl, each optionally fused with an optionally substituted C 6
-C
0 aryl; m is 0, 1, 2, or 3; and n is 0 or 1; each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, - 13- WO 2007/062078 PCT/US2006/045129 hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thioearbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, =O, =S, amino, and protected derivatives of amino groups; provided that if X is N and W is NH, then D is not phenyl; and provided further that if X is N and W is NH in compounds of Formulas VI, then R 6 , R o , and R 1 " do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere. [0009] In certain embodiments, the present invention provides a compound of Formula IV, V, or VI or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: R' is selected from hydrogen, halogen, OR 1 4 , NO 2 , CN, NRI 4 Ri 5 , an optionally substituted CI-C 6 alkyl, an optionally substituted Cj-C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, CO 2
R
4 , CONR 4
R
is ' , SO 3
RI
4 ,
SO
2 NR1 4
R'
15 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2
R'
9 ,
OC(S)NRI
4 Ris, SC(O)NR1 4 R s, and B AAC wherein A, B, and C are each independently selected from O, S, and N; R is selected from hydrogen, halogen, OR 14, NRI 4 R", an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl;
R
7 is selected from CO 2
RI
4 , CONRI 4
R
is , SO 3
R
4 , SOzNRI 4
R'
5 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2
R
9 , OC(S)NR 4
R
s 5 ,
SC(O)NRI
4
R
is , and B AA C wherein A, B, and C are each independently selected from O, S, and N. [001] In certain embodiments, the present invention provides a compound of Formula I, II, II, IV, V, or VI: -14- WO 2007/062078 PCT/US2006/045129 R1 R2) M R9 O"" U RT-Hn Z-L.' DRio RT Z N 1~~R /N8.1 I R N Y R 1 1 R R 6
R
6 (I) (I I) (II I) R ,R 2 )m
R
8 R R Q m R7 Z-L R R/ R O U
R
11 I RN R R 3 ON1-N R3 Ro- R R R R / /
R
6
R
6 RG (IV) (V) (VI) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: R' is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NR1 4 Ris, an optionally substituted C1-C6 alkyl, an optionally substituted C-C6 haloalkyl, an O/ -U4 14 5 14?(""h N R optionally substituted C,-C 6 heteroalkyl, C0 2 R , CONRR', S0 3
R
14
SO
2
NRI
4
R
5 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, ORI 4 , NR 4 R's, an optionally substituted CR-C 6 alkyl, an optionally substituted C-C6 haloalkyl, and an optionally substituted CI-C6 heteroalkyl; R and R 4 are independently selected from hydrogen, an optionally substituted C-C 6 alkyl, an optionally substituted C I-C 6 haloalkyl, and an optionally substituted C l-C 6 heteroalkyl;
R
5 is selected from hydrogen, halogen, OR' 4 , CC6 alkyl, 0-C 6 haloalkyl, C i -C6 heteroalkyl, and C I-C 6 haloheteroalkyl; R is selected from an optionally substituted CI-Clo alkyl, an optionally substituted Cj-C6o haloalkyl, and an optionally substituted C]-Clo heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R 6 is selected from (CH 2 )mR" 8 , C(O)NHR" 8 , C-CR", CR 3
=CRR"
8 , and CR 3 =RI; -15- WO 2007/062078 PCT/US2006/045129
R
7 is selected from CO 2
R
I4 , CONRI 4 R'", SO 3
RI
4 , SO 2
NRI
4
R
i s and a carboxylic acid bioisostere; 16 each R 8 and each R 9 is independently selected from hydrogen, OR , NR6 R 7 , an optionally substituted CI-C 6 alkyl, an optionally substituted C 1
-C
6 haloalkyl, an optionally substituted C 1
-C
6 heteroalkyl, (CH 2 )mRis, and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3
-C
8 ring;
R'
0 is selected from hydrogen, halogen, oxo, OR 6 , NR 6
R
7 , SR 6, an optionally substituted C 1
-C
6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R" is selected from hydrogen, halogen, OR 4 , NRI 4
R
5 , and SRI4; or R1 and R 4 are linked to form a optionally substituted heterocycle;
R
1 2 is selected from hydrogen, halogen, CI-C 6 alkyl, CI-C 6 haloalkyl, C,
C
6 heteroalkyl, and CI-C 6 haloheteroalkyl;
R
3 is selected from hydrogen, halogen, CN, NO 2 , CO 2
RI
4 , S(O)mR I4 , C 1
C
4 alkyl, C,-C 4 haloalkyl, C 1
-C
4 heteroalkyl, and CI-C 4 haloheteroalkyl; R 1 4 is selected from hydrogen, C 1
-C
6 alkyl, C-C 6 haloalkyl, CI-C 6 heteroalkyl, and C I-C 6 heterohaloalkyl; R1 s is selected from hydrogen, SO 2
R
1 9 , CI-C 6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl;
R
16 and R 17 are each independently selected from hydrogen, an optionally substituted Cz-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an-optionally substituted CI-C 6 heteroalkyl, and (CH 2 )mR' 8 ; or one of R 16 and R" 17 is an optionally substituted C 2
-C
6 alkyl and the other of R1 6 and R 17 is null; or R 16 and
R
7 are linked to form an optionally substituted C 3 -Cs ring;
R'
s is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R1 8 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system; R1 9 is selected from hydrogen, CI-C 3 alkyl, CI-C 3 haloalkyl, and an optionally substituted aryl; - 16- WO 2007/062078 PCT/US2006/045129 D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; L is NH or null; Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; U is selected from O, NR 4 , CR 3
R
4 , CO, and null; W is selected from O, NR 4 , CR 3
R
4 , CO, and null; X is N or CR 5 ; Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted C 1
-C
6 alkyl, an optionally substituted CI-C 6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl; Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6
-CI
0 aryl and an optionally substituted CI-C 8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted Ct-C 6 alkyl, an optionally substituted CI-C6 heteroalkyl, and an optionally substituted CI-C 6 haloalkyl, each optionally fused with an optionally substituted C 6
-CI
0 aryl; m is 0, 1, 2, or 3; and n is 0 or 1; provided that, if X is N, W is NH, and Y is not -N=CR 1 2 - orientated to form a dihydropyrazole, and Z or R 6 are not an optionally substituted non aromatic ring fused with an optionally substituted aromatic ring; or if X is N, W is NH, R 6 is alkoxy, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, Y is -N=CR 1 2 - orientated to form a dihydropyrazole, and Z is not an optionally substituted non-aromatic ring fused with an optionally substituted aromatic ring; then D is not a phenyl; -17- WO 2007/062078 PCT/US2006/045129 provided that, if X is N, W is NH, and Y is -N=CRI 2 - orientated to form a dihydropyrazole, then D is not a naphthyl; provided that, if U is NH; or if D and one of R'o and R" form a 5 hydroxypyrazole, X is N, and W is NH; or if E and one of R 1 0 and R 1 form a 5 hydroxypyrazole and X is N, and W is NH; or if E is phenyl, one of R 1 0 or R' 1 is (CH 2 )o 0
-
6 0H, X is C, W is NH, R 6 is an optionally substituted aryl or an optionally substituted heteroaryl, and Z is null, an optionally substituted alkyl, an optionally. substituted aryl, or an optionally substituted heteroaryl; or if E is phenyl, one of
R
i o or R" is -(CH 2
)
0 -60H, X is N, W is NH, Z is null, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, and R 6 is C 1
-C
6 alkyl, Ci-C 6 alkoxy, -(CH 2 )o0-60R 20 , an optionally substituted aryl, an optionally substituted heteroaryl, NR 21
R
2 or a heterocyclic methylene substituent as represented by formula VII; or if D is phenyl, one of R l0 or R" is -(CH 2
)
0
-
6 0H, X is C, W is NH, Z is aromatic, and R 6 is alkoxy, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; then Y is not -N=CR 2 -_ orientated to form a dihydropyrazole;
R
2 0 is selected from hydrogen, a substituted alkyl, a substituted aryl, and a substituted heteroaryl;
R
z ' and R" are each independently selected from hydrogen, alkyl, and aryl; or R 2 1 and R 22 taken together with the nitrogen to which they are attached represent a 5 or 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; B A AC
R
20 -?/v (VII) wherein A, B, C, and V are each independently selected from O, S, and NR20 NR". [0011] In certain embodiments, the invention provides a compound selected from: 3'-{[1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3 ylidenemethyl]amino}-2'-hydroxybiphenyl-3 -carboxylic acid (Compound 101); -18- WO 2007/062078 PCT/US2006/045129 2,4-Dihydroxybenzoic acid N'- { 1-[1-(3,5-dimethylphenyl)-2-oxo-6 trifluoromethyl- 1,2-dihydroindol-3-ylidene]ethyl } hydrazide (Compound 102); 3-{3-[(5-Chloro-2-hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo 2,3-dihydroindol-1l-yl}benzoic acid (Compound 103); 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl}benzoic acid (Compound 104); 3'-{ [1 -(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3 ylidenemethyl]amino} -4-fluoro-2'-hydroxybiphenyl-3-carboxylic acid (Compound 105); 2-(3'- { [1 -(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol 3 -ylidenemethyl]amino}-2'-hydroxybiphenyl-3 -yl)-2-methylpropionic acid (Compound 106); 3'- { [1-(3,4-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3 ylidenemethyl]amino}) -2'-hydroxybiphenyl-3-carboxylic acid (Compound 107); 4-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl}benzoic acid (Compound 108); 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl } benzoic acid (Compound 109); 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl}benzoic acid methyl ester (Compound 1 10); 3- { 3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl}benzoic acid methyl ester (Compound 111); 3-{3-[(5-Fluoro-2-hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo 2,3-dihydroindol-1-yl}benzoic acid (Compound 112); 3- { 3-[1 -(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol 3-ylideneamino]-2-oxo-2,3-dihydrobenzooxazol-7-yl}benzoic acid (Compound 113); 3-{3-[(2-Hydroxy-5,3',4'-trimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol- l-yl}benzoic acid (Compound 114); 3-Hydroxybenzoic acid V- { 1-[1 -(3,5-dimethylphenyl)-2-oxo-6 trifluoromethyl-1,2-dihydroindol-3-ylidene]ethyl } hydrazide (Compound 115); -19- WO 2007/062078 PCT/US2006/045129 1-(3,5-Dimethylphenyl)-3- {1-[2-(4-hydroxyphenyl)-2-oxo ethylamino]ethylidene}-6-trifluoromethyl-1,3-dihydroindol-2-one (Compound 116); 3- {3-[(5-Fluoro-2-hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo 6-trifluoromethyl-2,3-dihydroindol-1-yl } benzoic acid (Compound 117); 3-{3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl}benzoic acid (Compound 118); 3- { 3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol- l-yl}benzoic acid (Compound 119); 3-{3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo 2,3-dihydroindol-1-yl } benzoic acid (Compound 120); 4-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo 2,3-dihydroindol-1-yl } butyric acid (Compound 121); 2-Chloro-3-(4- { [1 -(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2 dihydroindol-3-ylidenemethyl]amino}-3-hydroxyphenyl)acrylic acid (Compound 122); 4-Hydroxybenzoic acid N- { 1-[1I-(3,5-dimethylphenyl)-2-oxo-6 trifluoromethyl-1,2-dihydroindol-3-ylidene]ethyl}hydrazide (Compound 123); 3- {3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-5-nitro-2-oxo 2,3-dihydroindol- I1-yl } benzoic acid (Compound 124); 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo 2,3-dihydroindol- 1-yl} benzoic acid (Compound 125); 3- {3-[(2-Hydroxy-5,3',5'-trimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol- 1-yl}benzoic acid (Compound 126); 4-Aminobenzoic acid N- { 1- [1 -(3,5-dimethylphenyl)-2-oxo-6 trifluoromethyl- 1,2-dihydroindol-3-ylidene]ethyl}hydrazide (Compound 127); 3-(7-{N'-[1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2 dihydroindol-3-ylidene]hydrazino}-1H-indol-3-yl)propionic acid (Compound 128); 4-{3-[N'-(4-Methylbenzoyl)hydrazinomethylidene]-2-oxo-2,3 dihydroindol-l-yl}benzoic acid (Compound 129;) 3- {2-Oxo-6-trifluoromethyl-3-[4-(3-trifluoromethylphenyl)-1H-pyrrol-2 ylmethylidene]-2,3-dihydroindol-1-yl}benzoic acid (Compound 130); - 20- WO 2007/062078 PCT/US2006/045129 3-(7- {N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4 ylidene]hydrazino } - H-indol-3-yl)propionic acid (Compound 131); 3-(3- { [4-(3,4-Dimethylphenyl)thiazol-2-ylamino]methylidene } -2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl)benzoic acid (Compound 132); 3-(3- { [4-(4-Methoxyphenyl)thiazol-2-ylamino]methylene }-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl)benzoic acid (Compound 133); 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylene]-2-oxo-6 trifluoromrnethyl-2,3-dihydroindol-1-yl}benzoic acid (Compound 134); 3-{3-[(4-(4-Methylphenyl)-2-thiazolylamino)methylene]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1l-yl }benzoic acid (Compound 135); 3-{3-[(3,4-Dimethylbenzoylhydrazino)methylidene]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1l-yl}benzoic acid (Compound 136); 3-{3-[(4-Chlorobenzoylhydrazino)methylidene]-2-oxo-6-trifluoromethyl 2,3-dihydroindol-1-yl}berizoic acid (Compound 137); 3-{3-[(4-Methoxybenzoylhydrazino)methylidene]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl}benzoic acid (Compound 138); 3-{3-[(3,4-Dimethylbenzoylhydrazino)methylidene]-2-oxo-6-chloro-2,3 dihydroindol-1-yl}benzoic acid (Compound 139); 1-(3,4-Dimethylphenyl)-3-[1-(2,4 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 140); 1-(3,4-Dimethylphenyl)-3-[1-(4-hydroxybenzoylhydrazino)ethylidene]-2 oxo-2,3-dihydroindole (Compound 141); 1-(3,4-Dimethylphenyl)-3-[(2,4 dihydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 142); 1-(3,5-Dimethylphenyl)-3-[ 1 -(2,4 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 143); 1-(3,5-Dimethylphenyl)-3-[1-(4-hydroxybenzoylhydrazino)ethylidene]-2 oxo-2,3-dihydroindole (Compound 144); 1-(3,5-Dimethylphenyl)-3-[(2,4 dihydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 145); -21 - WO 2007/062078 PCT/US2006/045129 1-(3,5-Dimethylphenyl)-3-[(4-hydroxybenzoylhydrazino)methylidene]-2 oxo-2,3-dihydroindole (Compound 146); 3-(3-[1-(3,4-Dihydroxybenzoylhydrazino)ethylidene]-2-oxo-6-chloro-2,3 dihydroindol-1-yl)benzoic acid (Compound 147); 1-(3,4-Dimethylphenyl)-3-[(4-hydroxybenzoylhydrazino)methylidene]-2 oxo-2,3-dihydroindole (Compound 148); 1-(3,4-Dimethylphenyl)-3-[(3,5-diisopropyl-2 hydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 149); 1-(3,5-Dimethylphenyl)-3-[1-(3,4 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 150); 1-(3,4-Dimethylphenyl)-3-[ 1 -(3,4 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 15 1); 3-(6-Chloro-3-[(2-hydroxy-3,5 dii sopropylbenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindol- I -yl)benzoic acid (Compound 152); 1-(3,4-Dimethylphenyl)-3-[ 1 -(2,5 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 153); 1-(3,4-Dimethylphenyl)-3-[1-(3-nitro-4 hydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 154); 1-(3,4-Dimethylphenyl)-3-[ 1 -(3-aminosulfonyl-4 chlorobenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 155); 1-(3,4-Dimethylphenyl)-3-[1 -(3-amino-4 hydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 156); 1-(3,4-Dimethylphenyl)-3-[1 -(4-methoxy-2 hydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 157); 3-{3-(1-(3,5-Dimethylphenyl)-2-oxo-2,3-dihydro-3 indolidene)methylamino-2-hydroxyphenyl}benzoic acid (Compound 158); 3- { 3 -(3-(3,5-Dimethylphenyl)-2-hydroxyphenyl)aminomethylidene)-2 oxo-2,3-dihydro-1-indolyl}benzoic acid (Compound 159); -22- WO 2007/062078 PCT/US2006/045129 3-{3-(1-(3,4-Dimethylphenyl)-2-oxo-2,3-dihydro-3 indolidene)methylamino-2-hydroxyphenyl}benzoic acid (Compound 160); 4- { 1 -(6-Fluoro-2-oxo-2,3-dihydro-3-(2-(3,5-dimethylphenyl) aminocarbonylphenyl)aminomethylidene)indolyl } butanoic acid (Compound 161); 4- { 1-(6-Chloro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)aminomethylidene)indolyl}butanoic acid (Compound 162); 3-{ 1-(6-Chloro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)aminomethylidene)indolyl}benzoic acid (Compound 163); 4- { 1-(5-Fluoro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)aminomethylidene)indolyl}butanoic acid (Compound 164); 3- {3-(1-(1-(3,5-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-3 indolidene)ethylamino)-2-hydroxyphenyl } benzoic acid (Compound 165); 3- {3-(1-(1-(3,4-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-3 indolidene)ethylamino)-2-hydroxyphenyl }benzoic acid (Compound 166); 3-{ 1-(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(5-chloro-2-hydroxy-3 cyclohexylphenyl)hydrazono)indolyl}benzoic acid (Compound 167); 3- { 1-(5-Fluoro-2-oxo-2,3-dihydro-3-(1 -(5-chloro-2-hydroxy-3 cyclohexylphenyl)amino)ethylidene)indolyl}benzoic acid (Compound 168); 3- { 1-(5-Fluoro-2-oxo-2,3-dihydro-3-(5-chloro-2-hydroxy-3 cyclohexylphenyl)aminomethylidene)indolyl } benzoic acid (Compound 169); 4- {2-Hydroxy-3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,5 dimethylphenyl)indolylidene)methylaminophenyl } butanoic acid (Compound 170); 4- {2-Hydroxy-3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,4 dimethylphenyl)indolylidene)methylaminophenyl } butanoic acid (Compound 171); 3- { 3-(7-(6-Trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5-dimethylphenyl)-3 indolylidene)methylamino)indolyl}propanoic acid (Compound 172); 3-{3-(7-(6-Trifluoromethyl-2-oxo-2,3-dihydro-1 -(3,4-dimethylphenyl)-3 indolylidene)methylamino)indolyl}propanoic acid (Compound 173); 4- {2-Hydroxy-3-(2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolylidene)methylaminophenyl } butanoic acid (Compound 174); - 23 - WO 2007/062078 PCT/US2006/045129 2-Chloro-3- {3-hydroxy-4-(2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolylidene)methylaminophenyl } propenoic acid (Compound 175); 2-Chloro-3-{3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,4 dimethylphenyl)indolylidene)methylaminophenyl } propenoic acid (Compound 176); 2-Ethyl-3-{3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,4 dimethylphenyl)indolylidene)methylaminophenyl}propenoic acid (Compound 177); 2-Ethyl-3-{ 3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolylidene)methylaminophenyl } propenoic acid (Compound 178); 2-Ethyl-3- {3-hydroxy-4-(2-oxo-2,3-dihydro-l1-(3,5 dimethylphenyl)indolylidene)methylaminophenyl } propenoic acid (Compound 179); 4-{2-Hydroxy-3-(4-(2-(3,4-dimethylphenyl)-3-oxo-3,4-dihydro-5 methyl)pyrazolidene)methylaminophenyl}butanoic acid (Compound 180); (Z)-4- { 1 -(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl } butanoic acid (Compound 181); (E)-4- { 1-(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl} butanoic acid (Compound 182); (Z)-3- { 1 -(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl}benzoic acid (Compound 183); (E)-3-{ 1-(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl } benzoic acid (Compound 184); 4- { 3 -(4-Oxo-2-thioxo-5-(3-(3,5-dimethylphenyl)-2 hydroxypheny)hydrozono)thiazolidinyl}butanoic acid (Compound 185); 3- {2-(3-(1 -(3,5-Dimethylphenyl)-6-chloro-2-oxo-2,3 dihydroindolidene)methylamino)phenylamino}benzoic acid (Compound 186); 3- {2-(3-(1-(3,5-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3 dihydroindolidene)methylamino)phenylamino}benzoic acid (Compound 187); 3-{ 2-(4-(2-(3,5-Dimethylphenyl)-5-methyl-3-oxo-3,4 dihydropyrazolidene)methylamino)phenylamino } benzoic acid (Compound 188); - 24 - WO 2007/062078 PCT/US2006/045129 (+)-3-Methyl-5- {2-hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 (3,5-dimethylphenyl)indolylidene)methylamino)phenyl }pentanoic acid (Compound 189); ()-3- { 1 -(6-Chloro-2-oxo-2,3-dihydro-3-(3-(1 -(3,5-dimethylphenyl)-2 oxo-2,3-dihydro)indolyl)aminomethylidene)indolyl} benzoic acid (Compound 190); 3- {4-(3-Hydroxy-6-methyl-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 (3,5-dimethylphenyl)indolyl)hydrazono)pyridinyl }benzoic acid (Compound 191); 3- {4-(3-Hydroxy-6-methyl-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 (3,5-dimethylphenyl)indolidene)methylamino)pyridinyl}benzoic acid (Compound 192); 3-{4-(3-Hydroxy-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1l-(3,5 dimethylphenyl)indolidene)methylamino)pyridinyl } benzoic acid (Compound 193); 3- {4-(3-Hydroxy-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolyl)hydrazono)pyridinyl}benzoic acid (Compound 194); 3-{ 5-(4-Hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,5 dimethylphenyl)indolidene)methylamino)pyridinyl } benzoic acid (Compound 195); 3-(5-(4-Hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,5 dimethylphenyl)indolyl)hydrazono)pyridinyl}benzoic acid (Compound 196); 3- {5-(4-Hydroxy-3-(4-(3-oxo-3,4-dihydro-5-methyl-2-(3,4 dimethylphenyl)pyrazolyl)hydrazono)pyridinyl}benzoic acid (Compound 197); 4- {2-(3-oxo-3,4-dihydro-5-methyl-4-(3-(3,4 dimethylphenyl)phenyl)hydrozono)pyrazolyl}butanoic acid (Compound 198); 3-{2-Amino-5-methyl-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,5 dimethylphenyl)indolylidene)methylamino)phenyl }benzoic acid (Compound 199); 3- { 1-(5-Fluoro-2-oxo-2,3-dihydro-3-(3-(3,4 dimethylphenyl)phenyl)aminomethylidene)indolyl}benzoic acid (Compound 200); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(3-(3,4 dimethylphenyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 201); - 25 - WO 2007/062078 PCT/US2006/045129 (3-(5-Fluoro-2-hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,4 dimethylphenyl)indolidene)methylamino)-l1-pyrazolyl)acetic acid (Compound 202); (3-(5-Fluoro-2-hydroxy-3-(3-(2-oxo-2,3-dihydro- 1-(3,5 dimethylphenyl)indolidene)methylamino)-l1-pyrazolyl)acetic acid (Compound 203); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 204); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 phenyl)ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 205); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(4 methyl)phenyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 206); 4-{2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3 methyl)phenyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 207); 4-{2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 methyl)phenyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 208); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-( 1 naphthyl)ethyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 209); 3- { 1-(5-Nitro-2-oxo-2,3-dihydro-3 -(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)aminomethylidene)indolyl } benzoic acid (Compound 210); 3- { 1-(5-Nitro-2-oxo-2,3-dihydro-3-(5-fluoro-2-hydroxy-3-(3,5 dimethylph'enyl)phenyl)aminomethy1idene)indolyl } benzoic acid (Compound 211); 2-Hydroxy-3-{3-(2-oxo-2,3-dihydro- 1-(3,5 dimethylphenyl)indolidene)methylamino}benzoic acid (Compound 212); 2-Hydroxy-3-{3-(6-trifluoromethyl-2-oxo-2,3-dihydro-1-(3,5 dimethylphenyl)indolidene)methylamino}benzoic acid (Compound 213); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(3-methyl-1 butenyl)phenyl)aminomethylidene)pyrazolyl} butanoic acid (Compound 214); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3 heptanylphenyl)hydrazono)pyrazolyl} butanoic acid (Compound 215); -26- WO 2007/062078 PCT/US2006/045129 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-(4 methyl)phenyl)ethenylphenyl)hydrazono)pyrazolyl } butanoic acid (Compound 216); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-(3 methyl)phenyl)ethenylphenyl)hydrazono)pyrazolyl}butanoic acid (Compound 217); 4- { 1 -(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2 methyl)phenyl)ethylphenyl)hydrazono)indolyl}butanoic acid (Compound 218); 2-{ 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)hydrazono)indolyl} acetic acid (Compound 219); 2-{1 -(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2 methyl)phenyl)ethylphenyl)hydrazono)indolyl}acetic acid (Compound 220); 4- {4-(2-(3-(6-Trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,4 dimethylphenyl)indolylidene)methylamino)thiazolyl } benzoic acid (Compound 221); 3-{ 1-(5-Nitro-2-oxo-2,3-dihydro-3-(2-hydroxy-5-methyl-3-(1 adamantane)phenyl)aminomethylidene)indolyl}benzoic acid (Compound 222); 3- { 1 -(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(4-hydroxy-5-(3,4 dimethylphenyl)pyridinyl)hydrazono)indolyl}benzoic acid (Compound 223); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-(2-methyl)phenyl) ethylphenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 224); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-(2-fl uoro)phenyl) ethylphenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 225); and a pharmaceutically acceptable salt, ester, or prodrug of any of those compounds. [0012] In certain embodiments, the invention provides a compound selected from: 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(1 -naphthyl) ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 226); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(3,5 dimethylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 227); - 27- WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 methoxyphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl }butanoic acid (Compound 228); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-fluoro-3 methyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 229); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-fluoro-3 methyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 230); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(4 phenylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 231); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-cyanophenyl) ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 232); 4- { 2-(5-Methyl-3 -oxo-3,4-dihydro-4(Z)-(2-hydroxy-3 -(2-(2 chlorophenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 233); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 234); 3-{2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 trifluoromethylphenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 235); 3- {2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 fluorophenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 236); 3- { 2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 methyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl }benzoic acid (Compound 237); 3- {(2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,5 dimethyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 238); - 28 - WO 2007/062078 PCT/US2006/045129 3-{2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,6 dimethyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 239); 3- {2-(5-Phenyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,5 dimethylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl} benzoic acid (Compound 240); 3-{2-(5-tert-Butyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,5 dimethylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 241); 3-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 methylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 242); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2-(2 fluorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 243); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 244); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(4-phenylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 245); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methoxyphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 246); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluoro-3 methylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 247); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 trifluoromethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 248); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 cyanophenyl)ethyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 249); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 chlorophenyl)ethyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 250); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 251); - 29 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-ethylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 252); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dichlorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 253); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,5 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 254); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluoro-6 trifluoro-methylphenyl)ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 255); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indanyl)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 256); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indenyl)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 257); (A)-4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-( 1 indanylmethyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 258); ()-3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1 indanylmethyl)phenyl)-hydrazono)pyrazolyl}benzoic acid (Compound 259); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 methylphenyl)ethyl)-phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 260); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluoro-3 methylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 261); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluorophenyl) ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 262); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 263); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dichlorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 264); 3- { 2 -(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methyl-6 trifluoromethylphenyl)ethyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 265); -30- WO 2007/062078 PCT/US2006/045129 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indanyl)phenyl) hydrazono)pyrazolyl}benzoic acid (Compound 266); 3- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indenyl)phenyl) hydrazono)pyrazolyl}benzoic acid (Compound 267); (E)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,4 difluorophenyl)-ethenyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 268); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-4-(3,4-dimethylphenyl) 2-pyridyl)hydrazono)pyrazolyl }benzoic acid (Compound 269); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-6-methyl-4-(3,4 dimethylphenyl)-2-pyridyl)hydrazono)pyrazolyl}butanoic acid (Compound 270); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-2-(3,4-dimethylphenyl) 4-pyridyl)hydrazono)pyrazolyl } benzoic acid (Compound 271); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-2-(3,5-dimethylphenyl) 4-pyridyl)hydrazono)pyrazolyl}benzoic acid (Compound 272); 3-{ 1-(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2 methylphenyl)-ethyl)phenyl)hydrazono)indolyl}benzoic acid (Compound 273); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 benzylphenyl)hydrazono)-pyrazolyl}butanoic acid (Compound 274); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(3 methylphenyl)propyl)-phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 275); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-phenylpropyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 276); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(2 methylphenyl)propyl)-phenyl)hydrazono)pyrazolyl } butanoic ' acid (Compound 277); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,4 difluorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 278); (E)-4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 pyridyl)ethyl)-phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 279); -31- WO 2007/062078 PCT/US2006/045129 4- {2-(5-Methyl-3 -oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-(Z)-ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 280); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 benzofuranyl)phenyl)-hydrazono)pyrazolyl } butanoic acid (Compound 281); (Z)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 bromoethenyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 282); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(3-methyl-1 butenyl)phenyl)-hydrazono)pyrazolyl } butanoic acid (Compound 283); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2 cyclopropylethenyl)-phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 284); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3 methylbutyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 285); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-5-fluoro-3-(3,5 dimethylphenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 286); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,4 dimethylphenyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 287); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(5-chloro-2-hydroxy-3 cyclohexylphenyl)-hydrazono)pyrazolyl } butanoic acid (Compound 288); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)-hydrazono)pyrazolyl} butanoic acid (Compound 289); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)-hydrazono)pyrazolyl } benzoic acid (Compound 290); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(5-chloro-2-hydroxy-3 cyclohexylphenyl)-hydrazono)pyrazolyl }butanoic acid (Compound 291); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,4 dimethylphenyl)phenyl)-hydrazono)pyrazolyl}benzoic acid (Compound 292); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(2 methylphenyl)propyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 293); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 benzofuranyl)phenyl)-hydrazono)pyrazolyl}benzoic acid (Compound 294); - 32- WO 2007/062078 PCT/US2006/045129 4- {2-(5 -Methyl-3 -oxo-2,3 -dihydro-4-(2-hydroxy-3-(3-(2 fluorophenyl)propyl)-phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 295); 3- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3,4 dimethylphenyl)-phenyl)aminomethylidene)pyrazolyl} benzoic acid (Compound 296); 3- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3,5 dimethylphenyl)-phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 297); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3,4 dimethylphenyl)-phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 298); 3-{ l-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)hydrazono)indolyl}propionic acid (Compound 299); 3-{ 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-benzylphenyl)hydrazono) indolyl}benzoic acid (Compound 300); 3- { 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2 methylphenyl)ethyl)phenyl)-hydrazono)indolyl }propionic acid (Compound 301); 3-{ 1-(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(3-(3 methylphenyl)propyl)-phenyl)aminomethylidene)indolyl }benzoic acid (Compound 302); ()-3- { 1 -(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(1,2-dihydro- 1 methyl-2-indolylphenyl)aminomethylidene)indolyl }benzoic acid (Compound 303); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2 methylphenylcarbonyl-amino)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 304); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(5-chloro-2-hydroxy-3-(2 methylphenyl-carbonylamino)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 305); 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(2-(2 fluorophenyl)ethyl)indolylidene)-hydrazinophenyl}benzoic acid (Compound 306); -33 - WO 2007/062078 PCT/US2006/045129 3- {2-Hydroxy-3-(2-oxo-2,3-dihydro- 1 -(2-(2 chlorophenyl)ethyl)indolylidene)-hydrazinophenyl } benzoic acid (Compound 307); 3- {3-Hydroxy-2-(5-methyl-3-oxo-2,3-dihydro-2-(3,4-dimethylphenyl) pyrazolylidene)hydrazino-4-pyridyl}benzoic acid (Compound 308); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methylphenyl) ethyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 309); 3- { 3-Hydroxy-2-(2-oxo-2,3-dihydro- 1-(3,5-dimethylphenyl)-3 indolylidene-hydrazino)-4-pyridyl}benzoic acid (Compound 310); 3-{ 1-(2-Oxo-2,3-dihydro-3-(3-hydroxy-6-methyl-4-(3,4-dimethylphenyl) 2-pyridyl)hydrazono)indolyl}benzoic acid (Compound 311); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-6-methyl-4-(3,4 dimethylphenyl)-2-pyridyl)hydrazono)pyrazolyl}benzoic acid (Compound 312); 3-{ 3-Hydroxy-4-(2-oxo-2,3-dihydro-1 -(3,5-dimethylphenyl)-6 trifluoromethyl-3-indolylidenehydrazino)-2-pyridyl} benzoic acid (Compound 313); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-2-(3,5-dimethylphenyl) 4-pyridyl)hydrazono)pyrazolyl}butanoic acid (Compound 314); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-5-phenyl-2 benzothienyl)-hydrazono)pyrazolyl}butanoic acid (Compound 315); 3-{3-Hydroxy-2-(5-methyl-3-oxo-2,3-dihydro-2-(3,4-dimethylphenyl)-4 pyrazolidene)hydrazino-5-benzothienyl } benzoic acid (Compound 316); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-(2,3 dimethoxycarbonylphenyl)phenyl)-hydrazono)pyrazolyl} butanoic acid (Compound 317); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3,5 diisopropylphenyl)-carbonylhydrazinomethylidene)pyrazolyl } butanoic acid (Compound 318); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)-aminomethylidene)pyrazolyl } butanoic acid (Compound 319); (+)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2,3-dihydro-1 methyl-2-oxo-3-indolyl)methyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 320); - 34 - WO 2007/062078 PCT/US2006/045129 3-{ 1-(2-Oxo-2,3-dihydro-5-fluoro-3-(2-hydroxy-3-(2-(2 methylphenyl)ethyl)phenyl)-hydrazono)indolyl } propionic acid (Compound 321); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,5 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 322); (-)-3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2,3-dihydro-1 methyl-2-oxo-3-indolyl)methyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 323); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1,2-dihydro- 1-methyl 2-oxo-3-indolylidene)methyl)phenyl)hydrazono)pyrazolyl }benzoic acid (Compound 324); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(5-fluoro-2 methylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 325); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(E)-(2-hydroxy-3-(2-(2,4 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 326); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 methylphenyl)hydrazono)-pyrazolyl}benzoic acid (Compound 327); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1,2-dihydro-l1-methyl 2-oxo-3-indolylidene)methyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 328); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(5-fluoro-2 methylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 329); 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 difluorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 330); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6 dimethylphenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 331); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 methylphenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 332); -35 - WO 2007/062078 PCT/US2006/045129 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 (E)-(2-(5-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 333); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(Z)-(2-(5-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 334); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 335); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(4 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 336); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 fluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 337); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-phenylethenyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 338); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-phenylethynyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 339); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 methylphenyl)ethynyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 340); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-ethynyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 341); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 fluorophenyl)ethynyl)-phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 342); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 trifluoromethylphenyl)-ethynyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 343); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 trifluoromethyl-phenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 344); -36 - WO 2007/062078 PCT/US2006/045129 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1-methyl-1-indenyl-2 )phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 345); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,3-dimethyl-2 indenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 346); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-5-methoxy-3-(2 indenyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 347); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(4,7-dimethyl-2 indenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 348); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(4,7-difluoro-2 indenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 349); 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-6-trifluoromethyl-1 -(2-(2 methylphenyl)-ethyl)-3(Z)-indolylidene)methylaminophenyl } benzoic acid (Compound 350); 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-6-trifluoromethyl- 1 -(2-indenyl)-3(Z) indolylidene)methylaminophenyl}benzoic acid (Compound 351); (-b)4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(1,2,3,4 tetrahydro)-naphthyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 352); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy- 3-(2-(3,4-dihydro) naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 353); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(1-indanylidene) methylphenyl)hydrazono)pyrazolyl}butanoic acid (Compound 354); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(5-fluoro-2 trifluoromethylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 355); 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(6-fluoro-2 trifluoro-methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 356); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(6-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 357); 4-.{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(4-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 358); - 37 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 359); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 360); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,5 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 361); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(4-fluoro-2 trifluoro-methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 362); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,4 difluorophenyl)-ethynyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 363); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-( 1 -(1,2,3,4 tetrahydro)-naphthylidene)methylphenyl)hydrazono)pyrazolyl } butanoic acid (Compound 364); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-fluoro-5 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 365); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3,5-dimethyl-4 isoxazolyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 366); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,5-dimethyl-4 isoxazolyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 367); 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro- 1 -(2(E)-(2-methylphenyl)ethenyl) 3(Z)-indolylidene)methylaminophenyl}benzoic acid (Compound 368); 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l1-(2(E)-(2,4-difluorophenyl)ethenyl) 3(Z)-indolylidene)methylaminophenyl}benzoic acid (Compound 369); 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(2-indenyl)-3(Z) indolylidene)methyl-aminophenyl}benzoic acid (Compound 370); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(5-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 371); - 38 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 methylphenyl)hydrazono)-pyrazolyl}butanoic acid (Compound 372); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 indanylidenemethyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 373); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 indanylmethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 374); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,4 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 375); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 376); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(4-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 377); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-fluoro-6 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 378); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,3 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 379); 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,3 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 380); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-fluoro-4 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 381); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 chlorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 382); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6 dichlorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 383); -39- WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3 chlorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 384); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,5 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 385); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-chloro-4 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 386); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 trifluoromethyl-4-fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 387); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,4 dichlorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 388); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-chloromethyl 4-fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 389); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,4 dichloromethylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 390); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro) naphthyl)phenyl)hydrazono)pyrazolyl }benzoic acid (Compound 353); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-8 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 392); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-8 methyl)-naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 393); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-7 methyl)-naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 394); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-7 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 395); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-6 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 396); -40 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-5 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 397); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-8 chloro)-naphthyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 398); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-7 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 399); and a pharmaceutically acceptable salt, ester, or prodrug of any of those compounds. [0013] In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective TPO modulator. In certain such embodiments, a compound Formula I, II, III, IV, V, or VI is a TPO mimic. [00141 In certain embodiments, the invention provides methods for modulating a TPO activity. Certain such methods comprise contacting a cell with one or more compounds of the present invention. Such methods include, but are not limited to, contacting TPO and/or a TPO receptor with one or more compounds of the present invention. [0015] In certain embodiments, the invention provides a method for identifying a compound that is capable of modulating TPO activity comprising: a) contacting a cell capable of a TPO activity with a compound of the present invention; and b) monitoring an effect on the cell. In certain such embodiments, the cell expresses a TPO receptor. [0016] In certain embodiments, the invention provides methods of treating a patient comprising administering to the patient a compound of the present invention. In certain embodiments, such a patient suffers from thrombocytopenia. In certain embodiments, one or more compounds of the present invention are administered to a patient before, during or after chemotherapy, bone marrow transplantation, and/or radiation therapy. In certain embodiments, one or more compounds of the invention are administered to a patient suffering from aplastic anemia, bone marrow failure, and/or idiopathic thrombocytopenia. In certain embodiments, one or more compounds of the present invention are administered to a patient suffering from a disease of the nervous system. In certain embodiments, one or more compounds of the present invention are administered to a patient suffering from amyotrophic lateral sclerosis, multiple sclerosis, or multiple dystrophy. In certain embodiments, one or more compounds of the present -41 - WO 2007/062078 PCT/US2006/045129 invention are administered to a patient with a nerve injury, including, but not limited to, a spinal cord injury. [0017] In certain embodiments, the invention provides pharmaceutical compositions comprising: i) a physiologically acceptable carrier, diluent, or excipient, or a combination thereof; and ii) one or more compounds of the present invention. [00181 In certain embodiments, the invention provides a selective TPO modulator. In certain embodiments, the invention provides a selective TPO receptor agonist. In certain embodiments, the invention provides a selective TPO receptor antagonist. In certain embodiments, the invention provides a selective TPO partial agonist. In certain embodiments, the invention provides a selective TPO receptor binding compound. In certain embodiments, the invention provides a TPO mimic. DETAILED DESCRIPTION [00191 It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "includes," and "included," is not limiting. [0020] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject .matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose. Definitions [0021] Unless specific definitions are provided, the nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard chemical symbols are used interchangeably with the full names represented by such symbols. Thus, for example, the terms "hydrogen" and "H" are understood to have identical meaning. Standard techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., - 42 - WO 2007/062078 PCT/US2006/045129 electroporation, lipofection). Reactions and purification techniques may be performed e.g., using kits according to manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein by reference in its entirety for any purpose. [0022] As used herein, the following terms are defined with the following meanings, unless expressly stated otherwise. [0023] The term "selective binding compound" refers to a compound that selectively binds to any portion of one or more target. [0024] The term "selective TPO receptor binding compound" refers to a compound that selectively binds to any portion of a TPO receptor. [0025] The term "selectively binds" refers to the ability of a selective binding compound to bind to a target receptor with greater affinity than it binds to a non-target receptor. In certain embodiments, selective binding refers to binding to a target with an affinity that is at least 10, 50, 100, 250, 500, or 1000 times greater than the affinity for a non-target. [0026] The term "target receptor" refers to a receptor or a portion of a receptor capable of being bound by a selective binding compound. In certain embodiments, a target receptor is a TPO receptor. [0027] The term "modulator" refers to a compound that alters an activity. For example, a modulator may cause an increase or decrease in the magnitude of a certain activity compared to the magnitude of the activity in the absence of the modulator. In certain embodiments, a modulator is an inhibitor, which decreases the magnitude of one or more activities. In certain embodiments, an inhibitor completely prevents one or more biological activities. In certain embodiments, a modulator is an activator, which increases the magnitude of at least one activity. In certain embodiments the presence of a modulator results in a activity that does not occur in the absence of the modulator. [0028] The term "selective modulator" refers to a compound that selectively modulates a target activity. [00291 The term "selective TPO modulator" refers to a compound that selectively modulates at least one TPO activity. The term selective TPO modulator -43 - WO 2007/062078 PCT/US2006/045129 includes, but is not limited to "TPO mimic" which refers to a compound, the presence of which results in at least one TPO activity. TPO mimics are described in WO 03/103686A1 and WO 01/21180, both of which are incorporated herein by reference in their entirety. [00301 The term "selectively modulates" refers to the ability of a selective modulator to modulate a target activity to a greater extent than it modulates a non-target activity. [0031] The term "target activity" refers to a biological activity capable of being modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, the proliferation and/or differentiation of progenitor cells, generation of platelets, and alleviation of symptoms of a disease or condition. [0032] The term "TPO activity" refers to a biological activity that results, either directly or indirectly from the presence of TPO. Exemplary TPO activities include, but are not limited to, proliferation and or differentiation of progenitor cells to produce platelets; hematopoiesis; growth and/or development of glial cells; repair of nerve cells; and alleviation of thrombocytopenia. [00331 The term "thrombocytopenia" refers to a condition wherein the concentration of platelets in the blood of a patient is below what is considered normal for a healthy patient. In certain embodiments, thrombocytopenia is a platelet count less than 450,000, 400,000, 350,000, 300,000, 250,000, 200,000, 150,000, 140,000, 130,000, 120,000, 110,000, 100,000, 75,000, or 50,000 platelets per microliter of blood. [00341 The term "receptor mediated activity" refers to any biological activity that results, either directly or indirectly, from binding of a ligand to a receptor. [0035] The term "agonist" refers to a compound, the presence of which results in a biological activity of a receptor that is the same as the biological activity resulting from the presence of a naturally occurring ligand for the receptor. 10036] The term "partial agonist" refers to a compound, the presence of which results in a biological activity of a receptor that is of the same type as that resulting from the presence of a naturally occurring ligand for the receptor, but of a lower magnitude. [0037} The term "antagonist" refers to a compound, the presence of which results in a decrease in the magnitude of a biological activity of a receptor. In certain embodiments, the presence of an antagonist results in complete inhibition of a biological activity of a receptor. - 44 - WO 2007/062078 PCT/US2006/045129 [0038] The term "alkyl" refers to an aliphatic hydrocarbon group. An alkyl may be a "saturated alkyl," which means that it does not contain any alkene or alkyne groups. An alkyl group may be an "unsaturated alkyl," which means that it comprises at least one alkene or alkyne group. An alkyl, whether saturated or unsaturated, may be branched or straight chain. Alkyls may be cyclic or non-cyclic. Cyclic alkyls may include multicyclic systemd including fused alkyl rings. Alkyls may be substituted or unsubstituted. Alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, each of which may be optionally substituted. [0039] In certain embodiments, an alkyl comprises 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that an alkyl group may comprise only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the term alkyll" also includes instances where no numerical range of carbon atoms is designated). [0040] The term "lower alkyl" refers to an alkyl comprising 1 to 5 carbon atoms. The term "medium alkyl" refers to an alkyl comprising 5 to 10 carbon atoms. An alkyl may be designated as "CI-C 4 alkyl" or similar designations. By way of example only, "C 1
-C
4 alkyl" indicates an alkyl having one, two, three, or four carbon atoms, e.g., the alkyl is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl, and butynyl. [00411 The term "alkenyl" refers to an alkyl group comprising at least one carbon-carbon double bond. [00421 The term "alkynyl" refers to an alkyl group comprising at least one carbon-carbon triple bond. [00431 The term "haloalkyl" refers to an alkyl in which at least one hydrogen atom is replaced with a halogen atom. In certain of the embodiments in which two or more hydrogen atom are replaced with halogen atoms, the halogen atoms are all the same as one another. In certain of such embodiments, the halogen atoms are not all the same as one another. [0044] The term "heteroalkyl" refers to a group comprising an alkyl and one or more heteroatoms. Certain heteroalkyls are acylalkyls, in which the one or more heteroatoms are within an alkyl chain. Examples of heteroalkyls include, but are not -45 - WO 2007/062078 PCT/US2006/045129 limited to, CH 3
C(=O)CH
2 -, CH 3
C(=O)CH
2
CH
2 -, CH 3
CH
2
C(=O)CH
2
CH
2 -,
CH
3
C(=O)CH
2
CH
2
CH
2 -, CH 3
OCH
2
CH
2 -, CH 3
NHCH
2 -, and the like. [0045] The term "straight-chain alkoxy" refers to a group comprising the formula: -(CH 2 )pO- wherein p is any integer. Straight-chain alkoxy does not include substituted or branched alkoxy groups. [0046] The term "non-straight-chain-alkoxy-heteroalkyl" refers to any heteroalkyl that is not a straight-chain alkoxy heteroalkyl. Thus, for example, non straight-chain-alkoxy heteroalkyls include, but are not limited to: 2,2-isopropyloxy; 1,2 propyloxy; 1,1-ethyloxy; methylamino; ethylamino; propylamino; methylpyrrolidino; and methylpiperidino. [0047] The term "olefin" refers to a C=C bond. [0048] The term "heterohaloalkyl" refers to a heteroalkyl in which at least one hydrogen atom is replaced with a halogen atom. [0049] The term "carbocycle" refers to a group comprising a covalently closed ring, wherein each of the atoms forming the ring is a carbon atom. Carbocylic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycles may be optionally substituted. [0050] The term "heterocycle" refers to a group comprising a covalently closed ring wherein at least one atom forming the ring is a heteroatom. Heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Any number of those atoms may be heteroatoms (i.e., a heterocyclic ring may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms). In heterocyclic rings comprising two or more heteroatoms, those two or more heteroatoms may be the same or different from one another. Heterocycles may be optionally substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom. For example, binding for benzo-fused derivatives, may be via a carbon of the benzenoid ring. Examples of heterocycles include, but are not limited to the following: -46 - WO 2007/062078 PCT/US2006/045129 D D D E E l E E E E D D D D F ~ F F EG G F D E F D "JD I-'E 1,"D l D D D E D E E EE D D D D F F E GF D E D D D -47.- WO 2007/062078 PCT/US2006/045129 E E D, E E E D D D D F'*l F E G _,F j G " F D D D D wherein D, E, F, and G independently represent a heteroatom. Each of D, E, F, and G may be the same or different from one another. [0051] The term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, and phosphorus, but are not limited to those atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may all be the same as one another, or some or all of the two or more heteroatoms may each be different from the others. [0052] The term "aromatic" refers to a group comprising a covalently closed ring having a delocalized n-electron system. Aromatic rings may be formed by five, six, seven, eight, nine, or more than nine atoms. Aromatics may be optionally substituted. Examples of aromatic groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl. The term aromatic includes, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from an aryl, a heteroaryl, a cycloalkyl, a non-aromatic heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a C 1 -6 alkoxy, a C 14 alkyl, a C 1
-
6 hydroxyalkyl, a
C
1 -6 aminoalkyl, a C 14 6 alkylamino, an alkylsulfenyl, an alkylsulfinyl, an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl. In certain embodiments, an aromatic group is substituted at one or more of the para, meta, and/or ortho positions. Examples of aromatic groups comprising substitutions include, but are not limited to, phenyl, 3-halophenyl, 4 -48 - WO 2007/062078 PCT/US2006/045129 halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3 methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4 trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4 morpholin-4-ylphenyl, 4-pyrrolidin-1-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin- 1 -yl)phenyl. [0053] The term "aryl" refers to an aromatic group wherein each of the atoms forming the ring is a carbon atom. Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups may be optionally substituted. 10054] The term "heteroaryl" refers to an aromatic group wherein at least one atom forming the aromatic ring is a heteroatom. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryl groups may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C 3 -8 heterocyclic groups comprising one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms. In certain embodiments, heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci.
6 -alkoxy, Ci6-alkyl, C1-6 hydroxyalkyl, C 1 .6-aminoalkyl, C 1 6 -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O-C 1 6 -alkyl, C 1 6 -alkyl, hydroxy-C 1 -6-alkyl, and amino-CIl- 6 -alkyl. [0055] The term "non-aromatic ring" refers to a group comprising a covalently closed ring that does not have a delocalized t-electron system. [0056] The term "cycloalkyl" refers to a group comprising a non-aromatic ring wherein each of the atoms forming the ring is a carbon atom. Cycloalkyl rings may -49- WO 2007/062078 PCT/US2006/045129 be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Cycloalkyls may include multicyclic systems (e.g., fused ring systems). Cycloalkyls may be optionally substituted. In certain embodiments, a cycloalkyl comprises one or more unsaturated bonds. Examples of cycloalkyls include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, and cycloheptene. [0057] The term "non-aromatic heterocycle" refers to a group comprising a non-aromatic ring wherein one or more atoms forming the ring is a heteroatom. Non aromatic heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Non-aromatic heterocycles may be optionally substituted. In certain embodiments, non-aromatic heterocycles comprise one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups. Examples of non-aromatic heterocycles include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H- 1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3 dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane. [0058] The term "arylalkyl" refers to a group comprising an aryl group bound to an alkyl group. [0059] The term "carbocycloalkyl" refers to a group comprising a carbocyclic cycloalkyl ring. Carbocycloalkyl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycloalkyl groups may be optionally substituted. [0060] The term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and cycloalkyls), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., cycloalkyls and non-aromatic heterocycles). Rings may be optionally substituted. Rings may form part of a ring system. - 50- WO 2007/062078 PCT/US2006/045129 [0061] The term "ring system" refers to a either a single ring or two or more rings, wherein, if two or more rings are present, the two or more of the rings are fused. The term "fused" refers to structures in which two or more rings share one or more bonds. [0062] The term "carboxylic acid bioisostere" refers to a group that is biologically equivalent to a carboxylic acid. For example, carboxylic acid bioisosteres include, but are not limited to, tetrazole, NHSO 2
R"
5 , OC(S)NR'ioR", SC(O)NR'oR", thiazolidinedione, oxazolidinedione, and 1-oxa-2,4-diazolidine-3,5-dione. In certain embodiments, a carboxylic acid bioisoster comprises the following structure: B AC )-4\0 wherein A, B, and C are each independently selected from O, S, and N. [0063] The term "spacer" refers to an atom or group of atoms that separate two or more groups from one another by a desired number of atoms. For example, in certain embodiments, it may be desirable to separate two or more groups by one, two, three, four, five, six, or more than six atoms. In such embodiments, any atom or group of atoms may be used to separate those groups by the desired number of atoms. Spacers are optionally substituted. In certain embodiments, a spacer comprises saturated or unsaturated alkyls, heteroalkyls and/or haloalkyls. In certain embodiments, a spacer comprises atoms that are part of a ring. [0064] Solely for the purposes of illustration, and without limiting the above definition, some examples of spacers are provided. Examples of 1 atom spacers include, but are not limited to, the following: A BA B A B where A and B represent groups which are separated by the desired number of atoms. Examples of 2 atom spacers include, but are not limited to, the following: B B B A A A A' A B B where A and B represent groups which are separated by the desired number of atoms. [00651 Examples of 3 atom spacers include, but are not limited to, the following: -51 - WO 2007/062078 PCT/US2006/045129 R ABA B B A A where A and B represent groups which are separated by the desired number of atoms. As is evident from the above examples, the atoms that create the desired separation may themselves be part of a group. That group may be, for example, an alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, or substituted alkyl all of which are optionally substituted. Thus the term "1 5 atom spacer" refers to a spacer that separates two groups by 1, 2, 3, 4, or 5 atoms and does not indicate the total size of the group that constitutes the spacer. [0066] As used herein, the term "linked to form a ring" refers to instances where two atoms that are bound either to a single atom or to atoms that are themselves ultimately bound, are each bound to a linking group, such that the resulting structure forms a ring. That resulting ring comprises the two atoms that are linked to form a ring, the atom (or atoms) that previously linked those atoms, and the linker. For example, if A and B below are "linked to form a ring" A B /\ the resulting ring includes A, B, C, and a linking group. Unless otherwise indicated, that linking group may be of any length and may be optionally substituted. Referring to the above example, resulting structures include, but are not limited to: \ R / R Y R X ZRR\XR R/ R A B A B A A B A B A B \c c \ / \/ ;; ;/\. /\; /C\ , and the like. [0067] In certain embodiments, the two substituents that together form a ring are not immediately bound to the same atom. For example, if A and B, below, are linked to form a ring: - 52- WO 2007/062078 PCT/US2006/045129 A B the resulting ring comprises A, B, the two atoms that already link A and B and a linking group. Examples of resulting structures include, but are not limited to: A B A B and the like. 10068] In certain embodiments, the atoms that together form a ring are separated by three or more atoms. For example, if A and B, below, are linked to form a ring: A B , the resulting ring comprises A, B, the 3 atoms that already link A and B, and a linking group. Examples of resulting structures include, but are not limited to: A\B , and the like. [0069] As used herein, the term "together form a bond" refers to the instance in which two substituents to neighboring atoms are null the bond between the neighboring atoms becomes a double bond. For example, if A and B below "together form a bond" A B Rx R Y the resulting structure is: RX RY 100701 The term "null" refers to a group being absent from a structure. For R' X, R" example, in the structure "'- '', where in certain instances X is N, if X is N, one of R' or R" is null, meaning that only three groups are bound to the N. 10071] The substituent "R" appearing by itself and without a number designation refers to a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl - 53 - WO 2007/062078 PCT/US2006/045129 (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon). [0072] The term "O-carboxy" refers to a group of formula RC(=O)O-. [0073] The term "C-carboxy" refers to a group of formula -C(=O)OR. [0074] The term "acetyl" refers to a group of formula -C(=O)CH 3 . [0075] The term "trihalomethanesulfonyl" refers to a group of formula
X
3
CS(=O)
2 - where X is a halogen. [0076] The term "cyano" refers to a group of formula -CN. [0077] The term "isocyanato" refers to a group of formula -NCO. [0078] The term "thiocyanato" refers to a group of formula -CNS. [00791 The term "isothiocyanato" refers to a group of formula -NCS. [00801 The term "sulfonyl" refers to a group of formula -S(=0)-R. [0081] The term "S-sulfonamido" refers to a group of formula -S(=0) 2 NR. [0082] The term "N-sulfonamido" refers to a group of formula RS(=O) 2 NH-. [0083] The term "trihalomethanesulfonamido" refers to a group of formula
X
3
CS(=O)
2 NR-. [00841 The term "O-carbamyl" refers to a group of formula -OC(=O)-NR. [0085] The term "N-carbamyl" refers to a group of formula ROC(=O)NH-. [0086] The term "O-thiocarbamyl" refers to a group of formula -OC(=S)-NR. [0087] The term "N-thiocarbamyl" refers to a group of formula ROC(= S)NH-. 10088] The term "C-amido" refers to a group of formula -C(=O)-NR 2 . [0089] The term "N-amido" refers to a group of formula RC(=O)NH-. [0090] The term "oxo" refers to a group of formula =0. [0091] The term "dihydropyrazolylene" refers to a di-radical of an optionally substituted dihydropyrazole ring, wherein the dihydropyrazole ring has the structure: NH >NH and wherein the two radicals may be at any positions on the ring. [00921 The term "pyrazolyl" refers to a radical of a pyrzole ring, wherein the pyrzole ring has the structure: NH and wherein the radical may be at any position on the ring. - 54 - WO 2007/062078 PCT/US2006/045129 [0093] The term "ester" refers to a chemical moiety with formula -(R)n-COOR', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon), where n is 0 or 1. [0094] The term "amide" refers to a chemical moiety with formula -(R)n-C(0)NHR' or -(R)n-NHC(O)R', where R and R' are independently selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), where n is 0 or 1. In certain embodiments, an amide may be an amino acid or a peptide. [0095] The terms "amine," "hydroxy," and "carboxyl" include such groups that have been esterified or amidified. Procedures and specific groups used to achieve esterification and amidification are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety. [0096] Unless otherwise indicated, the term "optionally substituted," refers to a group in which none, one, or more than one of the hydrogen atoms has been replaced with one or more group(s) individually and independently selected from: alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives of amino groups. Such protective derivatives (and protecting groups that may form such protective derivatives) are known to those of skill in the art and may be found in references such as Greene and Wuts, above. In embodiments in which two or more hydrogen atoms have been substituted, the substituent groups may together form a ring. (00971 Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds. [0098] The term "carrier" refers to a compound that facilitates the incorporation of another compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier for improving incorporation of certain organic compounds into cells or tissues. - 55 - WO 2007/062078 PCT/US2006/045129 [00991 The term "pharmaceutical agent" refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a patient. In certain embodiments, a pharmaceutical agent comprises an active agent, which is the agent that induces the desired therapeutic effect. In certain embodiments, a pharmaceutical agent comprises a prodrug. In certain embodiments, a pharmaceutical agent comprises inactive ingredients such as carriers, excipients, and the like. [0100] The term "therapeutically effective amount" refers to an amount of a pharmaceutical agent sufficient to achieve a desired therapeutic effect. [0101] The term "prodrug" refers to an pharmaceutical agent that is converted from a less active form into a corresponding more active form in vivo. [01021 The term "pharmaceutically acceptable" refers to a formulation of a compound that does not significantly abrogate the biological activity, a pharmacological activity and/or other properties of the compound when the formulated compound is administered to a patient. In certain embodiments, a pharmaceutically acceptable formulation does not cause significant irritation to a patient. [0103] The term "co-administer" refers to administering more than one pharmaceutical agent to a patient. In certain embodiments, co-administered pharmaceutical agents are administered together in a single dosage unit. In certain embodiments, co-administered pharmaceutical agents are administered separately. In certain embodiments, co-administered pharmaceutical agents are administered at the same time. In certain embodiments, co-administered pharmaceutical agents are administered at different times. [0104] The term "patient" includes human and animal subjects. [0105] The term "substantially pure" means an object species (e.g., compound) is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition). In certain embodiments, a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all species present. In certain embodiments, a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all species present in the composition. In certain embodiments, the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single species. - 56- WO 2007/062078 PCT/US2006/045129 10106] The term "tissue-selective" refers to the ability of a compound to modulate a biological activity in one tissue to a greater or lesser degree than it modulates a biological activity in another tissue. The biological activities in the different tissues may be the same or they may be different. The biological activities in the different tissues may be mediated by the same type of target receptor. For example, in certain embodiments, a tissue-selective compound may modulate receptor mediated biological activity in one tissue and fail to modulate, or modulate to a lesser degree, receptor mediated biological activity in another tissue type. [01071 The term "monitoring" refers to observing an effect or absence of any effect. In certain embodiments, one monitors cells after contacting those cells with a compound of the present invention. Examples of effects that may be monitored include, but are not limited to, changes in cell phenotype, cell proliferation, receptor activity, or the interaction between a receptor and a compound known to bind to the receptor. [01081 The term "cell phenotype" refers to physical or biological characteristics. Examples of characteristics that constitute phenotype included, but are not limited to, cell size, cell proliferation, cell differentiation, cell survival, apoptosis (cell death), or the utilization of a metabolic nutrient (e.g., glucose uptake). Certain changes or the absence of changes in cell phenotype are readily monitored using techniques known in the art. [0109] The term "cell proliferation" refers to the rate at which cells divide. In certain embodiments, cells are in situ in an organism. In certain embodiments, cell are grown in vitro in a vessel. The number of cells growing in a vessel can be quantified by a person skilled in the art (e.g., by counting cells in a defined area using a microscope or by using laboratory apparatus that measure the density of cells in an appropriate medium). One skilled in that art can calculate cell proliferation by determining the number of cells at two or more times. [0110] The term "contacting" refers to bringing two or more materials into close enough proximity that they may interact. In certain embodiments, contacting can be accomplished in a vessel such as a test tube, a petri dish, or the like. In certain embodiments, contacting may be performed in the presence of additional materials. In certain embodiments, contacting may be performed in the presence of cells. In certain of such embodiments, one or more of the materials that are being contacted may be inside a cell. Cells may be alive or may dead. Cells may or may not be intact. Certain compounds - 57- WO 2007/062078 PCT/US2006/045129 [0111] Certain compounds that modulate one or more TPO activity andlor bind to TPO receptors play a role in health. In certain embodiments, compounds of the present invention are useful for treating any of a variety of diseases or conditions. [0112] In certain embodiments, the present invention provides selective TPO modulators. In certain embodiments, the invention provides selective TPO receptor binding agents. In certain embodiments, the invention provides methods of making and methods of using selective TPO modulators and/or selective TPO receptor binding agents. In certain embodiments, selective TPO modulators are agonists, partial agonists, and/or antagonists for the TPO receptor. [0113] In certain embodiments, the present invention relates to compounds of Formula I, II, III, IV, V, or VI: RI- IR2) M RR R 9 O. R7- Rio R -i-n Z\ U -UR2 Z-L- DR R 8 N R R 8 RiW, y 0 Ix o 0 w N N Rio-E Rl / ,/ R R 6
R
6 (I) (II) (rIII R2m R
R
8 R R - R R R Z
R
9 D X / O URil-I 1 0
R
3 N IR x oR R R12 W N - 13 N -R 13 RIO -E! - R l /R I
R
6
R
6
R
6 (IV) (V) (VI) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof. [0114] In certain embodiments, R 1 is selected from hydrogen, halogen, OR 4
NO
2 , CN, NRI 4 R 5 , an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, CO 2
RI
4 , CONRI 4 Ri 5 , SO 3
R
14 ,
SO
2 NR1 4
R
is and a carboxylic acid bioisostere. In certain such embodiments, the carboxylic acid bioisostere is selected from tetrazole, NHSO 2
R'
9 , OC(S)NR 4
R
is ,
SC(O)NRI
4 Ri s, and -58 - WO 2007/062078 PCT/US2006/045129 B AAC wherein A, B, and C are each independently selected from O, S, and N. [0115] In certain embodiments, each R 2 is independently selected from hydrogen, halogen, OR 14 , NR1 4
R"
5 , an optionally substituted Ci-C 6 alkyl, an optionally substituted C,-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl. [0116] In certain embodiments, R 3 and R 4 are independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted C 1
-C
6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl. [01171 In certain embodiments, R 5 is selected from a group of hydrogen, halogen, OR 1 4 , CI-C 6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and C1-C 6 haloheteroalkyl. [0118] In certain embodiments, R 6 is selected from an optionally substituted C,-Co alkyl, an optionally substituted CI-CI 0 haloalkyl, or an optionally substituted C, Clo heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R 6 is (CH 2 )mR 1 8 or C(O)NHR 1 8 . In certain embodiments, R 6 is selected from an optionally substituted CI-Clo alkyl, an optionally substituted Ci-CI 0 haloalkyl, and an optionally substituted CI-C, 0 heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R 6 is selected from (CH 2 )mR"', C(O)NHR" 8 , C-CR" 8 ,
CR
3
=CR
4 R", and CR 3 =R8"; (01191 In certain embodiments, R 7 is selected from CO 2
R
4 , CONR 4
R
s 5 ,
SO
3
R)
4 , SO 2
NR
4
R'
5 and a carboxylic acid bioisostere. In certain such embodiments, the carboxylic bioisostere is selected from tetrazole, NHSO 2
R'
9 , OC(S)NR1 4 R", SC(0)NR 4
R
I
'
s , and B AAC wherein A, B, and C are each independently selected from O, S, and N. 101201 In certain embodiments, each R 8 and each R 9 is independently selected from hydrogen, OR' 6 , NR1 6
R
17 , an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted C,-C 6 heteroalkyl, (CH 2 )mR"', and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3
-C
8 ring. - 59 - WO 2007/062078 PCT/US2006/045129 [01211 In certain embodiments, R'o is selected from hydrogen, halogen, oxo, OR 6 , NR6 R 17 , SR 6 , an optionally substituted CI-C 6 alkyl, an optionally substituted Cj
C
6 haloalkyl, and an optionally substituted C -C 6 heteroalkyl. [0122] In certain embodiments, R 1 1 is selected from hydrogen, halogen, OR 14 ,
NRI
4
R
5 , and SRI4. In certain embodiments, R" and R4 are linked to form a optionally substituted heterocycle. [0123] In certain embodiments, RI 2 is selected from hydrogen, halogen, C 1
-C
6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and C,-C 6 haloheteroalkyl. [0124] In certain embodiments, R 1 3 is selected from hydrogen, halogen, CN,
NO
2 , CO 2
R
1 4 , S(O)mR' 1 4 , C,-C 4 alkyl, CI-C 4 haloalkyl, CJ-C 4 heteroalkyl, and CI-C 4 haloheteroalkyl. 10125] In certain embodiments, R 14 is selected from hydrogen, CI-C 6 alkyl,
CI-C
6 haloalkyl, C,-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl. [0126] In certain embodiments, R 1 5 is selected from hydrogen, SO 2
R
w 9 , C 1
-C
6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and Cz-C 6 heterohaloalkyl. (0127] In certain embodiments, R' 16 and R1 7 are each independently selected from hydrogen, an optionally substituted C 1
-C
6 alkyl, an optionally substituted C,-C 6 haloalkyl, an optionally substituted C,-C 6 heteroalkyl, and (CH 2 )mRu'. In certain embodiments, one of R 16 and R 17 is an optionally substituted C2-C6 alkyl and the other of R1 6 and R 17 is null. In certain embodiments, R 16 and R' 7 are linked to form an optionally substituted C 3
-C
8 ring. (0128] In certain embodiments, R 18 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R1 8 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system. (0129] In certain embodiments, R 19 is selected from hydrogen, C 1
-C
3 alkyl,
CI-C
3 haloalkyl, and an optionally substituted aryl. 10130] In certain embodiments, D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle. 10131] In certain embodiments, E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle. - 60- WO 2007/062078 PCT/US2006/045129 10132] In certain embodiments, L is NH or null. (0133] In certain embodiments, Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle. 10134] In certain embodiments, U is selected from O, NR 4 , CR 3
R
4 , CO, and null. 10135] In certain embodiments, W is selected from O, NR 4 , CR 3
R
4 , CO, and null. (0136] In certain embodiments, X is N or CR 5 . [01371 In certain embodiments, Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted CI-C 6 alkyl, an optionally substituted Cz-C 6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted N heteroaryl. In certain embodiments, if Y is AR 12 oriented in compounds of Formulas I or II to form a dihydropyrazolylene, then: (i) D is not naphthyl if X is N and W is NH, (ii) D is not phenyl if X is CH, W is NH, Z is phenyl, and R 0 io or R" is -(CH 2
)
0 -6OH, (iii)
R
11
-D-R
10 I is not pyrazolyl or optionally substituted 5-hydroxypyrazolyl, and (iv) U is not NH. In certain embodiments, if X is N and W is NH, then D is not phenyl. [0138] In certain embodiments, Z is selected from null, a 2-5 atom spacer selected from an optionally substituted C 6
-C
0 lo aryl and an optionally substituted CI-C 8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 heteroalkyl, and an optionally substituted CI-C 6 haloalkyl, each optionally fused with an optionally substituted C 6
-C
0 aryl. [01391 In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 0, 1, 2, or 3. [0140] In certain embodiments n is 0 or 1. [01411 In certain embodiments, if X is N and W is NH in compounds of Formulas III or VI, then R 6 , R'o, and R" do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere. [0142] In embodiments in which two or more of a particular group are present, the identities of those two or more particular groups are selected independently -61 - WO 2007/062078 PCT/US2006/045129 and, thus, may be the same or different from one another. For example, certain compounds of the invention comprise two or more R 14 groups. The identities of those two or more R 14 groups are each selected independently. Thus, in certain embodiments, those R1 4 groups are all the same as one another; in certain embodiments, those R 1 4 groups are all different from one another; and in certain embodiments, some of those R 4 groups are the same as one another and some are different from one another. This independent selection applies to any group that is present in a compound more than once. [0143] In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective TPO modulator. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective TPO receptor agonist. In certain embodiments, a compound of Formula 1, II, Ill, IV, V, or VI is a selective TPO receptor antagonist. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective TPO receptor partial agonist. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a tissue-specific selective TPO modulator. In certain embodiments, a compound of Formula I, II, III, IV, V, or VI is a selective TPO receptor binding compound. In certain embodiments, a compound Formula I, II, III, IV, V, or VI is a TPO mimic. [0144] In certain embodiments, the invention provides compounds selected from: 3'- { [1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3 ylidenemethyl]amino }-2'-hydroxybiphenyl-3-carboxylic acid (Compound 101); 2,4-Dihydroxybenzoic acid N'-{ 1-[1-(3,5-dimethylphenyl)-2-oxo-6 trifluoromethyl- 1,2-dihydroindol-3-ylidene]ethyl}hydrazide (Compound 102); 3-{ 3-[(5-Chloro-2-hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo 2,3-dihydroindol- 1-yl}benzoic acid (Compound 103); 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol- 1-yl}benzoic acid (Compound 104); 3'- { [1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3 ylidenemethyl] amino} -4-fluoro-2'-hydroxybiphenyl-3-carboxylic acid (Compound 105); 2-(3'- { [1 -(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol 3-ylidenemethyl]amino}-2'-hydroxybiphenyl-3-yl)-2-methylpropionic acid (Compound 106); 3'- { [1 -(3,4-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3 ylidenemethyl]amino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 107); - 62 - WO 2007/062078 PCT/US2006/045129 4-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl}benzoic acid (Compound 108); 3- { 3- [(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl}benzoic acid (Compound 109); 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl}benzoic acid methyl ester (Compound 110); 3- {3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl}benzoic acid methyl ester (Compound 111); 3-{3-[(5-Fluoro-2-hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo 2,3-dihydroindol-1 -yl}benzoic acid (Compound 112); 3- {3-[1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl- 1,2-dihydroindol 3-ylideneamino]-2-oxo-2,3-dihydrobenzooxazol-7-yl } benzoic acid (Compound 113); 3- {3-[(2-Hydroxy-5,3',4'-trimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl}benzoic acid (Compound 114); 3-Hydroxybenzoic acid N'- { 1-[1-(3,5-dimethylphenyl)-2-oxo-6 trifluoromethyl-1,2-dihydroindol-3-ylidene]ethyl } hydrazide (Compound 115); 1-(3,5-Dimethylphenyl)-3-{ 1 -[2-(4-hydroxyphenyl)-2-oxo ethylamino]ethylidene}-6-trifluoromethyl- 1,3-dihydroindol-2-one (Compound 116); 3- {3-[(5-Fluoro-2-hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo 6-trifluoromethyl-2,3-dihydroindol-1 -yl}benzoic acid (Compound 117); 3- {3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl } benzoic acid (Compound 118); 3-{3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl} benzoic acid (Compound 119); 3- {3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo 2,3-dihydroindol- 1-yl } benzoic acid (Compound 120); 4-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo 2,3-dihydroindol- 1 -yl}butyric acid (Compound 121); 2-Chloro-3-(4- { [1-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl- 1,2 dihydroindol-3-ylidenemethyl]amino } -3-hydroxyphenyl)acrylic acid (Compound 122); - 63 - WO 2007/062078 PCT/US2006/045129 4-Hydroxybenzoic acid N- { 1-[1 -(3,5-dimethylphenyl)-2-oxo-6 trifluoromethyl- 1,2-dihydroindol-3-ylidene]ethyl}hydrazide (Compound 123); 3- {3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-5-nitro-2-oxo 2,3-dihydroindol-1-yl} benzoic acid (Compound 124); 3- {3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo 2,3-dihydroindol-1-yl}benzoic acid (Compound 125); 3- {3-[(2-Hydroxy-5,3',5'-trimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl}benzoic acid (Compound 126); 4-Aminobenzoic acid N- { 1-[1-(3,5-dimethylphenyl)-2-oxo-6 trifluoromethyl-1,2-dihydroindol-3-ylidene]ethyl} hydrazide (Compound 127); 3-(7- {N'-[1 -(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl- 1,2 dihydroindol-3-ylidene]hydrazino } -1 H-indol-3-yl)propionic acid (Compound 128); 4-{3-[N'-(4-Methylbenzoyl)hydrazinomethy1idene]-2-oxo-2,3 dihydroindol- 1-yl } benzoic acid (Compound 129;) 3-{ 2-Oxo-6-trifluoromethyl-3-[4-(3-trifluoromethylphenyl)- 1 H-pyrrol-2 ylmethylidene]-2,3-dihydroindol-1-yl } benzoic acid (Compound 130); 3-(7-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4 ylidene]hydrazino}-1H-indol-3-yl)propionic acid (Compound 131); 3-(3-{[4-(3,4-Dimethylphenyl)thiazol-2-ylamino]methylidene}-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl)benzoic acid (Compound 132); 3-(3-{ [4-(4-Methoxyphenyl)thiazol-2-ylamino]methylene} -2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl)benzoic acid (Compound 133); 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylene]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl } benzoic acid (Compound 134); 3- { 3- [(4-(4-Methylphenyl)-2-thiazolylamino)methylene]-2-oxo-6 trifluoromethyl-2,3-dihydroindol- 1-yl } benzoic acid (Compound 135); 3- {3-[(3,4-Dimethylbenzoylhydrazino)methylidene]-2-oxo-6 trifluoromethyl-2,3-dihydroindol- l-yl}benzoic acid (Compound 136); 3- {3-[(4-Chlorobenzoylhydrazino)methylidene]-2-oxo-6-trifluoromethyl 2,3-dihydroindol-1-yl}benzoic acid (Compound 137); 3-{3-[(4-Methoxybenzoylhydrazino)methylidene]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-i-yl}benzoic acid (Compound 138); - 64 - WO 2007/062078 PCT/US2006/045129 3-{3-[(3,4-Dimethylbenzoylhydrazino)methylidene]-2-oxo-6-chloro-2,3 dihydroindol-1l-yl}benzoic acid (Compound 139); 1-(3,4-Dimethylphenyl)-3-[1-(2,4 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 140); 1-(3,4-Dimethylphenyl)-3-[1-(4-hydroxybenzoylhydrazino)ethylidene]-2 oxo-2,3-dihydroindole (Compound 141); 1-(3,4-Dimethylphenyl)-3-[(2,4 dihydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 142); 1-(3,5-Dimethylphenyl)-3-[1l-(2,4 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 143); 1-(3,5-Dimethylphenyl)-3-[1-(4-hydroxybenzoylhydrazino)ethylidene]-2 oxo-2,3-dihydroindole (Compound 144); 1-(3,5-Dimethylphenyl)-3-[(2,4 dihydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 145); 1-(3,5-Dimethylphenyl)-3- [(4-hydroxybenzoylhydrazino)methylidene]-2 oxo-2,3-dihydroindole (Compound 146); 3-(3-[1-(3,4-Dihydroxybenzoylhydrazino)ethylidene]-2-oxo-6-chloro- 2 ,3 dihydroindol-1-yl)benzoic acid (Compound 147); 1-(3,4-Dimethylphenyl)-3-[(4-hydroxybenzoylhydrazino)methylidene]-2 oxo-2,3-dihydroindole (Compound 148); 1-(3,4-Dimethylphenyl)-3-[(3,5-diisopropyl-2 hydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 149); 1-(3,5-Dimethylphenyl)-3-[1-(3,4 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 150); 1-(3,4-Dimethylphenyl)-3-[1-(3,4 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 151); -65- WO 2007/062078 PCT/US2006/045129 3-(6-Chloro-3-[(2-hydroxy-3,5 diisopropylbenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindol- I -yl)benzoic acid (Compound 152); 1-(3,4-Dimethylphenyl)-3-[1-(2,5 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 153); 1-(3,4-Dimethylphenyl)-3-[1 -(3-nitro-4 hydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 154); 1-(3,4-Dimethylphenyl)-3-[1 -(3 -amino sulfonyl-4 chlorobenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 155); 1-(3,4-Dimethylphenyl)-3 - [1-(3-amino-4 hydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 156); 1-(3,4-Dimethylphenyl)-3-[1-(4-methoxy-2 hydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 157); 3-{3-(1-(3,5-Dimethylphenyl)-2-oxo-2,3-dihydro-3 indolidene)methylamino-2-hydroxyphenyl} benzoic acid (Compound 158); 3- {3-(3-(3,5-Dimethylphenyl)-2-hydroxyphenyl)aminomethylidene)-2 oxo-2,3-dihydro- 1 -indolyl } benzoic acid (Compound 159); 3-{3-(1-(3,4-Dimethylphenyl)-2-oxo-2,3-dihydro-3 indolidene)methylamino-2-hydroxyphenyl} benzoic acid (Compound 160); 4- { 1 -(6-Fluoro-2-oxo-2,3-dihydro-3-(2-(3,5-dimethylphenyl) aminocarbonylphenyl)aminomethylidene)indolyl} butanoic acid (Compound 161); 4-{ 1-(6-Chloro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)amrninomethylidene)indolyl}butanoic acid (Compound 162); 3- { 1-(6-Chloro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)aminomethylidene)indolyl }benzoic acid (Compound 163); 4- { 1-(5-Fluoro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)amrninomethylidene)indolyl}butanoic acid (Compound 164); 3-{3-(1-(1-(3,5-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-3 indolidene)ethylamino)-2-hydroxyphenyl} benzoic acid (Compound 165); 3- {3-(1-(1-(3,4-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-3 indolidene)ethylamino)-2-hydroxyphenyl}benzoic acid (Compound 166); 3-{ 1-(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(5-chloro-2-hydroxy-3 cyclohexylphenyl)hydrazono)indolyl}benzoic acid (Compound 167); - 66 - WO 2007/062078 PCT/US2006/045129 3- { 1-(5-Fluoro-2-oxo-2,3-dihydro-3-(1-(5-chloro-2-hydroxy-3 cyclohexylphenyl)amino)ethylidene)indolyl}benzoic acid (Compound 168); 3- { 1-(5-Fluoro-2-oxo-2,3-dihydro-3-(5-chloro-2-hydroxy-3 cyclohexylphenyl)aminornethylidene)indolyl } benzoic acid (Compound 169); 4- {2-Hydroxy-3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,5 dimethylphenyl)indolylidene)methylaminophenyl)} butanoic acid (Compound 170); 4- {2-Hydroxy-3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l -(3,4 dimethylphenyl)indolylidene)methylaminophenyl } butanoic acid (Compound 171); 3- { 3-(7-(6-Trifluoromethyl-2-oxo-2,3-dihydro- 1-(3,5-dimethylphenyl)-3 indolylidene)methylamino)indolyl}propanoic acid (Compound 172); 3- {3-(7-(6-Trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,4-dimethylphenyl)-3 indolylidene)methylamino)indolyl}propanoic acid (Compound 173); 4- {2-Hydroxy-3-(2-oxo-2,3-dihydro-l -(3,5 dimethylphenyl)indolylidene)methylaminophenyl} butanoic acid (Compound 174); 2-Chloro-3- {3-hydroxy-4-(2-oxo-2,3-dihydro- 1-(3,5 dimethylphenyl)indolylidene)methylaminophenyl}propenoic acid (Compound 175); 2-Chloro-3- {3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1-(3,4 dimethylphenyl)indolylidene)methylaminophenyl}propenoic acid (Compound 176); 2-Ethyl-3-{ 3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,4 dimethylphenyl)indolylidene)methylaminophenyl}propenoic acid (Compound 177); 2-Ethyl-3- {3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolylidene)methylaminophenyl } propenoic acid (Compound 178); 2-Ethyl-3- {3-hydroxy-4-(2-oxo-2,3-dihydro-l1-(3,5 dimethylphenyl)indolylidene)methylaminophenyl}propenoic acid (Compound 179); 4-{2-Hydroxy-3-(4-(2-(3,4-dimethylphenyl)-3-oxo-3,4-dihydro-5 methyl)pyrazolidene)mrnethylaminophenyl}butanoic acid (Compound 180); - 67 - WO 2007/062078 PCT/US2006/045129 (Z)-4- {1-(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl} butanoic acid (Compound 181); (E)-4- { 1-(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl} butanoic acid (Compound 182); (Z)-3- { 1-(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl}benzoic acid (Compound 183); (E)-3- { 1-(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl} benzoic acid (Compound 184); 4- {3-(4-Oxo-2-thioxo-5-(3-(3,5-dimethylphenyl)-2 hydroxypheny)hydrozono)thiazolidinyl}butanoic acid (Compound 185); 3- {2-(3-(1 -(3,5-Dimethylphenyl)-6-chloro-2-oxo-2,3 dihydroindolidene)methylamino)phenylamino } benzoic acid (Compound 186); 3-{2-(3-(1-(3,5-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3 dihydroindolidene)methylamino)phenylamino}benzoic acid (Compound 187); 3- {2-(4-(2-(3,5-Dimethylphenyl)-5-methyl-3-oxo-3,4 dihydropyrazolidene)methylamino)phenylamino} benzoic acid (Compound 188); (+)-3-Methyl-5- {2-hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 (3,5-dimethylphenyl)indolylidene)methylarnino)phenyl } pentanoic acid (Compound 189); (£)-3-{ 1-(6-Chloro-2-oxo-2,3-dihydro-3-(3-(1-(3,5-dimethylphenyl)-2 oxo-2,3-dihydro)indolyl)aminomethylidene)indolyl } benzoic acid (Compound 190); 3- { 4-(3-Hydroxy-6-methyl-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 (3,5-dimethylphenyl)indolyl)hydrazono)pyridinyl } benzoic acid (Compound 191); 3-{4-(3-Hydroxy-6-methyl-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-1 (3,5-dimethylphenyl)indolidene)methylamino)pyridinyl }benzoic acid (Compound 192); 3-{4-(3-Hydroxy-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1-(3,5 dimethylphenyl)indolidene)methylamino)pyridinyl } benzoic acid (Compound 193); 3- {4-(3-Hydroxy-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-1-(3,5 dimethylphenyl)indolyl)hydrazono)pyridinyl } benzoic acid (Compound 194); -68- WO 2007/062078 PCT/US2006/045129 3- { 5-(4-Hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolidene)methylamino)pyridinyl } benzoic acid (Compound 195); 3- {5-(4-Hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,5 dimethylphenyl)indolyl)hydrazono)pyridinyl}benzoic acid (Compound 196); 3-{5-(4-Hydroxy-3-(4-(3-oxo-3,4-dihydro-5-methyl-2-(3,4 dimethylphenyl)pyrazolyl)hydrazono)pyridinyl } benzoic acid (Compound 197); 4- { 2-(3-oxo-3,4-dihydro-5-methyl-4-(3-(3,4 dimethylphenyl)phenyl)hydrozono)pyrazolyl}butanoic acid (Compound 198); 3- { 2-Amino-5-methyl-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolylidene)methylamino)phenyl } benzoic acid (Compound 199); 3- { 1 -(5-Fluoro-2-oxo-2,3-dihydro-3-(3-(3,4 dimethylphenyl)phenyl)aminomethylidene)indolyl }benzoic acid (Compound 200); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(3-(3,4 dimethylphenyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 201); (3-(5-Fluoro-2-hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,4 dimethylphenyl)indolidene)methylamino)-l1-pyrazolyl)acetic acid (Compound 202); (3-(5-Fluoro-2-hydroxy-3-(3-(2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolidene)methylamino)- I -pyrazolyl)acetic acid (Compound 203); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 204); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 phenyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 205); 4-{2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(4 methyl)phenyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 206); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3 methyl)phenyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 207); - 69- WO 2007/062078 PCT/US2006/045129 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 methyl)phenyl)ethyl)phenyl)hydrazono)pyrazoly } butanoic acid (Compound 208); 4-{2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(1 naphthyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 209); 3- { l-(5-Nitro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)aminomethylidene)indolyl } benzoic acid (Compound 210); 3- { 1 -(5-Nitro-2-oxo-2,3-dihydro-3-(5-fluoro-2-hydroxy-3-(3,5 dimethylphenyl)phenyl)aminomethylidene)indolyl } benzoic acid (Compound 211); 2-Hydroxy-3-{3-(2-oxo-2,3-dihydro-l1-(3,5 dimethylphenyl)indolidene)methylamino}benzoic acid (Compound 212); 2-Hydroxy-3-{3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolidene)methylamino}benzoic acid (Compound 213); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(3-methyl- 1 butenyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 214); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3 heptanylphenyl)hydrazono)pyrazolyl}butanoic acid (Compound 215); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-(4 methyl)phenyl)ethenylphenyl)hydrazono)pyrazolyl} butanoic acid (Compound 216); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-(3 methyl)phenyl)ethenylphenyl)hydrazono)pyrazolyl } butanoic acid (Compound 217); 4- { 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2 methyl)phenyl)ethylphenyl)hydrazono)indolyl} butanoic acid (Compound 218); 2- { 1-(2-Oxo-2,3-dibydro-3-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)hydrazono)indolyl } acetic acid (Compound 219); 2- { 1 -(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2 methyl)phenyl)ethylphenyl)hydrazono)indolyl } acetic acid (Compound 220); 4- {4-(2-(3-(6-Trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,4 dimethylphenyl)indolylidene)methylamino)thiazolyl}benzoic acid (Compound 221); - 70- WO 2007/062078 PCT/US2006/045129 3- { 1-(5-Nitro-2-oxo-2,3-dihydro-3-(2-hydroxy-5-methyl-3-(1 adamantane)phenyl)aminomethylidene)indolyl}benzoic acid (Compound 222); 3-{ 1-(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(4-hydroxy-5-(3,4 dimethylphenyl)pyridinyl)hydrazono)indolyl} benzoic acid (Compound 223); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-(2-methyl)phenyl) ethylphenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 224); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-(2-fluoro)phenyl) ethylphenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 225); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(1-naphthyl) ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 226); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(3,5 dimethylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 227); 4- { 2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 methoxyphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl }butanoic acid (Compound 228); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-fluoro-3 methyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl} butanoic acid (Compound 229); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-fluoro-3 methyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 230); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(4 phenylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 231); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-cyanophenyl) ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 232); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 chlorophenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl} butanoic acid (Compound 233); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 234); -71 - WO 2007/062078 PCT/US2006/045129 3- {2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 trifluoromethylphenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 235); 3- {2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 fluorophenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 236); 3- {2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 methyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 237); 3-{2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,5 dimethyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 238); 3- {2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,6 dimethyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 239); 3- {2-(5-Phenyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3 -(2-(2,5 dimethylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl} benzoic acid (Compound 240); 3- {2-(5-tert-Butyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,5 dimethylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl} benzoic acid (Compound 241); 3- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 methylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 242); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2-(2 fluorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 243); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 244); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(4-phenylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 245); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methoxyphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 246); - 72 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluoro-3 methylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 247); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 trifluoromethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 248); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 cyanophenyl)ethyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 249); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 chlorophenyl)ethyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 250); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 251); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-ethylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 252); 4- {2-(5-Methyl-3 -oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dichlorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 253); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,5 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 254); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluoro-6 trifluoro-methylphenyl)ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 255); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indanyl)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 256); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indenyl)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 257); (-)-4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1 indanylmethyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 258); (-)-3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1 indanylmethyl)phenyl)-hydrazono)pyrazolyl}benzoic acid (Compound 259); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 methylphenyl)ethyl)-phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 260); - 73 - WO 2007/062078 PCT/US2006/045129 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluoro-3 methylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 261); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluorophenyl) ethyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 262); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 263); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dichlorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl }benzoic acid (Compound 264); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methyl-6 trifluoromethylphenyl)ethyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 265); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indanyl)phenyl) hydrazono)pyrazolyl}benzoic acid (Compound 266); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indenyl)phenyl) hydrazono)pyrazolyl}benzoic acid (Compound 262); (E)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,4 difluorophenyl)-ethenyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 268); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-4-(3,4-dimethylphenyl) 2-pyridyl)hydrazono)pyrazolyl } benzoic acid (Compound 269); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-6-methyl-4-(3,4 dimethylphenyl)-2-pyridyl)hydrazono)pyrazolyl}butanoic acid (Compound 270); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-2-(3,4-dimethylphenyl) 4-pyridyl)hydrazono)pyrazolyl}benzoic acid (Compound 271); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-2-(3,5-dimethylphenyl) 4-pyridyl)hydrazono)pyrazolyl}benzoic acid (Compound 272); 3- { 1-(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2 methylphenyl)-ethyl)phenyl)hydrazono)indolyl } benzoic acid (Compound 273); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 benzylphenyl)hydrazono)-pyrazolyl }butanoic acid (Compound 274); - 74- WO 2007/062078 PCT/US2006/045129 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(3 methylphenyl)propyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 275); 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-phenylpropyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 276); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(2 methylphenyl)propyl)-phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 277); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,4 difluorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 278); (E)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 pyridyl)ethyl)-phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 279); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-(Z)-ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 280); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 benzofuranyl)phenyl)-hydrazono)pyrazolyl} butanoic acid (Compound 281); (Z)-4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 bromoethenyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 282); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(3-methyl-I butenyl)phenyl)-hydrazono)pyrazolyl } butanoic acid (Compound 283); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2 cyclopropylethenyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 284); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3 methylbutyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 285); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-5-fluoro-3-(3,5 dimethylphenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 286); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,4 dimethylphenyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 287); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(5-chloro-2-hydroxy-3 cyclohexylphenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 288); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 289); - 75- WO 2007/062078 PCT/US2006/045129 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)-hydrazono)pyrazolyl}benzoic acid (Compound 290); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(5-chloro-2-hydroxy-3 cyclohexylphenyl)-hydrazono)pyrazolyl } butanoic acid (Compound 291); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,4 dimethylphenyl)phenyl)-hydrazono)pyrazolyl}benzoic acid (Compound 292); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(2 methylphenyl)propyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 293); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 benzofuranyl)phenyl)-hydrazono)pyrazolyl}benzoic acid (Compound 294); 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(2 fluorophenyl)propyl)-phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 295); 3- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3,4 dimethylphenyl)-phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 296); 3-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3,5 dimethylphenyl)-phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 297); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3,4 dimethylphenyl)-phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 298); 3-{ 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)hydrazono)indolyl}propionic acid (Compound 299); 3-{ 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-benzylphenyl)hydrazono) indolyl}benzoic acid (Compound 300); 3- { 1 -(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2 methylphenyl)ethyl)phenyl)-hydrazono)indolyl}propionic acid (Compound 301); 3-{ 1-(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(3-(3 methylphenyl)propyl)-phenyl)aminomethylidene)indolyl}benzoic acid (Compound 302); -76 - WO 2007/062078 PCT/US2006/045129 (=)-3- { 1-(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(1,2-dihydro-1 methyl-2-indolylphenyl)aminomethylidene)indolyl } benzoic acid (Compound 303); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2 methylphenylcarbonyl-amino)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 304); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(5-chloro-2-hydroxy-3-(2 methylphenyl-carbonylamino)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 305); 3- {2-Hydroxy-3-(2-oxo-2,3-dihydro- 1 -(2-(2 fluorophenyl)ethyl)indolylidene)-hydrazinophenyl}benzoic acid (Compound 306); 3- {2-Hydroxy-3-(2-oxo-2,3-dihydro- 1 -(2-(2 chlorophenyl)ethyl)indolylidene)-hydrazinophenyl } benzoic acid (Compound 307); 3-{3-Hydroxy-2-(5-methyl-3-oxo-2,3-dihydro-2-(3,4-dimethylphenyl) pyrazolylidene)hydrazino-4-pyridyl}benzoic acid (Compound 308); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 309); 3-{3-Hydroxy-2-(2-oxo-2,3-dihydro-l1-(3,5-dimethylphenyl)-3 indolylidene-hydrazino)-4-pyridyl}benzoic acid (Compound 310); 3- { I -(2-Oxo-2,3-dihydro-3-(3-hydroxy-6-methyl-4-(3,4-dimethylphenyl) 2-pyridyl)hydrazono)indolyl}benzoic acid (Compound 311); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-6-methyl-4-(3,4 dimethylphenyl)-2-pyridyl)hydrazono)pyrazolyl } benzoic acid (Compound 312); 3- {3-Hydroxy-4-(2-oxo-2,3-dihydro-l1-(3,5-dimethylphenyl)-6 trifluoromethyl-3-indolylidenehydrazino)-2-pyridyl }benzoic acid (Compound 313); 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-2-(3,5-dimethylphenyl) 4-pyridyl)hydrazono)pyrazolyl}butanoic acid (Compound 314); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-5-phenyl-2 benzothienyl)-hydrazono)pyrazolyl}butanoic acid (Compound 315); 3- { 3 -Hydroxy-2-(5-methyl-3-oxo-2,3-dihydro-2-(3,4-dimethylphenyl)-4 pyrazolidene)hydrazino-5-benzothienyl}benzoic acid (Compound 316); - 77 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-(2,3 dimethoxycarbonylphenyl)phenyl)-hydrazono)pyrazolyl }butanoic acid (Compound 317); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3,5 diisopropylphenyl)-carbonylhydrazinomethylidene)pyrazolyl } butanoic acid (Compound 318); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)-arninomethylidene)pyrazolyl} butanoic acid (Compound 319); (d)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2,3-dihydro-1 methyl-2-oxo-3-indolyl)methyl)phenyl)hydrazono)pyrazolyl } butanoice acid (Compound 320); 3-{ 1-(2-Oxo-2,3-dihydro-5-fluoro-3-(2-hydroxy-3-(2-(2 methylphenyl)ethyl)phenyl)-hydrazono)indolyl}propionic acid (Compound 321); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,5 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 322); (4-)-3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2,3-dihydro- 1 methyl-2-oxo-3-indolyl)methyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 323); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1,2-dihydro-l1-methyl 2-oxo-3-indolylidene)methyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 324); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(5-fluoro-2 methylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 325); 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4(E)-(2-hydroxy-3-(2-(2,4 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 326); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 rnethylphenyl)hydrazono)-pyrazolyl } benzoic acid (Compound 327); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1,2-dihydro- 1-methyl 2 -oxo-3-indolylidene)methyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 328); -78 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(5-fluoro-2 methylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 329); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 difluorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 330); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6 dimethylphenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 331); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 methylphenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 332); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(5-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 333); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(Z)-(2-(5-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 334); 4-{2-(5 -Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 335); 4- {2-(5 -Methyl-3 -oxo-2,3-dihydro-4-(2-hydroxy-3 (E)-(2-(4 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 336); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 fluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 337); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-phenylethenyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 338); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-phenylethynyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 339); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 methylphenyl)ethynyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 340); -79 - WO 2007/062078 PCT/US2006/045129 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-ethynyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 341); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 fluorophenyl)ethynyl)-phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 342); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 trifluoromethylphenyl)-ethynyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 343); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 trifluoromethyl-phenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 344); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1-methyl-I -indenyl-2 )phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 345); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,3-dimethyl-2 indenyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 346); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-5-methoxy-3-(2 indenyl)-phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 347); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(4,7-dimethyl-2 indenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 348); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(4,7-difluoro-2 indenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 349); 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-6-trifluoromethyl- 1-(2-(2 methylphenyl)-ethyl)-3 (Z)-indolylidene)methylaminophenyl } benzoic acid (Compound 350); 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-6-trifluoromethyl- 1 -(2-indenyl)-3(Z) indolylidene)methylaminophenyl }benzoic acid (Compound 351); (+)4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 -(2-(1,2,3,4 tetrahydro)-naphthyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 352); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro) naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 353); 4-({2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(1-indanylidene) methylphenyl)hydrazono)pyrazolyl}butanoic acid (Compound 354); - 80 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(5-fluoro-2 trifluoromethylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 355); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(6-fluoro-2 trifluoro-methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 356); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(6-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 357); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(4-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 358); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 359); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 360); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,5 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 361); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(4-fluoro-2 trifluoro-methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 362); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,4 difluoropheniyl)-ethynyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 363); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(1 -(1,2,3,4 tetrahydro)-naphthylidene)methylphenyl)hydrazono)pyrazolyl} butanoic acid (Compound 364); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-fluoro-5 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 365); -81 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3,5-dimethyl-4 isoxazolyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 366); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,5-dimethyl-4 isoxazolyl)ethyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 367); 3- {2-Hydroxy-3-(2-oxo-2,3-dihydro- 1 -(2(E)-(2-methylphenyl)ethenyl) 3(Z)-indolylidene)methylaminophenyl}benzoic acid (Compound 368); 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro- 1-(2(E)-(2,4-difluorophenyl)ethenyl) 3(Z)-indolylidene)methylaminophenyl}benzoic acid (Compound 369); 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro- 1-(2-indenyl)-3(Z) indolylidene)methyl-aminophenyl}benzoic acid (Compound 370); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(5-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 371); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 methylphenyl)hydrazono)-pyrazolyl}butanoic acid (Compound 372); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 indanylidenemethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 373); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 indanylmethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 374); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,4 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 375); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 376); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(4-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl }benzoic acid (Compound 377); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-fluoro-6 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 378); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,3 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 379); - 82 - WO 2007/062078 PCT/US2006/045129 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,3 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 380); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-fluoro-4 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 381); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 chlorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 382); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6 dichlorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 383); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3 chlorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 384); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,5 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 385); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-chloro-4 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 386); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 trifluoromethyl-4-fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 387); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,4 dichlorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}bUtanoic acid (Compound 388); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-chloromethyl 4-fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 389); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,4 dichloromethylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 390); - 83 - WO 2007/062078 PCT/US2006/045129 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro) naphthyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 353); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-8 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 392); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-8 methyl)-naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 393); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-7 methyl)-naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 394); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-7 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 395); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-6 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 396); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-5 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 397); 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-8 chloro)-naphthyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 398); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-7 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 399); and a pharmaceutically acceptable salt, ester, amide, or prodrug of any of those compounds. In certain embodiments, such compounds are selective TPO modulators. [0145] Certain compounds of the present inventions may exist as stereoisomers including optical isomers. The present disclosure is intended to include all stereoisomers and both the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are known in the art or that may be excluded by synthesis schemes known in the art designed to yield predominantly one enantiomer relative to another. Certain Synthesis Methods [0146] In certain embodiments, certain compounds of the present invention can by synthesized using the following Schemes. Scheme I - 84- WO 2007/062078 PCT/US2006/045129
(HO)
2
B
° 131-Ri R RR R 2 Rio Br Pd(PPh 3
)
4 , 2M Na 2
CO
3 Toluene/Ethanol R 13 1. HBr, HOAc 2. HOAc, HNO 3 3. Pd/C, H 2 , KOAc R R R 1. NaNO 2 R NNH 2O y O NRI N 5 Z'R NH 2 6 Z-R 7 4 6 [0147] The process of Scheme I is a multi-step synthetic sequence that commences with the palladium catalyzed cross-coupling of a phenylboronic acid such as structure 2 and an aryl bromide such as structure 1 to form the biaryl structure 3. Deprotection of the methyl ether is followed by nitration and hydrogenation to give the biphenyl amino acid such as structure 4. The amino group is then diazotized under standard conditions and is treated with the appropriate coupling partner to give the final product of structure 6. "R" may be present 0, 1, 2, or 3 times and each R is independently selected from the groups in the "optionally substituted" definition provided above. Scheme II - 85 - WO 2007/062078 PCT/US2006/045129 N O
R
7 -Z-Br, Cul, heat N H R13 R 1 3 8 'R7 8 Z--R7 7 R 1. NaNO 2 Rio 2. HO- R -R11 \I1Ho N
NH
2 R NH / RH 4 R12 N ,' N H 0 K N
R
l Z -.. R7 9 [0148] The process of Scheme II is a multi-step synthetic sequence that commences with the copper catalyzed cross-coupling of an oxindole such as structure 7 and an aryl or alkyl bromide to provide an N-substituted oxindole of structure 8. This is then followed by coupling the N-substituted oxindole with the diazonium salt of the biphenyl amino acid such as structure 4 to give the final product of structure 9. "R" may be present 0, 1, 2, or 3 times and each R is independently selected from the groups in the "optionally substituted" definition provided above. Scheme III - 86- WO 2007/062078 PCT/US2006/045129 R 2 R-Z-Br, Culhat R O2 o R 12 x 0 or N ) N N CH(OEt) 3 H R13 R' 3 8 ZR7 R 1 3 10 Z-R7 7 X = OEt, or N(CH 3
)
2
M-NH
2
R
1 0 N
H
12 NH RR R P RR R O2 N M R
R
13 ZR S~NO [0149] The process of Scheme III is a multi-step synthetic sequence that commences with the copper catalyzed cross-coupling of an oxindole such as structure 7 and an aryl or alkyl bromide to provide an N-substituted oxindole of structure 8. This is then converted into the structure 10 via reaction with either dimethylformamide dimethylacetal (or equivalent) or triethylorthoformate. This is then reacted with an amine to give the structure 11. "R" may be present 0, 1, 2, or 3 times and each R is independently selected from the groups in the "optionally substituted" definition provided above. Scheme IV R R RR O/ \ / base R N 0 H N
R
13 8 NZ 7 R H R 1 3 R 12 13 [0150] The process of Scheme IV is a single synthetic step which joins the arylated oxindole 8 from Scheme I and an appropriately substituted pyrrolecarboxaldehye - 87- WO 2007/062078 PCT/US2006/045129 12 in the presence of base to give 13. "R" may be present 0, 1, 2, or 3 times and each R is independently selected from the groups in the "optionally substituted" definition provided above. Scheme V R7 R 9
R
7
R
9 R '
R
8 o o RRH R N, O> 14 15 [0151] The process in Scheme V is a single synthetic step which reaction 14 ~with p~~Phosgene, or some synthetic equivalent, to yield 15. "R" may be present 0, 1, 2, or 3 times and each R is independently selected from the groups in the "optionally substituted" definition provided above. Scheme VI N NNH Rx -_,S CO2H ii. AICIs Q 18 Z , __ HO v "HN'N R R Z-x base O N 0O K N:N R'1 3
R
6 1 R' R 6 16 17
N
QR' or -Z-R 7 Q 19
R
x = R' or R 7 [01511 The process inof Scheme V is a single synthetic synthetp whic sequence thation 14 with phosgcommences with benzothiopme synthene formation from arylt, to yhioether 16. This is thent 0, 1, 2, or 3d into the structure 19 via reaction with diazonium slthe groups in the "optionally substituted"18. definition provided above. Scheme VI -88 +Z RX ~ O i. thionyl chloride / ~ . HO -R-.--2 ii. AICI 3 QO N. Z-~Rx baseN 16 17 Ny Q =R6or -Z-R 7 Q/19 Rx = R 6 or R7 [01521 The process of Scheme VI is a multi-step synthetic sequence that commences with benzothiophene formation from aryl thioether 16. This is then converted into the structure 19 via reaction with diazonium salt 18. Scheme VII - 88 - WO 2007/062078 PCT/US2006/045129
R
10 Ph 3 BrP-,_R , z NO 2 21 R11 o- -R> .X1 R X p(3 X X NaHMDSITHF
X
3 20
NO
2
X
1 , X 2 , X 3 = N or CH 22 SPd/C, H 2 , MeOH; or Zn dust, EtOH
R
11 Z~R R3 1. NaNO 2
R
11 NNH r O 3 O N NH 2 YN 5 'R7 N 23 24
ZR
7 [0153] The process of Scheme VII is a multi-step synthetic sequence that commences with the Wittig olefination of a benzaldehyde such as structure 20 and a phosphonium bromide such as structure 21 to form the olefin 22. Reduction of the nitro group (and/or the olefin) gives the phenyl amine such as structure 23. The amino group is then diazotized under standard conditions and is treated with the appropriate coupling partner to give the final product of structure 24. "R" is selected from the groups in the "optionally substituted" definition provided above. Scheme VIII - 89 - WO 2007/062078 PCT/US2006/045129 M
R
5 NH O DMFDMA O M-NH 2 N or Q CH(OEt) 3 Q Q = R 6 or -Z-R 7 or V = OEt, or N(CH 3
)
2 27 25 MeC(OEt) 3 26 26
R
7
R
8 0 RR R R N O H R R 9
R
7 R1 RID ' Ra XX 3 Z , ,
R
8 .x 3 R2R -R 2 R R Rn 7 SN OHO ;or X" X 2 , X 3 = N orCH [0154] The process of Scheme VIII is a multi-step synthetic sequence that commences with enamine or enol ether formation of an N-substituted oxindole of structure 25 or its analogs. This is then converted into the structure 27 via reaction with an amine partner. "R" may be present 0, 1, 2, or 3 times and each R is independently selected from the groups in the "optionally substituted" definition provided above. Scheme IX - 90- WO 2007/062078 PCT/US2006/045129 M I NNH 1) NaNO 2 NNH
M-NH
2 1 O 28 2) O N N R 6 25 R 6 29 29
R
7
R
8
R
9
R
7 RM9 RR R;or 3
R
9
X
1
X
2 , X 3 = N or CH [0155] The general process of Scheme IX starts with diazotization of amino compounds 28 under standard condition followed by a coupling reaction with compounds of structure 25 to afford the hydrazone products of structure 29. "R" may be present 0, 1, 2, or 3 times and each R is independently selected from the groups in the "optionally substituted" definition provided above. [0156 One of skill in the art will recognize that analogous synthesis schemes may be used to synthesize similar compounds. One of skill will recognize that compounds of the present invention may be synthesized using other synthesis schemes. In certain embodiments, the invention provides a salt corresponding to any of the compounds provided herein. [0157] In certain embodiments, the invention provides a salt corresponding to a selective TPO modulator. In certain embodiments, the invention provides a salt corresponding to a selective TPO receptor binding agent. In certain embodiments, a salt is obtained by reacting a compound with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. In certain embodiments, a salt is obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as choline, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, 4-(2 hydroxyethyl)-morpholine, 1-(2-hydroxyethyl)-pyrrolidine, ethanolamine and salts with -91 - WO 2007/062078 PCT/US2006/045129 amino acids such as arginine, lysine, and the like. In certain embodiments, a salt is obtained by reacting a free acid form of a selective TPO modulator or selective TPO binding agent with multiple molar equivalents of a base, such as bis-sodium, bis ethanolamine, and the like. [0158] In certain embodiments, a salt corresponding to a compound of the present invention is selected from acetate, ammonium, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, cholinate, clavulanate, citrate, dihydrochloride, diphosphate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabanine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subaceatate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, tromethamine, trimethylammonium, and valerate salts. [01591 In certain embodiments, one or more carbon atoms of a compound of the present invention are replaced with silicon. See e.g., WO 03/037905Al; Tacke and Zilch, Endeavour, New Series, 10, 191-197 (1986); Bains and Tacke, Curr. Opin. Drug Discov Devel. Jul:6(4):526-43(2003), all of which are incorporated herein by reference in their entirety. In certain embodiments, compounds of the present invention comprising one or more silicon atoms possess certain desired properties, including, but not limited to, greater stability and/or longer half-life in a patient, when compared to the same compound in which none of the carbon atoms have been replaced with a silicon atom. Certain Assays 10160] In certain embodiments, assays may be used to determine the level of TPO modulating activity of the compounds of the present invention. For example, the potency of the compounds of the present invention as selective TPO modulators may be determined in a luciferase assay, such as those described in Lamb, et al., Nucleic Acids Research, 23: 3283-3289(1995) and/or Seidel et al., Proc. Nat. Acad. Sci. USA; 92: 3041 3045 (1995), both of which are incorporated herein by reference in their entirety. 101611 In vitro proliferation and/or differentiation assays may also be used, such as those described by Bartley et al., Cell, 77: 1117-1124 (1994) and/or Cwirla, et al., Science, 276: 1696-1699 (1997), both of which are incorporated herein by reference in their entirety. -92 - WO 2007/062078 PCT/US2006/045129 Certain Pharmaceutical Agents [0162] In certain embodiments, at least one selective TPO modulator, or pharmaceutically acceptable salt, ester, amide, and/or prodrug thereof, either alone or combined with one or more pharmaceutically acceptable carriers, forms a pharmaceutical agent. Techniques for formulation and administration of compounds of the present invention may be found for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990, which is incorporated herein by reference in its entirety. [0163] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes. [0164] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is a liquid (e.g., a suspension, elixir and/or solution). In certain of such embodiments, a liquid pharmaceutical agent comprising one or more compounds of the present invention is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. 10165] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is a solid (e.g., a powder, tablet, and/or capsule). In certain of such embodiments, a solid pharmaceutical agent comprising one or more compounds of the present invention is prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents. [01661 In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. [0167] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises a delivery system. Examples of - 93 - WO 2007/062078 PCT/US2006/045129 delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical agents including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used. [0168] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises one or more tissue-specific delivery molecules designed to deliver the pharmaceutical agent to specific tissues or cell types. For example, in certain embodiments, pharmaceutical agents include liposomes coated with a tissue-specific antibody. [01691 In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises a co-solvent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water miscible organic polymer, and an aqueous phase. In certain embodiments, such co solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 8 0rTM , and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80rM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose. [0170] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises a sustained-release system. A non limiting example of such a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers. In certain embodiments, sustained-release systems may, depending on their chemical nature, release compounds over a period of hours, days, weeks or months. [01711 Certain compounds used in pharmaceutical agent of the present invention may be provided as pharmaceutically acceptable salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many - 94 - WO 2007/062078 PCT/US2006/045129 acids, including but fot limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. [0172] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention comprises an active ingredient in a therapeutically effective amount. In certain embodiments, the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art. [0173] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is formulated as a prodrug. In certain embodiments, prodrugs are useful because they are easier to administer than the corresponding active form. For example, in certain instances, a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form. In certain instances, a prodrug may have improved solubility compared to the corresponding active form. In certain embodiments, a prodrug is an ester. In certain embodiments, such prodrugs are less water soluble than the corresponding active form. In certain instances, such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility. ,In certain embodiments, the ester in such prodrugs is metabolically hydrolyzed to carboxylic acid. In certain instances the carboxylic acid containing compound is the corresponding active form. In certain embodiments, a prodrug comprises a short peptide (polyaminoacid) bound to an acid group. In certain of such embodiments, the peptide is metabolized to form the corresponding active form. [0174] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is useful for treating a conditions or disorder in a mammalian, and particularly in a human patient. Suitable administration routes include, but are not limited to, oral, rectal, transmucosal, intestinal, enteral, topical, suppository, through inhalation, intrathecal, intraventricular, intraperitoneal, intranasal, intraocular and parenteral (e.g., intravenous, intramuscular, intramedullary, and subcutaneous). In certain embodiments, pharmaceutical intrathecals are administered to achieve local rather than systemic exposures. For example, pharmaceutical agents may be injected directly in the area of desired effect (e.g., in the renal or cardiac area). [0175] In certain embodiments, a pharmaceutical agent comprising one or more compounds of the present invention is administered in the form of a dosage unit (e.g., tablet, capsule, bolus, etc.). In certain embodiments, such dosage units comprise a -95- WO 2007/062078 PCT/US2006/045129 selective TPO modulator in a dose from about 1 p.g/kg of body weight to about 50 mg/kg of body weight. In certain embodiments, such dosage units comprise a selective TPO modulator in a dose from about 2 pg/kg of body weight to about 25 mg/kg of body weight. In certain embodiments, such dosage units comprise a selective TPO modulator in a dose from about 10 ftg/kg of body weight to about 5 mg/kg of body weight. In certain embodiments, pharmaceutical agents are administered as needed, once per day, twice per day, three times per day, or four or more times per day. It is recognized by those skilled in the art that the particular dose, frequency, and duration of administration depends on a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the pharmaceutical agent. [01761 In certain embodiments, a pharmaceutical agent comprising a compound of the present invention is prepared for oral administration. In certain of such embodiments, a pharmaceutical agent is formulated by combining one or more compounds of the present invention with one or more pharmaceutically acceptable carriers. Certain of such carriers enable compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient. In certain embodiments, pharmaceutical agents for oral use are obtained by mixing one or more compounds of the present invention and one or more solid excipient. Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). In certain embodiments, such a mixture is optionally ground and auxiliaries are optionally added. In certain embodiments, pharmaceutical agents are formed to obtain tablets or dragee cores. In certain embodiments, disintegrating agents (e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate) are added. [0177] In certain embodiments, dragee cores are provided with coatings. In certain of such embodiments, 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 tablets or dragee coatings. - 96 - WO 2007/062078 PCT/US2006/045129 (0178] In certain embodiments, pharmaceutical agents for oral administration are push-fit capsules made of gelatin. Certain of such push-fit capsules comprise one or more compounds of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In certain embodiments, pharmaceutical agents for oral administration are soft', sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft capsules, one or more compounds of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. [01791 In certain embodiments, pharmaceutical agents are prepared for buccal administration. Certain of such pharmaceutical agents are tablets or lozenges formulated in conventional manner. [01801 In certain embodiments, a pharmaceutical agent is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In certain of such embodiments, a pharmaceutical agent comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical agents for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical agents for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical agents for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. 10181] In certain embodiments, a pharmaceutical agent is prepared for transmucosal administration. In certain of such embodiments penetrants appropriate to -97 - WO 2007/062078 PCT/US2006/045129 the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. [0182] In certain embodiments, a pharmaceutical agent is prepared for administration by inhalation. Certain of such pharmaceutical agents for inhalation are prepared in the form of an aerosol spray in a pressurized pack or a nebulizer. Certain of such pharmaceutical agents comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In certain embodiments using a pressurized aerosol, the dosage unit may be determined with a valve that delivers a metered amount. In certain embodiments, capsules and cartridges for use in an inhaler or insufflator may be formulated. Certain of such formulations comprise a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. [01831 In certain embodiments, a pharmaceutical agent is prepared for rectal administration, such as a suppositories or retention enema. Certain of such pharmaceutical agents comprise known ingredients, such as cocoa butter and/or other glycerides. [0184] In certain embodiments, a pharmaceutical agent is prepared for topical administration. Certain of such pharmaceutical agents comprise bland moisturizing bases, such as ointments or creams. Exemplary suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, lanolin and water in oil emulsions such as EucerinTM, available from Beiersdorf (Cincinnati, Ohio). Exemplary suitable cream bases include, but are not limited to, NiveaTM Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose CreamTM, available from Johnson & Johnson (New Brunswick, New Jersey), hydrophilic ointment (USP) and LubridermTM, available from Pfizer (Morris Plains, New Jersey). [0185] In certain embodiments, the formulation, route of administration and dosage for a pharmaceutical agent of the present invention can be chosen in view of a particular patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. I p. 1, which is incorporated herein by reference in its entirety). In certain embodiments, a pharmaceutical agent is administered as a single dose. In certain embodiments, a pharmaceutical agent is administered as a series of two or more doses administered over one or more days. - 98 - WO 2007/062078 PCT/US2006/045129 10186] In certain embodiments, a pharmaceutical agent of the present invention is administered to a patient between about 0.1% and 500%, 5% and 200%, 10% and 100%, 15% and 85%, 25% and 75%, or 40% and 60% of an established human dosage. Where no human dosage is established, a suitable human dosage may be inferred from ED 50 or ID 50 values, or other appropriate values derived from in vitro or in vivo studies. (0187] In certain embodiments, a daily dosage regimen for a patient comprises an oral dose of between 0.1 mg and 2000 mg, 5 mg and 1500 mg, 10 mg and 1000 mg, 20 mg and 500 mg, 30 mg and 200 mg, or 40 mg and 100 mg of a compound of the present invention. In certain embodiments, a daily dosage regimen is administered as a single daily dose. In certain embodiments, a daily dosage regimen is administered as two, three, four, or more than four doses. [0188] In certain embodiments, a pharmaceutical agent of the present invention is administered by continuous intravenous infusion. In certain of such embodiments, from 0.1 mg to 500 mg of a composition of the present invention is administered per day. [0189] In certain embodiments, a pharmaceutical agent of the invention is administered for a period of continuous therapy. For example, a pharmaceutical agent of the present invention may be administered over a period of days, weeks, months, or years. [0190] Dosage amount, interval between doses, and duration of treatment may be adjusted to achieve a desired effect. In certain embodiments, dosage amount and interval between doses are adjusted to maintain a desired concentration on compound in a patient. For example, in certain embodiments, dosage amount and interval between doses are adjusted to provide plasma concentration of a compound of the present invention at an amount sufficient to achieve a desired effect. In certain of such embodiments the plasma concentration is maintained above the minimal effective concentration (MEC). In certain embodiments, pharmaceutical agents of the present invention are administered with a dosage regimen designed to maintain a concentration above the MEC for 10-90% of the time, between 30-90% of the time, or between 50-90% of the time. 10191] In certain embodiments in which a pharmaceutical agent is administered locally, the dosage regimen is adjusted to achieve a desired local concentration of a compound of the present invention. 10192] In certain embodiments, a pharmaceutical agent may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing - 99- WO 2007/062078 PCT/US2006/045129 the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the .manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. [0193] In certain embodiments, a pharmaceutical agent is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Certain Combination Therapies [0194] In certain embodiments, one or more pharmaceutical agents of the present invention are co-administered with one or more other pharmaceutical agents. In certain embodiments, such one or more other pharmaceutical agents are designed to treat the same disease or condition as the one or more pharmaceutical agents of the present invention. In certain embodiments, such one or more other pharmaceutical agents are designed to treat a different disease or condition as the one or more pharmaceutical agents of the present invention. In certain embodiments, such one or more other pharmaceutical agents are designed to treat an undesired effect of one or more pharmaceutical agents of the present invention. In certain embodiments, one or more pharmaceutical agents of the present invention are co-administered with another pharmaceutical agent to treat an undesired effect of that other pharmaceutical agent. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are administered at the same time. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are administered at the different times. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are prepared together in a single formulation. In certain embodiments, one or more pharmaceutical agents of the present invention and one or more other pharmaceutical agents are prepared separately. [0195] Examples of pharmaceutical agents that may be co-administered with a pharmaceutical agent of the present invention include, but are not limited to, anti-cancer - 100 - WO 2007/062078 PCT/US2006/045129 treatments, including, but not limited to, chemotherapy and radiation treatment; corticosteroids, including but not limited to prednisone; immunoglobulins, including, but not limited to intravenous immunoglobulin (IVIg); analgesics (e.g., acetaminophen); anti inflammatory agents, including, but not limited to non-steroidal anti-inflammatory drugs (e.g., ibuprofen, COX-1 inhibitors, and COX-2, inhibitors); salicylates; antibiotics; antivirals; antifungal agents; antidiabetic agents (e.g., biguanides, glucosidase inhibitors, insulins, sulfonylureas, and thiazolidenediones); adrenergic modifiers; diuretics; hormones (e.g., anabolic steroids, androgen, estrogen, calcitonin, progestin, somatostan, and thyroid hormones); immunomodulators; muscle relaxants; antihistamines; osteoporosis agents (e.g., biphosphonates, calcitonin, and estrogens); prostaglandins, antineoplastic agents; psychotherapeutic agents; sedatives; poison oak or poison sumac products; antibodies; and vaccines. Certain Indications [0196] In certain embodiments, the invention provides methods of treating a patient comprising administering one or more compounds of the present invention. In certain embodiments, such patient suffers from thrombocytopenia. In certain such embodiments, thrombocytopenia results from chemotherapy and/or radiation treatment. In certain embodiments, thrombocytopenia results bone marrow failure resulting from bone marrow transplantation and/or aplastic anemia. In certain embodiments thrombocytopenia is idiopathic. In certain embodiments, one or more compounds of the present invention are administered to a patient to in conjunction with harvesting peripheral blood progenitor cells and/or in conjunction with platelet apheresis. Such administration may be done before, during, and/or after such harvesting. [0197] In certain embodiments, one or more compounds of the present invention are administered to a patient who suffers from a condition affecting the nervous system, including, but are not limited to, diseases affecting the nervous system and injuries to the nervous system. Such diseases, include, but not limited to, amyotrophic lateral sclerosis, multiple sclerosis, and multiple dystrophy. Injury to the nervous system include, but are not limited to spinal cord injury or peripheral nerve damage, including, but not limited to, injury resulting from trauma or from stroke. In certain embodiments, one or more compounds of the present invention are used to promote growth and/or development of glial cells. Such glial cells may repair nerve cells. In certain embodiments, compounds of the present invention are used to treat psychological disorders, including, but not limited to, cognitive disorders. - 101 - WO 2007/062078 PCT/US2006/045129 EXAMPLES [0198] The following examples, including experiments and results achieved, are provided for illustrative purposes only and are not to be construed as limiting the present invention. Where chemical structures depict atoms having an unfilled valency, it is to be understood that the valency is satisfied with one or more hydrogen atoms. Example 1 C0 2 H HO HN H CF 3 3'- { [1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3(Z) ylidenemethyl]amino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 101) 10199] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 13.05 (s, 1H), 11.35 (d, J = 13.3 Hz, 1H), 9.40 (s, 1H), 8.12 (t, J= 1.6 Hz, 1H), 7.97 (d, J= 7.9 Hz, 1H), 7.95 (ddd, J= 7.7,1.6, 1.3 Hz, 1H), 7.81-7.78 (m, 2H), 7.60 (t, J= 7.7 Hz, 1H), 7.44 (dq, J = 7.9, 0.9 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.12 (s, 1H), 7.11 (m, 2H), 7.07 (dd, J= 7.8, 1.5 Hz, 1H), 6.94 (q, J= 0.9 Hz, 1H), 2.36(s, 6H). Example 2 OH HO 0 NH HN N
CF
3 2,4-Dihydroxybenzoic acid N'- { 1-[1-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2 dihydroindol-3(Z)-ylidene]ethyl}hydrazide (Compound 102) [0200] This compound was prepared as described in Scheme VIII. IH NMR (500 MHz, CD 3 OD) 6 8.49 (s, IH), 7.71 (m, 1H), 7.67 (m, 1H), 7.34 (mn, 1H), 7.16 (s, 1H), 7.04 (s, 2H), 6.93 (s, 1H), 6.39 (m, 1H), 6.34 (s, 1H), 2.64 (s, 3H), 2.41 (s, 6H). - 102- WO 2007/062078 PCT/US2006/045129 Example 3 SHO G H HN- N O,
CO
2 H 3-{3-[(5-Chloro-2-hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl} benzoic acid (Compound 103) [0201] This compound was prepared as described in Scheme II. 'H NMR (500MHz, DMSO- d 6 ) 8 13.29 (s, 1H), 12.95 (s, 1H), 9.36 (s, 1H), 8.08 (t, J= 1.7 Hz, 1H), 8.04 (ddd, J= 7.7, 1.7, 1.2 Hz, 1H), 7.82 (m, 2H), 7.74 (t, J = 7.7 Hz, 1H), 7.65 (d, J = 2.6 Hz, 1H), 7.34 (m, 1H), 7.33 (td, J= 7.6, 1.3 Hz, 1H), 7.27 (dd, J= 8.0, 1.8 Hz, 1H), 7.23 (d, J= 8.0 Hz, IH), 7.22 (td, J= 7:6, 0.9 Hz, 1H), 6.94 (din, J 7.6 Hz, 1H), 6.93 (d, J= 2.6 Hz, 1H), 2.28 (s, 3H), 2.27 (s, 3H). Example 4 HO HN-N 0 = I N C0 2 H 3-{3 -[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 -dihydroindol-1 yl}benzoic acid (Compound 104) [0202] This compound was prepared as described in Scheme II. 'H NMR (500MHz, DMSO- d 6 ) 13.29 (s, 1H), 13.04 (s, 1H), 9.11 (s, 1H), 8.08 (t, J = J = 1.8 Hz, 1H), 8.04 (ddd, J J = 7.7, 1.8, 1.2 Hz, 1H), 7.83 (ddd, J = 7.7, 1.8, 1.2 Hz, 1H), 7.75 (mn, 1H), 7.74 (t, J= 7.7 Hz, 1H), 7.69 (dd, J = 7.7, 1.6 Hz, 1H), 7.31 (td, J = 7.6, 1.3 Hz, 1H), 7.22 (td, J = 7.6, 0.9 Hz, 1H), 7.15 (m, 2H), 7.06 (t, J = 7.7 Hz, 1H), 7.00 (m, 1H), 6.95 (m, 1H), 6.94 (dd, J = 7.7, 1.6 Hz, 1H), 2.33 (s, 6H). Example 5 - 103 - WO 2007/062078 PCT/US2006/045129 COzH F HO HN N
CF
3 3'- { [1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl- 1,2-dihydroindol-3(Z) ylidenemethyl]amino}-4-fluoro-2'-hydroxybiphenyl-3-carboxylic acid (Compound 105) [02031 This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) .813.35 (s, 1H), 11.34 (d, J = 13.3 Hz, 1H), 9.41 (s, 1H), 9.08 (d, J = 13.3 Hz, 1H), 8.01 (dd, J = 7.2, 2.3 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.79 (dd, J = 7.9, 1.5 Hz, 1H), 7.78 (ddd, J= 8.4, 4.4, 2.3 Hz, 1H), 7.44 (dq, J= 7.9, 0.9 Hz, 1H), 7.42 (dd, J = 10.6, 8.4 Hz, 1H), 7.13 (t,J = 7.9 Hz, 1H), 7.12 (m, 1H), 7.10 (mn, 2H), 7.06 (dd, J= 7.9, 1.5 Hz, 1H), 6.94 (m, 1H), 2.36 (s, 6H). Example 6 H0 2 C X 0 HOgC HN 2-(3'-{[1 -(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3(Z) ylidenemethyl]amino}-2'-hydroxybiphenyl-3-yl)-2-methylpropionic acid (Compound 106) [0204] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 812.39 (s, 1H), 11.36 (d, J = 13.3 Hz, 1H), 9.32 (s, 1H), 9.08 (d, J = 13.3 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.76 (dd, J = 7.9, 1.5 Hz, 1H), 7.54 (m, 1H), 7.45-7.42 (m, 3H), 7.35 (m, 1H), 7.12 (t, J = 7.9 Hz, 1H), 7.12 (m, 1H), 7.11 (m, 2H), 7.02 (dd, J= 7.9, 1.5 Hz, 1H), 6.95 (q, J= 0.8 Hz, 1H), 2.37 (s, 6H), 1.52 (s, 6H). Example 7 -104- WO 2007/062078 PCT/US2006/045129
CO
2 H HO HN 0 Q
CF
3 3'- { [ -(3,4-Dimethylphenyl)-2-oxo-6-trifluoromethyl- 1,2-dihydroindol-3 (Z) ylidenemethyl]amino} -2'-hydroxybiphenyl-3-carboxylic acid (Compound 107) [0205] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 6 13.03 (s, 1H), 11.31 (d, J= 13.7 Hz, 1H), 9.38 (s, 1H), 9.06 (d, J = 13.7 Hz, 1H), 8.09 (t, J.= 1.5 Hz, 1H), 7.91-7.95 (m, 2H), 7.77 (m, 2H), 7.58 (t, J= 7.3 Hz), 7.41 (dd, J= 7.8, 1.0 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 7.19 (dd, J= 7.8, 2.0 Hz, 1H), 7.11 (t, J= 7.8 Hz, 1H), 7.04 (dd, J= 7.8, 1.5 Hz, 1H), 6.90 (d, J= 1.5 Hz, 1H), 2.29 (s, 3H), 2.28 (s, 3H). Example 8 HO HN- N N
HO
2 C 4-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3-dihydroindol-1 yl}benzoic acid (Compound 108) 10206] This compound was prepared as described in Scheme II. 'H NMR (500MHz, DMSO- d 6 ) 8 13.18 (s, 1H), 13.05 (s, 1H), 9.13 (s, 1H), 8.14 (d, J = 8.5 Hz, 2H), 7.75 (m, 1H), 7.70 (m, 2H), 7.69 (dd, J = 7.8, 1.6 Hz, 1H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.23 (td, J = 7.6, 0.7 Hz, 1H), 7.15 (s, 2H), 7.06 (t, J = 7.8 Hz, 1H),, 7.03 (m, IH), 7.00 (s, 1H), 6.94 (dd, J= 7.8, 1.6 Hz, 1H), 2.33 (s, 6H). Example 9 - 105 - WO 2007/062078 PCT/US2006/045129 HO HN- N 0 I O CF E CO 2 H 3-{ 3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6-trifluoromethyl-2,3 dihydroindol-1-yl}benzoic acid (Compound 109) [02071 This compound was prepared as described in Scheme 11. IH NMR (500MHz, DMSO- d 6 ) .13.30 (s, 1H), 13.20 (s, 1H), 9.27 (s, 1H), 8.11 (t, J = 1.8 Hz, 1H), 8.07 (ddd, J= 7.8, 1.8, 1.2 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.86 (ddd, J = 7.8, 1.8, 1.2 Hz, 1H), 7.77 (t, J= 7.8 Hz, 1H), 7.74 (dd, J = 7.8, 1.6 Hz, 1H), 7.56 (dq, J= 7.9, 0.7 Hz, 1H), 7.15 (m, 2H), 7.09 (t, J = 7.8 Hz, 1H), 7.08 (m, 1H), 7.01 (m, 1H), 6.99 (dd, J= 7.8, 1.6 Hz, 1H), 2.33 (s, 6H). Example 10 O HN-
-
CF3 0= N
CO
2
CH
3 3-{3-[(2-Hydroxy-3 ,5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6-trifluoromethl-2,3 dihydroindol-1-yl}benzoic acid methyl ester (Compound 110) [0208] This compound was prepared as described in Scheme II. 'H NMR (500MHz, DMSO- d 6 ) 4 13.20 (s, 1H), 9.27 (s, 1H), 8.15 (dd, J = 2.1, 1.6 Hz, 1H), 8.10 (ddd, J = 7.9, 1.6, 1.1 Hz, 1H), 7.94 (d, J= 7.9 Hz, 1H), 7.90 (ddd, J = 7.9, 2.1, 1.1 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 7.74 (dd, J = 7.9, 1.6 Hz, 1H), 7.57 (dq, J = 7.9, 0.8 Hz, 1H), 7.15 (m, 2H), 7.09 (t, J = 7.9 Hz, 1H), 7.08 (m, 1H), 7.01 (m, 1H), 7.00 (dd, J = 7.9, 1.6 Hz, 1H), 3.90 (s, 3H), 2.33 (s, 6H). Example 11 - 106- WO 2007/062078 PCT/US2006/045129 HOHNN
HN-
N
COG
2 CH3 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3-dihydroindol-1 yl}benzoic acid methyl ester (Compound 1 11) 10209] This compound was prepared as described in Scheme II. 1 H NMR (500MHz, DMSO- d 6 ) 8 13.04 (s, 1H), 9.11 (s, 1H), 8.12 (m, 1H), 8.06 (ddd, J= 7.8, 1.6, 1.2 Hz, 1H), 7.87 (ddd, J = 7.8, 2.2, 1.2 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.75 (m, 1H), 7.69 (dd, J= 7.8, 1.6 Hz, 1H), 7.31 (td, J = 7.6, 1.2 Hz, 1H), 7.22 (td, J = 7.6, 0.9 Hz, IH), 7.15 (min, 2H), 7.06 (t, J= 7.8 Hz, 1H), 7.00 (m, 1H), 6.95 (m, 1H), 6.94 (dd, J = 7.8, 1.6 Hz, 1H), 3.90 (s, 3H), 2.33 (s, 6H). Example 12 F
HN-
N N -J CO2H 3-{3-[(5-Fluoro-2-hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl}benzoic acid (Compound 112) [0210] This compound was prepared as described in Scheme II. 'H NMR (500MHz, DMSO-d 6 ) 8 13.29 (s, 1H), 12.97 (s, 1H), 9.06 (s, 1H), 8.08 (m, 1H), 8.04 (ddd, J = 7.8, 2.2, 1.1 Hz, 1H), 7.83 (min, 1H), 7.81 (d, J= 7.6 Hz, 1H), 7.74 (t, J = 7.8 Hz, 1H), 7.45 (dd, J= 9.5, 3.0 Hz, 1H), 7.33 (t, J= 7.6 Hz, 1H), 7.22 (t, J= 7.6 Hz, 1H), 7.19 (s, 2H), 7.02 (s, 1H), 6.94 (d, J= 7.6 Hz, 1H), 6.75 (dd, J= 9.5, 3.0 Hz, 1H), 2.33 (s, 6H). Example 13
HO
2 C o/N, 0 0N
CF
3 -107- WO 2007/062078 PCT/US2006/045129 3-(3-[1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3 ylideneamino]-2-oxo-2,3-dihydrobenzooxazol-7-yl}benzoic acid (Compound 113) [0211] As described in Scheme V, a biphasic mixture of 3'-{N'-[1-(3,5 Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-3-ylidene]-hydrazino } -2' hydroxy-biphenyl-3-carboxylic acid (153 mg, 0.28 mmol, 1.0 equiv) in dichloromethane (6 mL) and 1:1 saturated aqueous sodium bicarbonate/2.0 M aqueous sodium hydroxide (6 mL) was added triphosgene (83 mg, 0.28 mmol, 3.0 equiv) at rt. The mixture was stirred for 4h and then acidified with 6M HC1. The organic layer was removed and the aqueous layer extracted twice with dichloromethane. The combined organics were washed once with water and once with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient: 9:1 hexanes / EtOAc to 3:2 hexanes / EtOAc to 59.9:40:0.1 hexanes / EtOAc / HOAc), then triturated with methanol to afford Compound 113. IH NMR (500 MHz, DMSO-d 6 ) 8 13.25 (s, 1H), 8.45 (dd, J= 2.0, 1.5 Hz, 1H), 8.09 (ddd, J = 7.8, 2.0, 1.0 Hz, IH), 8.05 (ddd, J= 8.3, 1.5, 1.0 Hz, 1H), 7.86 (d, J= 8.1 Hz, 1H), 7.73 (dd, J= 7.8, 7.8 Hz, 1H), 7.64 (dd, J= 8.0, 1.2 Hz, 1H), 7.46 (min, 2H), 7.36 (dd, J= 7.8, 1.2 Hz, 1H), 7.21 (s, 3H), 6.86 (d, J= 1.6 Hz, IH), 2.38 (s, 6H). Example 14 HO HN.N 0
N
1 Hoc H02C-O 3- {3-[(2-Hydroxy-5,3',4'-trimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl}benzoic acid (Compound 114) [0212] This compound was preapred as described as in Scheme II. 'H NMR (500 MHz, DMSO-d 6 ) 8 13.28 (s, 1H), 13.03 (s, 1H), 8.81 (s, 1H), 8.08 (dd, J= 1.5, 1.0 Hz, 1H), 8.04 (ddd, J = 7.8, 1.5, 1.5 Hz, 1H), 7.83 (ddd, J= 7.9, 2.2, 1.2 Hz, 1H), 7.75 (m, 2H), 7.51 (d, J = 2.1 Hz, 1H), 7.30 (m, 2H), 7.23 (m, 3H), 6.94 (d, J = 7.9 Hz, 1H), 6.76 (dd, J= 2.1, 0.7 Hz, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H). Example 15 - 108 - WO 2007/062078 PCT/US2006/045129 HO N 0 NH HN 0 N qCF 3 3-Hydroxybenzoic acid 1'-{ 1-[1 -(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2 dihydroindol-3(Z)-ylidene]ethyl}hydrazide (Compound 115) (02131 This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 8 11.76 (s, 1H), 11.08 (s, 1H), 9.84 (s, 1H), 7.70 (d, J= 8.3 Hz, 1H), 7.35 (m, 4H), 7.13 (s, 1H), 7.07 (s, 2H), 7.02 (dt, J= 5.2, 3.7 Hz, 1H), 6.92 (d, J= 1.5 Hz, 1H), 2.58 (s, 3H), 2.36 (s, 6H). Example 16 OH 0 HN o0N NaCF3 H CFz 1-(3,5-Dimethylphenyl)-3(Z)- { 1 -[2-(4-hydroxyphenyl)-2-oxo-ethylamino]ethylidene } -6 trifluoromethyl-1,3-dihydroindol-2-one (Compound 116) [02141 This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, Methanol-d4) 5 8.54 (s, 1 H), 7.98 (d, J = 8.8 Hz, 2 H), 7.65 (d, J = 8.3 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.15 (s, 1 H), 7.03 (s, 2 H), 6.93 (s, I H), 6.90 (d, J= 8.3 Hz, 2 H), 5.14 (s, 2 H), 2.67 (s, 3 H), 2.41 (s, 6 H). Example 17 F HO HN-N N CF 3 C0 2 H 3-{3-[(5-Fluoro-2-hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl } benzoic acid (Compound 117) -109- WO 2007/062078 PCT/US2006/045129 [0215] This compound was prepared as described in Scheme II. 'H NMR (500MHz, DMSO- d 6 ) 5 13.28 (s, 1H), 13.09 (s, 1H), 9.18 (s, 1H), 8.09 (d, J= 2 Hz, 1H), 8.07 (m, 1H), 8.0 (d, J= 7.8 Hz, 1H), 7.87 (m, 1H), 7.77 (t, J = 7.9 Hz, 1H), 7.58 (d, J= 7.8 Hz, 1H), 7.52 (dd, J= 9.4, 3.1 Hz, 1H), 7.19 (s, 2H), 7.07 (s, 1H), 7.03 (s, 1H), 6.82 (dd, J= 9.5 Hz, 1H), 2.33 (s, 6H). Example 18 HOHNN
HN-
N O CFz
CO
2 H 3-{3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6-trifluoromethyl-2,3 dihydroindol-1-yl}benzoic acid (Compound 118) (0216] This compound was prepared as described in Scheme II. 'H NMR (500MHz, DMSO-d 6 ) 8 13.28 (s, 1H), 13.18 (s, 1H), 9.23 (s, 1H), 8.11 (t, J = 1.7 Hz, IH), 8.07 (dd, J = 7.6, 1.2 Hz, 1H), 7.94 (d, J = 7.8 H1z, 1H), 7.85 (m, 1H), 7.78 (d, J = 8.1 Hz, IH), 7.73 (m, 1H), 7.57 (t, J= 8.8 Hz, 1H), 7.33 (s, IH), 7.24 (dd, J = 13.9, 4.9 Hz, 2H), 7.09 (m, I1H), 6.99 (dd, J = 7.7, 1.6 Hz, 1H), 2.26 (s, 3H), 2.25 (s, 3H). Example 19 HO HN-N N
CO
2 H 3-{3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3-dihydroindol-1 yl}benzoic acid (Compound 119) [02171 This compound was prepared as described in Scheme II. 1H NMR (500MHz, DMSO-d 6 ) 6 13.28 (s, 1H), 13.04 (s, 1H), 9.09 (s, IH), 8.08 (m, 1H), 8.04 (dt, J = 7.8, 1.4 Hz, 1H), 7.83 (ddd, J = 8.0, 2.2, 1.2 Hz, 1H), 7.74 (t, J = 7.7 Hz, 2H), 7.68 (dd, J= 7.8, 1.5 Hz, 1H), 7.31 (m, 2H), 7.23 (m, 3H), 7.06 (t, J= 7.9 Hz, 1H), 6.94 (dt, J = 5.9, 3.9 Hz, 2H), 2.26 (s, 3H), 2.25 (s, 3H). Example 20 -110- WO 2007/062078 PCT/US2006/045129 HO HN
CO
2 H 3-{3(Z)-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo-2,3 dihydroindol-1-yl}benzoic acid (Compound 120) 10218] This compound was prepared as described in Scheme III. 'H NMR (500MHz, DMSO-d 6 ) 6 13.23 (s, 1H), 11.15 (d, J= 13.2 Hz, 1H), 9.08 (s, 1H), 8.88 (dd, J = 13.18 Hz, 1H), 8.04 (m, 1H), 7.99 (m, 1H), 7.81 (m, 2H), 7.70 (m, 2H), 7.33 (s, 1H), 7.24 (m, 2H), 7.09 (m, 3H), 6.93 (m, 2H), 2.27 (s, 3H), 2.26 (s, 3H). Example 21 HO HN-N 0 CO2 H 4-{3(Z)- [(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3-dihydroindol- 1 yl}butyric acid (Compound 121) [0219] This compound was prepared as described in Scheme III. 'H NMR (500MHz, DMSO-d 6 ) 6 13.02 (s, 1H), 12.14 (s, 1H), 9.06 (s, 1H), 7.63 (dd, J = 7.8, 1.5 Hz, 2H), 7.33 (td, J = 7.7, 1.1 Hz, 1H), 7.21 (t, 1H), 7.13 (m, 3H), 7.03 (t, J = 7.8 Hz, 1H), 7.00 (s, 1H), 6.91 (m, 1H), 3.85 (t, J 6.8 Hz, 2H), 2.33 (m, 8H), 1.88 (t, J = 6.8 Hz, 2H). Example 22
CO
2 H Cl HO HN 0 I oN CF 3 2-Chloro-3-(4- { [1-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl- 1,2-dihydroindol-3 (Z) ylidenemethyl]amino}-3-hydroxyphenyl)acrylic acid (Compound 122) - 111 - WO 2007/062078 PCT/US2006/045129 [02201 This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-da) 8 11.20 (d, J= 14.2 Hz, 1 H), 10.6 (br s, 1 H), 9.06 (d, J= 12.7 Hz, 1 H), 7.94 (d, J= 8.3 Hz, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.63 (s, 2 H), 7.43 (d, J= 8.8 Hz, 1 H), 7.45-7.29 (m, 1 H), 7.13 (s, 1 H), 7.11 (s, 2 H), 6.94 (s, 1 H), 2.37 (s, 6 H). Example 23 OH 0 H HN 0 N - CF 3 4-Hydroxybenzoic acid V- { 1-[1 -(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2 dihydroindol-3(Z)-ylidene]ethyl }hydrazide (Compound 123) [0221] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 12.04 (s, 1H), 10.92 (s, IH), 10.11 (s, 1H), 7.82 (dt, J= 6.0, 4.8 Hz, 2H), 7.66 (d, J= 8.2 Hz, 1H), 7.33 (d, J= 7.8 Hz, 1H), 7.12 (s, 1H), 7.06 (s, 2H), 6.91 (s, 1H), 6.85 (d, J= 8.3 Hz, 2H), 2.60 (s, 3H), 2.36 (s, 6H). Example 24 HO HN.N N NO 2 HO2C' 3- { 3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-5-nitro-2-oxo-2,3 dihydroindol-1-yl } benzoic acid (Compound 124) (02221 This compound was prepared as described in Scheme II. 'H NMR (500 MHz, DMSO-d 6 ) 8 13.29 (s, 1H), 13.11 (s, 1H), 9.29 (s, 1H), 8.52 (d, J= 2.4 Hz, 1H), 8.20 (dd, J = 8.8, 2.4 Hz, 1H), 8.10 (m, 2H), 7.84 (m, 2H), 7.78 (dd, J = 7.8, 7.8 Hz, 1H), 7.15 (d,J= 0.9 Hz, 2H), 7.10 (m, 2H), 7.01 (dd, J= 7.6, 1.6 Hz, 2H), 2.33 (s, 6H). Example 25 -112- WO 2007/062078 PCT/US2006/045129 HOHN 0 I
CO
2 H 3- { 3 (Z)-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo-2,3 dihydroindol-1-yl} benzoic acid (Compound 125) [0223] This compound was prepared as described in Scheme III. 'H NMR (500MHz, DMSO-d 6 ) 6 13.2 (s, 1H), 11.17 (d, J = 13.7 Hz, 1H), 9.11 (s, 1H), 8.89 (d, J = 13.2 Hz, 1H), 8.04 (t, J= 1.8 Hz, 1H), 7.99 (m, 1H), 7.80 (m, 2H), 7.71 (m, 2H), 7.14 (m, 2H), 7.10 (m, 2H), 7.06 (m, 1H), 7.00 (s, 1H), 6.94 (m, 2H), 2.32 (s, 6H). Example 26 HO
HN.
N OZZ
HO
2 C / 3-{3-[(2-Hydroxy-5,3',5'-trimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3-dihydroindo[l-l yl}benzoic acid (Compound 126) [0224] This compound was prepared as described in Scheme II. 'H NMR (500 MHz, CD 3 OD-d 4 ) 6 8.10 (mn, 2H), 7.75 (d, J= 6.8 Hz, 1H), 7.68 (m, 2H), 7.54 (d, J = 2.0 Hz, 1H), 7.26 (ddd, J = 7.8, 7.3, 1.0 Hz, 1H), 7.19 (dd, J = 7.3, 7.3 Hz, 1H), 7.10 (s, 2H), 6.99 (s, 1H), 6.93 (d, J= 7.8 Hz, 1H), 6.74 (d, J= 2.0 Hz, 1H), 2.36 (s, 3H), 2.35 (s, 6H). Example 27
NH
2 O NH HN 0
CF
3 4-Aminobenzoic acid N'-{ 1-[1-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2 dihydroindol-3(Z)-ylidene]ethyl } hydrazide (Compound 127) -113- WO 2007/062078 PCT/US2006/045129 10225] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 8 11.83 (s, 1H), 10.71 (s, 1H), 7.67 (m, 3H), 7.35 (d, J= 7.8 Hz, 1H), 7.12 (s, 1H), 7.06 (s, 2H), 6.91 (s, 2H), 6.60 (d, J = 8.8 Hz, 2H), 5.84 (s, 2H), 2.57 (s, 3H), 2.36 (s, 6H). Example 28
HO
2 C /NP H HN- N NO=
CF
3 3-(7-{N'-[ 1 -(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindo 1-3 ylidene]hydrazino}-1H-indol-3-yl)propionic acid (Compound 128) [0226] This compound was prepared as described in Scheme II. 'H NMR (500MHz, DMSO-d 6 ) 8 13.48 (s, 1H), 12.11 (s, 1H), 10.78 (s, 1H), 8.39 (d,J= 8.3 Hz, IH), 7.56 (d, J = 8.1 Hz, 1H), 7.39 (d, J= 7.8 Hz, 1H), 7.27 (d, J = 2.7 Hz, 1H), 7.18 (s, 2H), 7.11 (m, 1H), 7.05 (t, J = 7.7 Hz, 1H), 7.00 (s, 1H), 2.98 (t, J= 7.32 Hz, 2H), 2.63 (t, J = 7.8Hz, 2H), 2.37 (s, 6H). Example 29 Me HN HO2C 4- { 3(Z)-[N'-(4-Methylbenzoyl)hydrazinomethylidene]-2-oxo-2,3-dihydroindol- 1 yl}benzoic acid (Compound 129) [02271 This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 5 13.8 (s, 1 H), 8.17 (d, J= 8.3 Hz, 2 H), 7.82 (d, J= 7.8 Hz, 2 H), 7.78 (d, J= 7.8 Hz, 1 H), 7.70 (J = 8.3 Hz, 2 H), 7.46 (dd, J= 7.8, 7.8 Hz, 1 H), 7.43 (d, J = 8.3 Hz, 2 H1), 7.28 (dd, J= 7.8, 7.8 Hz, 1 H), 7.00 (d, J= 7.8 Hz, 1 H), 2.40 (s, 3 H). Example 30 -114- WO 2007/062078 PCT/US2006/045129
CF
3 0 I N
CF
3
CO
2 H 3- {2-Oxo-6-trifluoromethyl-3 (Z)-[4-(3-trifluoromethylphenyl)- 1IH-pyrrol-2 ylmethylidene]-2,3-dihydroindol-1-yl}benzoic acid (Compound 130) [02281 This compound was prepared as described in Scheme IV. 'H NMR (500MHz, Acetone-d6) 5 13.70 (s, 1H), 8.27 (s, 1H), 8.2 (d, J= 7.8Hz, 1H), 7.91 (m, 5H), 7.82 (m, 5H), 7.59 (s, 1H), 7.47 (d, J = 7.8Hz, 1H), 7.13 (s, 1H), 6.74 (m, 1H). Example 31 HOzC N H HN-N N-N 3-(7-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4 ylidene]hydrazino} -1H-indol-3-yl)propionic acid (Compound 131) [02291 This compound was prepared as described in Scheme II. 'H NMR (500MHz, DMSO- d 6 ) 8 12.10 (s, 1H), 10.62 (s, 1H), 7.75 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.27 (d, J= 6.8 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 2.97 (t, J 7.4 Hz, 1H), 2.62 (t, J = 7.8Hz, IH), 2.43 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H). Example 32
CO
2 H N o
F
3 C / NO FC NH
S.,
3-(3(Z)-{ [4-(3,4-Dimethylphenyl)thiazol-2-ylamino]methylidene }-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl)benzoic acid (Compound 132) -115- WO 2007/062078 PCT/US2006/045129 [0230] This compound was prepared as described in Scheme III. 'H NMR (500 MHz, acetone-d6) 8 8.98 (s, 1H), 8.24 (s, 1H), 8.16 (d, J= 7.8 Hz, 1H), 7.99 (d, J= 7.8 Hz, 1H), 7.88 (d,J= 8.5 Hz, 1H), 7.79 (m, 2H), 7.74 (d, J= 7.8 Hz, 1H), 7.48 (s, 1H), 7.47 (d, J= 9.0 Hz, 1H), 7.21 (m, 2H), 2.33 (s, 3H), 2.29 (s, 3H). Example 33 q CO 2 H N O
F
3 C/ ~N 3-(3(Z)- {[4-(4-Methoxyphenyl)thiazol-2-ylamino]methylene}-2-oxo-6-trifluoromethyl 2,3-dihydroindol- 1 -yl)benzoic acid (Compound 133) [0231] This compound was prepared as described in Scheme III. 1 H NMR (500 MHz, acetone-d6) 8 8.98 (s, 1H), 8.24 (s, 1H), 8.16 (dt, J= 7.8, 1.2 Hz, 1H), 8.00 (d, J= 8.1 Hz, 1H), 7.96 (d, J= 9.3 Hz, 2H), 7.88 (d, J = 7.8 Hz, 1H), 7.79 (t, J= 7.8 Hz, 1H), 7.46 (d, J= 7.3 Hz, 1H), 7.41 (s, 1H), 7.19 (s, 1H), 7.01 (d, J 8.8 Hz, 2H), 3.85 (s, 3H). Example 34 F3C N 0 NH OH 3-{3(Z)-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylene]-2-oxo-6 trifluoromethyl-2,3-dihydroindol- 1-yl } benzoic acid (Compound 134) [0232] This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 5 11.35 (d, J= 13.4 Hz, 1H), 9.24 (s, 1H), 9.10 (d, J= 13.2 Hz, 1H), 8.00 (m, 2H), 7.99 (d, J= 8.3 Hz, 1H), 7.74 (m, 2H), 7.68 (t, J= 7.6 Hz, 1H), 7.46 (d, J= 7.3 Hz, 1H1), 7.14 (s, 2H), 7.08 (t,J = 7.9 Hz, 1H), 7.03 (s, 1H), 6.99 (m, 2H1), 2.32 (s, 6H). Example 35 -116- WO 2007/062078 PCT/US2006/045129 FF O N -F HO N o HN 3-{3(Z)-[(4-(4-Methylphenyl)-2-thiazolylamino)methylene]-2-oxo-6-trifluoromethy1-2,3 dihydroindol-1 -yl}benzoic acid (Compound 135) [0233] This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 13.25 (s, 2H), 11.81 (d,J= 12.1, 1H), 11.41 (d,J = 13.0, 1H), 8.96 (d, J= 12.1, 1H), 8.59 (d,J = 13.0, 1H), 8.35 (m, 1H), 8.11-8.00 (m, 5H), 7.93 (d, J= 8.2, 2H), 7.84 (d, J = 8.2, 2H), 7.84 (m, 1H), 7.81-7.72 (m, 3H), 7.67 (m, 1H), 7.65 (s, 1H), 7.55 (mn, 1H), 7.47 (dq, J 7.9, 0.7, 1H), 7.27 (d, J= 8.1, 4H), 7.04 (s, 1H), 6.98 (s, 1H), 2.35 (s, 3H), 2.34 (s, 3H). Example 36 I 0 NH HN 0 N H F HO 3-{3(Z)-[(3,4-Dimethylbenzoylhydrazino)methylidene]-2-oxo-6-trifluoromethyl- 2
,
3 dihydroindol-1l-yl}benzoic acid (Compound 136) 10234] This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 13.24 (br s, 1H), 11.30 (d, J = 13.0, 1H), 10.28 (d, J= 13.0, 1H), 8.42 (br s, 1H), 8.10-7.96 (m, 2H), 7.82-7.64 (m, 4H), 7.38 (d, J = 8.1, 1H), 7.31 (d, J = 7.6, 1H), 7.01 (s, 1H), 6.95 (br s, 1H), 2.31 (s, 6H). Example 37 -117- WO 2007/062078 PCT/US2006/045129 0 NH o HN 0 N - F HO FF 3- {3(Z)-[(4-Chlorobenzoylhydrazino)methylidene]-2-oxo-6-trifluoromethyl-2,3 dihydroindol-1 -yl}benzoic acid (Compound 137) [0235] This compound was prepared as described in Scheme III. IH NMR (500 MHz, DMSO-d 6 ) 15.42 (s, 1H), 13.24 (s, 1H), 11.47 (s, 1H), 8.43 (s, 1H), 8.10-7.89 (m, 4H), 7.84-7.70 (m, 3H), 7.65 (d, J= 8.4, 2H), 7.38(d, J 7.7, 1H), 7.01 (s, IH). Example 38 O NH I HN 0 / N F H FF 3-{3(Z)-[(4-Methoxybenzoylhydrazino)methylidene]-2-oxo-6-trifluoromethyl-2,3 dihydroindol-1 -yl}benzoic acid (Compound 138) [0236] This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 11.32 (s, 1H), 11.30 (d, J = 12.2, 1H), 10.27 (d, J = 12.2, 1H), 8.43 (s, 1H), 8.11-7.65 (m, 7H), 7.38 (d, J= 8.1, IH), 7.09 (d,J= 8.5, 2H), 7.01 (s, 1H), 3.85 (s, 3H). Example 39 O NH I HN 0 / N HO O 3-{3(Z)-[(3,4-Dimethylbenzoylhydrazino)methylidene]-2-oxo-6-chloro-2,3-dihydroindol 1-yl}benzoic acid (Compound 139) -118- WO 2007/062078 PCT/US2006/045129 [0237] This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 13.22 (s, 1H), 11.20 (br, 2H), 8.25 (s, IH), 8.05-7.93 (m, 4H), 7.88 (m, 1H), 7.78 (m, 1H), 7.74-7.69 (m, 5H), 7.68-7.64 (m, 3H), 7.60 (m, 2H), 7.54 (s, 1H), 7.32-7.29 (m, 2H), 7.14 (m, 1H), 7.07 (dd, J = 8.2, 1.9, 1H), 6.83 (d, J = 1.9, 1H), 6.78 (m, 1H), 2.30 (s, 12H). Example 40 HO HO O o 1-(3,4-Dimethylphenyl)-3(Z)-[1 -(2,4-dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3 dihydroindole (Compound 140) [0238] This compound was prepared as described in Scheme VIII. IH NMR (300 MHz, DMSO-d 6 ) 11.76 (s, 1H), 11.43 (s, 1H), 10.73 (s, 1H), 10.25 (s, IH), 7.73 (d, J = 8.6, 1H), 7.51 (m, 1H), 7.32 (d, J = 8.1, 1H), 7.21 (d, J = 2.0, 1H), 7.14 (dd, J = 8.1, 2.0, 1H), 7.07-6.99 (m, 2H), 6.79 (m, 1H), 6.38 (dd, J 8.6, 2.4, 1H), 6.34 (d, J= 2.4, 1H), 2.47 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H). Example 41 HO H 0 o N 1 -(3,4-Dimethylphenyl)-3(Z)-[I-(4-hydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3 dihydroindole (Compound 141) [0239] This compound was prepared as described in Scheme VIII. 'H NMR (300 MHz, DMSO-d 6 ) 11.44 (s, 1H), 10.75 (s, 1H), 10.21 (s, 1H), 7.81 (d, J = 8.8, 2H), 7.51 (m, 1H), 7.32 (d, J = 8.2, 11-1), 7.21 (d, J = 2.0, 1H), 7.14 (dd, J = 8.2, 2.0, 1H), 7.07-6.99 (m, 2H), 6.88 (d, J= 8.8, 2H), 6.79 (m, 1H), 2.47 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H). -119- WO 2007/062078 PCT/US2006/045129 Example 42 OH HOo 0 NH HN 0 N' 1 -(3,4-Dimethylphenyl)-3(Z)-[(2,4-dihydroxybenzoylhydrazino)methylidene]-2-oxo-2,3 dihydroindole (Compound 142) [0240] This compound was prepared as described in Scheme VIII. 'H NMR (300 MHz, DMSO-d 6 ) 12.04 (s, 1H), 11.94 (s, 1H), 11.02 (s, 1H), 10.28 (s, 1H), 10.25 (s, 1H), 9.64 (d, J = 11.5, 1H), 8.11 (s, 1H), 7.80 (m, 1H), 7.76-7.70 (m, 2H), 7.58 (d, J = 10.4, IH), 7.55-7.50 (m, 2H), 7.42 (d, J = 11.5, 1H), 7.34-7.27 (m, 2H), 7.23 (d, J = 1.6, 1H), 7.18-6.96 (m, 7H), 6.79-6.71 (m, 2H), 6.40-6.31 (m, 4H), 2.29 (s, 6H), 2.28 (s, 3H), 2.27 (s, 3H). Example 43 OH HO O NH HN 0 N 1-(3,5-Dimethylphenyl)-3(2)-[1-(2,4-dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3 dihydroindole (Compound 143) [02411 This compound was prepared as described in Scheme VIII. 'H NMR (300 MHz, DMSO-d 6 ) 11.77 (s, 1H), 11.44 (s, 1H), 10.73 (s, 1H), 10.26 (s, 1H), 7.73 (d, J 8.8, 1H), 7.51 (m, 1H), 7.09-7.01 (m, 5H), 6.82 (m, 1H), 6.38 (dd, J= 8.8, 2.3, 1H), 6.34 (d, J = 2.3, 1H), 2.47 (s, 3H), 2.35 (s, 6H). Example 44 - 120 - WO 2007/062078 PCT/US2006/045129 OH 0 HN 0 N 1-(3,5-Dimethylphenyl)-3(Z)-[1 -(4-hydroxybenzoyhydrazino)ethylidene]-2-oxo-2,3 dihydroindole (Compound 144) [0242] This compound was prepared as described in Scheme VIII. 1 H NMR (300 MHz, DMSO-d 6 ) 11.45 (s, 1H), 10.76 (s, 1H), 10.22 (s, 1H), 7.81 (d, J = 8.8, 2H), 7.51 (m, 1H), 7.09-6.97 (m, 5H), 6.88 (d, J= 8.8, 2H), 6.82 (m, 1H), 2.48 (s, 3H), 2.35 (s, 6H). Example 45 OH HO O NH HN 1-(3,5-Dimethylphenyl)-3(Z)-[(2,4-dihydroxybenzoylhydrazino)methylidene]-2-oxo- 2
,
3 dihydroindole (Compound 145) [0243] This compound was prepared as described in Scheme VIII. IH NMR (300 MHz, DMSO-d 6 ) 11.98 (m, 2H), 11.02 (s, 2H), 10.28 (s, 1H), 10.26 (s, 1H), 9.65 (d, J= 11.6, 1H), 8.12 (s, 1H), 7.80 (m, 1H), 7.77-7.70 (m, 2H), 7.56-7.50 (m, 2H), 7.42 (d, J = 11.6, 1H), 7.08-6.96 (m, 10H), 6.83-6.72 (m, 2H), 6.40-6.31 (m, 4H), 2.35 (s, 6H), 2.33 (s, 6H). Example 46 - 121 - WO 2007/062078 PCT/US2006/045129 OH 0 NH HN 0 N 1-(3,5-Dimethylphenyl)-3(Z)-[(4-hydroxybenzoylhydrazino)methylidene]-2-oxo-2,3 dihydroindole (Compound 146) 102441 This compound was prepared as described in Scheme VIII. 'H NMR (300 MHz, DMSO-d 6 ) 11.00 (s, 2H), 10.20 (s, 1H), 10.19 (s, IH), 9.65 (min, 1H), 8.10 (s, 1H), 7.84-7.74 (m, 5H), 7.54 (min, IH), 7.40 (d, J = 10.3, 1H), 7.10-6.95 (m, 10H), 6.91 6.84 (in, 4H), 6.78 (min, 1H), 3.18 (s, 1H), 3.16 (s, 1H), 2.35 (s, 6H), 2.33 (s, 6H). Example 47 O NH I HN 0 / o 3-(3(Z)-[1 -(3,4-Dihydroxybenzoylhydrazino)ethylidene]-2-oxo-6-chloro-2,3 dihydroindol- I -yl)benzoic acid (Compound 147) [0245] This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 11.55 (s, 1H), 8.02 (dt, J = 7.6, 1.5, 1H), 7.98 (t, J = 1.5, 1H), 7.78-7.65 (m, 4H), 7.53 (d, J = 8.2, 1H), 7.30 (d, J = 8.2, 1H), 7.10 (dd, J = 8.2, 2.0, 1H), 6.84 (d, J = 2.0, 1H), 2.52 (s, 3H), 2.30 (s, 6H). Example 48 OH 0 NH HN 0 N - 122 - WO 2007/062078 PCT/US2006/045129 1-(3,4-Dimethylphenyl)-3(Z)-[(4-hydroxybenzoylhydrazino)methylidene]-2-oxo-2,3 dihydroindole (Compound 148) [0246] This compound was prepared as described in Scheme VIII. 1 H NMR (500 MHz, DMSO-d 6 ) 10.99 (s, 2H), 10.19 (s, 1H), 10.18 (s, 1H), 9.64 (d, J= 12.0, 1H), 8.09 (s, 1H), 7.83-7.74 (m, 5H), 7.54 (m, 1H), 7.40 (mn, 1H), 7.31 (d, J = 8.0, 1H), 7.29 (d, J = 8.0, 1H), 7.23 (m, 1H), 7.18-7.14 (m, 2H), 7.10 (dd, J = 8.0, 2.0, 1H), 7.07-7.02 (m, 2H), 7.00-6.97 (m, 3H), 6.89-6.84 (m, 4H), 6.77 (m, 1H), 6.73 (m, 1H), 2.30 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H). Example 49 HO O NH HN N 1-(3,4-Dimethylphenyl)-3(Z)-[(3,5-diisopropyl-2 hydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 149) [0247] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 12.29 (s, 1H), 12.22 (s, 1H), 11.52 (s, 2H), 9.71 (d, J = 10.6, 1H), 8.14 (s, 1H), 7.82 (m, 1H), 7.68-7.58 (m, 2H), 7.54-7.48 (m, 2H), 7.34-7.23 (m, 5H), 7.19-7.16 (mn, 2H), 7.13-6.96 (m, 5H), 6.78 (m, 1H), 6.74 (m, 1H), 3.27 (m, 2H), 2.86 (m, 2H), 2.31 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H), 1.23 (d, J = 6.8, 6H), 1.23 (d, J = 6.8, 6H), 1.20 (d, J= 6.8, 6H), 1.20 (d, J= 6.8, 6H). Example 50 OH HO_ O N H HN 0 N 1-(3,5-Dimethylphenyl)-3(Z)-[ 1 -(3,4-dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3 dihydroindole (Compound 150) - 123 - WO 2007/062078 PCT/US2006/045129 [02481 This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 11.47 (s, 1H), 7.51 (m, 1H), 7.35 (d, J= 1.5, 1H), 7.30 (dd, J 8.3, 1.5, 1H), 7.10-7.01 (m, 5H), 6.86-6.80 (mn, 2H), 2.47 (s, 3H), 2.35 (s, 6H). Example 51 OH HO N 0 NH 1-(3,4-Dimethylphenyl)-3(Z)-[ 1 -(3,4-dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3 dihydroindole (Compound 151) [0249] This compound was prepared as described in Scheme VIII. 1H NMR (500 MHz, DMSO-d 6 ) 11.47 (br s, 1H), 10.68 (br s, 1H), 9.70 (br s, 1H), 9.31 (br s, IH), 7.50 (m, IH), 7.36-7.27 (m, 3H), 7.21 (s, 1H), 7.14 (m, 1H), 7.06-6.99 (m, 2H), 6.83 (m, 1H), 6.79 (m, 1H), 2.47 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H). Example 52 I HO o NH HN 0 HON 3-(6-Chloro-3(Z)-[(2-hydroxy-3,5-diisopropylbenzoylhydrazino)methylidene]-2-oxo-2,3 dihydroindol-1 -yl)benzoic acid (Compound 152) 102501 This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 13.22 (s, 2H), 12.25 (s, 1H), 12.16 (s, 1H), 11.58 (s, 2H), 8.32 8.25 (m, 2H), 8.06-7.94 (m, 5H), 7.81-7.55 (m, 9H), 7.33-7.24 (m, 2H), 7.20-7.04 (m, 2H), 6.83 (d, J = 1.6, 1H), 6.79 (d, J = 1.6, 1H), 3.26 (m, 2H), 2.86 (m, 2H), 1.23 (d, J = 6.3, 6H), 1.22 (d, J = 6.3, 6H), 1.20 (d,J = 6.8, 6H), 1.19 (d, J= 6.8, 6H). Example 53 - 124 - WO 2007/062078 PCT/US2006/045129 OH HO H N O N 1 -(3,4-Dimethylphenyl)-3(Z)-[ 1 -(2,5-dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3 dihydroindole (Compound 153) [0251] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 11.49 (s, 1H), 10.77 (s, 1H), 10.72 (s, 1H), 9.14 (s, 1H), 7.51 (m, 1H), 7.32 (d, J = 8.0, 1H), 7.23 (d, J= 3.0, 1H), 7.21 (d, J = 2.0, 1H), 7.14 (dd, J = 8.0, 2.0, 1H), 7.06-7.00 (m, 2H), 6.89 (dd, J = 8.8, 3.0, 1H), 6.83 (d, J = 8.8, 1H), 6.79 (m, 1H), 2.48 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H). Example 54 HO H O O 00 N 1-(3,4-Dimethylphenyl)-3(Z)- [ 1 -(3-nitro-4-hydroxybenzoylhydrazino)ethylidene]-2-oxo 2,3-dihydroindole (Compound 154) 10252] This compound was prepared as described in Scheme VIII. IH NMR (500 MHz, DMSO-d 6 ) 11.30 (s, 1H), 9.84 (s, 1H), 8.36 (d, J = 2.3, 1H), 7.98 (dd, J= 8.7, 2.3; 1H), 7.42 (ddd, J = 7.7, 1.2, 0.5, 1H), 7.29 (d, J = 7.9, 1H), 7.16 (d, J = 8.7, 1H), 7.16 (d, J= 2.1, 1H), 7.10 (dd, J= 7.9, 2.1, 1H), 6.96 (td, J= 7.7, 1.2, 1H), 6.90 (td, J= 7.7, 1.2, 1H), 6.76 (ddd, J= 7.7, 1.2, 0.5, 1H), 5.05 (br s, 1H), 2.60 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H). Example 55 - 125 - WO 2007/062078 PCT/US2006/045129 Cl S.-NH H N O N 1-(3,4-Dimethylphenyl)-3(Z-[1 -(3 -aminosulfonyl-4-chlorobenzoylhydrazino)ethylidene] 2-oxo-2,3-dihydroindole (Compound 155) 10253] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 11.48 (s, 1H), 11.29 (s, 1H), 8.52 (d, J = 2.2, 1H), 8.13 (dd, J = 8.3, 2.2, 1H), 7.86 (d, J= 8.3, 1H), 7.79 (s, 2H), 7.52 (m, 1H), 7.32 (d, J = 8.0, 1H), 7.22 (d, J = 2.2, 1H), 7.15 (dd, J = 8.0, 2.2, 1H), 7.07-7.01 (m, 2H), 6.79 (m, 1H), 2.50 (m, 3H), 2.30 (s, 3H), 2.29 (s, 3H). Example 56 OH ' NH 2 O NH HN 0 N 1-(3,4-Dimethylphenyl)-3(Z)-[ 1 -(3-amino-4-hydroxybenzoylhydrazino)ethylidene]-2 oxo-2,3-dihydroindole (Compound 156) (0254] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 7.54-7.42 (m, 3H), 7.31 (m, 1H), 7.17 (s, 1H), 7.11 (m, 1H), 7.08 7.00 (m, 2H), 6.88 (br s, 1H), 6.78 (m, 1H), 4.61 (br s, 1H), 3.91 (s, 2H), 2.53 (s, 3H), 2.34 (s, 3H), 2.33 (s, 3H). Example 57 - 126 - WO 2007/062078 PCT/US2006/045129 HO HO NH HN 0 N 1 -(3 ,4-Dimethylphenyl)-3(Z)-[1-(4-methoxy-2-hydroxybenzoylhydrazino)ethylidene]-2 oxo-2,3-dihydroindole (Compound 157) [0255] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 11.91 (s, IH), 11.44 (s, IH), 10.83 (s, IH), 7.83 (d, J = 8.8, 1H), 7.51 (m, 1H), 7.32 (d, J = 8.0, 1H), 7.21 (d, J = 1.9, 1H), 7.14 (dd, J = 8.0, 1.9, IH), 7.06-7.00 (m, 2H), 6.79 (m, IH), 6.57 (dd, J = 8.8, 2.4, 1H), 6.51 (d, J = 2.4, 1H), 3.80 (s, 3H), 2.48 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H). Example 58 HO 0HO K HN N/ 3-{3(Z)-(1-(3,5-Dimethylphenyl)-2-oxo-2,3-dihydro-3-indolidene)methylamino-2 hydroxyphenyl } benzoic acid (Compound 158) 102561 This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 11.16 (d, J= 13.0, 1H), 9.26 (s, 1H), 8.84 (d, J = 13.0, 1H), 8.12 (t, J = 1.7, 1H), 7.94 (ddd, J = 7.7, 1.7, 1.2, 1H), 7.81-7.72 (mn, 3H), 7.60 (t, J = 7.7, 1H), 7.13-7.05 (m, 6H), 7.01 (dd, J = 7.7, 1.5, 1H), 6.85 (m, 1H), 2.35 (s, 6H). Example 59 - 127- WO 2007/062078 PCT/US2006/045129 N C F. 0 NH OH 3-{3(Z)-(3-(3,5-Dimethylphenyl)-2-hydroxyphenyl)aminomethylidene)-2-oxo- 2
,
3 dihydro-1I-indolyl}benzoic acid (Compound 159) [0257] This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 11.20 (d, J = 13.1, 1H), 9.17 (br s, 1H), 8.95 (d, J = 13.1, 1H), 8.02 (s, 1H), 7.97 (d, J = 7.7, 1H), 7.76-7.66 (m, 4H), 7.14 (s, 2H), 7.07 (t, J= 7.7, 1H), 7.00 (s, 1H), 6.97 (d, J = 7.7, 1H), 6.90-6.86 (m, 2H), 2.32 (s, 6H). Example 60 HO H 0 0 N 3-{3(Z)-(1 -(3,4-Dimethylphenyl)-2-oxo-2,3-dihydro-3-indolidene)methylamino-2 hydroxyphenyl }benzoic acid (Compound 160) (0258] This compound was prepared as described in Scheme VIII. IH NMR (500 MHz, DMSO-d 6 ) 13.03 (s, 1H), 11.14 (d, J = 13.0, 1H), 9.25 (s, 1H), 8.83 (d, J = 13.0, 1H), 8.11 (t,J = 1.7, 1H), 7.94 (ddd, J = 7.7, 1.7, 1.1, 1H), 7.80-7.75 (m, 2H), 7.73 (dd, J = 7.8, 1.5, 1H), 7.59 (t, J = 7.7, 1H), 7.32 (d, J = 8.0, 1H), 7.25 (d, J = 2.1, 1H), 7.18 (dd, J= 8.0, 2.1, 1H-), 7.10 (t, J = 7.8, 1H), 7.07-7.03 (m, 2H), 7.00 (dd, J= 7.8, 1.5, 1H), 6.81 (m, 1H), 2.30 (s, 3H), 2.30 (s, 3H). Example 61 F HO 0 NH - 128 - WO 2007/062078 PCT/US2006/045129 4-{ 1-(6-Fluoro-2-oxo-2,3-dihydro-3(Z)-(2-(3,5-dimethylphenyl) aminocarbonylphenyl)aminomethylidene)indolyl} butanoic acid (Compound 161) [02591 This compound was prepared as described in Scheme III. iH NMR (500 MHz, DMSO-d 6 ) 12.11 (s, IH), 12.00 (d, J = 12.8, 1H), 10.32 (s, 1H), 8.67 (d, J = 12.8, 1H), 7.84 (d, J = 8.2, 1H), 7.80 (dd, J = 7.9, 1.5, 1H), 7.63 (m, 1H), 7.60 (dd, J 9.3, 2.6, 1H), 7.35 (s, 2H), 7.23 (m, 1H), 7.01 (dd, J = 8.5, 4.3, 1H), 6.91 (ddd, J = 9.5, 8.5, 2.6, 1H), 6.79 (s, 1H), 3.77 (t, J = 7.3, 2H), 2.29 (s, 6H), 2.26 (t, J = 7.3, 2H), 1.80 (qn, J= 7.3, 3H). Example 62 HO 0 N o Cl 0 4-{ 1 -(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)aminomethylidene)indolyl}butanoic acid (Compound 162) [02601 This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 11.25 (d, J= 12.9, 1H), 10.68 (s, 1H), 8.65 (d, J = 12.9, 1H), 8.05 (s, 1H), 7.60 (d, J = 8.0, 1H), 7.57 (dd, J = 7.9, 1.3, 1H), 7.16 (d, J = 1.8, 1H), 7.11 (m, 2H), 7.02 (dd, J = 7.9, 7.7, 1H), 7.02 (m, 1H), 7.00 (dd, J = 8.0, 1.8, 1H), 6.94 (dd, J = 7.7, 1.3, 1H), 3.94 (t, J 7.2, 2H), 2.43 (t, J= 7.2, 2H), 2.35 (mn, 6H), 2.01 (qn, J 7.2, 2H). Example 63 HO HN 0 N HOO Ho ct 3-{ 1-(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)aminomethylidene)indolyl}benzoic acid (Compound 163) [0261] This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 13.25 (s, 1H), 11.17 (d, J = 13.3, 1H), 9.15 (s, 1H), 8.94 (d, J = 13.3, 1H), 8.03-7.99 (m, 2H), 7.80 (m, 1H), 7.80 (d, J = 8.1, 1H), 7.72 (t, J = 7.8, 1H), - 129- WO 2007/062078 PCT/US2006/045129 7.70 (d, J= 7.8, 1H), 7.16 (dd, J = 8.1, 1.9, 1H), 7.14 (s, 2H), 7.06 (t, J = 7.8, 1H), 7.00 (s, 1H), 6.97 (dd, J= 7.8, 1.2, 1H), 6.88 (d, J= 1.9, 1H), 2.32 (s, 6H). Example 64 HO 0 ll N 0 4-{ 1 -(5-Fluoro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)aminomethylidene)indolyl } butanoic acid (Compound 164) [02621 This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 11.30 (d, J= 12.8, 1H), 10.69 (s, 1H), 8.69 (d, J = 12.8, 1H), 8.06 (s, 1H), 7.58 (dd, J = 8.2, 1.4, 1H), 7.45 (dd, J = 9.3, 2.6, 1H), 7.11 (m, 2H), 7.07-7.01 (m, 3H), 6.94 (dd, J 7.7, 1.5, 1H), 6.86 (ddd, J = 9.7, 8.2, 2.6, IH), 3.92 (t, J = 7.2, 2H), 2.41 (t, J 7.2, 2H), 2.35 (m, 6H), 2.00 (qn, J = 7.2, 2H). Example 65 HOR I 0 HO N F F 3-{3-( (1-(1-(3,5-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-3(Z) indolidene)ethylamino)-2-hydroxyphenyl}benzoic acid (Compound 165) 102631 This compound was prepared as described in Scheme VIII. IH NMR (500 MHz, DMSO-d 6 ) 11.86 (s, 1H), 8.31 (t, J= 1.5, 1H), 8.06 (d,J = 7.8, 1H), 7.77 (d, J = 7.8, 1H), 7.53 (t, J= 7.8, 1H), 7.46 (d, J= 8.1, 1H), 7.33 (dq, J= 8.1, 0.9, 1H), 7.30 (dd, J= 7.7, 1.3, 1H), 7.13 (dd, J= 7.7, 1.3, 1H), 7.06 (s, 2H), 7.02 (t,J = 7.7, 1H), 6.99 6.97 (m, 2H), 2.42 (s, 3H), 2.37 (s, 6H). Example 66 - 130- WO 2007/062078 PCT/US2006/045129 H0 HO HoH 0 N F F 3-{3-(1-(1-(3,4-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-3(Z) indolidene)ethylamino)-2-hydroxyphenyl}benzoic acid (Compound 166) [02641 This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 11.91 (s, 1H), 8.32 (br s, 1H), 8.06 (d, J = 7.8, 1H), 7.76 (d, J = 7.8, 1H), 7.54 (t, J = 7.8, 1H), 7.48 (d, J = 8.1, 1H), 7.35-7.28 (m, 3H), 7.18 (s, 1H), 7.16-7.10 (min, 2H), 7.08 (s, 1H), 7.04 (t, J 7.6, 1H), 2.49 (s, 3H1), 2.33 (s, 3H), 2.32 (s, 3H). Example 67 Cl HN.. N HN HO~/ F 3-{ 1-(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(5-chloro-2-hydroxy-3 cyclohexylphenyl)hydrazono)indolyl}benzoic acid (Compound 167) [02651 This compound was prepared as described in Scheme II. 'H NMR (500 MHz, DMSO-d 6 ) 13.30 (s, 1H), 13.03 (s, 1H), 9.44 (s, 1H), 8.11 (dd, J = 2.1, 1.7, 1H), 8.08 (ddd, J = 7.8, 1.7, 1.2, 1H), 7.99 (d, J = 8.0, 1H), 7.85 (ddd, J = 7.8, 2.1, 1.2, 1H), 7.77 (t, J= 7.8, 1H), 7.56 (d, J = 2.5, 1H), 7.54 (dq, J= 8.0, 0.8, 1H), 7.04 (m, 1H), 6.92 (d, J = 2.5, 1H), 2.97 (m, 1H), 1.81-1.67 (min, 5H), 1.44-1.31 (min, 4H), 1.25 (min, 1H). Example 68 - OH N 0 NH F OH CI 3- { 1-(5-Fluoro-2-oxo-2,3-dihydro-3-(1-(5-chloro-2-hydroxy-3(Z) cyclohexylphenyl)amino)ethylidene)indolyl}benzoic acid (Compound 168) - 131- WO 2007/062078 PCT/US2006/045129 [0266] This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 11.93 (s, 1H), 8.00-7.97 (m, 2H), 7.72-7.66 (m, 2H), 7.34 (dd, J= 10.1, 1.8, 1H), 7.23 (d, J = 2.5, 1H), 7.12 (d, J = 2.5, 1H), 6.91-6.84 (m, 2H), 2.95 (m, 1H), 2.49 (s, 3H), 1.82-1.67 (m, 5H), 1.43-1.32 (m, 4H), 1.29-1.20 (m, 1H). Example 69 0 OH N C, b 3-{ 1 -(5-Fluoro-2-oxo-2,3-dihydro-3-(5-chloro-2-hydroxy-3(Z) cyclohexylphenyl)aminomethylidene)indolyl}benzoic acid (Compound 169) [0267] This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 11.09 (d, J = 13.2, 1H), 9.38 (br s, 1H), 8.91 (d, J = 13.2, 1H), 8.02 (t, J = 1.8, 1H), 7.99 (ddd, J = 7.8, 1.8, 1.2, 1H), 7.77 (ddd, J = 7.8, 1.8, 1.2, 1H), 7.70 (t, J= 7.8, 1H), 7.67 (min, 1H), 7.66 (d, J= 2.3, 1H), 6.90 (d, J = 2.3, 1H), 6.90-6.87 (min, 2H), 2.95 (m, 1H), 1.81-1.66 (m, 5H), 1.44-1.22 (m, 5H). Example 70 0 OH HO HN 0 F 4- {2-Hydroxy-3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5-dimethylphenyl)-3(Z) indolylidene)methylaminophenyl}butanoic acid (Compound 170) [02681 This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 11.27 (d, J = 13.6, 1H), 9.01 (d, J = 13.6, 1H), 7.94 (d, J = 8.1, 1H), 7.60 (d, J = 7.6, 1H), 7.41 (d, J = 8.1, 1H), 7.12 (s, 1H), 7.10 (s, 2H), 6.94 (t, J = 7.6, 1H), 6.93 (s, 1H), 6.88 (d, J = 7.6, 1H), 2.65 (t, J = 7.4, 2H), 2.37 (s, 6H), 2.23 (t, J = 7.4, 2H), 1.77 (qn, J = 7.4, 2H). Example 71 - 132 - WO 2007/062078 PCT/US2006/045129 0 OH HO HN 0 NF F F 4- { 2-Hydroxy-3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1-(3,4-dimethylphenyl)- 3(Z) indolylidene)methylaminophenyl}butanoic acid (Compound 171) 10269] This compound was prepared as described in Scheme VIII. 'H NMR (300 MHz, DMSO-d 6 ) 8.72 (s, 1H), 7.76 (d, J = 7.6, 1H), 7.44 (m, 1H), 7.38-7.30 (m, 2H), 7.22 (d, J= 1.7, 1H), 7.15 (dd, J= 8.0, 1.7, 1H), 6.97-6.89 (m, 3H), 2.70 (t,J= 7.2, 2H), 2.36 (s, 6H), 2.33 (t, J= 7.2, 2H), 1.87 (qn, J= 7.2, 2H). Example 72 O OH H 0 HN F 3-{3-(7-(6-Trifluoromethyl-2-oxo-2,3-dihydro- 1-(3,5-dimethylphenyl)-3(Z) indolylidene)methylamino)indolyl}propanoic acid (Compound 172) [0270] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 12.10 (s, 1H), 11.32 (m, 1H), 10.94 (d, J= 12.8, 1H), 8.92 (d, J= 12.8, IH), 7.95 (d,J= 7.8, 1H), 7.43 (d,J= 7.8, 1H), 7.40 (mn, 1H), 7.30 (d,J= 7.8, 1H), 7.19 (d, J= 2.4, 1H), 7.14 (m, 1H), 7.12 (m, 2H), 7.09 (t, J= 7.8, 1H), 6.94 (m, 1H), 2.94 (t, J= 7.6, 2H), 2.61 (t, J = 7.6, 2H), 2.37 (s, 6H). Example 73 - 133- WO 2007/062078 PCT/US2006/045129 O OH H H HN 0 N F FF 3-{3-(7-(6-Trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,4-dimethylphenyl)-3(Z) indolylidene)methylamino)indolyl}propanoic acid (Compound 173) [0271] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 12.09 (s, 1H), 11.33 (d, J= 2.2, 1H), 10.92 (d, J= 12.8, 1H), 8.91 (d, J= 12.8, 1H), 7.94 (d, J = 8.0, 1H), 7.43 (d, J = 8.0, 1H), 7.40 (m, 1H), 7.37 (d, J = 8.0, 1H), 7.30-7.28 (m, 2H), 7.22 (dd, J= 8.0, 2.0, 1H), 7.19 (d, J = 2.2, 1H), 7.09 (t, J = 8.0, 1H), 6.92 (d, J = 1.6, 1H), 2.94 (t, J= 7.7, 2H), 2.60 (t, J= 7.7, 2H), 2.32 (s, 3H), 2.31 (s, 3H). Example 74 O OH HO HN 0 N 4-{2-Hydroxy-3-(2-oxo-2,3-dihydro-1l-(3,5-dimethylphenyl)-3(Z) indolylidene)methylaminophenyl}butanoic acid (Compound 174) [0272] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 12.07 (s, 1H), 11.08 (d, J= 13.0, 1H), 8.77 (d, J= 13.0, 1H), 7.74 (m, 1H), 7.54 (d, J = 7.8, 1H), 7.10-7.02 (m, 5H), 6.91 (m, 1H), 6.85-6.81 (m, 2H), 2.64 (m, 2H), 2.36 (s, 6H), 2.23 (m, 2H), 1.77 (m, 2H). Example 75 - 134 - WO 2007/062078 PCT/US2006/045129 O OH Cl HO 2-Chloro-3(Z)-{3-hydroxy-4-(2-oxo-2,3-dihydro-1 -(3,5-dimethylphenyl)-3(Z) indolylidene)methylaminophenyl}propenoic acid (Compound 175) [0273] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 13.48 (br s, 1H), 11.06 (d, J = 12.6, 1H), 10.61 (s, 1H), 8.84 (d, J = 12.6, 1H), 7.85 (s, 1H), 7.78-7.73 (m, 3H), 7.41 (d, J = 7.4, 1H), 7.10-7.05 (m, 5H), 6.84 (m, 1H), 2.36 (s, 6H). Example 76 O OH CI 'N HO HN 0 N FF F 2-Chloro-3(Z)- { 3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,4 dimethylphenyl)-3(Z)-indolylidene)methylaminophenyl}propenoic acid (Compound 176) [0274] This compound was prepared as described in Scheme VIII. IH NMR (500 MHz, DMSO-d 6 ) 13.53 (s, 1H), 11.22 (d, J= 13.2, 1H), 10.72 (s, 1H), 9.08 (d, J= 13.2, 1H), 7.95 (d,J = 7.8, 1H), 7.87 (s, 1H), 7.81 (d,J = 8.5, 1H), 7.75 (d, J= 1.8, 1H), 7.44 (m, 1H), 7.43 (dd, J = 8.5, 1.8, 1H), 7.36 (d, J = 8.0, 1H), 7.28 (d, J = 2.1, 1H), 7.21 (dd, J = 8.0, 2.1, 1H), 6.92 (m, 1H), 2.32 (s, 3H), 2.31 (s, 3H). Example 77 - 135- WO 2007/062078 PCT/US2006/045129 O OH HO HN 0 N F F F 2-Ethyl-3 (E)- {3 -hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,4 dimethylphenyl)-3 (Z)-indolylidene)methylaminophenyl } propenoic acid (Compound 177) 10275] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, acetone-d6) 11.42 (d, J = 12.9, IH), 9.53 (s, 1H), 8.93 (d, J= 12.9, 1H), 7.87 (d, J= 8.1, 1H), 7.73 (d, J = 8.1, 1H), 7.59 (s, 1H), 7.38 (m, 1H), 7.36 (d, J = 8.1, 1H), 7.32 (d, J = 2.1, 1H), 7.25 (dd, J = 8.1, 2.1, 1H), 7.22 (d, J= 1.7, 1H), 7.11 (dd, J 8.1, 1.7, 1H), 7.06 (m, 1H), 2.59 (q, J = 7.4, 2H), 2.36 (s, 6H), 1.19 (t, J= 7.4, 3H). Example 78 O OH HO HN 0 N' F F F 2-Ethyl-3(E)- { 3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1-(3,5 dimethylphenyl)-3(Z)-indolylidene)methylaminophenyl}propenoic acid (Compound 178) [0276] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, acetone-d6) 11.42 (d, J = 12.8, 1H), 9.54 (s, 1H), 8.94 (d, J = 12.8, 1H), 7.87 (d, J = 8.0, 1H), 7.74 (d, J = 8.5, 1H), 7.59 (s, 1H), 7.38 (dq, J = 8.0, 0.9, 1H), 7.22 (d, J - 1.7, 1H), 7.16 (min, 2H), 7.13 (m, 1H), 7.11 (dd, J= 8.5, 1.7, 1H), 7.08 (s, 1H), 2.59 (q, J= 7.4, 2H), 2.40 (m, 6H), 1.19 (t, J = 7.4, 3H). Example 79 - 136- WO 2007/062078 PCT/US2006/045129 0 OH HO H O 2-Ethyl-3(E)-{3-hydroxy-4-(2-oxo-2,3-dihydro-1 -(3,5-dimethylphenyl)-3(Z) indolyiidene)methylaminophenyl}propenoic acid (Compound 179) [0277] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, acetone-d6) 11.24 (d, J = 12.3, 1H), 9.40 (br s, 1H), 8.71 (d, J = 12.3, 1H), 7.70 (m, 1H), 7.67 (d, J = 8.4, 1H), 7.59 (s, 1H), 7.21 (d, J = 1.8, 1H), 7.14 (m, 2H), 7.11-7.02 (m, 4H), 6.90 (m, 1H), 2.60 (q, J= 7.4, 2H), 2.39 (s, 6H), 1.19 (t,J = 7.4, 3H). Example 80 0 OH HO HN o N-N 4-{2-Hydroxy-3-(4(Z)-(2-(3,4-dimethylphenyl)-3-oxo-3,4-dihydro-5 methyl)pyrazolidene)methylaminophenyl}butanoic acid (Compound 180) [0278] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, methanol-d 4 ) 8.46 (s, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.3, 1H), 7.43 (m, 1H), 7.14 (d, J = 8.3, 1H), 7.01-6.88 (m, 2H), 6.92 (t, J = 7.3, 1H), 2.70 (t, J = 7.3, 2H), 2.35 (t, J = 7.3, 2H), 2.31 (s, 3H), 2.29 (s, 3H), 2.25 (s, 3H), 1.87 (qn, J= 7.3, 2H). Example 81 HO HN O N 0 0 HO -137 - WO 2007/062078 PCT/US2006/045129 (Z)-4-{ 1-(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl}butanoic acid (Compound 181) [0279] This compound was prepared as described in Scheme VIII. 'H NMR (300 MHz, CDC1 3 ) 10.08 (d, J= 12.8, 1H), 7.30 (dt, J = 12.8, 0.8, 1H), 7.06 (s, 3H), 7.03 (dd, J = 7.8, 1.8, 1H), 6.95 (t, J = 7.8, 1H), 6.89 (dd, J = 7.8, 1.8, 1H), 3.64 (t, J= 6.8, 2H), 3.35 (d, J = 0.8, 2H), 2.40 (t, J= 7.4, 2H), 2.37 (s, 6H), 1.97 (m, 2H). Example 82 NZ OH NH 0 00 HO (E)-4-{ 1-(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl}butanoic acid (Compound 182) [0280] This compound was prepared as described in Scheme VIII. lH NMR (500 MHz, CDCI 3 ) 7.91 (dt, J= 13.8, 1.5, 1H), 7.13 (dd, J= 7.8, 1.6, 1H), 7.06 (s, 1H), 7.04 (s, 2H), 6.99 (t, J= 7.8, 1H), 6.90 (dd, J= 7.8, 1.6, 1H), 6.81 (d, J= 13.8, 1H), 3.64 (t, J= 6.7, 2H), 3.23 (d, J= 1.5, 2H), 2.39 (t, J 7.3, 2H), 2.38 (s, 6H), 1.96 (m, 2H). Example 83 HO HN N H0 (Z)-3- { 1 -(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl } benzoic acid (Compound 183) [0281] This compound was prepared as described in Scheme VIII. 'H NMR (300 MHz, acetone-d 6 ) 10.28 (d, J = 12.8, 1H), 8.15 (m, 1H), 8.04 (ddd, J = 7.9, 1.7, 1.2, 1H), 7.90 (s, 1H), 7.82 (dt, J= 12.8, 1.1, 1H), 7.72 (ddd, J= 7.9, 2.1, 1.2, 1H), 7.63 (t, J = 7.9, 1H), 7.34 (dd, J = 7.8, 1.5, 1H), 7.08 (m, 2H), 7.00 (m, 1H), 6.98 (t, J = 7.8, 1H), 6.86 (dd, J= 7.8, 1.5, 1H), 3.54 (d,J = 1.1, 2H), 2.33 (s, 3H), 2.33 (s, 3H). Example 84 - 138 - WO 2007/062078 PCT/US2006/045129 oI OH NH 1 N 0 N0 HOO (E)-3- { 1-(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl}benzoic acid (Compound 184) [0282] This compound was prepared as described in Scheme VIII. 'H NMR (300 MHz, acetone-d 6 ) 8.12 (in, 1H), 8.04 (dt, J = 7.8, 1.5, 1H), 7.98 (dt, J = 13.6, 1.8, 1H), 7.84 (d, J = 13.6, 1H), 7.69 (ddd, J = 7.8, 2.0, 1.5, 1H), 7.63 (t, J = 7.8, 1H), 7.33 (dd, J= 7.8, 1.6, 1H), 7.09 (m, 2H), 7.01 (t, J= 7.8, 1H), 7.01 (m, 1H), 6.92 (dd, J= 7.8, 1.6, 1H), 3.57 (d, J= 1.8, 2H), 2.34 (m, 6H). Example 85 0 OH sN SO N- OH 4- {3-(4-Oxo-2-thioxo-5-(3-(3,5-dimethylphenyl)-2 hydroxypheny)hydrozono)thiazolidinyl}butanoic acid (Compound 185) 10283] This compound was prepared as described in Scheme I. 1H NMR (500 MHz, methanol-d 4 ) 8.51 (s, 1H), 7.13-7.09 (m, 2H), 7.02-6.89 (m, 3H), 4.21 (m, 2H), 2.36 (s, 3H), 2.35 (s, 3H), 2.33 (m, 2H), 2.03 (m, 2H). Example 86 HO . 0 HN 0 N CI 3-{2-(3(Z)-(1-(3,5-Dimethylphenyl)-6-chloro-2-oxo-2,3 dihydroindolidene)methylamino)phenylamino}benzoic acid (Compound 186) - 139- WO 2007/062078 PCT/US2006/045129 (0284] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 10.96 (d, J = 13.0, 1H), 8.90 (d, J = 13.0, 1H), 7.94 (m, 1H), 7.82 (m, 1H), 7.75 (d, J = 8.2, 1H), 7.34-7.28 (m, 2H), 7.27-7.24 (m, 2H), 7.24 (t, J = 7.8, 1H), 7.13 (td, J = 7.6, 1.2, 1H), 7.10 (dd, J = 8.2, 2.0, 1H), 7.07 (m, 1H), 6.97 (m, 2H), 6.93 (m, 1H), 6.68 (d, J = 2.0, 1H), 2.32 (s, 6H). Example 87 HO - N "P H 0 HN 0 N' F F F 3-{2-(3-(1-(3,5-Dimethylphenyl)-6-trifluoromethyl-2-oxo- 2
,
3 dihydroindolidene)methylamino)phenylamino}benzoic acid (Compound 187) [02851 This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 11.13 (d, J = 13.2, 1H), 9.07 (d, J= 13.2, 1H), 7.99 (s, 1H), 7.95 (d, J = 8.0, 1H), 7.88 (m, 1H), 7.42 (dd, J = 8.0, 1.0, 1H), 7.34 (td, J = 7.5, 1.1, 1H), 7.32-7.26 (m, 3H), 7.25 (t, J= 7.6, 1H), 7.17 (td, J= 7.5, 1.1, 1H), 7.10 (m, IH), 7.00 (m, 2H), 6.95 (m, 1H), 6.86 (d, J = 1.0, 1H), 2.33 (s, 6H). Example 88 HON 0 HN 0 N-N 3- { 2-(4-(2-(3,5-Dimethylphenyl)-5-methyl-3-oxo-3,4 dihydropyrazolidene)methylamino)phenylamino}benzoic acid (Compound 188) [02861 This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 11.50 (d, J = 12.0, 1H), 8.66 (d, J = 12.0, 1H), 8.08 (s, 1H), 7.86 (m, 1H), 7.67 (d, J = 2.0, 1H), 7.62 (dd, J = 8.3, 2.0, 1H), 7.38-7.33 (m, 2H), 7.32-7.29 (m, 2H), 7.30 (t, J = 7.7, 1H), 7.23 (td, J = 7.6, 1.3, 1H), 7.10 (d, J = 8.3, 1H), 7.02 (m, 1H), 2.28 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H). Example 89 - 140 - WO 2007/062078 PCT/US2006/045129 0 o HO HO 0 F N (+)-3-Methyl-5- {2-hydroxy-3-(3(Z)-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolylidene)methylamrnino)phenyl}pentanoic acid (Compound 189) 10287] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 11.29 (d, J = 13.4, 1H), 9.01 (d, J = 13.4, 1H), 7.94 (d, J = 8.0, 1H), 7.58 (dd, J= 8.0, 1.5, IH), 7.41 (dq, J = 8.0, 0.7, 1H), 7.13 (m, 1H), 7.10 (m, 2H), 6.95-6.91 (m, 2H), 6.89 (dd, J= 7.7, 1.5, 1H), 2.71-2.58 (m, 2H), 2.37 (s, 6H), 2.31 (dd, J = 15.0, 5.5, 1H), 2.04 (dd, J= 15.0, 8.5, 1H), 1.87 (m, 1H), 1.56 (m, 1H), 1.42 (m, 1H), 0.95 (d, J = 6.6, 3H). Example 90 N 0 N H0 2 / (-)-3-{ l-(6-Chloro-2-oxo-2,3-dihydro-3-(3(Z)-(1-(3,5-dimethylphenyl)-2-oxo-2,3 dihydro)indolyl)aminomethylidene)indolyl}benzoic acid (Compound 190) [0288] This compound was prepared as described in Scheme III. IH NMR (500 MHz, DMSO-d 6 ) 13.20 (s, 1H), 7.93 (ddd, J = 7.8, 1.6, 1.1, 1H), 7.73 (m, 1H), 7.58 (t, J = 7.8, 1H), 7.35 (m, 1H), 7.30 (dd, J = 7.8, 1.8, 1H), 7.23 (td, J = 7.7, 1.2, 1H), 7.14 7.08 (m, 4H), 7.00 (s, 2H), 6.89 (t, J = 7.7, 1H), 6.67 (d, J = 7.8, 1H), 6.63 (d, J = 2.0, 1H), 6.31 (m, 1H), 2.33 (s, 6H). Example 91 - 141 - WO 2007/062078 PCT/US2006/045129 HO / O HO N 0 HN F \ / F 3-{4-(3-Hydroxy-6-methyl-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-1 -(3,5 dimethylphenyl)indolyl)hydrazono)pyridinyl}benzoic acid (Compound 191) [0289] This compound was prepared as described in Scheme IX. 'H NMR (300 MHz, DMSO-d 6 ) 8.52 (s, 1H), 8.16 (m, 1H), 7.98 (m, 1H), 7.96 (m, 1H), 7.60-7.52 (m, 2H), 7.59 (t,J = 7.8, IH), 7.20-7.16 (m, 3H), 6.98 (s, 1H), 2.50 (s, 3H), 2.37 (s, 6H). Example 92 HO / O HO .- N HN 0 F F 3- {4-(3-Hydroxy-6-methyl-2-(3(Z)-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolidene)methylamino)pyridinyl}benzoic acid (Compound 192) [0290] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 9.06 (s, 1H), 8.55 (s, 1H), 8.20 (m, 1H), 7.99 (d, J = 7.8, 1H), 7.93 (d, J = 7.8, 1H), 7.61 (s, 1H), 7.56 (t, J = 7.8, IH), 7.48 (d, J 7.8, 1H), 7.13 (m, 1H), 7.11 (m, 2H), 6.94 (m, 1H), 2.50 (s, 3H), 2.37 (s, 6H). Example 93 HO N 0 HO N HN N F SF 3-{4-(3-Hydroxy-2-(3(Z)-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolidene)methylamino)pyridinyl}benzoic acid (Compound 193) - 142 - WO 2007/062078 PCT/US2006/045129 (0291] This compound was prepared as described in Scheme VIII. 1H NMR (500 MHz, DMSO-d 6 ) 9.13 (d, J = 12.9, 1H), 8.52 (s, 1H), 8.24 (m, 1H), 8.17 (m, 1H), 8.03-7.99 (m, 2H), 7.84 (m, 1H), 7.65 (t, J = 7.7, 1H), 7.50 (dq, J = 7.9, 0.6, 1H), 7.14 (m, 1H), 7.12 (m, 2H), 6.95 (q, J= 0.8, 1H), 2.37 (s, 6H1). Example 94 HO N 0 I -N H NO N HN F 3-{4-(3-Hydroxy-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1-(3,5 dimethylphenyl)indolyl)hydrazono)pyridinyl}benzoic acid (Compound 194) [0292] This compound was prepared as described in Scheme IX. 'H NMR (500 MHz, DMSO-d 6 ) 13.22 (s, 1H), 8.50 (s, 1H), 8.21 (m, IH), 8.16 (d, J = 7.7, 1H), 8.04 (d, J = 7.8, 1H), 8.01 (d, J = 7.7, 1H), 7.80 (d, J = 5.4, 1H), 7.68 (t, J = 7.7, 1H), 7.60 (dq, J= 7.8, 0.7, IH), 7.19 (m, 1H), 7.17 (m, 2H), 6.98 (m, 1H), 2.37 (s, 3H), 2.37 (s, 3H). Example 95 HO HO HN O N F F 3-{5-(4-Hydroxy-3-(3(Z)-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolidene)methylamino)pyridinyl}benzoic acid (Compound 195) [0293] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 11.10 (d, J = 13.8, IH), 8.95 (d, J = 13.8, 1H), 8.39 (t, J = 1.7, 1H), 8.35 (d, J = 1.3, 1H), 8.10 (d, J = 1.3, 1H), 7.98 (ddd, J = 7.7, 1.7, 1.2, 1H), 7.88 (ddd, J= 7.7, 1.7, 1.2, 1H), 7.86 (d, J= 7.9, 1H), 7.53 (t, J= 7.7, 1H), 7.43 (dq, J = 7.9, 0.9, 1H), 7.12 (m, 1H), 7.10 (m, 2H), 6.94 (m, 1H), 2.37 (s, 6H). Example 96 - 143 - WO 2007/062078 PCT/US2006/045129 HO / ' N HO HN.N N F FF 3-{ 5-(4-Hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolyl)hydrazono)pyridinyl}benzoic acid (Compound 196) [0294] This compound was prepared as described in Scheme IX. 'H NMR (300 MHz, DMSO-d 6 ) 12.91 (s, 1H), 8.39 (t,J= 1.7, 1H), 8.17 (d,J= 1.4, 1H), 8.06 (d, J = 1.4, IH), 7.99 (m, 1H), 7.94-7.86 (m, 2H), 7.53 (m, 1H), 7.53 (t, J = 7.7, 1H), 7.18 7.15 (m, 3H), 6.97 (m, 1H), 2.37 (s, 6H). Example 97 HO N HO HN. N N o N-N 3- { 5-(4-Hydroxy-3-(4-(3-oxo-3,4-dihydro-5-methyl-2-(3,4 dimethylphenyl)pyrazolyl)hydrazono)pyridinyl}benzoic acid (Compound 197) [0295] This compound was prepared as described in Scheme IX. IH NMR (500 MHz, DMSO-d 6 ) 13.43 (s, 1H), 12.99 (s, 1H), 12.33 (s, 1H), 8.40 (t, J = 1.6, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 7.99 (m, 1H), 7.91 (m, 1H), 7.71 (m, 1H), 7.63 (dd, J = 8.1, 1.9, 1H), 7.55 (t, J = 7.7, IH), 7.21 (d, J = 8.1, 1H), 2.31 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H). Example 98 OH N-N NN O N-NH - 144 - WO 2007/062078 PCT/US2006/045129 4-{2-(3-oxo-3,4-dihydro-5-methyl-4-(3-(3,4 dimethylphenyl)phenyl)hydrozono)pyrazolyl } butanoic acid (Compound 198) [0296] This compound was prepared as described in Scheme I. 1H NMR (300 MHz, CDCl 3 ) 13.45 (s, 1H), 7.58 (s, IH), 7.47-7.31 (m, 4H), 7.26 (s, 1H), 7.22 (d, J = 7.7, 1H), 3.84 (t, J = 6.8, 2H), 2.42 (t, J = 6.8, 2H), 2.34 (s, 3H), 2.07 (qn, J= 6.8, 2H), 2.31 (s, 3H), 2.27 (s, 3H). Example -99 HO
H
2 N HN 0 NF F 3- {2-Amino-5-mnethyl-3-(3(Z)-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolylidene)methylamino)phenyl }benzoic acid (Compound 1991 [0297] This compound was prepared as described in Scheme VIII. H NMR (500 MHz, DMSO-d 6 ) 10.91 (d,J= 13.1, 1H), 8.94 (d, J= 13.1, 1H), 7.98-7.93 (m, 3H), 7.65 (m, IH), 7.62 (t, J = 7.6, 1H), 7.43-7.40 (m, 2H), 7.12 (m, 1H), 7.09 (m, 2H), 6.93 (d, J= 1.4, 1H), 6.81 (m, 1H), 4.38 (br s, 2H), 2.36 (s, 6H), 2.33 (s, 3H). Example 100 HN 0 N HO 3- { 1-(5-Fluoro-2-oxo-2,3-dihydro-3(Z)-(3-(3,4 dimethylphenyl)phenyl)aminomethylidene)indolyl } benzoic acid (Compound 200) [0298] This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 13.23 (s, 1H), 10.85 (d,J = 12.8, 1H), 8.96 (d,J= 12.8, 1H), 8.06 (m, 1H), 7.99 (m, IH), 7.82-7.78 (m, 2H), 7.74-7.69 (m, 2H), 7.56 (s, 1H), 7.51-7.39 (m, 4H), 7.26 (d, J= 7.8, 1H), 6.94-6.86 (m, 2H), 2.32 (s, 3H), 2.28 (s, 3H). Example 101 - 145 - WO 2007/062078 PCT/US2006/045129 0 N -N 0 4- { 2-(5-Methyl-2-oxo-2,3-dihydro-4(Z)-(3-(3,4 dimethylphenyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 201) 10299] This compound was prepared as described in Scheme VIII. 1 H NMR (300 MHz, methanol-d 4 ) 8.52 (s, 1H), 7.63 (s, 1H), 7.49-7.43 (m, 2H), 7.41-7.30 (m, 2H), 7.23-7.09 (m, 2H), 3.80 (t, J= 6.8, 2H), 2.34 (s, 3H), 2.30 (s, 3H), 2.28 (mi, 2H), 2.26 (s, 3H), 2.01 (qn, J = 6.8, 2H). Example 102 .~F OH O l O= HO HN 0 N' F F (3-(5-Fluoro-2-hydroxy-3-(3(Z)-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,4 dimethylphenyl)indolidene)methylamino)- 1I-pyrazolyl)acetic acid (Compound 202) 10300] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 13.26 (s, 1H), 11.35 (s, 1H), 11.26 (d, J = 13.0, 1H), 9.06 (d, J = 13.0, 1H), 7.97 (d, J= 2.4, 1H), 7.93 (d, J = 7.9, 1H), 7.71 (dd, J = 10.3, 2.8, 1H), 7.46 (dq, J = 7.9, 0.9, 1H), 7.42 (dd, J = 9.5, 2.8, 1H), 7.36 (d, J = 8.0, 1H), 7.29 (d, J = 2.1, 1H), 7.22 (dd, J= 8.0, 2.1, 1H), 7.03 (d, J= 2.4, 1H), 6.94 (m, 1H), 5.15 (s, 2H), 2.32 (s, 3H), 2.31 (s, 3H). Example 103 OH q HN (3-(5-Fluoro-2-hydroxy-3-(3(Z)-(2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolidene)methylamino)-1-pyrazolyl)acetic acid (Compound 203) - 146- WO 2007/062078 PCT/US2006/045129 [0301] This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 13.26 (s, 1H), 11.30 (s, 1H), 11.13 (d, J= 12.7, 1H), 8.83 (d, J= 12.7, 1H), 7.96 (d,J = 2.4, 1H), 7.75 (m, 1H), 7.66 (dd, J= 10.4, 2.8, 1H), 7.35 (dd, J= 9.6, 2.8, 1H), 7.11-7.07 (m, 5H), 7.01 (d,J= 2.4, IH), 6.87 (m, 1H), 5.14 (s, 2H), 2.36 (s, 6H). Example 104 OH 0 NN 0 HN OH 4-{2-(5-Methyl-2-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2 phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 204) 10302] This compound was prepared as described in Scheme VIII. 'H NMR (300 MHz, methanol-d 4 ) 8.47 (s, 1H), 7.42 (m, 1H), 7.28-7.14 (m, 5H), 6.94-6.85 (m, 2H), 3.81 (t, J= 6.7, 2H), 3.02-2.84 (m, 4H), 2.32 (t, J= 7.6, 2H), 2.26 (s, 3H), 2.00 (m, 2H). Example 105 H 0 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 phenyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 205) [0303] This compound was prepared as described in Scheme VII. 'H NMR (300 MHz, methanol-d4) 7.54 (m, 1H), 7.28-7.12 (m, 5H), 6.92-6.84 (m, 2H), 3.79 (t, J= 6.8, 2H), 3.00-2.84 (m, 4H), 2.34 (t, J = 7.4, 2H), 2.26 (s, 3H), 2.01 (m, 2H). Example 106 - 147 - WO 2007/062078 PCT/US2006/045129 OH 0 N NN 0 HN OH 4-{2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(4 methyl)phenyl)ethyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 206) 10304] This compound was prepared as described in Scheme VII. 'IH NMR (300 MHz, methanol-d 4 ) 7.53 (m, 1H), 7.11-7.03 (m, 4H), 6.91-6.86 (m, 2H), 3.79 (t, J= = 6.6, 2H), 2.93 (m, 2H), 2.85 (m, 2H), 2.34 (t, J= 7.3, 2H), 2.28 (s, 3H), 2.26 (s, 3H), 2.01 (m, 2H). Example 107 OH N N 0 N HN OH 4-{2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3 methyl)phenyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 207) [03051 This compound was prepared as described in Scheme VII. 'H NMR (300 MHz, methanol-d 4 ) 7.53 (m, 1H), 7.12 (m, 1H), 7.04-6.87 (m, 5H), 3.79 (t, J = 6.6, 2H), 2.98-2.82 (m, 4H), 2.34 (t, J = 7.3, 2H), 2.29 (s, 3H), 2.26 (s, 3H), 2.01 (m, 2H). Example 108 OH N-N 0 'N HN OH 4- { 2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 methyl)phenyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 208 [0306] This compound was prepared as described in Scheme VII. H NMR (300 MHz, methanol-d 4 ) 7.54 (m, 1H), 7.16-7.04 (m, 4H), 6.93-6.84 (m, 2H), 3.80 (t, J = 6.7, 2H), 2.90 (m, 4H), 2.34 (t, J = 7.3, 2H), 2.28 (s, 3H), 2.26 (s, 3H), 2.01 (rn, 2H). - 148 - WO 2007/062078 PCT/US2006/045129 Example 109 OH N-N N.NH OH 4-{2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(1 naphthyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 209) [0307] This compound was prepared as described in Scheme VII. IH NMR (300 MHz, methanol-d 4 ) 8.17 (d, J = 7.9, 1H), 7.86 (d, J = 7.9, IH), 7.71 (d, J = 7.9, 1H), 7.57-7.43 (m, 3H), 7.36 (m, 1H), 7.31 (m, 1H), 6.91-6.86 (m, 2H), 3.80 (t, J = 6.6, 2H1), 3.37 (dd, J= 9.2, 6.5, 2H), 3.09 (dd, J 9.2, 6.5, 2H), 2.35 (t, J= 7.3, 2H), 2.27 (s, 3H), 2.02 (m, 2H). Example 110
I
HO HN MNN 01 9 H0 3- { 1 -(5-Nitro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)aminomethylidene)indolyl} benzoic acid (Compound 210) [0308] This compound was prepared as described in Scheme III. 'H NMR (500 MHz, DMSO-d 6 ) 13.28 (s, 1H), 11.26 (d, J = 13.4, 1H), 9.29 (d, J= 13.4, 1H), 9.26 (s, 1H), 8.82 (d, J = 2.4, 1H), 8.06-8.03 (m, 2H), 8.02 (dd, J = 8.8, 2.4, 1H), 7.82 (ddd, J = 8.1, 2.1, 1.3, 1H), 7.79 (m, 1H), 7.75 (t, J = 8.1, 1H), 7.14 (m, 2H), 7.09 (t, J = 7.7, IH), 7.06 (d, J= 8.8, 1H), 7.01 (dd, J = 7.7, 1.5, 1H), 7.01 (m, 1H), 2.33 (s, 6H1). Example 111 - 149- WO 2007/062078 PCT/US2006/045129 F HO HN -1 9 HO O 0 o 3- { 1 -(5-Nitro-2-oxo-2,3-dihydro-3(Z)-(5-fluoro-2-hydroxy-3-(3,5 dimethylphenyl)phenyl)aminomethylidene)indolyl}benzoic acid (Compound 211) [0309] This compound was prepared as described in Scheme III. 1H NMR (300 MHz, acetone-d 6 ) 11.43 (d, J = 13.3, 1H), 9.15 (d, J = 13.3, 1H), 8.67 (d, J = 2.3, 1H), 8.24 (t, J = 1.7, 1H), 8.15 (m, 1H), 8.08 (dd, J = 8.8, 2.3, 1H), 7.88 (m, 1H), 7.78 (t, J = 7.8, IH), 7.66 (dd, J = 10.0, 2.9, 1H), 7.14 (m, 2H), 7.14 (d, J = 8.8, 1H), 7.04 (m, 1H), 6.78 (dd, J= 9.2, 2.9, 1H), 2.34 (s, 6H). Example 112 0 o') HO HN 0 N 2-Hydroxy-3-{3(Z)-(2-oxo-2,3-dihydro-1l-(3,5 dimethylphenyl)indolidene)methylamino}benzoic acid (Compound 212) [03101 This compound was prepared as described in Scheme VIII. 'H NMR (500 MHz, DMSO-d 6 ) 11.02 (d, J= 12.8, 1H), 8.84 (d, J= 12.8, 1H), 7.96 (dd, J= 8.1, 1.5, 1H), 7.74 (mn, IH), 7.52 (dd, J = 8.1, 1.5, 1H), 7.10-7.06 (m, 5H), 7.04 (t, J = 8.1, 1H), 6.85 (m, iH), 2.36 (s, 3H), 2.36 (s, 3H). Example 113 o HO HN 0 N' F F F 2-Hydroxy-3-{3(Z)-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolidene)methylamino}benzoic acid (Compound 213) - 150 - WO 2007/062078 PCT/US2006/045129 [03111 This compound was prepared as described in Scheme VIII. 1H NMR (500 MHz, DMSO-d 6 ) 11.18 (d, J 12.9, 1H), 9.07 (d, J = 12.9, 1H), 8.00 (dd, J = 8.0, 1.4, 1H), 7.93 (d, J = 7.8, 1H), 7.57 (dd, J = 8.0, 1.4, 1H), 7.44 (dq, J= 7.8, 0.9, 1H), 7.36 (d, J= 8.1, 1H), 7.28 (d, J = 2.1, 1H), 7.21 (dd, J= 8.1, 2.1, 1H), 7.06 (t, J = 8.0, 1H), 6.92 (m, 1H), 2.32 (s, 3H), 2.31 (s, 3H). Example 114 o 0 N-N 0 4- { 2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3-methyl-i (Z) butenyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 214) 10312] This compound was prepared as described in Scheme VIII. 'H NMR (300 MHz, methanol-d 4 ) 8.49 (s, 1H), 7.49 (d, J= 7.6, 1H), 7.02-6.90 (m, 2H), 6.30 (d, J = 11.1, 1H), 5.65 (dd, J= 11.1, 10.3, 1H), 3.80 (t, J= 6.7, 2H), 2.66 (m, 1H), 2.31 (t, J= 7.5, 2H), 2.27 (s, 3H), 2.00 (m, 2H), 1.01 (d, J = 6.7, 6H). Example 115 0 N-N OH HN.N OH 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3 heptanylphenyl)hydrazono)pyrazolyl } butanoic acid (Compound 215) [0313] This compound was prepared as described in Scheme VII. 1H NMR (300 MHz, methanol-d4) 7.53 (dd, J = 7.6, 1.5, IH), 6.97 (dd, J=. 7.6, 1.5, IH), 6.91 (t, J = 7.6, 1H), 3.79 (t, J= 6.7, 2H), 2.65 (t, J = 7.7, 2H), 2.34 (t, J = 7.3, 2H), 2.26 (s, 3H), 2.01 (m, 2H), 1.60 (m, 2H), 1.42-1.27 (m, 8H), 0.90 (t, J= 6.8, 3H). Example 116 - 151 - WO 2007/062078 PCT/US2006/045129 rfo 01 NN 0 N-N 0 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3(Z)-(2-(4 methyl)phenyl)ethenylphenyl)hydrazono)pyrazolyl}butanoic acid (Compound 216) [0314] This compound was prepared as described in Scheme VII. 'H NMR (300 MHz, methanol-d 6 ) 7.60 (d, J = 7.9, 1H), 7.50-7.41 (m, 4H), 7.21-7.08 (m, 3H), 7.01 (t, J = 7.9, 1H), 3.79 (t, J = 6.6, 2H), 2.34 (s, 3H), 2.34 (t, J= 7.3, 2H), 2.27 (s, 3H), 2.01 (m, 2H). Example 117 0 -N N 0 N-N 0 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3(Z)-(2-(3-methyl)phenyl) ethenylphenyl)hydrazono)pyrazolyl}butanoic acid (Compound. 217) 10315] This compound was prepared as described in Scheme VII. 'H NMR (300 MHz, methanol-d 4 ) 7.59 (d, J = 7.8, IH), 7.09-6.95 (m, 4H), 6.88 (d, J = 7.8, 1H), 6.79 (t, J = 7.8, 1H), 6.73 (d, J = 12.2, IH), 6.59 (d, J = 12.2, IH), 3.79 (t, J = 6.7, 2H), 2.34 (t, J= 7.3, 2H), 2.27 (s, 3H), 2.20 (s, 3H), 2.01 (m, 2H). Example 118 OH 0 =0 c3 o N-j OH 4-{I-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2-methyl)phenyl)ethylphenyl) hydrazono)indolyl}butanoic acid (Compound 218) [03161 This compound was prepared as described in Scheme VII. 'H NMR (500 MHz, DMSO-d 6 ) 13.04 (s, 1H), 9.13 (br s, 1H), 7.61 (dd, J = 7.7, 0.7, 1H), 7.51 (dd, J = 7.7, 1.6, 1H), 7.33 (td, J = 7.7, 1.2, 1H), 7.23 (m, 1H), 7.20 (d, J = 7.7, T H), 7.16 - 152- WO 2007/062078 PCT/US2006/045129 7.07 (n, 4H), 6.91 (t, J= 7.7, 1H), 6.83 (dd, J= 7.7, 1.5, 1H), 3.84 (t, J= 7.1, 2H), 2.89 2.79 (m, 4H), 2.32 (t, J= 7.1, 2H), 2.29 (s, 3H), 1.88 (qn, J= 7.1, 2H). Example 119
S
HO HN. N 0 HO 2-{ 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl)phenyl) hydrazono)indolyl}acetic acid (Compound 219) (0317] This compound was prepared as described in Scheme II. 1 H NMR (500 MHz, methanol-d 4 ) 7.66 (dd, J = 7.7, 1.6, 1H), 7.65 (m, 1H), 7.27 (td, J = 7.7, 1.1, 1H), 7.14-7.10 (m, 3H), 7.01 (m, IH), 6.99 (t, J = 7.7, 1H), 6.95 (d, J= 7.7, 1H), 6.89 (dd, J= 7.7, 1.6, 1H), 4.55 (s, 2H), 2.36 (s, 6H). Example 120 HN. N o 0 N SO HO 2-{ 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2-methyl)phenyl)ethylphenyl) hydrazono)indolyl} acetic acid (Compound 220) [0318] This compound was prepared as described in Scheme VII. 'H NMR (500 MHz, DMSO-d 6 ) 12.95 (s, 1H), 9.16 (s, 1H), 7.62 (dd, J = 7.6, 1.0, 1H), 7.53 (dd, J = 7.7, 1.6, 1H), 7.30 (td, J = 7.6, 1.2, 1H), 7.23 (m, 1H), 7.16-7.07 (m, 5H), 6.91 (t, J = 7.7, 1H), 6.84 (dd, J 7.7, 1.6, 1H), 4.59 (s, 2H), 2.89-2.79 (m, 4H), 2.29 (s, 3H). Example 121 - 153 - WO 2007/062078 PCT/US2006/045129 0 HO N ys HN 0 N F >F F 4-{4-(2-(3(Z)-(6-Trifluoromethyl-2-oxo-2,3-dihydro-1-(3,4-dimethylphenyl) indolylidene)methylamino)thiazolyl}benzoic acid (Compound 221) 10319] This compound was prepared as described in Scheme VIII. 1 H NMR (500 MHz, DMSO-d 6 ) 12.99 (s, 2H), 11.83 (d, J = 12.2, 1H), 11.39 (d, J = 12.2, 1H), 8.95 (d, J= 12.2, 1H), 8.56 (d, J= 12.2, 1H), 8.32 (d, J= 7.8, 1H), 8.16 (d, J = 8.5, 2H), 8.08 (d, J= 8.5, 2H), 8.08 (m, 1H), 8.03 (d, J = 8.5, 2H), 8.02 (d, J= 8.5, 2H), 7.93 (s, 1H), 7.91 (s, 1H), 7.51 (d, J = 7.8, 1H), 7.44 (dq, J = 7.8, 0.9, 1H), 7.37 (d, J = 7.9, IH), 7.36 (d, J= 7.9, 1H), 7.30 (d, J = 2.1, 1H), 7.24 (d, J = 2.1, 1H), 7.23 (dd, J = 7.9, 2.1, 1H), 7.18 (dd, J = 7.9, 2.1, 1H), 6.91 (m, 1H), 6.85 (m, 1H), 2.32 (s, 3H), 2.31 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H). Example 122 HN N N00 3- { 1 -(5-Nitro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-5-methyl-3-( 1 -adamantane)phenyl) aminomethylidene)indolyl}benzoic acid (Compound 222) 10320] This compound was prepared as described in Scheme III. 1 H NMR (500 MHz, DMSO-d 6 ) 13.28 (s, IH), 11.22 (d, J = 13.7, 1H), 9.19 (d, J = 13.7, 1H), 8.81 (d, J = 2.4, 1H), 8.40 (s, 1H), 8.09-8.04 (m, 2H), 8.01 (dd, J = 8.8, 2.4, IH), 7.83-7.73 (m, 2H), 7.50 (d, J = 1.5, 1H), 7.07 (d, J = 8.8, 1H), 6.79 (d, J = 1.5, 1H), 2.33 (s, 3H), 2.09-2.06 (m, 6H), 2.05-2.02 (m, 3H), 1.75-1.72 (m, 6H). Example 123 - 154 - WO 2007/062078 PCT/US2006/045129 O N
I
H HN, 0 N 3-{ 1-(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(4-hydroxy-5-(3,4-dimethylphenyl) pyridinyl)hydrazono)indolyl}benzoic acid (Compound 223) [0321] This compound was prepared as described in Scheme I. 'H NMR (500 MHz, methanol-d 4 ) 8.25 (s, 1H), 8.11 (dt, J = 7.7, 1.6, 1H), 8.07 (t, J= 1.6, 1H), 7.90 (d, J = 7.8, 1H), 7.82 (m, 1H), 7.66 (t, J = 7.7, 1H), 7.62 (m, 1H), 7.48 (m, 1H), 7.42 (m, 1H), 7.34 (m, 1H), 7.17 (d, J= 7.8, 1H), 7.08 (br s, 1H), 2.30 (s, 3H), 2.28 (s, 3H). Example 124 OH 0 N 0 >OH 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-methyl)phenyl) ethylphenyl)aminomethylidene)pyrazolyl }butanoic acid (Compound 224) [0322] This compound was prepared as described in Scheme VIII. 'H NMR (300 MHz, methanol-d 4 ) 8.47 (s, 1H), 7.43 (m, IH), 7.15-7.03 (m, 4H), 6.93-6.86 (m, 2H), 3.81 (t, J = 6.8, 2H), 2.90 (m, 4H), 2.32 (t, J = 7.4, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 2.00 (m, 2H). Example 125 OH N-N 0 NH OH F 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-fluoro)phenyl) ethylphenyl)aminomethylidene)pyrazolyl} butanoic acid (Compound 225) - 155 - WO 2007/062078 PCT/US2006/045129 [0323] This compound was prepared as described in Scheme VIII. 'H NMR (300 MHz, methanol-d 4 ) 8.47 (s, 1H), 7.43 (m, 1H), 7.23-7.14 (m, 2H), 7.07-6.97 (m, 2H), 6.90-6.85 (m, 2H), 3.81 (t, J 6.8, 2H), 2.96 (m, 4H), 2.32 (t, J= 7.3, 2H), 2.26 (s, 3H), 2.00 (m, 2H). Example 126 0 N-N O N 70 [0324] 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-( 1 naphthyl)ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 226) 10325] This compound was prepared as described in Scheme VIII. 'H NMR (500MHz, DMSO) 8.48 (s, 1H), 8.17 (d, J= 8.6 Hz, 1H), 7.85 (d, J= 7.4 Hz, 1H), 7.71 (d, J= 7.4 Hz, 1H), 7.55-7.28 (m, 5H), 6.91-6.88 (m, 2H), 3.82 (t, J= 6.7 Hz, 2H), 3.37 (dd, J = 9.3, 6.4 Hz, 2H), 3.10 (dd, J 9.3, 6.4 Hz, 2H), 2.33 (t, J= 7.5 Hz, 2H), 2.27 (s, 31-), 2.01 (m, 2H). Example 127 O N-N 0 N - 0 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(3,5-dimethylphenyl) ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 227) [0326] This compound was prepared as described in Scheme VIII. 'H NMR (300MHz, CD 3 OD) 8.47 (br s, 1H), 7.42 (m, 1H), 6.94-6.88 (m, 2H), 6.82-6.79 (m, 3H), 3.80 (t, J= 6.7 Hz, 2H), 2.92 (m, 2H), 2.79 (m, 2H), 2.32 (t, J= 7.5 Hz, 2H), 2.26 (s, 3H), 2.24 (s, 6H), 2.00 (m, 2H). Example 128 -156- WO 2007/062078 PCT/US2006/045129 o 0 N A 0 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-methoxyphenyl) ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 228) [0327.] This compound was prepared as described in Scheme VIII. 'H NMR (300MHz, CD 3 OD) 8.47 (s, 1H), 7.41 (mn, IH), 7.24-7.04 (m, 3H), 6.94-6.78 (m, 4H), 3.82 (s, 3H), 3.81 (m, 2H), 2.89 (s, 4H), 2.36-2.24 (m, 5H), 2.01 (m, 2H). Example 129 0 N N 0 N 0 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-fluoro-3-methyl phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl }butanoic acid (Compound 229) [03281 This compound was prepared as described in Scheme VIII. 'H NMR (300MHz, CD 3 OD) 7.47-7.30 (m, 1H), 7.07-6.85 (m, 6H), 3.82 (m, 2H), 2.98-2.88 (m, 4H), 2.30-2.20 (m, 8H), 2.00 (m, 2H). Example 130 0 NO N 0 N A 0 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-fluoro-3-methyl phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 230) [0329] This compound was prepared as described in Scheme VIII. 'H NMR (300MHz, CD 3 OD) 8.45 (s, 1H), 7.64 (d, J= 7.6 Hz, 1H), 7.56-7.32 (m, 4H), 7.16 (m, 1H), 6.91 (s, 2H), 3.81 (t, J= 6.5 Hz, 2H), 3.12-2.93 (m, 4H), 2.29 (t, J= 7.4 Hz, 2H), 2.25 (m, 3H), 2.00 (m, 2H). Example 131 -157- WO 2007/062078 PCT/US2006/045129 o f 0 N N 0 6\/ \/ 4- { 2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(4-phenylphenyl) ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 231) 10330] This compound was prepared as described in Scheme VIII. 'H NMR (300MHz, CD 3 OD) 7.59-7.56 (m, 3H), 7.51 (d, J= 7.8 Hz, 2H), 7.46-7.37 (m, 4H), 7.33 7.26 (m, 4H), 6.95-6.91 (m, 2H), 3.81 (t, J= 6.5 Hz, 2H), 3.04-2.92 (m, 4H), 2.32 (t, J= 7.7 Hz, 2H), 2.27 (s, 3H), 2.02 (m, 2H). Example 132 0 N O N 0 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-cyanophenyl) ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 232) [0331] This compound was prepared as described in Scheme VIII. 'H NMR (300MHz, CD 3 OD) 8.45 (s, 1H), 7.65 (d, J= 7.5 Hz, 1H), 7.55 (t, J= 7.5 Hz, 1H), 7.48 7.32 (m, 3H), 6.92-6.81 (m, 2H), 3.80 (t, J = 6.7 Hz, 2H), 3.13 (m, 2H), 3.05 (m, 2H), 2.30 (m, 2H), 2.26 (s, 3H), 2.01 (m, 2H). Example 133 0 N N 0 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-chlorophenyl) ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 233) [0332] This compound was prepared as described in Scheme VIII. 'H NMR (300MHz, CD 3 OD) 8.47 (s, 1H), 7.43 (m, 1H), 7.35 (m, IH), 7.24-7.14 (m, 3H), 6.93 - 158- WO 2007/062078 PCT/US2006/045129 6.85 (m, 2H), 3.81 (t, J 6.7 Hz, 2H), 3.08-2.94 (m, 4H), 2.32 (t, J= 7.5 Hz, 2H), 2.26 (s, 3H), 2.00 (m, 2H). Example 134 0 N 0 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,6-dimtethylphenyl) ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 234) [0333] This compound was prepared as described in Scheme VIII. 'H NMR (300MHz, CD 3 OD) 8.48 (s, 1H), 7.45 (m, 1H), 6.98-6.87 (m, 5H), 3.81 (t, J= 6.9 Hz, 2H), 2.93 (m, 2H), 2.83 (m, 2H), 2.32 (t, J = 7.1 Hz, 2H), 2.29 (s, 6H), 2.27 (s, 3H), 2.00 (m, 2H). Example 135 ,: C 0 2H N 0 O2 F N 0 F F 3-{2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 trifluoromethylphenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 235) [03341 This compound was prepared as described in Scheme VIII. IH NMR (300MHz, DMSO) 8.81 (s, 1H), 8.66 (dd, J = 2.2, 1.5 Hz, IH), 8.24 (ddd, J= 8.2, 2.2, 1.1 Hz, 1H), 7.84 (ddd,.J= 7.7, 1.5, 1.1 Hz, 1H), 7.78 (dd, J= 8.0, 1.6 Hz, 1H), 7.70 (m, 1H), 7.66-7.59 (m, 3H), 7.44 (m, 1H), 7.03 (dd, J= 7.7, 1.6 Hz, 1H), 6.97 (dd, J = 8.0, 7.7 Hz, 1H), 3.05-2.93 (m, 4H). Example 136 - 159 - WO 2007/062078 PCT/US2006/045129 . CO 2 H N N 0 F ~ F F 3- {2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-fluorophenyl) ethyl)phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 236) [0335] This compound was prepared as described in Scheme VIII. IH NMR (300MHz, DMSO) 9.84 (s, 1H), 8.79 (s, 1H), 8.65 (dd, J= 2.2, 1.6 Hz, 1H), 8.23 (ddd, J = 8.2, 2.2, 1.1 Hz, 1H), 7.84 (ddd, J= 7.8, 1.6, 1.1 Hz, IH), 7.75 (m, 1H), 7.62 (dd, J= 8.2, 7.8 Hz, 1H), 7.33 (m, 1H), 7.25 (m, 1H), 7.18-7.09 (m, 2H), 7.01 (dd, J= 7.8, 1.5 Hz, 1H), 6.93 (t, J= 7.8 Hz, 1H), 3.00-2.85 (m, 4H). Example 137
CO
2 H y N 0 F N O FF 3-{2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-methyl phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 237) [0336] This compound was prepared as described in Scheme VIII. 'H NMR (300MHz, DMSO) 9.80 (s, 1H), 8.80 (m, 1H), 8.65 (dd, J= 2.2, 1.5 Hz, 1H), 8.23 (ddd, J = 8.2, 2.2, 1.1 Hz, 1H), 7.84 (ddd, J= 7.8, 1.5, 1.1 Hz, 1H), 7.77 (m, 1H), 7.63 (dd, J= 8.2, 7.8 Hz, 1H), 7.22 (m, 1H), 7.17-7.05 (m, 4H), 6.96 (t,J = 7.8 Hz, 1H), 2.90 (m, 2H), 2.82 (m, 2H), 2.29 (s, 3H). Example 138 C O,H N 0 F N 0 FF 3-{2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,5-dimethyl phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 238) - 160- WO 2007/062078 PCT/US2006/045129 [0337] This compound was prepared as described in Scheme VIII. 'H NMR (300MHz, CD 3 OD) 8.65 (dd, J = 2.2, 1.6 Hz, 1H), 8.60 (s, 1H), 8.23 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 7.92 (ddd, J= 7.8, 1.6, 1.0 Hz, 1H), 7.56 (dd, J= 8.1, 7.8 Hz, 1H), 7.47 (m, 1H), 7.00-6.86 (m, 5H), 2.93 (m, 2H), 2.85 (m, 2H), 2.25 (s, 3H), 2.24 (s, 3H). Example 139 C , 0 2H F N 0 FF 3- { 2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,6-dimethyl phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 239) [0338] This compound was prepared as described in Scheme VIII. 'H NMR (300MHz, CD 3 OD) 8.66 (dd, J= 2.1, 1.6 Hz, 1H), 8.60 (s, 1H), 8.25 (ddd, J= 8.1, 2.1, 1.0 Hz, 1H), 7.92 (ddd, J = 7.7, 1.6, 1.0 Hz, 1H), 7.57 (dd, J= 8.1, 7.7 Hz, 1H), 7.48 (m, 1H), 6.99-6.94 (m, 5H), 2.95 (m, 2H), 2.85 (m, 2H), 2.31 (s, 6H). Example 140 , C2OH N N 0 0 3-{2-(5-Phenyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,5-dimethylphenyl) ethyl)phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 240) [0339] This compound was prepared as described in Scheme VIII. 'H NMR (300MHz, DMSO) 8.79 (dd, J= 2.1, 1.6 Hz, 1H), 8.69 (br s, 1H), 8.36 (ddd, J= 8.2, 2.1, 1.1 Hz, 1H), 7.94-7.89 (m, 2H), 7.78 (ddd, J= 7.8, 1.6, 1.1 Hz, 1H), 7.67-7.51 (m, 5H), 7.08-7.00 (m, 3H), 6.96-6.88 (m, 2H), 2.87 (m, 2H), 2.77 (m, 2H), 2.25 (s, 6H). Example 141 - 161 - WO 2007/062078 PCT/US2006/045129 CO2H y N 0 N 0 3-{2-(5-tert-Butyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,5-dimethylphenyl) ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 241) [0340] This compound was prepared as described in Scheme VIII. 'H NMR (300MHz, CD 3 OD) 8.65 (dd, J = 2.1, 1.7 Hz, 1H), 8.58 (s, 1H), 8.25 (m, 1H), 7.83 (m, 1H), 7.50 (t, J= 7.9 Hz, 1H), 7.36 (m, 1H), 6.99-6.84 (m, 5H), 2.95-2.80 (m, 4H), 2.24 (s, 3H), 2.23 (s, 3H), 1.47 (s, 9H). Example 142 ? COH N 0 Y2-0 NO 3- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-methylphenyl) ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 242) [0341] This compound was prepared as described in Scheme VIII. 'H NMR (500MHz, DMSO) 11.86 (d, J= 13.6 Hz, 1H), 9.50 (br s, 1H), 8.71 (d, J= 13.6 Hz, 1H), 8.66 (dd, J= 2.1, 1.6 Hz, 1H), 8.26 (ddd, J= 8.1, 2.1, 1.1 Hz, 1H), 7.71 (ddd, J= 7.7, 1.6, 1.1 Hz, 1H), 7.64 (dd, J= 8.0, 1.5 Hz, 1H), 7.53 (dd, J= 8.1, 7.7 Hz, 1H), 7.22 (m, 1H), 7.16-7.07 (m, 3H), 6.98 (dd, J= 7.6, 1.5 Hz, 1H), 6.94 (m, 1H), 2.88 (m, 2H), 2.82 (m, 2H), 2.32 (s, 3H), 2.29 (s, 3H). Example 143 CO2H N 0 N-N O 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2-(2-fluorophenyl) ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 243) - 162- WO 2007/062078 PCT/US2006/045129 [0342] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.53 (m, 1H), 7.23-7.15 (m, 2H), 7.07-6.97 (m, 2H), 6.91-6.83 (m, 2H), 3.79 (t, J = 6.6 Hz, 2H), 2.95 (s, 4H), 2.34 (t, J= 7.3 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H). Example 144 c0 2 H N 0 , N-N O 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dimethylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 244) [0343] This compound was prepared as described in Scheme VII. IH NMR (300MHz, CD 3 OD) 7.54 (m, 1H), 6.93-6.88 (m, 2H), 6.83-6.79 (m, 3H), 3.79 (t, J= 6.6 Hz, 2H), 2.92 (m, 2H), 2.80 (m, 2H), 2.34 (t, J = 7.4 Hz, 2H), 2.26 (s, 3H), 2.25 (s, 6H), 2.01 (m, 2H). Example 145 rfCO H co 2 H N 0 N-N O 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(4-phenylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 245) [0344] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.61-7.49 (m, 5H), 7.41 (t, J= 7.4 Hz, 2H), 7.33-7.26 (m, 3H), 6.96 6.87 (m, 2H), 3.80 (t, J= 6.7 Hz, 2H), 3.02-2.94 (m, 4H), 2.33 (t, J= 7.4 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H). Example 146 - 163 - WO 2007/062078 PCT/US2006/045129
CO
2 H N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methoxyphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 246) 103451 This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD30D) 7.51 (m, 1H), 7.19-7.04 (m, 2H), 6.93-6.78 (m, 4H), 3.82 (s, 3H), 3.79 (t, J= 6.8 Hz, 2H), 2.88 (s, 4H), 2.34 (t, J = 7.5 Hz, 2H), 2.25 (s, 3H), 2.01 (m, 2H). Example 147 coH 02H N-N O 4-{2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluoro-3-methylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 247) [0346] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.52 (m, 1H), 7.22-6.83 (m, 5H), 3.79 (t, J = 6.7 Hz, 2H), 2.92 (s, 4H), 2.34 (t, J= 7.5 Hz, 2H), 2.26-2.22 (m, 6H), 2.01 (qn, J= 7.0 Hz, 2H). Example 148 C0 2 H N-N N-N 0 F F 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-trifluoromethylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 248) [0347] This compound was prepared as described in Scheme VII. 1H NMR (300MHz, CD 3 OD) 7.65 (d, J = 7.6 Hz, 1H), 7.58-7.47 (in, 2H), 7.44-7.32 (m, 2H), 6.96 6.86 (m, 2H), 3.79 (t, J= 6.6 Hz, 2H), 3.07 (mn, 2H), 2.97 (m, 2H), 2.35 (t, J= 7.5 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H). Example 149 - 164 - WO 2007/062078 PCT/US2006/045129 C0 2 H N-N 0 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-cyanophenyl)ethyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 249) [0348] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, DMSO) 9.60 (s, 1H), 7.78 (d, J= 7.5 Hz, 1H), 7.64 (t, J= 7.5 Hz, 1H), 7.53 7.47 (m, 2H), 7.41 (t, J = 7.5 Hz, 1H), 6.95-6.84 (m, 2H), 3.69 (t, J= 6.6 Hz, 2H), 3.05 (m, 2H), 2.99 (m, 2H), 2.26 (t, J= 7.0 Hz, 2H), 2.20 (s, 3H), 1.86 (m, 2H). Example 150 cOH N A 0 N-N O 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-chlorophenyl)ethyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 250) [0349] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.53 (m, 1H), 7.35 (m, 1H), 7.24-7.14 (m, 3H), 6.92-6.83 (m, 2H), 3.79 (t, J= 6.7 Hz, 2H), 3.08-2.92 (m, 4H), 2.34 (t, J= 7.3 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H). Example 151 C0 2 H N-N 0 4- {2-(5-Methyl-3-ox o-2, 3 -dihydro-4-(2-hydroxy-3-(2-(2,6-dimethylphenyl) ethyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 251) [0350] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.54 (d, J= 7.6 Hz, 1H), 6.97-6.85 (m, 5H), 3.79 (t, J= 6.7 Hz, 2H), - 165- WO 2007/062078 PCT/US2006/045129 2.93 (m, 2H), 2.82 (m, 2H), 2.34 (t, J = 7.4 Hz, 2H), 2.30 (s, 6H), 2.26 (s, 3H), 2.01 (m, 2H). Example 152 C02H N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-ethylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 252) [0351] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.54 (mn, IH), 7.19-7.06 (m, 4H), 6.93-6.86 (m, 2H), 3.79 (t, J= 6.7 Hz, 2H), 2.92 (s, 4H), 2.66 (q, J= 7.5 Hz, 2H), 2.34 (t, J = 7.3 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H), 1.19 (t, J= 7.5 Hz, 3H). Example 153 O2H N 0, N-N O cI CI 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6-dichlorophenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 253) [0352] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, DMSO) 13.60 (s, 1H), 12.07 (s, 1H), 9.43 (s, 1H), 7.50-7.43 (m, 3H), 7.27 (m, 1H), 6.91 (m, 1H), 6.83 (m, 1H), 3.69 (t, J= 6.7 Hz, 2H), 3.15 (m, 2H), 2.89 (m, 2H), 2.25 (t, J= 7.6 Hz, 2H), 2.20 (s, 3H), 1.85 (m, 2H). Example 154 r-co2H -N N 0 N-N O - 166 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,5-dimethylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 254) [0353] This compound was prepared as described in Scheme VII. 1 H NMR (300MHz, CD 3 OD) 7.54 (m, 1H), 7.00-6.95 (m, 2H), 6.92-6.85 (m, 3H), 3.79 (t, J= 6.7 Hz, 2H), 2.93-2.80 (m, 4H), 2.34 (t, J= 7.4 Hz, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 2.01 (m, 2H). Example 155 rlcoH N 0 Oz N-N 0 F
F
F 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluoro-6-trifluoro methylphenyl)ethyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 255) [0354] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.56 (m, IH), 7.52 (m, 1H), 7.47-7.31 (m, 2H), 6.96-6.87 (m, 2H), 3.80 (t, J = 6.7 Hz, 2H), 3.11 (m, 2H), 2.95 (m, 2H), 2.34 (t, J= 7.4 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H). Example 156
CO,
2 H N 0 N-N 0 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indanyl)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 256) [03551 This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.55 (dd, J= 7.9, 1.5 Hz, 1H), 7.24-7.20 (m,.2H), 7.16-7.12 (m, 2H), 7.06 (dd, J= 7.9, 1.5 Hz, 1H), 6.92 (t, J = 7.9 Hz, 1H), 4.01 (m, 1H), 3.80 (t, J= 6.7 Hz, 2H), 3.35 (dd, J = 15.3, 8.2 Hz, 2H), 3.02 (dd, J= 15.3, 7.6 Hz, 2H), 2.34 (t, J = 7.4 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H). Example 157 -167- WO 2007/062078 PCT/US2006/045129 Co 2 H O N 0 N-N O 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 -(2-indenyl)phenyl) hydrazono)pyrazolyl }butanoic acid (Compound 257) [0356] - This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 12.11 (br s, 1H), 9.53 (br s, 1H), 7.59 (m, 1H), 7.52-7.45 (m, 3H), 7.36 (m, 1H), 7.28 (m, 1H), 7.19 (m, 1H), 7.10 (m, 1H), 3.89 (s, 2H), 3.70 (t, J= 6.7 Hz, 2H), 2.26 (t, J= 7.2 Hz, 2H), 2.21 (s, 3H), 1.87 (m, 2H). Example 158 C0 2 H N 0 (-)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1 -indanylmethyl)phenyl) hydrazono)pyrazolyl} butanoic acid (Compound 258) 103571 This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.58 (dd, J= 7.7, 1.1 Hz, 1H), 7.19 (m, 1H), 7.13-7.06 (m, 3H), 6.98 6.91 (m, 2H), 3.79 (t, J= 6.7 Hz, 2H), 3.51 (m, 1H), 3.19 (dd, J= 13.8, 6.1 Hz, 1H), 2.93 (m, 1H), 2.78 (m, 1IH), 2.72 (dd, J= 13.8, 9.4 Hz, 1H), 2.34 (t, J= 7.3 Hz, 2H), 2.27 (s, 3H), 2.10 (m, IH), 2.01 (m, 2H), 1.78 (m, 1H). Example 159 q CO2 NZ 0 N-Nd 0 (-)-3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1 -indanylmethyl)phenyl) hydrazono)pyrazolyl}benzoic acid (Compound 259) [03581 This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 8.58 (dd, J= 1.9, 1.5 Hz, 1H), 8.49 (s, 1H), 8.12 (m, 1H), 7.83 (ddd, J= 7.8, 1.5, 1.0 Hz, 1H), 7.62 (dd, J= 7.6, 1.7 Hz, 1H), 7.48 (t, J= 7.8 Hz, 1H), 7.19 (m, 1H), 7.15-7.07 (m, 3H), 7.00-6.93 (m, 2H), 3.53 (m, 1H), 3.21 (dd, J= 14.0, 5.8 Hz, 1H), - 168 - WO 2007/062078 PCT/US2006/045129 2.94 (m, 1H), 2.80 (m, 1H), 2.74 (dd, J= 14.0, 9.4 Hz, 1H), 2.38 (s, 3H), 2.12 (m, 1H), 1.80 (m, 1H). Example 160
CO
2 H N 0 N-N O 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methylphenyl)ethyl) phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 260) 103591 This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.78 (s, IH), 9.64 (s, 1H), 8.56 (t, J= 1.6 Hz, 1H), 8.20 (m, 1H), 7.79 (m, 1H), 7.60 (t, J= 7.9 Hz, 1H), 7.56 (m, 1H), 7.22 (m, 1H), 7.16-7.08 (m, 3H), 7.02 (d, J= 7.5 Hz, 1H), 6.97 (t, J= 7.5 Hz, 1H), 3.60 (m, 2H), 2.90 (m, 2H), 2.83 (m, 2H), 2.35 (s, 3H), 2.29 (s, 3H), 1.76 (m, 2H). Example 161 /COzH C0 2 H NNo N 0 N-N O 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluoro-3-methylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 261) [0360] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.75 (br s, 1H), 13.15 (br s, 1H), 9.66 (br s, 1H), 8.55 (dd, J= 2.2, 1.6 Hz, 1H), 8.20 (ddd, J= 8.2, 2.2, 1.0 Hz, 1H), 7.79 (ddd, J= 7.8, 1.6, 1.0 Hz, 1H), 7.60 (dd, J= 8.2, 7.8 Hz, 1H), 7.55 (dd, J = 7.4, 2.2 Hz, 1H), 7.16-7.10 (m, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.99-6.93 (m, 2H), 2.94 (m, 2H), 2.88 (m, 2H), 2.34 (s, 3H), 2.23 (d, J= 1.7 Hz, 3H). Example 162 - 169- WO 2007/062078 PCT/US2006/045129 " CO 2 H N N 0 N-N 0 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 -(2-(2-fluorophenyl) ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 262) [0361] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.75 (s, 1H), 9.68 (s, 1H), 8.55 (t, J = 1.7 Hz, 1H), 8.20 (m, 1H), 7.78 (m, 1H), 7.59 (t, J= 7.9 Hz, 1H), 7.55 (m, 1H), 7.33 (m, 1H), 7.25 (m, 1H), 7.17 7.11 (m, 2H), 6.97-6.92 (m, 2H), 2.95 (m, 2H), 2.90 (m, 2H), 2.34 (s, 3H). Example 163 C O H N-N O 3- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6-dimethylphenyl) ethyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 263) [03621 This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.79 (s, 1I-H), 9.55 (s, 1H), 8.56 (t, J= 1.7 Hz, 1H), 8.20 (ddd, J= 7.9, 1.7, 1.1 Hz, 1H), 7.79 (ddd, J= 7.9, 1.7, 1.1 Hz, 1H), 7.60 (t, J= 7.9 Hz, 1H), 7.57 (dd, J = 7.8, 1.6 Hz, 1H), 7.05-6.98 (m, 5H), 2.83 (m, 2H), 2.78 (m, 2H), 2.35 (s, 31-I), 2.32 (s, 6H). Example 164 q CO,H NN 0 N-N O CI 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6-dichlorophenyl) ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 264) - 170- WO 2007/062078 PCT/US2006/045129 [0363] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 9.59 (br s, 1H), 8.55 (s, 1H), 8.20 (d, J= 7.6 Hz, 1H), 7.78 (d, J= 7.6 Hz, 1H), 7.64-7.54 (m, 2H), 7.48-7.43 (m, 2H), 7.28 (dd, J= 8.4, 7.5 Hz, 1H), 7.00-6.86 (m, 2H), 3.17 (m, 2H), 2.93 (m, 2H), 2.35 (s, 3H). Example 165 COH O N 0 N-N 0 F F /\ F 3- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methyl-6 trifluoromethylphenyl)ethyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 265) [03641 This compound was prepared as described in Scheme VII. 1H NMR (500MHz, DMSO) 9.58 (br s, 1H), 8.55 (s, 1H), 8.21 (d, J= 7.6 Hz, 1H), 7.79 (m, 1H), 7.64-7.50 (m, 5H), 7.02-6.88 (m, 2H), 3.04 (m, 2H), 2.92 (m, 2H), 2.35 (s, 3H). Example 166 . C 0 2 H N 0 N-N 0 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indanyl)phenyl) hydrazono)pyrazolyl } benzoic acid (Compound 266) [0365] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.78 (br s, 1H), 9.67 (br s, 1H), 8.56 (s, 1H), 8.20 (d, J= 7.9 Hz, 1H), 7.78 (m, 1H), 7.60 (t, J= 7.9 Hz, 1H), 7.56 (d, J= 7.7 Hz, 1H), 7.28-7.12 (m, 5H), 6.98 (t, J= 7.6 Hz, 1H), 4.03 (m, I H), 3.29 (dd, J = 15.6, 7.9 Hz, 2H), 2.98 (dd, J = 15.6, 8.1 Hz, 2H), 2.35 (s, 3H). Example 167 6. CO 2 H N-N 0 - 171 - WO 2007/062078 PCT/US2006/045129 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-( 2 -indenyl)phenyl) hydrazono)pyrazolyl}benzoic acid (Compound 267) [0366] This compound was prepared as described in Scheme VII. lH NMR (500MHz, DMSO) 8.57 (s, 1H), 8.21 (d, J= 8.0 Hz, 1H), 7.79 (m, 1H), 7.65 (d, J= 8.0 Hz, 1H), 7.60 (t, J= 8.0 Hz, 1H), 7.53-7.50 (m, 2H), 7.47 (m, 1H), 7.41 (m, 1H), 7.29 (t, J= 7.4 Hz, 1H), 7.20 (t, J= 7.4 Hz, 1H), 7.13 (t, J= 7.6 Hz, 1H), 3.91 (s, 2H), 2.36 (s, 3H). Example 168 COH N 0H N 0 F
-
- F (E)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,4-difluorophenyl) ethenyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 268) [0367] This compound was prepared as described in Scheme VIII. 1 H NMR (500MHz, CD 3 OD) 8.48 (br s, 1H), 7.78 (m, 1H), 7.57-7.43 (m, 3H), 7.25 (d, J = 15.8 Hz, 1H), 7.03-6.95 (m, 3H), 3.81 (t, J= 6.5 Hz, 2H), 2.27 (t, J= 7.7 Hz, 2H), 2.26 (s, 3H), 2.00 (m, 2H). Example 169 CO H N 0 N-N 0 N 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-4-(3,4-dimethylphenyl)-2 pyridyl)hydrazono)pyrazolyl}benzoic acid (Compound 269) [0368] This compound was prepared as described in Scheme VII. lH NMR (500MHz, CD30D) 8.62 (m, 1H), 8.21 (m, 1H), 8.03 (m, 1H), 7.93-7.87 (m, 2H), 7.61 (m, 1H), 7.58-7.53 (m, 2H), 7.37 (m, 1H), 2.42 (s, 3H), 2.38 (s, 3H), 2.37 (s, 3H). Example 170 - 172 - WO 2007/062078 PCT/US2006/045129 C0 2 H N 0N N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-6-methyl-4-(3,4-dimethylphenyl)-2 pyridyl)hydrazono)pyrazolyl}butanoic acid (Compound 270) [0369] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, CD 3 OD) 7.66 (s, 1H), 7.55 (s, 1H), 7.49 (d, J = 7.1 Hz, IH), 7.33 (d, J= 7.1 Hz, 1H), 3.79 (t, J= 6.6 Hz, 2H), 2.62 (s, 3H), 2.37 (s, 3H), 2.35 (s, 3H), 2.35 (m, 2H), 2.28 (s, 3H), 2.01 (m, 2H). Example 171
SCO
2 H N 0 N-N 0 O 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-2-(3,4-dimethylphenyl)-4 pyridyl)hydrazono)pyrazolyl}benzoic acid (Compound 271) 10370] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, CD 3 OD) 8.62 (s, 1H), 8.23-8.12 (m, 2H), 7.97 (m, IH), 7.89 (m, 1IH), 7.60 7.51 (m, 3H), 7.41 (m, IH), 2.42 (s, 3H), 2.39 (s, 3H), 2.39 (s, 3H). Example 172 COzH Co 2 H I-e N 0 N-N "0 _N 3- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-2-(3,5-dimethylphenyl)-4 pyridyl)hydrazono)pyrazolyl}benzoic acid (Compound 272) [0371] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, CD 3 OD) 8.52 (t, J= 1.6 Hz, 1H), 8.17 (d, J= 6.3 Hz, 1H), 8.14 (mn, 1H), 7.87 (d, J= 6.3 Hz, 1H), 7.81 (d, J= 7.8 Hz, 1H), 7.49 (t, J= 7.8 Hz, 1H), 7.37 (s, 2H), 7.31 (s, 1H), 2.44 (s, 6H), 2.38 (s, 3H). Example 173 - 173 - WO 2007/062078 PCT/US2006/045129 N CO 2 H FI F QNZ 0 F 0 N-N 0 3- {I -(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2-methylphenyl) ethyl)phenyl)hydrazono)indolyl}benzoic ac.id (Compound 273) 10372] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.20 (s, 1H), 9.34 (s, 1H), 8.11 (dd, J= 2.0, 1.6 Hz, 1H), 8.08 (ddd, J = 7.8, 1.6, 1.2 Hz, 1H), 7.92 (d, J= 8.0 Hz, 1H), 7.86 (ddd, J= 7.8, 2.0, 1.2 Hz, 1H) ,7.77 (t, J= 7.8 Hz, 1H), 7.62 (dd, J= 7.8, 1.7 Hz, 1H), 7.55 (dq, J= 8.0, 0.6 Hz, 1H), 7.22 (m, 1H), 7.15-7.07 (m, 3H), 7.06 (m, 1H), 6.95 (t, J= 7.8 Hz, 1H), 6.91 (dd, J= 7.8, 1.7 Hz, 1H), 2.88 (m, 2H), 2.82 (min, 2H), 2.28 (s, 3H). Example 174 C0 2 H rco2 N -N N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-benzylphenyl)hydrazono) pyrazolyl}butanoic acid (Compound 274) [0373] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 7.49 (d, J = 7.7 Hz, 1H), 7.30-7.26 (m, 2H), 7.23-7.16 (mn, 3H), 6.92 (t, J= 7.7 Hz, 1H), 6.86 (dd, J= 7.7, 1.4 Hz, 1H), 4.02 (s, 2H), 3.69 (t, J= 6.7 Hz, 2H), 2.24 (t, J= 7.2 Hz, 2H), 2.19 (s, 3H), 1.85 (m, 2H). Example 175 co2H N 0 N-N 0 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(3-methylphenyl)propyl) phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 275) [0374] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 9.43 (s, 1H), 7.47 (d, J= 7.4 Hz, 1H), 7.16 (t, J= 7.4 Hz, 1H), 7.03 - 174 - WO 2007/062078 PCT/US2006/045129 6.90 (m, 5H), 3.69 (t, J= 6.8 Hz, 2H), 2.67 (t, J= 7.7 Hz, 2H), 2.58 (m, 2H), 2.27 (s, 3H), 2.25 (t, J= 7.3 Hz, 2H), 2.19 (s, 3H), 1.85 (m, 4H). Example 176 N-N 0 0H 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-phenylpropyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 276) [0375] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 9.44 (s, 1H), 7.47 (d, J= 7.4 Hz, 1H), 7.28 (t, J= 7.4 Hz, 2H), 7.21 (m, 2H), 7.17 (tt, J= 7.4, 1.4 Hz, 1H), 6.96 (dd, J= 7.4, 1.6 Hz, 1H), 6.92 (t, J= 7.4 Hz, 1H), 3.69 (t, J = 6.8 Hz, 2H), 2.68 (t, J = 7.7 Hz, 2H), 2.62 (m, 2H), 2.25 (t, J = 7.2 Hz, 2H), 2.19 (s, 3H), 1.86 (t, J= 7.4 Hz, 4H). Example 177
CO
2 H N 0 O N-N O 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(2-methylphenyl)propyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 277) [0376] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.59 (s, 1H), 12.09 (s, IH), 9.45 (s, 1H), 7.48 (dd, J= 7.8, 1.2 Hz, 1H), 7.15-7.04 (m, 4H), 6.98 (dd, J= 7.8, 1.2 Hz, 1H), 6.93 (t, J= 7.8 Hz, 1H), 3.69 (t, J = 6.7 Hz, 2H), 2.72 (t, J= 7.7 Hz, 2H), 2.60 (t, J= 8.1 Hz, 2H), 2.25 (t, J= 7.3 Hz, 2H), 2.23 (s, 3H), 2.19 (s, 3H), 1.86 (m, 2H), 1.78 (m, 2H). Example 178 co 2 H N 0 OH N-N O F -175- WO 2007/062078 PCT/US2006/045129 4- { 2 -(5-Methyl-3-oxo-2,3-dihydro-4.-(2-hydroxy-3-(2-(2,4-difluorophenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 278) 103771 This compound was prepared as described in Scheme VII. 'H NMR (300MHz, DMSO) 7.48 (mn, 1H), 7.34 (td, J= 8.5, 6.9 Hz, 1H), 7.16 (ddd, J= 10.2, 9.5, 2.4 Hz, 1H), 7.01 (tdd, J= 8.5, 2.4, 0.8 Hz, 1H), 6.94-6.84 (min, 2H), 3.69 (t, J= 6.7 Hz, 2H), 2.95-2.80 (m, 4H), 2.25 (t, J= 7.2 Hz, 2H), 2.19 (s, 3H), 1.86 (m, 2H). Example 179 C02H NN N-N 0 (E)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-pyridyl)ethyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 279) [03781 This compound was prepared as described in Scheme VII. 'H NMR (500MHz, CD 3 OD) 8.56 (br s, 1H), 8.19 (br s, 1H), 7.77 (m, 1H), 7.55 (dd, J= 7.8, 1.5 Hz, 1H), 7.38-7.28 (m, 2H), 6.98 (dd, J= 7.8, 1.5 Hz, 1H), 6.89 (t, J= 7.8 Hz, 1H), 3.80 (t, J= 6.7 Hz, 2H), 3.17 (m, 2H), 3.08 (m, 2H), 2.35 (m, 2H), 2.26 (s, 3H), 2.01 (m, 2H). Example 180 C0 2 H N 0 N-N 0 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-( 2
-(
2 ,6-dimethylphenyl)-(Z) ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 280) [0379] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.48 (d, J= 7.0 Hz, 1H), 7.09-6.95 (m, 3H), 6.88 (d, J= 12.1 Hz, 1H), 6.70 (d, J= 12.1 Hz, 1H), 6.55 (t, J= 7.8 Hz, 1H), 6.44 (d, J= 7.8 Hz, 1H), 3.79 (t, J = 6.7 Hz, 2H), 2.34 (t, J= 7.5 Hz, 2H), 2.24 (s, 3H), 2.13 (s, 6H), 2.01 (m, 2H). Example 181 - 176 - WO 2007/062078 PCT/US2006/045129 CO2H NN 0 N-N 0 o 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2 -hydroxy-3 -(2-benzofuranyl)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 281) 10380] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 7.71 (d, J = 7.4 Hz, 1H), 7.69-7.62 (m, 3H), 7.48 (s, 1H), 7.34 (t, J= 7.4 Hz, 1H), 7.27 (t, J= 7.4 Hz, 1H), 7.17 (m, 1H), 3.71 (t, J= 6.6 Hz, 2H), 2.26 (t, J= 7.1 Hz, 2H), 2.22 (s, 3H), 1.87 (m, 2H). Example 182 C0 2 H N N )0 N-N 0 Br (Z)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-bromoethenyl)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 282) [03811 This compound was prepared as described in Scheme VII. IH NMR (300MHz, CD 3 OD) 7.71-7.59 (m, 2H), 7.48 (d, J= 7.9 Hz, 1H), 7.41 (d, J= 13.8 Hz, 1H), 7.25-7.19 (m, 2H), 7.09-6.95 (m, 3H), 6.71 (d, J= 7.9 Hz, 1H), 3.79 (t, J= 6.6 Hz, 4H), 2.34 (t, J= 7.3 Hz, 4H), 2.26 (s, 6H), 2.01 (m, 4H). Example 183
CO
2 H N 0 N-N0 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(3-methyl-1 -butenyl)phenyl) hydrazono)pyrazolyl } butanoic acid (Compound 283) [0382] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.60 (dd, J= 7.3, 1.6 Hz, 1H), 7.00-6.90 (m, 2H), 6.30 (d, J = 11.3 Hz, 1H), 5.65 (dd, J= 11.3, 10.4 Hz, 1H), 3.79 (t, J = 6.6 Hz, 2H), 2.68 (m, 1H), 2.34 (t, J = 7.3 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H), 1.01 (d, J= 6.6 Hz, 6H). - 177 - WO 2007/062078 PCT/US2006/045129 Example 184 CO2H NL 0 N-N 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2-cyclopropylethenyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 284) [0383] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.59 (d, J= 7.8 Hz, 1H), 7.22 (d, J= 7.8 Hz, 1H), 6.95 (t, J = 7.8 Hz, 1H), 6.33 (d, J= 11.0 Hz, 1H), 5.21 (t, J= 11.0 Hz, 1H), 3.79 (t, J= 6.6 Hz, 2H), 2.33 (t, J= 7.4 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H), 1.71 (m, 1H), 0.81 (m, 2H), 0.48 (m, 2H). Example 185 Co2H N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-methylbutyl)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 285) [0384] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.51 (d, J= 7.6 Hz, 1H), 6.96 (d, J= 7.6 Hz, 1H), 6.91 (t, J= 7.6 Hz, 1H), 3.78 (t, J= 6.6 Hz, 2H), 2.66 (t, J= 7.9 Hz, 2H), 2.32 (t, J= 7.4 Hz, 2H), 2.25 (s, 3H), 2.01 (m, 2H), 1.62 (m, 1H), 1.49 (m, 2H), 0.97 (d, J= 6.6 Hz, 6H). Example 186
CO
2 H N 0 N-N 0 F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-5-fluoro-3-(3,5 dimethylphenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 286) [0385] This compound was prepared as described in Scheme I. 'H NMR (300MHz, CD 3 OD) 7.38 (dd, J= 9.4, 3.1 Hz, 1H), 7.13 (s, 2H), 7.04 (s, 1H), 6.78 (dd, J= - 178- WO 2007/062078 PCT/US2006/045129 9.2, 3.1 Hz, 1H), 3.78 (t, J= 6.7 Hz, 2H), 2.36 (s, 6H), 2.33 (tl J= 7.3 Hz, 2H), 2.27 (s, 3H), 2.00 (m, 2H). Example 187
CO
2 H N 0 N-N 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,4-dimethylphenyl)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 287) (0386] This compound was prepared as described in Scheme I. 'H NMR (300MHz, CD30D) 7.66 (m, 1H), 7.28 (s, 1H), 7.23-7.20 (m, 2H), 7.08-6.99 (m, 2H), 3.78 (t, J= 6.7 Hz, 2H), 2.33 (m, 2H), 2.32 (s, 3H), 2.31 (s, 3H), 2.27 (s, 3H), 2.00 (m, 2H). Example 188
CO
2 H N, 0 N-N 0 cl 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(5-chloro-2-hydroxy-3-cyclohexylphenyl) hydrazono)pyrazolyl}butanoic acid (Compound 288) [0387] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.47 (d, J= 2.0 Hz, IH), 6.96 (d, J= 2.0 Hz, 1H), 3.78 (t, J = 6.8 Hz, 2H), 2.93 (m, 1H), 2.34 (t, J= 7.1 Hz, 2H), 2.26 (s, 3H), 2.00 (m, 2H), 1.91-1.72 (m, 5H), 1.58-1.27 (m, 5H). Example 189 CO2H N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,5-dimethylphenyl)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 289) -179- WO 2007/062078 PCT/US2006/045129 10388] This compound was prepared as described in Scheme I. 'H NMR (500MHz, Acetone-d 6 ) 10.58 (br s, 1H), 8.28 (br s, 1H), 7.70 (dd, J= 7.6, 1.9 Hz, 1H), 7.11 (m,2H), 7.08 (t, J= 7.6 Hz, 1H), 7.04 (dd, J= 7.6, 1.9 Hz, 1H), 7.03 (m, 1H), 3.78 (t, J= 7.0 Hz, 2H), 2.38 (t, J= 7.4 Hz, 2H), 2.34 (m, 6H), 2.23 (s, 3H), 2.00 (m, 2H). Example 190
SCO,
2 H o N 0 N-N 0 3- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,5-dimethyiphenyl)phenyl) hydrazono)pyrazolyl } benzoic acid (Compound 290) 10389] This compound was prepared as described in Scheme I. 'H NMR (500MHz, DMSO) 13.75 (s, IH), 9.56 (s, IH), 8.56 (t,.J= 1.8 Hz, IH), 8.19 (ddd, J= 8.0, 1.8, 1.0 Hz, 1H), 7.78 (ddd, J= 8.0, 1.8, 1.0 Hz, 1H), 7.68 (dd, J= 5.5, 4.1 Hz, 1H), 7.59 (t, J= 8.0 Hz, 1H), 7.17 (m, 2H), 7.11 (d, J= 4.1 Hz, 1H), 7.11 (d, J 5.5 Hz, 1H), 7.03 (s, 1H), 2.36 (s, 3H), 2.34 (s, 6H). Example 191 COH N 0 N-N 0 C' 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(5-chloro-2-hydroxy-3-cyclohexylphenyl) hydrazono)pyrazolyl} butanoic acid (Compound 291) [0390] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, DMSO) 8.53 (m, 1H), 8.19 (d, J= 7.7 Hz, 1H), 7.79 (d, J= 7.7 Hz, 1H), 7.59 (t, J= 7.7 Hz, 1H), 7.48 (d, J= 2.2 Hz, IH), 7.04 (d, J= 2.2 Hz, I H), 2.97 (m, 1H), 2.35 (s, 3H), 1.84-1.67 (m, 6H), 1.46-1.20 (m, 4H). Example 192 - 180- WO 2007/062078 PCT/US2006/045129 Co 0 2 N 0 N-N 0 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,4-dimethylphenyl)phenyl) hydrazono)pyrazolyl}benzoic acid (Compound 292) [0391] This compound was prepared as described in Scheme I. IH NMR (300MHz, CD 3 OD) 8.60 (s, 1H), 8.17 (d, J= 7.8 Hz, 1H), 7.84 (d, J= 7.8 Hz, 1H), 7.71 (m, 1H), 7.50 (t, J = 7.8 Hz, IH), 7.30 (m, 1H), 7.25-7.22 (m, 2H), 7.10-7.02 (m, 2H), 2.39 (s, 3H), 2.33 (s, 3H), 2.32 (s, 3H). Example 193
C
N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-( 3
-(
2 -methylphenyl)propyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 293) [03921 This compound was prepared as described in Scheme VII. 'H NMR (300MHz, DMSO) 13.75 (s, 1H), 9.61 (s, 1H), 8.55 (t, J= 1.6 Hz, 1H), 8.20 (dd, J= 7.9, 1.2 Hz, 1H), 7.78 (d, J= 7.9 Hz, 1H), 7.59 (t, J= 7.9 Hz, 1H), 7.55 (dd, J= 7.9, 1.2 Hz, 1H), 7.16-7.03 (mn, 5H), 6.97 (t, J= 7.9 Hz, 1H), 2.75 (t, J= 7.8 Hz, 2H), 2.62 (t, J= 7.8 Hz, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 1.80 (m, 2H). Example 194 - C0 2
I
H O, N 0 N-N 0 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-benzofuranyl)phenyl) hydrazono)pyrazolyl } benzoic acid (Compound 294) [0393] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 8.57 (t, J= 1.7 Hz, 1H), 8.20 (m, 1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.73 (m, 1H), 7.70 (dd, J = 7.9, 1.3 Hz, 1H), 7.65 (d, J= 7:9 Hz, 1H), 7.61 (t, J= 7.9 Hz, - 181 - WO 2007/062078 PCT/US2006/045129 1H), 7.49 (min, 1H), 7.36 (td, J= 7.5, 1.2 Hz, 1H), 7.29 (td, J= 7.5, 0.8 Hz, 1H), 7.24 (t, J = 7.9 Hz, 1H), 2.36 (s, 3H). Example 195 SCO2H
,,-'__
c 0 2H F N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(2-fluorophenyl)propyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 295) [0394] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, DMSO) 13.74 (s, 1H), 9.61 (s, 1H), 8.55 (t, J= 1.6 Hz, 1H), 8.20 (mn, 1H), 7.78 (mn, 1H), 7.59 (t, J= 7.9 Hz, 1H), 7.54 (m, 1H), 7.31 (mn, 1H), 7.24 (m, 1H), 7.16 7.11 (m, 2H), 7.02 (min, 1H), 6.97 (t, J= 7.7 Hz, 1H), 2.72 (t, J= 7.7 Hz, 2H), 2.67 (t, J= 7.7 Hz, 2H), 2.34 (s, 3H), 1.85 (m, 2H). Example 196
C
O 2 H
NZ
N 0 NO 3-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3,4-dimethylphenyl) phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 296) [0395] This compound was prepared as described in Scheme VIII. 'H NMR (500MHz, DMSO) 11.77 (m, 1H), 9.37 (s, 1H), 8.73 (m, 1H), 8.64 (m, 1H), 8.25 (ddd, J = 8.1, 2.2, 1.0 Hz, 1H), 7.76 (m, 1H), 7.70 (ddd, J= 7.7, 1.6, 1.0 Hz, 1H), 7.52 (dd, J= 8.1, 7.7 Hz, 1H), 7.34 (m, 1H), 7.26 (dd, J= 7.8, 1.7 Hz, 1H), 7.23 (d, J= 7.8 Hz, 1H), 7.10-7.05 (m, 2H), 2.33 (s, 3H), 2.29 (s, 3H), 2.27 (s, 3H). Example 197
C
0 2H N o - 182- WO 2007/062078 PCT/US2006/045129 3-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 297) [0396] This compound was prepared as described in Scheme VIII. 'H NMR (500MHz, DMSO) 11.78-(s, 1H), 8.74 (br s, 1H), 8.65 (m, 1H), 8.24 (m, 1H), 7.76 (m, 1H), 7.70 (m, 1H), 7.52 (t, J= 7.9 Hz, 1H), 7.16 (s, 2H), 7.10-7.05 (m, 2H), 7.01 (s, 1H), 2.33 (s, 9H). Example 198 C0 2 H N 0 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3,4-dimethylphenyl) phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 298) (0397] This compound was prepared as described in Scheme VIII. IH NMR (500MHz, DMSO) 8.53 (s, 1H), 7.64 (m, 1H), 7.33 (d, J= 1.6 Hz, 1H), 7.25 (dd, J= 7.7, 1.6 Hz, 1H), 7.21 (d, J= 7.7 Hz, 1H), 7.02-6.97 (m, 2H), 3.64 (t, J= 6.7 Hz, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 2.19 (t, J= 7.4 Hz, 2H), 2.18 (s, 3H), 1.82 (m, 2H). Example 199 C O2 H 0 2 H N-N O 3- { 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)hydrazono)indolyl}propionic acid (Compound 299) [03981 This compound was prepared as described in Scheme II. 'H NMR (500MHz, CD 3 OD) 7.63 (dd, J= 7.7, 1.6 Hz, 1H), 7.61 (m, 1H), 7.27 (td, J= 7.7, 1.2 Hz, 1H), 7.12-7.08 (m, 4H), 7.00 (m, 1H), 6.98 (t, J= 7.7 Hz, 1H), 6.88 (dd, J= 7.7, 1.6 Hz, 1H), 4.10 (t, J= 7.2 Hz, 2H), 2.71 (t, J= 7.2 Hz, 2H), 2.36 (s, 6H). Example 200 - 183 - WO 2007/062078 PCT/US2006/045129 . CO,H o N-N 0 3- { 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-benzylphenyl)hydrazono)-indolyl } benzoic acid (Compound 300) [0399] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.01 (s, 1H), 9.37 (br s, 1H), 8.07 (dd, J = 2.0, 1.7 Hz, 1H), 8.05 (ddd, J= 7.8, 1.7, 1.2 Hz, 1H), 7.82 (ddd, J= 7.8, 2.0, 1.2 Hz, 1H), 7.74 (t, J= 7.8 Hz, 1H), 7.72 (dd, J= 7.5, 1.0 Hz, 1H), 7.57 (dd, J= 8.1, 1.5 Hz, 1H), 7.29 (td, J = 7.5, 1.0 Hz, 1H), 7.28 (t, J= 7.1 Hz, 2H), 7.23 (m, 2H), 7.20 (td, J= 7.5, 1.0 Hz, 1H), 7.18 (tt, J 7.1, 1.5 Hz, 1H), 6.94-6.90 (m, 2H), 6.75 (dd, J= 7.7, 1.5 Hz, 1H), 4.02 (s, 2H). Example 201 0 2 H N 0 Ofz o N-N@ 3-{ 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2-methylphenyl)ethyl)phenyl) hydrazono)indolyl}propionic acid (Compound 301) 104001 This compound was prepared as described in Scheme VII. 'H NMR (500MHz, CD 3 OD) 7.61 (d, J= 7.6 Hz, IH), 7.49 (dd, J= 8.0, 1.4 Hz, 1H), 7.29 (td, J= 7.6, 0.9 Hz, 1H), 7.17-7.03 (m, 6H), 6.86 (dd, J= 8.0, 7.5 Hz, 1H), 6.73 (dd, J= 7.5, 1.4 Hz, 1H), 4.13 (t, J= 7.3 Hz, 2H), 2.90 (s, 4H), 2.71 (t, J= 7.3 Hz, 2H), 2.30 (s, 3H). Example 202
CO
2 H N C 1 3- { 1 -(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(3-(3-methylphenyl)propyl) phenyl)aminomethylidene)indolyl}benzoic acid (Compound 302) [0401] This compound was prepared as described in Scheme VIII. 'H NMR (500MHz, DMSO) 11.13 (d, J= 13.4 Hz, 1H), 9.17 (br s, 1H), 8.89 (d, J= 13.4 Hz, 1H), 8.03-8.00 (m, 2H), 7.79 (m, 1H), 7.78 (d, J= 8.1 Hz, 1H), 7.72 (t, J= 7.9 Hz, 1IH), 7.55 -184- WO 2007/062078 PCT/US2006/045129 (dd, J= 7.9, 1.5 Hz, 1H), 7.15 (t, J= 7.5 Hz, 1H), 7.14 (dd, J= 8.1, 2.0 Hz, 1H), 7.02 6.96 (m, 3H), 6.93 (t, J= 7.9 Hz, 1H), 6.88 (dd, J= 7.9, 1.5 Hz, 1H), 6.86 (d, J= 2.0 Hz, 1H), 2.67 (t,J= 7.7 Hz, 2H), 2.58 (m, 2H), 2.27 (s, 3H), 1.83 (m, 2H). Example 203 0 o -N 0 CI - N cN o (+)-3-{ 1-(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(1,2-dihydro-1-methyl-2 indolylphenyl)aminomethylidene)indolyl}benzoic acid (Compound 303) (0402] This compound was prepared as described in Scheme VIII. IH NMR (500MHz, DMSO) 11.14 (d, J= 13.2 Hz, 1H), 9.78 (br s, 1H), 8.94 (d, J= 13.2 Hz, 1H), 8.03-7.99 (m, 2H), 7.79 (m, 1H), 7.79 (d, J= 8.1 Hz, 1H), 7.72 (t, J= 7.7 Hz, 1H), 7.67 (dd, J= 8.1, 1.2 Hz, 1H), 7.16 (dd, J = 8.1, 2.0 Hz, 1H), 7.14-7.08 (m, 3H), 7.03 (t, J= 7.8 Hz, 1H), 6.87 (d, J= 2.0 Hz, 1H), 6.76-6.70 (m, 2H), 4.65 (dd, J= 11.2, 8.7 Hz, 1H), 3.41 (dd, J= 15.6, 8.7 Hz, 1H), 2.72 (dd, J= 15.6, 11.2 Hz, 1H), 2.62 (s, 3H). Example 204 CO2 H N 0 N-N 0 0 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-methylphenylcarbonyl amino)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 304) [0403] This compound was prepared as described in Scheme VII. iH NMR (500MHz, DMSO) 13.57 (brs, 1H), 12.12 (brs, 1H), 10.50 (s, IH), 10.27 (brs, 1H), 7.63 (m, 1H), 7.54 (m, 1H), 7.45 (m, 1H), 7.37-7.32 (m, 2H), 7.24 (m, 1H), 7.02 (m, 1H), 3.70 (t, J= 6.7 Hz, 2H), 2.44 (s, 3H), 2.26 (t, J= 7.3 Hz, 2H), 2.21 (s, 3H), 1.87 (m, 2H). Example 205 - 185- WO 2007/062078 PCT/US2006/045129 N-N 00 N coz Cl 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(5-chloro-2-hydroxy-3-(2-methylphenyl carbonylamino)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 305) [0404] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 10.30 (br s, 1H), 7.65 (d, J = 7.3 Hz, 1H), 7.48-7.40 (m, 3H), 7.36 7.32 (m, 2H), 3.69 (t, J= 6.7 Hz, 2H), 2.43 (s, 3H), 2.26 (t, J= 7.3 Hz, 2H), 2.21 (s, 3H), 1.86 (m, 2H). Example 206 00 0 N.N N F 3- { 2-Hydroxy-3-(2-oxo-2,3-dihydro- 1 -(2-(2-fluorophenyl)ethyl)indolylidene) hydrazinophenyl}benzoic acid (Compound 306) [0405] This compound was prepared as described in Scheme IX. 1H NMR (500MHz, DMSO) 13.03 (s, 1H), 12.97 (s, 1H), 9.23 (s, 1H), 8.12 (t, J = 1.7 Hz, 1H), 7.95 (ddd, J= 7.7, 1.7, 1.2 Hz, 1H), 7.79 (ddd, J= 7.7, 1.7, 1.2 Hz, 1H), 7.67 (dd, J= 8.1, 1.6 Hz, 1H), 7.62 (m, 1H), 7.60 (t, J= 7.7 Hz, 1H), 7.34-7.23 (m, 3H), 7.15-7.07 (m, 5H), 6.98 (dd, J= 7.7, 1.6 Hz, 1H), 4.04 (dd, J= 7.2, 6.8 Hz, 2H), 3.02 (t, J= 7.2 Hz, 2H). Example 207 -186- WO 2007/062078 PCT/US2006/045129 00 0 N.N o N Cl 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l1-(2-(2-chlorophenyl)ethyl)indolylidene) hydrazinophenyl}benzoic acid (Compound 307) 10406] This compound was prepared as described in Scheme IX. 'H NMR (500MHz, DMSO) 13.03 (s, 1H), 12.97 (s, 1H), 9.23 (s, 1H), 8.12 (t, J = 1.6 Hz, 1H), 7.94 (ddd, J= 7.7, 1.6, 1.2 Hz, 1H), 7.79 (ddd, J= 7.7, 1.6, 1.2 Hz, 1H), 7.68 (dd, J= 7.8, 1.6 Hz, 1H), 7.62 (min, 1H), 7.60 (t, J= 7.7 Hz, 1H), 7.41 (mn, 1H), 7.34 (min, 1H), 7.29 (td, J = 7.7, 1.2 Hz, 1H), 7.27-7.22 (m, 2H), 7.13-7.06 (m, 3H), 6.98 (dd, J= 7.8, 1.6 Hz, 1H), 4.05 (t, J= 7.3 Hz, 2H), 3.10 (t, J= 7.3 Hz, 2H). Example 208 N
N
o@ N-N 3-{3-Hydroxy-2-(5-methyl-3-oxo-2,3-dihydro-2-(3,4-dimethylphenyl) pyrazolylidene)hydrazino-4-pyridyl}benzoic acid (Compound 308) [0407] This compound was prepared as described in Scheme IX. 'H NMR (500MHz, DMSO) 8.53 (t, J= 1.6 Hz, 1H), 8.20-8.15 (m, 2H), 8.04 (ddd, J= 7.7, 1.6, 1.1 Hz, 1H), 7.71-7.64 (mn, 3H), 7.61 (dd, J= 8.4, 2.3 Hz, 1H), 7.22 (d, J= 8.4 Hz, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H). Example 209 - 187- WO 2007/062078 PCT/US2006/045129 OH N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 309) [0408] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.75 (s, 1H), 9.66 (s, 1H), 8.10 (d, J= 8.8 Hz, 2H), 8.04 (d, J= 8.8 Hz, 2H), 7.56 (d, J= 7.6 Hz, 1H), 7.22 (dd, J= 7.3, 1.6 Hz, 1H), 7.16-7.08 (m, 3H), 7.02 (d, J= 7.6 Hz, 1H), 6.97 (t, J= 7.6 Hz, 1H), 2.93-2.87 (m, 2H), 2.86-2.80 (m, 2H), 2.35 (s, 3H), 2.29 (s, 3H). Example 210 0 O N 0 N' 3- { 3-Hydroxy-2-(2-oxo-2,3-dihydro- 1-(3,5-dimethylphenyl)-3-indolylidene-hydrazino) 4-pyridyl}benzoic acid (Compound 310) [0409] This compound was prepared as described in Scheme IX. 'H NMR (500MHz, DMSO) 13.02 (br s, 1H), 9.68 (br s, 1H), 8.52 (br s, 1H), 8.25 (br s, 1H), 8.16 (br s, 1H), 7.96 (d, J= 7.1 Hz, 1H), 7.76 (d, J= 7.1 Hz, IH), 7.61 (t, J= 7.7 Hz, IH), 7.60 (m, 1H), 7.35 (td, J= 7.6, 1.2 Hz, 1H), 7.21 (td, J= 7.6, 0.7 Hz, 1H), 7.16-7.13 (m, 3H), 6.89 (d, J= 7.6 Hz, 1H), 2.37 (s, 6H). Example 211 C0 2 H N-N 0 - 188 - WO 2007/062078 PCT/US2006/045129 3-{ I-(2-Oxo-2,3-dihydro-3-(3-hydroxy-6-methyl-4-(3,4-dimethylphenyl)-2 pyridyl)hydrazono)indolyl } benzoic acid (Compound 311) [04101 This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 12.93 (s, 1H), 8.07 (t, J = 1.7 Hz, IH), 8.04 (m, 1H), 7.81-7.74 (m, 2H), 7.74-7.60 (m, 3H), 7.42 (s, 1H), 7.35 (t, J= 7.6 Hz, 1H), 7.23 (t, J= 7.6 Hz, 1H), 7.20 (d,J = 7.9 Hz, 1H), 6.92 (d,J= 7.6 Hz, 1H), 2.47 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H). Example 212 _ CO zH N 0 N-N 0 N 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-6-methyl-4-(3,4-dimethylphenyl)-2 pyridyl)hydrazono)pyrazolyl } benzoic acid (Compound 312) [0411] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 8.50 (dd, J= 2.1, 1.6 Hz, 1H), 8.15 (ddd, J= 8.1, 2.1, 1.0 Hz, 1H), 7.82 (ddd, J= 7.7, 1.6, 1.0 Hz, 1H), 7.71 (s, IH), 7.62-7.54 (m, 2H), 7.62 (dd, J= 8.1, 7.7 Hz, IH), 7.34 (d, J= 7.8 Hz, IH), 2.63 (s, 3H), 2.38 (s, 3H), 2.32 (s, 6H). Example 213 0 N,-N 0 N F F F O 3-{3-Hydroxy-4-(2-oxo-2,3-dihydro- 1-(3,5-dimethylphenyl)-6-trifluoromethyl-3 indolylidenehydrazino)-2-pyridyl }benzoic acid (Compound 313) [0412] This compound was prepared as described in Scheme IX. 'H NMR (500MHz, DMSO) 13.25 (s, 1H), 8.42 (t, J= 1.5 Hz, 1H), 8.32 (d, J= 6.1 Hz, 1H), 8.10 (dd, J= 7.8, 1.5 Hz, 1H), 8.10 (m, 1H), 8.03 (d, J= 7.9 Hz, 1H), 7.93 (d, J= 6.1 Hz, 1H), 7.72 (t, J= 7.8 Hz, 1H), 7.61 (dq, J= 7.9, 0.8 Hz, 1H), 7.19 (m, 1H), 7.17 (m, 2H), 6.99 (m, 1H), 2.37 (s, 6H). Example 214 - 189- WO 2007/062078 PCT/US2006/045129 CO2 H NN 0 N-N 0 _N 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-2-(3,5-dimethylphenyl)-4 pyridyl)hydrazono)pyrazolyl } butanoic acid (Compound 314) [0413] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, CD 3 OD) 7.89 (m, IH), 7.80 (m, 1H), 7.45 (s, 2H), 7.19 (s, IH), 3.79 (t, J= 6.6 Hz, 2H), 2.41 (s, 6H), 2.36 (t, J= 7.3 Hz, 2H), 2.28 (s, 3H), 2.01 (m, 2H). Example 215
CO
2 H N 0 N-N 0 S 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-5-phenyl-2-benzothienyl) hydrazono)pyrazolyl} butanoic acid (Compound 315) [04141 This compound was prepared as described in Scheme VI. 'H NMR (500MHz, DMSO) 12.13 (s, 1H), 11.25 (s, 1H), 8.04 (d,J= 1.8 Hz, 1H), 7.89 (d, J= 8.4 Hz, IH), 7.74 (m, 2H), 7.70 (dd, J= 8.4, 1.8 Hz, 1H), 7.51 (t, J= 7.6 Hz, 2H), 7.40 (tt, J = 7.6, 1.0 Hz, 1H), 3.85 (t,J= 6.7 Hz, 2H), 2.31-2.23 (m, 5H), 1.92 (m, 2H). Example 216 0 0 O \S N. N NN 3-{ 3 -Hydroxy-2-(5-methyl-3-oxo-2,3-dihydro-2-(3,4-dimethylphenyl)-4 pyrazolidene)hydrazino-5-benzothienyl}benzoic acid (Compound 316) - 190- WO 2007/062078 PCT/US2006/045129 [0415] This compound was prepared as described in Scheme VI. 'H NMR (500MHz, DMSO) 8.29 (t, J= 1.6 Hz, 1H), 8.18 (d, J= 1.7 Hz, 1H), 8.01 (ddd, J= 7.8, 1.6, 0.9 Hz, 1H), 7.97 (ddd, J= 7.8, 1.6, 0.9 Hz, 1H), 7.96 (d, J= 8.3 Hz, 1H), 7.73 (dd, J = 8.3, 1.7 Hz, 1H), 7.69 (d, J= 1.7 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.62 (dd, J= 8.3, 1.7 Hz, 1H), 7.22 (d, J= 8.3 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H). Example 217 COH N 0 / N-N 0 0 N-N60 0 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-(2,3-dimethoxycarbonylphenyl)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 317) [0416] This compound was prepared as described in Scheme I. 'H NMR (500MHz, DMSO) 12.13 (s, 1H), 7.99 (dd, J= 7.6, 1.2 Hz, 1H), 7.75 (dd, J= 7.6, 1.2 Hz, 1H), 7.71 (t, J= 7.6 Hz, 1H), 7.58-7.55 (m, 2H), 7.50 (m, 1H), 7.15 (m, 1H), 3.86 (s, 3H), 3.69 (t, J= 7.0 Hz, 2H), 3.63 (s, 3H), 2.26 (t, J= 7.0 Hz, 2H), 2.18 (s, 3H), 1.86 (qn, J 7.0 Hz, 2H). Example 218 O N-N N 0 N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3,5-diisopropylphenyl) carbonylhydrazinomethylidene)pyrazolyl}butanoic acid (Compound 318) [0417] This compound was prepared as described in Scheme VIII. 'H NMR (500MHz, CD 3 OD) 7.77 (br s, IH), 7.30-7.23 (m, 2H), 3.84 (t, J= 6.7 Hz, 2H), 2.96-2.82 (m, 2H), 2.34 (t, J= 7.5 Hz, 2H), 2.20 (s, 3H), 2.03 (m, 2H), 1.28 (d, J= 7.0 Hz, 6H), 1.23 (d, J= 6.7 Hz, 6H). Example 219 - 191 - WO 2007/062078 PCT/US2006/045129 . cC02H NOH NN 0 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(3,5-dimethylphenyl)phenyl) aminomethylidene)pyrazolyl}butanoic acid (Compound 319) [0418] This compound was prepared as described in Scheme VIII. 'H NMR (500MHz, CDsOD) 8.52 (br s, 1H), 7.55 (m, 1H), 7.11-7.09 (m, 2H), 7.06-7.01 (m, 3H), 3.79 (t, J= 6.8 Hz, 2H), 2.36 (s, 6H), 2.29 (t, J= 7.5 Hz, 2H), 2.27 (s, 3H), 1.99 (m, 2H). Example 220 C02,H N 0 N-N 0 (+)-4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2,3-dihydro- 1 -methyl-2-oxo-3 indolyl)methyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 320) [04191 This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.64 (dd, J=8.0, 1.3 Hz, 1H), 7.32 (td, J=7.7, 0.9 Hz, 1H), 7.01-6.91 (m, 2H), 6.84 (dd, J=8.0, 7.6 Hz, IH), 6.78 (m, 1H), 6.62 (dd, J=7.6, 1.3 Hz, 1H), 3.79 (t, J=6.7 Hz, 2H), 3.51 (d, J=14.4 Hz, 1H), 3.20 (s, 3H), 2.81 (d, J=14.4 Hz, 1H), 2.33 (t, J=7.5 Hz, 3H), 2.27 (s, 3H), 2.01 (m, 2H). Example 221 0 2 H N 0 F N-N 3- { 1 -(2-Oxo-2,3-dihydro-5-fluoro-3-(2-hydroxy-3-(2-(2-methylphenyl)ethyl)phenyl) hydrazono)indolyl}propionic acid (Compound 321) [0420] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.10 (s, IH), 9.24 (s, 1H), 8.08 (t, J=1.8 Hz, 1H), 8.04 (m, 1H), 7.82 (m, 1H), 7.74 (t, J=7.7 Hz, 1H), 7.61 (dd, J=7.9, 1.6 Hz, 1H), 7.55 (dd, J=8.2, 2.6 Hz, 1H), 7.22 (m, 1H), 7.16-7.07 (mn, 4H), 6.96-6.92 (m, 2H), 6.88 (dd, J=7.6, 1.6 Hz, 1H), 2.87 (m, 2H), 2.81 (m, 2H), 2.28 (s, 3H). - 192 - WO 2007/062078 PCT/US2006/045129 Example 222 C0211 r '-CO2H N 0 N-N 0 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,5-dimethylphenyl) ethyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 322) 10421] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.77 (s, 1H), 9.62 (s, 1H), 8.56 (m, 1H), 8.21 (m, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.63-7.53 (m, 2H), 7.08-6.88 (m, 5H), 2.87 (m, 2H), 2.77 (m, 2H), 2.35 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H). Example 223
N
C O H N-N 00 (:A)-3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2,3-dihydro-1-methyl-2-oxo-3 indolyl)methyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 323) 10422] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 8.59 (dd, J=2.1, 1.6 Hz, 1H), 8.19 (ddd, J=8.2, 2.1, 1.0 Hz, 11H), 7.82 (ddd, J=7.7, 1.6, 1.0 Hz, 1H), 7.60 (dd, J=8.1, 1.4 Hz, 1H), 7.49 (dd, J=8.2, 7.7 H-z, IH), 7.32 (td, J=7.6, 1.2 Hz, I H), 7.00-6.93 (m, 2H), 6.83-6.79 (m, 2H), 6.60 (dd, J=7.6, 1.4 Hz, 1H), 3.51 (d, J=14.4 Hz, 1H), 3.20 (s, 3H), 2.80 (d, J=14.4 Hz, 1H), 2.34 (s, 3H1). Example 224 1CO1: N I N-N 00 N 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1,2-dihydro- -methyl-2-oxo-3 indolylidene)methyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 324) [04231 This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.65 (br s, 1H), 13.16 (br s, 1H), 10.54 (s, 1H), 8.53 (dd, J=2.1, 1.6 - 193 - WO 2007/062078 PCT/US2006/045129 Hz, 1H), 8.20 (ddd, J=8.2, 2.1, 1.0 Hz, 1H), 7.84-7.76 (m, 3H), 7.59 (dd, J=8.2, 7.9 Hz, 1H), 7.46 (m, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.34 (td, J=7.6, 1.0 Hz, 1H), 7.16 (m, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.93 (td, J=7.6, 1.0 Hz, 1H), 3.24 (s, 3H), 2.37 (s, 3H). Example 225 SC0 2 1-H N 0 N-N 0 F 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(5-fluoro-2-methylphenyl) ethyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 325) [0424] This compound was prepared as described in Scheme VII. IH NMR (500MHz, DMSO) 13.77 (s, 1H), 13.15 (s, 1H), 9.66 (s, 1H), 8.55 (dd, J=2.1, 1.6 Hz, 1H), 8.20 (ddd, J=8.2, 2.1, 1.0 Hz, 1H), 7.79 (ddd, J=7.8, 1.6, 1.1 Hz, IH), 7.60 (dd, J=8.2, 7.8 Hz, 1H), 7.57 (dd, J=7.9, 1.6 Hz, 1H), 7.17 (dd, J=8.2, 6.1 Hz, 1H), 7.07 (dd, J=10.3, 2.8 Hz, IH), 7.02 (dd, J=7.6, 1.6 Hz, 1H), 6.97 (m, 1H), 6.92 (ddd, J=8.6, 8.2, 2.8 Hz, 1H), 2.90 (m, 2H), 2.83 (m, 2H), 2.35 (s, 3H), 2.25 (s, 3H). Example 226 rfCO H NZ 0 N-N 0 F \_ F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(E)-(2-hydroxy-3-(2-(2,4-difluorophenyl) ethenyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 326) [0425] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, DMSO) 7.85 (m, 1H), 7.62-7.45 (m, 3H), 7.36-7.14 (m, 3H), 7.01 (m, IH), 3.69 (t, J = 6.5 Hz, 2H), 2.25 (t, J= 7.2 Hz, 2H), 2.20 (s, 3H), 1.86 (m, 2H). Example 227 - 194- WO 2007/062078 PCT/US2006/045129
SCO
2 H N 0 N-N 0 3-{2-(5-Methyl-3-oxo- 2 ,3-dihydro-4-(2-hydroxy-3-methylphenyl)hydrazono) pyrazolyl}benzoic acid (Compound 327) [0426] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 8.61 (dd, J=2.1, 1.5 Hz, 1H), 8.20 (ddd, J=8.1, 2.1, 1.0 Hz, 1H), 7.84 (ddd, J=7.7, 1.5, 1.0 Hz, 1H), 7.54 (m, 1H), 7.52 (dd, J=8.1, 7.7 Hz, 1H), 6.97 (m, 1H), 6.88 (t, J=7.8 Hz, 1H), 2.36 (s, 3H), 2.28 (s, 3H). Example 228 COzH -N 0 N-N 00 N 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1,2-dihydro- 1-methyl-2-oxo-3 indolylidene)methyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 328) [0427] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.54 (s, 1H), 10.41 (br s, 1H), 8.42 (br, 1H), 7.76 (s, 1H) ,7.74 (m, 1H), 7.43-7.37 (m, 2H), 7.33 (t, J=7.8 Hz, IH), 7.12 (t, J=7.8 Hz, 1H), 7.06 (d, J=7.8 Hz, 1H), 6.92 (t, J=7.8 Hz, 1H), 3.69 (t, J=6.6 Hz, 2H), 3.23 (s, 3H), 2.26 (t, J=7.1 Hz, 2H), 2.21 (s, 3H), 1.87 (m, 2H). Example 229 rlCO H N 0 N-N 0 F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(5-fluoro-2-methylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 329) [0428] This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.53 (mn, 1H), 7.09 (dd, J=8.4, 6.1 Hz, 1H), 6.93-6.84 (m, 3H), 6.78 - 195 - WO 2007/062078 PCT/US2006/045129 (td, J=8.4, 2.8 Hz, 1H), 3.79 (t, J=6.7 Hz, 2H), 2.96-2.82 (m, 4H), 2.35 (t, J=7.4 Hz, 2H), 2.25 (s, 3H), 2.23 (s, 3H), 2.01 (m, 2H). Example 230 rC0 2
H
N O N-N 0 F F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6-difluorophenyl) ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 330) [04291 This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.53 (m, 1H), 7.21 (m, 1H), 6.91-6.76 (m, 4H), 3.79 (t, J = 6.6 Hz, 2H), 3.03-2.92 (m, 4H), 2.34 (t, J = 7.3 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H). Example 231 CO H N
-
0 N-N O 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6-dimethylphenyl) ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 331) [0430] This compound can be prepared as described in Scheme VII. Example 232 0 2 H N 0 N-N O 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-methylphenyl) ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 332) [0.4311 This compound can be prepared as described in Scheme VII. Example 233 - 196 - WO 2007/062078 PCT/US2006/045129
CO
2 H -N 0 N-N 0 F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(5-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 333) 104321 This compound was prepared as described in Scheme VII. 'H NMR (300MHz, CD 3 OD) 7.63 (d, J = 8.0 Hz, 1H), 7.49-7.29 (m, 4H), 7.18 (dd, J = 8.3, 6.2 Hz, 1H), 7.03 (m, 1H), 6.89 (td, .J = 8.3, 2.3 Hz, 1H), 3.79 (t, J = 6.6 Hz, 2H), 2.40 (s, 3H), 2.34 (t, J= 7.4 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H). [0433] [0432] This compound can be prepared as described in Scheme VII. Example 234 Co,H N 0 F N-N 0 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(Z)-(2-(5-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 334) 10434] This compound can be prepared as described in Scheme VII. Example 235
CO
2 H NN 0 N-N 0 F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 335) [04351 This compound can be prepared as described in Scheme VII. Example 236 - 197 - WO 2007/062078 PCT/US2006/045129 C0 2 H N N N 0 N-N 0 F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(4 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 336) [0436] This compound can be prepared as described in Scheme VII. Example 237 C02H N N O N-N O F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-fluorophenyl) ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 337) (0437] This compound can be prepared as described in Scheme VII. Example 238 COH N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-phenylethenyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 338) [0438] This compound can be prepared as described in Scheme VII. Example 239
CO
2 H N -0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-phenylethynyl) phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 339) [0439] This compound can be prepared as described in Scheme VII. - 198 - WO 2007/062078 PCT/US2006/045129 Example 240
CO
2 H N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-( 2 -(2-methylphenyl)ethynyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 340) 10440] This compound can be prepared as described in Scheme VII. Example 241 co 2 H N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-( 2 -(2,6-dimethylphenyl) ethynyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 341) [0441] This compound can be prepared as described in Scheme VII. Example 242 CO2H rfo2 N 0 \ N-N 0 F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluorophenyl)ethynyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 342) [0442] This compound can be prepared as described in Scheme VII. Example 243
CO
2 H N 0 NF F 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-( 2 -(2-trifluoromethylphenyl) ethynyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 342) [0443] This compound can be prepared as described in Scheme VII. - 199- WO 2007/062078 PCT/US2006/045129 Example 244
CO
2 H N 0 N-N O F F F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-trifluoromethyl phenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 344) [04441 This compound can be prepared as described in Scheme VII. Example 245 COH N 0 N - N \I O N-N O 6-/I 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1-methyl-l-indenyl-2-)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 345) This compound can be prepared as described in Scheme VII. Example 246 C0 2 H N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,3-dimethyl-2 indenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 346) 10445] This compound can be prepared as described in Scheme VII. Example 247
CO
2 H N 0 N-N 0 -0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-5-methoxy-3-(2-indenyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 347) - 200 - WO 2007/062078 PCT/US2006/045129 (0446] This compound can be prepared as described in Scheme VII. Example 248 C0 2 H N N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(4,7-dimethyl-2 indenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 348) [0447] This compound can be prepared as described in Scheme VII. Example 249 co 2 H N-N 0 N-N 0 F F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(4,7-difluoro-2 indenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 349) [04481 This compound can be prepared as described in Scheme VII. Example 250 00 0 N 0N I- F ,F F 3- {2-Hydroxy-3-(2-oxo-2,3-dihydro-6-trifluoromethyl- 1 -(2-(2-methylphenyl)-ethyl) 3(Z)-indolylidene)methylaminophenyl}benzoic acid (Compound 350) [04491 This compound was prepared as described in Scheme VIII. 'H NMR (500MHz, DMSO) 13.05 (s, 1H), 11.29 (d, J = 13.4 Hz, 1H), 9.39 (s, 1H), 8.95 (d,J= 13.4 Hz, 1H), 8.13 (m, 1H), 7.95 (dd, J = 7.8, 1.0 Hz, IH), 7.83 (d, J = 8.1 Hz, 1H), 7.80 (m, 1H), 7.75 (d,J= 8.1 Hz, 1H), 7.61 (t,J= 7.8 Hz, 1H), 7.31 (d, J= 7.8 Hz, 1H), 7.20 -201 - WO 2007/062078 PCT/US2006/045129 (m, 1H), 7.16-7.07 (m, 5H), 7.05 (d, J= 7.8 Hz, 1H), 4.06 (t, J= 7.4 Hz, 2H), 2.93 (t, J= 7.4 Hz, 2H), 2.32 (s, 3H). Example 251 00 0 N 0 N I F F 3-{2-Hydroxy-3-( 2 -oxo- 2 ,3-dihydro-6-trifluoromethyl-.1-(2-indenyl)-3(Z) indolylidene)methylaminophenyl}benzoic acid (Compound 351) [0450] This compound can be prepared as described in Scheme VIII. Example 252 C02H O, N N 0 N-N 0 (d-)4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(1,2,3,4-tetrahydro) naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 352) [0451] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, CD 3 OD) 7.57 (dd,.1 = 8.0, 1.6 Hz, 1H), 7.11-7.04 (m, 5H), 7.00 (t,J = 8.0 Hz, 1H), 3.79 (t, J = 6.7 Hz, 2H), 3.39 (m, 1H), 3.05-2.80 (m, 4H), 2.34 (t, J = 7.3 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H), 2.10-1.91 (m, 2H). Example 253
CO
2 H ,N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro) naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 353) [0452] This compound can be prepared as described in Scheme VII. Example 254 - 202- WO 2007/062078 PCT/US2006/045129
CO
2 H N o N-N 0 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(1-indanylidene) methylphenyl)hydrazono)pyrazolyl} butanoic acid (Compound 354) [0453] This compound can be prepared as described in Scheme VII. Example 255
CO
2 H N 0 N-N 0 F F F F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(5-fluoro-2 trifluoromethylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 355) [0454] This compound can be prepared as described in Scheme VII. Example 256 CO2H o N 0 N-N 0 F F F F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(6-fluoro-2-trifluoro methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 356) [0455] This compound can be prepared as described in Scheme VII. Example 257 COH N-N O F - 203 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 (E)-(2-(6-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 357) S[04561 This compound can be prepared as described in Scheme VII. Example 258
CO
2 H N N 0,p O N-N O F 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 (E)-(2-(4-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 358) [0457] This compound can be prepared as described in Scheme VII. Example 259
CO
2 H N N c-OH o N-N O F 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 (E)-(2-(3-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 359) [0458] This compound can be prepared as described in Scheme VII. Example 260 C0 2 H N 0 N-N 0 F F 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-( 2 -(2,6-difluorophenyl) ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 360) [0459] This compound can be prepared as described in Scheme VII. Example 261 - 204 - WO 2007/062078 PCT/US2006/045129 I
CO
2 H N 0 N-N 0 F F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,5-difluorophenyl) ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 361) 104601 This compound can be prepared as described in Scheme VII. Example 262 co 2 H o N-N 0 F F F - F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(4-fluoro-2-trifluoro methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 362) [0461] This compound can be prepared as described in Scheme VII. Example 263
CO
2 H N 0 N-N 0 F N- F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,4-difluorophenyl) ethynyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 363) [0462] This compound can be prepared as described in Scheme VII Example 264
CO
2 H -N N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-( 1 -(1,2,3,4-tetrahydro) naphthylidene)methylphenyl)hydrazono)pyrazolyl}butanoic acid (Compound 364) [0463] This compound can be prepared as described in Scheme VII. - 205 - WO 2007/062078 PCT/US2006/045129 Example 265 c0 2 H r o N N \--0 N-N 0 F 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-fluoro-5 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 365) [0464] This compound can be prepared as described in Scheme VII. Example 266 co 2 H -N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3,5-dimethyl-4 isoxazolyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 366) 104651 This compound can be prepared as described in Scheme VII. Example 267 co2H N 0 N-N O 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,5-dimethyl-4 isoxazolyl)ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 367) [0466] This compound can be prepared as described in Scheme VII. Example 268 - 206 - WO 2007/062078 PCT/US2006/045129 00 0~~ N I I N 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-1 -(2(E)-(2-methylphenyl)ethenyl)-3(Z) indolylidene)methylaminophenyl} benzoic acid (Compound 368) [0467] This compound can be prepared as described in Scheme VIII. Example 269 00 0 N
N
F F 3- { 2-Hydroxy-3-(2-oxo-2,3-dihydro- 1 -(2(E)-(2,4-difluorophenyl)ethenyl)-3(Z) indolylidene)methylaminophenyl}benzoic acid (Compound 369) [0468] This compound can be prepared as described in Scheme VIII. Example 270 00 0~~ 0I~ N 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro- 1 -(2-indenyl)-3(Z)-indolylidene)methyl aminophenyl}benzoic acid (Compound 370) [0469] This compound can be prepared as described in Scheme VIII. Example 271 - 207 - WO 2007/062078 PCT/US2006/045129 ,,,_,C0,1 N 0N N-N 0 F 3-{2-(5-Methyl-3 -oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(5-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 371) [0470] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.72 (s, 1H), 13.13 (br s, 1H), 10.23 (s, 1H), 8.54 (dd, J = 2.1, 1.6 Hz, 1H), 8.21 (ddd, J = 8.0, 2.1, 1.0 Hz, 1H), 7.79 (ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.65 (dd, J= 7.9, 1.3 Hz, 1H), 7.60 (dd, J= 8.0, 7.8 Hz, 1H), 7.60 (dd, J= 7.9, 1.3 Hz, 1H), 7.55 (dd, J = 10.6, 2.8 Hz, 1H), 7.50 (d, J = 15.9 Hz, 1H), 7.35 (dd, J = 15.9, 1.5 Hz, 1H), 7.26 (dd, J = 8.4, 6.2 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 7.04 (td, J = 8.4, 2.8 Hz, 1H), 2.39 (s, 3H), 2.35 (s, 3H). Example 272
CO
2 H N-N 0 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-methylphenyl)hydrazono) pyrazolyl}butanoic acid (Compound 372) 10471] This compound was prepared as described in Scheme VII. 'H NMR (500MHz, DMSO) 13.57 (br s, 1H), 12.11 (br s, 1H), 9.45 (br s, 1H), 7.46 (d,J = 7.8 Hz, 1H), 6.95 (m, 1H), 6.89 (t, J = 7.8 Hz, 1H), 3.69 (t, J = 6.8 Hz, 2H), 2.25 (t, J = 7.2 Hz, 2H), 2.24 (s, 3H), 2.19 (s, 3H), 1.86 (m, 2H). Example 273 C02H N 0 N-N 0 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 indanylidenemethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 373) [0472] This compound can be prepared as described in Scheme VII. - 208 - WO 2007/062078 PCT/US2006/045129 Example 274 C0 2 H N- N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 indanylmethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 374) [0473] This compound can be prepared as described in Scheme VII. Example 275 0 N 02F N-N O F F 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,4-difluorophenyl) ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 375) [0474] This compound can be prepared as described in Scheme VII. Example 276 ,
,CO
2 H O N 0 N-N 0 F F 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6-difluorophenyl) ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 376) [0475] This compound can be prepared as described in Scheme VII. Example 277
CO
z H N N N-N 0 F - 209 - WO 2007/062078 PCT/US2006/045129 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(4-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 377) 10476] This compound can be prepared as described in Scheme VII. Example 278 CO,H cO z N-N 0 F 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-fluoro-6 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 378) [0477] This compound can be prepared as described in Scheme VII. Example 279 C O 2 H N N0 N-N O F F 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,3-difluorophenyl) ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 379) [0478] This compound can be prepared as described in Scheme VII. Example 280
CO
2 H N 0 N-N 0 F F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,3-difluorophenyl) ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 380) [0479] This compound can be prepared as described in Scheme VII. Example 281 -210- WO 2007/062078 PCT/US2006/045129
CO
2 H IN 0 N-N 0 F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-fluoro-4 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 381) [0480] This compound can be prepared as described in Scheme VII. Example 282 co 2 H O N 0 N-N O 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-chlorophenyl) ethenyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 382) [0481] This compound can be prepared as described in Scheme VII. Example 283
CO
2 H N 0N N-N O ci cI 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6-dichlorophenyl) ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 383) [0482] This compound can be prepared as described in Scheme VII. Example 284
CO
2 H N 0 N-N 0 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3-chlorophenyl) ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 384) -211- WO 2007/062078 PCT/US2006/045129 [0483] This compound can be prepared as described in Scheme VII. Example 285
CO
2 H O N L 0 N-N 0 F F 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,5-difluorophenyl) ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 385) [0484] This compound can be prepared as described in Scheme VII. Example 286 co 2 H N o N-N O F 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-chloro-4 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 386) [0485] This compound can be prepared as described in Scheme VII. Example 287 , C O z 2 H N 0 N-N O
\F
3 C F F 3- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-trifluoromethyl-4 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 387) [0486] This compound can be prepared as described in Scheme VII. Example 288 -212- WO 2007/062078 PCT/US2006/045129
CO
2 H N 0 N-N O CI 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,4-dichlorophenyl) ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 388) (0487] This compound can be prepared as described in Scheme VII. Example 289 co 2 H 1-e NN 0 N-N O 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-chloromethyl-4 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 389) [0488] This compound can be prepared as described in Scheme VII. Example 290 ._cO 2 H o NN 0 N-N O CI 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,4 dichloromethylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl }benzoic acid (Compound 390) [04891 This compound can be prepared as described in Scheme VII. Example 291 :
CO
2 H N 0 2 N-N 0 -213- WO 2007/062078 PCT/US2006/045129 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro) naphthyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 353) 104901 This compound can be prepared as described in Scheme VII. Example 292
CO
2 H N -No 1 4 F N-N 0 /\S / \ 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-8-fluoro) naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 392) 104911] This compound can be prepared as described in Scheme VII. Example 293 co0 2 H N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-8-methyl) naphthyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 393) [0492] This compound can be prepared as described in Scheme VII. Example 294 CO2H c2 -N 0 N-N 0 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-7-methyl) naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 394) [0493] This compound can be prepared as described in Scheme VII. Example 295 -214- WO 2007/062078 PCT/US2006/045129 C0 2 H N N 0 O- F N-N 0 4- {2-(5-Methyl-3-oxo- 2 ,3-dihydro-4-(2-hydroxy-.3-(2-(3,4-dihydro-7-fluoro) naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 395) [0494] This compound can be prepared as described in Scheme VII. Example 296 C0 2 H N 0N N-N 0F 4-{2-(5-Methyl-3-oxo- 2 ,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-6-fluoro) naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 396) [0495] This compound can be prepared as described in Scheme VII. Example 297 cozH N -N N-N 0 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-5-fluoro) naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 397) [0496] This compound can be prepared as described in Scheme VII. Example 298
CO
2 H NN 0 N-N-25 -215 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-8-chloro) naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 398) 10497] This compound can be prepared as described in Scheme VII. Example 299 qN C0 2 H1 O F N-N 0 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-7-fluoro) naphthyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 399) [04981 This compound can be prepared as described in Scheme VII. -216-

Claims (40)

1. A compound of Formula I, II, III, IV, V, or VI: R1(R 2 )m R 9 R 9 O/ U 7 - -RIO R7-@ inZ O U m R Z-L DRi R ZN SR 8 R " I 0 R3 N R 5 X W X 0 0 w / / R-E-R R 6 R R 6 (I) (II) (III) Ri i R2)m R 8 R 8 Q R7 Z-L Ro R12 Z-46 R R 9 D 13 .- , N R 9 0 RR R R 0O R 3 .N R O IR12 1 /R 12 WX N 13 O RIO- R11 N - 1R1 R R I R 6 R 6 R 6 (IV) (V) (VI) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: R' is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NRI 4 R is , an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted C,-C 6 heteroalkyl, CO 2 RI 4 , CONRI 4 R"s, SO 3 RI 4 SO 2 NR' 4 R' 5 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, OR 14 , NR' 4 R' s, an optionally substituted CI-C 6 alkyl, an optionally substituted C1-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R 3 and R 4 are independently selected from hydrogen, an optionally substituted C,-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted C,-C 6 heteroalkyl; R s is selected from hydrogen, halogen, OR' 4 , CI-C 6 alkyl, CJ-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI-C 6 haloheteroalkyl; R 6 is selected from an optionally substituted Cz-Clo alkyl, an optionally substituted CI-Clo haloalkyl, and an optionally substituted Cl-Clo heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R 6 is selected from (CH 2 )mR", C(O)NHR's, C=CR is , CR =CR 4 R i , and CR 3 =R" 8 ; -217- WO 2007/062078 PCT/US2006/045129 R 7 is selected from CO 2 R 1 4 , CONRI 4 Ri 5 , SO 3 RI 4 , SO 2 NRI 4 R i s and a carboxylic acid bioisostere; each R 8 and each R 9 is independently selected from hydrogen, OR 16 , NR1 6 R 17 , an optionally substituted CI-C 6 alkyl, an optionally substituted C,-C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, (CH 2 )mR' 8 , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R? are linked to form an optionally substituted C 3 -Cs ring; R 1 0 is selected from hydrogen, halogen, oxo, OR 6 , NR 6 R 7 , SR 16, an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted C 1 -C 6 heteroalkyl; R" is selected from hydrogen, halogen, OR14, NR14R is 5 , and SR 14 ; or R and R 4 are linked to form a optionally substituted heterocycle; R 12 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 C 6 heteroalkyl, and CI-C 6 haloheteroalkyl; R 13 is selected from hydrogen, halogen, CN, NO 2 , CO 2 RI 4 , S(O)mR 14 , CI C 4 alkyl, C -C 4 haloalkyl, C 1 -C 4 heteroalkyl, and C I-C 4 haloheteroalkyl; R 14 is selected from hydrogen, CI-C 6 alkyl, CI-C 6 haloalkyl, C 1 -C 6 heteroalkyl, and C 1 -C 6 heterohaloalkyl; R is 5 is selected from hydrogen, S0 2 R' 9 , C 1 -C 6 alkyl, CI-C 6 haloalkyl, C 1 -C 6 heteroalkyl, and C, -C 6 heterohaloalkyl; R 16 and R' 7 are each independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, and (CHz)mR1 8 ; or one of R 16 and R" 7 is an optionally substituted C 2 -C 6 alkyl and the other of R 16 and R 17 is null; or RI 6 and R 17 are linked to form an optionally substituted C 3 -C 8 ring; R' 1 8 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R 18 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system; R' 9 is selected from hydrogen, CI-C 3 alkyl, C 1 -C 3 haloalkyl, and an optionally substituted aryl; -218- WO 2007/062078 PCT/US2006/045129 D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; L is NH or null; Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; U is selected from O, NR 4 , CR 3 R 4 , CO, and null; W is selected from O, NR 4 , CR 3 R 4 , CO, and null; X is N or CR; Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted C 1 -C 6 alkyl, an optionally substituted CI-C 6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl; Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6 -Cl 0 aryl and an optionally substituted CI-C 8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted CI-C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, and an optionally substituted CI-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -C 10 aryl; m is 0, 1, 2, or 3; and n is 0 or 1; each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, =O, =S, amino, and protected derivatives of amino groups; -219- WO 2007/062078 PCT/US2006/045129 N provided that if Y is "R 12 oriented in compounds of Formulas I or II to form a dihydropyrazolylene, then: (i) D is not naphthyl if X is N and W is NH, (ii) D is not phenyl if X is CH, W is NH, Z is phenyl, and Rio or R" is -(CH 2 ) 0 - 6 0H, R"1-D-Rio (iii) I is not pyrazolyl or optionally substituted 5 hydroxypyrazolyl, and (iv) U is not NH; provided further that if X is N and W is NH, then D is not phenyl; and provided further that if X is N and W is NH in compounds of Formulas III or VI, then R 6 , R i0 , and R" do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
2. A compound of Formula I, II, or III: R1 ,'(R2) m R 9 R 9 R mRZ D R R 8 N R/ /N 1 5 R R " I 0 R3 N R X 1W ,x R- - X0 1- 1 NN Rio-E R" R 6 R6 R 6 (I) (II) (III) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: R 1 is selected from hydrogen, halogen, OR' 4 , NO 2 , CN, NRI 4 R'", an optionally substituted CI-C 6 alkyl, an optionally substituted C,-C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, CO 2 RI 4 , CONR 4 R" 5 , SO 3 R 4 , SO 2 NRI 4 R 15 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, OR 14 , NRI 4 R 5 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, and an optionally substituted C,-C 6 heteroalkyl; R 3 and R 4 are independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; - 220 - WO 2007/062078 PCT/US2006/045129 R 5 is selected from hydrogen, halogen, OR 1 4 , Cl-C 6 alkyl, CI-C 6 haloalkyl, CI-C6 heteroalkyl, and C-C 6 haloheteroalkyl; R 6 is selected from an optionally substituted Cz-Clo alkyl, an optionally substituted Ci-Clo haloalkyl, an optionally substituted CI-Clo heteroalkyl, (CH 2 )mR i s , C(O)NHRi 8 , C-CR' 8 , CR 3 =CR 4 Ri 8 , and CR 3 =R' 8 ; R 7 is selected from CO 2 R 14 , CONRR 1 5 R", SO 3 R I4 , SO 2 NRI 4 R' 5 and a carboxylic acid bioisostere; each R 8 and each R 9 is independently selected from hydrogen, OR 16 , NR16R1 7, an optionally substituted C-C6 alkyl, an optionally substituted C,-C 6 haloalkyl, an optionally substituted C,-C 6 heteroalkyl, (CH 2 )mR' 18 , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -C 8 ring; R1 0 is selected from hydrogen, halogen, oxo, ORI 6 , NRI 6 R 7 , SR 6 , an optionally substituted C1-C6 alkyl, an optionally substituted C,-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R 1 1 is selected from hydrogen, halogen, OR 4 , NRI 4 R 1 5 , and SR' 4 ; or R" and R 4 are linked to form a optionally substituted heterocycle; R' 2 is selected from hydrogen, halogen, CI-C 6 alkyl, Ci-C 6 haloalkyl, C] C6 heteroalkyl, and Cl-C 6 haloheteroalkyl; R 14 is selected from hydrogen, CI-C 6 alkyl, CI-Cs haloalkyl, C-C 6 heteroalkyl, and C1-C6 heterohaloalkyl; R' 5 is selected from hydrogen, SO 2 R 1 9 , CI-C6 alkyl, CI-C6 haloalkyl, CI-C6 heteroalkyl, and CI-C6 heterohaloalkyl; R 1 6 and R 7 are each independently selected from hydrogen, an optionally substituted C-C 6 alkyl, an optionally substituted C-C6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, and (CH 2 )mR' 8 ; or one of R 1 6 and R 17 is an optionally substituted C2-C6 alkyl and the other of R' 6 and R1 7 is null; or R 1 6 and R 1 7 are linked to form an optionally substituted C3-C8 ring; R' s is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R'8 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system; - 221 - WO 2007/062078 PCT/US2006/045129 R 1 9 is selected from hydrogen, C 1 -C 3 alkyl, CI-C 3 haloalkyl, and. an optionally substituted aryl; D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; L is NH or null; Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; U is selected from O, NR 4 , CR 3 R 4 , CO, and null; W is selected from O, NR 4 , CR 3 R 4 , CO, and null; X is N or CR'; Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted CI-C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl; Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6 -C, 0 aryl and an optionally substituted CI-Cs heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted C 1 -C 6 alkyl, an optionally substituted CI-C 6 heteroalkyl, and an optionally substituted C 1 -C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -CI 0 aryl; m is 0, 1, 2, or 3; and n is 0 or l; each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamnido, N-sulfonamido, C-carboxy, O-carboxy, - 222 - WO 2007/062078 PCT/US2006/045129 isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, =O, =S, amino, and protected derivatives of amino groups; N provided that if Y is R 12 oriented in compounds of Formulas I or II to form a dihydropyrazolylene, then: (i) D is not naphthyl if X is N and W is NH, (ii) D is not phenyl if X is CH, W is NH, Z is phenyl, and R1 0 or R" is -(CH 2 ) 0 - 6 0H, R" 1 -D-RIo (iii) I is not pyrazolyl or optionally substituted 5 hydroxypyrazolyl, and (iv) U is not NH; provided further that if X is N and W is NH, then D is not phenyl; and provided further that if X is N and W is NH in compound of Formula III, then R 6 , Ro , and R" do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
3. The compound of claim 2, wherein: R' is selected from a halogen, OR 14 , NO 2 , CN, NRI 4 Ri 5 , CI-C 4 alkyl, C, 14 14 I C 4 haloalkyl, an optionally substituted C 1 -C 4 heteroalkyl, CO 2 R , CONR R" , SO 3 RI 4 , SO 2 NRI 4 R' 5 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2 R' 9 , OC(S)NR 4 R 5 , SC(O)NRI4R 5 , and B A)C 0 o, wherein A, B, and C are each independently selected from O, S, and NR 2 0 ; each R 2 is independently selected from hydrogen, halogen, OR 14 , NRI 4 R' 5 , CI-C 4 alkyl, CI-C 4 haloalkyl, CI-C 4 heteroalkyl, and CI-C 4 heterohaloalkyl; R 3 and R 4 are independently selected from hydrogen, CI-C 4 alkyl, CI-C 4 haloalkyl, and an optionally substituted C 1 -C 4 heteroalkyl; R 5 is selected from hydrogen, OR" 4 , CI-C 4 alkyl, CI-C 4 haloalkyl, CI-C 4 heteroalkyl, and CI-C 4 haloheteroalkyl; R 6 is selected from CI-Clo alkyl, CI-Clo haloalkyl, an optionally substituted C-Clo heteroalkyl, (CH 2 )mR" 8 , C(O)NHR", C=CR", CR 3 =CR 4 R 8 , and CR 3 =R 8 ; - 223 - WO 2007/062078 PCT/US2006/045129 R 7 is selected from CO 2 R 1 4 , CONRI 4 R 5 , SO 3 R 1 4 , SO 2 NRI 4 R' 5 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2 R 9 , OC(S)NR' 4 R s 5 , SC(O)NRI4R 1 5 , and B A) C wherein A, B, and C are each independently selected from O, S, and N; each R and each R 9 is independently selected from hydrogen, OR 16 , NR1 6 R 1 7 , CI-C4 alkyl, CI-C4 haloalkyl, an optionally substituted CI-C 4 heteroalkyl, (CH2)mR' 8 , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -C 8 ring; Ri 0 is selected from hydrogen, halogen, oxo, C-C4 alkyl, CI-C 4 haloalkyl, and an optionally substituted CI-C4 heteroalkyl; R" 1 is selected from hydrogen, halogen, ORI 4, NR 4 R is ' 5 , and SR1 4 ; or R and R 4 are linked to form a optionally substituted heterocycle; R1 2 is selected from hydrogen, halogen, CI-C 4 alkyl, CI-C 4 haloalkyl, C, C4 heteroalkyl, and CI-C 4 haloheteroalkyl; R 3 is selected from hydrogen, halogen, CN, NO 2 , CO 2 RI 4 , S(O)mR 4 , C1 C 4 alkyl, CI-C 4 haloalkyl, C I-C 4 heteroalkyl, and CI-C4 haloheteroalkyl; RI 4 is selected from hydrogen, C-C 4 alkyl, CI-C 4 haloalkyl, C,-C 4 heteroalkyl, and CI-C 4 heterohaloalkyl; R 1 5 is selected from hydrogen, SO 2 R 1 9 , CI-C 4 alkyl, CI-C 4 haloalkyl, and C1-C4 heteroalkyl; R 1 6 and R1 7 are each independently selected from hydrogen, CI-C 4 alkyl, CI-C 4 haloalkyl, an optionally substituted CI-C4 heteroalkyl, and (CH 2 )mRl 8 ; or one of R 16 and R 17 is C2-C6 alkyl and the other of RI 6 and R 17 is null; or R' 6 and R 17 are linked to form an optionally substituted C 4 -C 7 ring; R1 9 is selected from hydrogen, CI-C3 alkyl, C 1 -C 3 haloalkyl, and aryl; G is selected from O, S, and NR' 4 ; J is selected from O, S, NR 1 4 , and CRI 4 R' 5 ; K is O or S; Y is selected from: - 224 - WO 2007/062078 PCT/US2006/045129 R1 2 R 12 -R13 '--R 13 . -R G -R R 2 , and K
4. A compound of Formula IV, V, or VI: SR 2)m R 8 Z-L R R R7 R R. LRi R11' 0 RN R . x11W O /R12 0 R 1 2 W No Nz Rio--R 11 NR / 'R1 3 1 R R 6 R 6 (IV) (V) (VI) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: R 1 is selected from hydrogen, halogen, OR" 4 , NO 2 , CN, NR" 4 R 5 , an optionally substituted CI-C 6 alkyl, an optionally substituted C1-C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, CO 2 RI 4 , CONR" 4 Rs , SO 3 R 4 SO 2 NRI 4 Ri 5 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, OR 14 , NRI 4 R is , an optionally substituted Ci-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl; R and R 4 are independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R 5 is selected from hydrogen, halogen, OR" 4 , C,-C 6 alkyl, C1-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI-C 6 haloheteroalkyl; R is selected from an optionally substituted CI-Clo alkyl, an optionally substituted CI-C 0 lo haloalkyl, an optionally substituted CI-C 0 lo heteroalkyl, (CH 2 )mRs , C(O)NHR' s , CECR s , CR 3 =CR 4 R'", and CR 3 =R' 8 ; R 7 is selected from CO 2 R 4 , CONRi 4 R" 5 , SO 3 R' 4 , SO 2 NR1 4 R" and a carboxylic acid bioisostere; each R 8 and each R 9 is independently selected from hydrogen, OR 6 , NR16R1 7, an optionally substituted Ci-C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, (CH2)mR' 1 8 , and null; or R 8 - 225 - WO 2007/062078 PCT/US2006/045129 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -Cs ring; R i0 is selected from hydrogen, halogen, oxo, OR' 6 , NR'1 6 R 7 , SR 1 6 , an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R" is selected from hydrogen, halogen, OR 14 , NR 4 R 15 , and SRI4; or R" and R 4 are linked to form a optionally substituted heterocycle; R 12 is selected from hydrogen, halogen, CI-C 6 alkyl, CI-C 6 haloalkyl, Cj C 6 heteroalkyl, and CI-C 6 haloheteroalkyl; R 3 is selected from hydrogen, halogen, CN, NO 2 , CO 2 RI 4 , S(O)mRl 4 , CI C 4 alkyl, CI-C 4 haloalkyl, C,-C 4 heteroalkyl, and CI-C 4 haloheteroalkyl; R 14 is selected from hydrogen, CI-C 6 alkyl, Ci-C 6 haloalkyl, CI-C 6 heteroalkyl, and C 1 -C 6 heterohaloalkyl; R is 5 is selected from hydrogen, SO z R' 9 , CI-C 6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl; R1 6 and R1 7 are each independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted C,-C 6 heteroalkyl, and (CH 2 )mR1 8 ; or one of R' 16 and R" is an optionally substituted C 2 -C 6 alkyl and the other of R1 6 and R1 7 is null; or RI 6 and R 7 are linked to form an optionally substituted C 3 -C 8 ring; R' 8 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R' 8 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system; RI 9 is selected from hydrogen, CI-C 3 alkyl, CI-C 3 haloalkyl, and an optionally substituted aryl; D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; - 226 - WO 2007/062078 PCT/US2006/045129 L is NH or null; Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; U is selected from O, NR 4 , CR 3 R 4 , CO, and null; W is selected from O, NR 4 , CR 3 R 4 , CO, and null; X is N or CR 5 ; Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6 -Cl 0 aryl and an optionally substituted CI-C 8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted CI-C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, and an optionally substituted CI-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -Co aryl; m is 0, 1, 2, or 3; and nis 0 or 1; each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, =0, =S, amino, and protected derivatives of amino groups; provided that if X is N and W is NH, then D is not phenyl; and provided further that if X is N and W is NH in compounds of Formulas VI, then R 6 , R"o, and R" 1 do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
5. The compound of claim 4, wherein: R' is selected from hydrogen, halogen, OR 1 4 , N02, CN, NR1 4 R 15 , an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted C 1 -C 6 heteroalkyl, CO 2 RI 4 , CONR I4 R s ' 5 , SO 3 R I4 - 227 - WO 2007/062078 PCT/US2006/045129 SO 2 NRI 4 R 1 5 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2 R' 9 , OC(S)NRI 4 R 5 , SC(O)NRI 4 R 5 , and B wherein A, B, and C are each independently selected from O, S, and N; and R 7 is selected from CO 2 RI 4 , CONRI 4 Ris, SO 3 RI 4 , SO 2 NR) 4 R is and a carboxylic acid bioisostere selected from tetrazole, NHSO 2 Ri", OC(S)NR' Ris, SC(O)NR1 4 R 5 , and B AC I o0, wherein A, B, and C are each independently selected from O, S, and N.
6. A compound of Formula I, II, III, IV, V, or VI: R R(7) R 9 R 9 O- R - nZ-LR D I R 8 z N c 1u 5 R 8 R/- N R R " I ,, O R3,N R 5 xW / / I NN-" R'o-E-R1 R 6 R 6 R 6 (I) (II) (III) R Rm R7R ZL\ /Rlo R R 7 R 9 D13 N R 9 R 5 W R3 NR R XRO O R12 R 1 2 W N - R 13 ~~N 1 3 RIo-E-R R /R I R 6 R 6 R 6 (IV) (V) (VI) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: R' is selected from hydrogen, halogen, OR' 14 , NO 2 , CN, NR 1 4 R 5 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted C,-C 6 heteroalkyl, CO 2 RI 4 , CONRI 4 R' i s , SO 3 R 4 , SO 2 NRI 4 R 15 and a carboxylic acid bioisostere; - 228 - WO 2007/062078 PCT/US2006/045129 each R 2 is independently selected from hydrogen, halogen, OR' 4 , NRI 4 R 5 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C,-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R 3 and R 4 are independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R 5 is selected from hydrogen, halogen, OR 1 4 , CI-C 6 alkyl, C 1 -C 6 haloalkyl, CI-C 6 heteroalkyl, and CI-C 6 haloheteroalkyl; R 6 is selected from an optionally substituted CI-Clo alkyl, an optionally substituted CI-Clo haloalkyl, and an optionally substituted CI-Clo heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R 6 is selected from (CH 2 )mR' s , C(O)NHR" 8 , C=-CR" 8 , CR 3 =CR 4 R" 8 , and CR 3 =R"; R 7 is selected from CO 2 R I4 , CONRI 4 R' 5 , SO 3 RI 4 , SO 2 NRI 4 R 5 and a carboxylic acid bioisostere; 8 16 each R 8 and each R 9 is independently selected from hydrogen, OR , NRI 6 R 17 , an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, (CH 2 )mRu', and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -C 8 ring; Ri 0 is selected from hydrogen, halogen, oxo, OR 6 , NR"' 6 R 7 , SR 6 , an optionally substituted C I-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R" 1 is selected from hydrogen, halogen, ORI 4 , NR' 4 R is , and SRI4; or R I and R 4 are linked to form a optionally substituted heterocycle; R 12 is selected from hydrogen, halogen, C 1 -C 6 alkyl, CI-C 6 haloalkyl, C, C 6 heteroalkyl, and CI-C 6 haloheteroalkyl; R" is selected from hydrogen, halogen, CN, NO 2 , CO 2 RI 4 , S(O)mR I4 , C C 4 alkyl, CI-C 4 haloalkyl, CI-C 4 heteroalkyl, and CI-C 4 haloheteroalkyl; R' 4 is selected from hydrogen, CI-C 6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and Ci-C 6 heterohaloalkyl; R 15 is selected from hydrogen, SO 2 R' 9 , CI-C 6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and Ci-Cs heterohaloalkyl; R 16 and R 1 7 are each independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally - 229 - WO 2007/062078 PCT/US2006/045129 substituted CI-C6 heteroalkyl, and (CH 2 ).mR'; or one of R 6 and R 1 7 is an optionally substituted C2-C6 alkyl and the other of R1 6 and R 17 is null; or R1 6 and R 1 7 are linked to form an optionally substituted C3-Cs ring, R1 8 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle, wherein when R 1 8 contains a non-aromatic heterocycle or carbocycle, the attachment position may be either on the non-aromatic heterocycle or carbocycle or on the aromatic ring system; R' 9 is selected from hydrogen, C 1 -C 3 alkyl, CI-C3 haloalkyl, and an optionally substituted aryl; D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; L is NH or null; Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; U is selected from O, NR 4 , CR R 4 , CO, and null; W is selected from O, NR 4 , CR 3 R 4 , CO, and null; X is N or CRs; Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted CI-C 6 alkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl; Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C6-CI0o aryl and an optionally substituted CI-Cs heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and - 230 - WO 2007/062078 PCT/US2006/045129 a 1-5 atom spacer of selected from an optionally substituted CI-C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, and an optionally substituted CI-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -C 1 0 aryl; m is 0, 1,2, or 3; and n is 0 or 1; provided that, if X is N, W is NH, and Y is not -N=CR 1- orientated to form a dihydropyrazole, and Z or R 6 are not an optionally substituted non aromatic ring fused with an optionally substituted aromatic ring; or if X is N, W is NH, R 6 is alkoxy, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, Y is -N=CR' 2 - orientated to form a dihydropyrazole, and Z is not an optionally substituted non-aromatic ring fused with an optionally substituted aromatic ring; then D is not a phenyl; provided that, if X is N, W is NH, and Y is -N=CR 12 - orientated to form a dihydropyrazole, then D is not a naphthyl; provided that, if U is NH; or if D and one of R1 0 and R 1 " form a 5 hydroxypyrazole, X is N, and W is NH; or if E and one of R io and R" form a 5 hydroxypyrazole and X is N, and W is NH; or if E is phenyl, one of Ro or R" is (CH 2 )o-6OH, X is C, W is NH, R 6 is an optionally substituted aryl or an optionally substituted heteroaryl, and Z is null, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; or if E is phenyl, one of Ri o or R" is -(CH 2 )o- 6 OH, X is N, W is NH, Z is null, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, and R 6 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -(CH 2 )0-6OR 20 , an optionally substituted aryl, an optionally substituted heteroaryl, NR 2 'R 22 or a heterocyclic methylene substituent as represented by formula VII; or if D is phenyl, one of R 1 0 or R" is -(CH 2 )0-60H, X is C, W is NH, Z is aromatic, and R 6 is alkoxy, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; then Y is not -N=CR 12 - orientated to form a dihydropyrazole; R 2 0 is selected from hydrogen, a substituted alkyl, a substituted aryl, and a substituted heteroaryl; R 21 and R 2 2 are each independently selected from hydrogen, alkyl, and aryl; or R 2 1 and R 22 taken together with the nitrogen to which they are attached represent a 5 or 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; -231- WO 2007/062078 PCT/US2006/045129 B "AC R 20 / v (VII) wherein A, B, C, and V are each independently selected from O, S, and NR 2 0
7. A compound of Formula 1, II, III, IV, V, or VI: R Rm RR ) R 9 Z-R DRI R7 n O R R 6 RR" R m RN 5Z-L Ro R OR R 9 R 1 I RO R0 0N1Y N0 R1OE-_R, ON ZR 3 O/Nio // R 6 R 6 R 6 (IV) () (VI) wherein: 1 R2)m RB 12 R84,- R 7 R' is selected from hydrogen, halogen, OR 4 , NO 2 , CN, NR 4 R, an optionally substituted C,-C 6 alkyl, an optionally substituted C,-C 6 haloalkyl, an 0 R12 1 12 W" optionally substituted C,-C 6 heteroalkyl, CO 2 R' 4 , CONRI 4 R's, SO 3 R' /N-13 / N -IR13 RI-ER R 6 R 6 R 6 (IV) Mv (vI) SO 2 wherein:R 4 R and a carboxylic acid bioisostere; R 2 is selected from hydrogen, halogen, OR 14 , NO2R 4 R,an optionally optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted C-C 6 heteroalkyl, C2R , CONRR , S3R S02NR14 R 15 and a carboxylic acid bioisostere; Ris selected from hydrogen, halogen, OR 4 , R ~ , an optionally substituted CI-C6 alkyl, an optionally substituted CI-C6 haloalkyl, and an optionally substituted C I-C6 heteroalkyl; R 3 and R 4 are independently selected from hydrogen, an optionally substituted C,-C 6 alkyl, an optionally substituted C,-C 6 haloalkyl, and an optionally substituted C,-C 6 heteroalkyl; - 232 - WO 2007/062078 PCT/US2006/045129 R s is selected from hydrogen, halogen, OR 4 , C1-C 6 alkyl, CI-C 6 haloalkyl, C I-C 6 heteroalkyl, and C i-C 6 haloheteroalkyl; R 6 is selected from an optionally substituted Cl-C 0 lo alkyl, an optionally substituted CI-Clo haloalkyl, or an optionally substituted CI-C 0 lo heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R 6 is (CH 2 )mR 1 8 or C(O)NHR'i; R is selected from CO 2 R' 4 , CONRI 4 R" 5 , SO 3 R 4 , SO 2 NRI 4 R" and a carboxylic acid bioisostere; R and R 9 are each independently selected from hydrogen, OR 16 , NRI 6 R , an optionally substituted CI-C 6 alkyl, an optionally substituted C I-C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, (CH 2 )mR' 1 8 , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -C 8 ring; R i 0 is selected from hydrogen, halogen, oxo, OR' 6 , NRI' 6 R 7 , SR' 6 , an optionally substituted C,-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted C I-C 6 heteroalkyl; R" is selected from hydrogen, halogen, OR 14 , NRI 4 R 5 , and SR1 4 ; or R I 1 and R 4 are linked to form a optionally substituted heterocycle; R1 2 is selected from hydrogen, halogen, CI-C 6 alkyl, CI-C 6 haloalkyl, C, C 6 heteroalkyl, and CI-C 6 haloheteroalkyl; R 3 is selected from hydrogen, halogen, CN, NO 2 , CO 2 R 4 , S(O)mR 4 , C 1 C 4 alkyl, C,-C 4 haloalkyl, CI-C 4 heteroalkyl, and CI-C 4 haloheteroalkyl; R 14 is selected from hydrogen, CI-C 6 alkyl, C,-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl; R 15 is selected from hydrogen, SO 2 R 1 9 , CI-C 6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl; R 6 and R 17 are each independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, and (CH 2 )mR' 8 ; or one of R1 6 and R 17 is an optionally substituted C 2 -C 6 alkyl and the other of R' 16 and R 17 is null; or R 16 and R 17 are linked to form an optionally substituted C 3 -C 8 ring; R1 8 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally- containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle; -233- WO 2007/062078 PCT/US2006/045129 R 1 9 is selected from hydrogen, C 1 -C 3 alkyl, CI-C 3 haloalkyl, and an optionally substituted aryl; D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; L is NH or null; Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; U is selected from O, NR 4 , CR 3 R 4 , CO, and null; W is selected from O, NR 4 , CR 3 R 4 , CO, and null; X is N or CR 5 ; Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted CI-C 6 alkyl, an optionally substituted C,-C 6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl; Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6 -C 1 0 aryl and an optionally substituted C 1 -C 8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 heteroalkyl, and an optionally substituted CI-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -CI 0 aryl; m is 0, 1, or 2; and n is 0 or 1; each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic heterocycle, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, - 234 - WO 2007/062078 PCT/US2006/045129 isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, =O, =S, amino, and protected derivatives of amino groups; N A12 provided that if Y is R 1 oriented in compounds of Formulas I or II to form a dihydropyrazolylene, then: (i) D is not naphthyl if X is N and W is NH, (ii) D is not phenyl if X is CH, W is NH, Z is phenyl, and R i0 or R1 I is -(CH 2 ) 0 - 6 0H, R11-D -RI 1 O (iii) I is not pyrazolyl or optionally substituted 5 hydroxypyrazolyl, and (iv) U is not NH; provided further that if X is N and W is NH, then D is not phenyl; and provided further that if X is N and W is NH in compounds of Formulas III or VI, then R 6 , R , and R" 1 do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
8. A compound of Formula I, II, or III: Ri R m 2 ) 9 0 .. R9 7 R, R nZ O UR Z-L DR R 8 N R N RSR B R y. O 1 R 5 R 8 R1I /1 0 N N R ER" / / R 6 R 6 R 6 (1) (II) (III) wherein: R' is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NRI 4 R', an optionally substituted C1-C6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted CI-C6 heteroalkyl, CO 2 RI 4 , CONRI 4 Ri 5 , SO 3 R' 4 , SO 2 NR1 4 R 5 and a carboxylic acid bioisostere; R 2 is selected from hydrogen, halogen, OR 14 , NR 1 4 R 5 , an optionally substituted CI-C6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C6 heteroalkyl; - 235 - WO 2007/062078 PCT/US2006/045129 R 3 and R 4 are independently selected from hydrogen, an optionally substituted C,-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R 5 is selected from hydrogen, halogen, OR 1 4 , CI-C 6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI -C 6 haloheteroalkyl; R 6 is selected from an optionally substituted CI-Cro alkyl, an optionally substituted CI-Cl 0 haloalkyl, an optionally substituted CI-C 0 lo heteroalkyl, (CH 2 )mR' 8, and C(O)NHR' 8 ; R 7 is selected from CO 2 R 14 , CONRI 4 R 15 , SO 3 R 14 , SO 2 NRI 4 RI 5 and a carboxylic acid bioisostere; R 8 and R 9 are each independently selected from hydrogen, OR 6 , NR 6 R" 7 , an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, (CH 2 )mR' 8 , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -C 8 ring; R i0 is selected from hydrogen, halogen, oxo, ORI 6 , NR1 6 R 1 7 , SR 1 6, an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R" is selected from hydrogen, halogen, OR14, NRI 4 R 5 , and SR'"; or RI and R 4 are linked to form a optionally substituted heterocycle; RI 2 is selected from hydrogen, halogen, CI-C 6 alkyl, CI-C 6 haloalkyl, C, C 6 heteroalkyl, and CI-C 6 haloheteroalkyl; R 14 is selected from hydrogen, CI-C 6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl; R1 5 is selected from hydrogen, SO 2 R 1 9 , CI-C 6 alkyl, CI-C 6 haloalkyl, Ci-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl; R' 6 and R 17 are each independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, and (CH 2 )mR' 8 ; or one of R 16 and R 17 is an optionally substituted C 2 -C 6 alkyl and the other of RI 6 and R 1 7 is null; or R 16 and R1 7 are linked to form an optionally substituted C 3 -Cs ring; R1 8 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle; -236 - WO 2007/062078 PCT/US2006/045129 R 1 9 is selected from hydrogen, CI-C3 alkyl, CI-C 3 haloalkyl, and an optionally substituted aryl; D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; L is NH or null; Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; U is selected from O, NR 4 , CRR 4 , CO, and null; W is selected from O, NR 4 , CR 3 R 4 , CO, and null; X is N or CRs 5 ; Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl; Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6 -CI 0 aryl and an optionally substituted Ci-Cg heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted Cl-C 6 alkyl, an optionally substituted CI-C 6 heteroalkyl, and an optionally substituted CI-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -CIo aryl; m is 0, 1, or 2; and n is 0 or 1; N provided that if Y is R 12 oriented in compounds of Formulas I or II to form a dihydropyrazolylene, then: (i) D is not naphthyl if X is N and W is NH, - 237 - WO 2007/062078 PCT/US2006/045129 (ii) D is not phenyl if X is CH, W is NH, Z is phenyl, and R i 0 or R" 1 is -(CH 2 )0- 6 0H, R11-D-RIO (iii) I -is not pyrazolyl or optionally substituted 5 hydroxypyrazolyl, and (iv) U is not NH; provided further that if X is N and W is NH, then D is not phenyl; and provided further that if X is N and W is NH in compound of Formula III, then R, R i , and R" do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
9. The compound of claim 2, wherein: R' is selected from a halogen, ORI 4 , NO 2 , CN, NR1 4 Ri s , CI-C4 alkyl, C 1 C 4 haloalkyl, an optionally substituted C 1 -C 4 heteroalkyl, CO 2 RI 4 , CONRI 4 R 5 , SO 3 R 14 , SO 2 NR1 4 R' is and a carboxylic acid bioisosteres selected from tetrazole, NHSO 2 R 9, OC(S)NRI 4 Ri 5 , SC(O)NRI 4 R 5 , and B AAC wherein A, B, and C are each independently selected from O, S, and NR 20 ; R 2 is selected from hydrogen, halogen, OR 14 , NRI 4 R 5 , CI-C4 alkyl, CI-C 4 haloalkyl, CI-C 4 heteroalkyl, and CI-C 4 heterohaloalkyl; R 3 and R 4 are independently selected from hydrogen, C 1 -C 4 alkyl, C-C 4 haloalkyl, and an optionally substituted CI-C4 heteroalkyl;. R 5 is selected from hydrogen, OR 14 , CI-C 4 alkyl, CI-C 4 haloalkyl, CI-C4 heteroalkyl, and CI-C 4 haloheteroalkyl; R 6 is selected from C 1 -Clo alkyl, CI-Clo haloalkyl, an optionally substituted CI-C1 0 heteroalkyl, (CH 2 )mR' 8 , and C(O)NHR' 18 ; R 7 is selected from CO 2 R ', CONRI 4 R 1 5 , SO 3 RI 4 , SO 2 NR 4 R s ' 5 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2 R' 9 , OC(S)NRI 4 R , SC(O)NR 14 R 15 , and B A-C wherein A, B, and C are each independently selected from O, S, and N; - 238 - WO 2007/062078 PCT/US2006/045129 R 8 and R 9 are each independently selected from hydrogen, OR 16 , NRI 6 R 17 , CI-C 4 alkyl, CI-C 4 haloalkyl, an optionally substituted CI-C 4 heteroalkyl, (CH2)mR'18 and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R and R 9 are linked to form an optionally substituted C 3 -C 8 ring; R 1 0 is selected from hydrogen, halogen, oxo, CI-C 4 alkyl, CI-C 4 haloalkyl, and an optionally substituted CI-C 4 heteroalkyl; R 12 is selected from hydrogen, halogen, CI-C 4 alkyl, CI-C 4 haloalkyl, Ci Ca heteroalkyl, and CI-C 4 haloheteroalkyl; R' 3 is selected from hydrogen, halogen, CN, NO 2 , CO 2 R 1 4 , S(O)mR I4 , C 1 C 4 alkyl, C 1 -C 4 haloalkyl, CI-C 4 heteroalkyl, and Ci-C 4 haloheteroalkyl; R 1 4 is selected from hydrogen, CI-C 4 alkyl, C,-C 4 haloalkyl, CI-C 4 heteroalkyl, and CI-C 4 heterohaloalkyl; R is is selected from hydrogen, SO 2 R' 9 , CI-C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 heteroalkyl; R 16 and R 17 are each independently selected from hydrogen, CI-C 4 alkyl, CI-C 4 haloalkyl, an optionally substituted CI-C 4 heteroalkyl, and (CH 2 )mR' 8 ; or one of R 1 6 and R 17 is C 2 -C 6 alkyl and the other of R 16 and R 1 7 is null; or RI 6 and R 17 are linked to form an optionally substituted C 4 -C 7 ring; R 9 is selected from hydrogen, C 1 -C 3 alkyl, CI-C 3 haloalkyl, and aryl; G is selected from O, S, and NRI 4 ; J is selected from O, S, NR 14 , and CRI 4 RI; K is O or S; L is NH or null; and Y is selected from: R12 /R12 I - 13 -R 1 I -Rla -R13 ~ R 12 , and K
10. A compound of Formula IV, V, or VI: -239- WO 2007/062078 PCT/US2006/045129 R1 (R2). R 8 R 8 O R' O nZL R12 12 W -nR N.u R 9 R 1 3 R EN R 9 R11,I R 3 .N Rs X " 0OIR1 2 1 __ R 12 W /N -R13 /N R13 RRI R 6 R 6 R s (IV) (V) (VI) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein: R' is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NRI 4 Ri 5 , an optionally substituted CI-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Cz-C 6 heteroalkyl, CO 2 R 4 , CONRI 4 Ris, SO 3 RI, SO 2 NR 4 aR" 5 and a carboxylic acid bioisostere; R 2 is selected from hydrogen, halogen, OR 14 , NR' 4 R" 5 , an optionally substituted C,-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R 3 and R 4 are independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl; R 5 is selected from hydrogen, halogen, ORI 4 , C -C 6 alkyl, C I-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI-C 6 haloheteroalkyl; R6 is selected from an optionally substituted CI-C 0 lo alkyl, an optionally substituted CI-C 0 lo haloalkyl, an optionally substituted Cj-Cj 0 heteroalkyl, (CH 2 )mR' 8 , and C(O)NHR18; R 7 is selected from CO 2 RI 4 , CONRI 4 R' 5 , SO 3 R 14 , SOzNRI 4 R' 5 and a carboxylic acid bioisostere; R 8 and R 9 are each independently selected from hydrogen, OR 16 , NR' 6 R 7 , an optionally substituted CI-C 6 alkyl, an optionally substituted C -C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, (CH 2 )mR 18 , and null; or R 8 and R 9 taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -C 8 ring; R 1 0 is selected from hydrogen, halogen, oxo, OR 6 , NR' 6 R 7 , SR 6 , an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted C,-C 6 heteroalkyl; -240 - WO 2007/062078 PCT/US2006/045129 R" is selected from hydrogen, halogen, OR14, NR1 4 RIS, and SR' 4 ; or R" and R 4 are linked to form a optionally substituted heterocycle; R 12 is selected from hydrogen, halogen, CI-C 6 alkyl, CI-C 6 haloalkyl, C 1 C 6 heteroalkyl, and C I-C 6 haloheteroalkyl; R 3 is selected from hydrogen, halogen, CN, NO 2 , CO 2 RI 4 , S(O)mRI 4 , C- 1 C 4 alkyl, C l-C 4 haloalkyl, C I-C 4 heteroalkyl, and C I-C 4 haloheteroalkyl; R 14 is selected from hydrogen, CI-C 6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl; R 15 is selected from hydrogen, SO 2 R 9 , C I-C 6 alkyl, CI-C 6 haloalkyl, C I-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl; R 16 and R1 7 are each independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted C,-C 6 haloalkyl, an optionally substituted C,-C 6 heteroalkyl, and (CH 2 )mR 8 ; or one of R 16 and R 7 is an optionally substituted C 2 -C 6 alkyl and the other of R 1 6 and R 1 7 is null; or R 1 6 and R 7 are linked to form an optionally substituted C 3 -C 8 ring; R1 8 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle; R 1 9 is selected from hydrogen, CI-C 3 alkyl, Ci-C 3 haloalkyl, and an optionally substituted aryl; D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; L is NH or null; Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; U is selected from O, NR 4 , CR 3 R 4 , CO, and null; W is selected from O, NR 4 , CR 3 R 4 , CO, and null; X is N or CR 5 ; Z is selected from: - 241 - WO 2007/062078 PCT/US2006/045129 null, a 2-5 atom spacer selected from an optionally substituted C 6 -Co 10 aryl and an optionally substituted CI-C 8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, and an optionally substituted C I -C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -C lo aryl; m is 0, 1, or 2; and n is 0 or 1; provided that if X is N and W is NH, then D is not phenyl; and provided further that if X is N and W is NH in compounds of Formulas VI, then R 6 , R"o, and R" do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
11. The compound of claim 4, wherein: R' is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NRI 4 R 5 , an optionally substituted C,-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, CO 2 RI 4 , CONR 4 R" 5 , SO 3 R 4 , SO 2 NRR14R 5 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2 R' 9 , OC(S)NR 4 RIs, SC(O)NRI 4 R is 5 , and B AAC wherein A, B, and C are each independently selected from O, S, and N; and R 7 is selected from CO 2 R 14 , CONR 14 R s , SO 3 R I4 , SO 2 NR1 4 RI5 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2 RI 9 , OC(S)NR 14 Ri, SC(O)NRI 4 R is , and B AAC 0-L, wherein A, B, and C are each independently selected from O, S, and N.
12. A compound of Formula I, II, III, IV, V, or VI: - 242 - WO 2007/062078 PCT/US2006/045129 R , R 2 )m R 9 R RO R Z L R1DRo R7 - n Z N SR 8 IN I R R11" IY 0 R3 N R 5 x.W 0 0 w N I-N Rio-E-R"1 / / 1 R 6 R 6 R 6 (1) (II) (III) Ri Wz 8 1 R 8 R Q R Z-L Rio R 2 R ,RI 1 0 D )-0 N R 9 O R 1 R s R 9 R 1 1 R 1 3 R 3 'N R 5 1 0 /R 12 - R 12 W O N13 /N 3 Rio- ER o R R R 6 R 6 R 6 (IV) (V) (VI) wherein: R' is selected from hydrogen, halogen, OR 1 4 , NO 2 , CN, NRI 4 Ris' 5 , an optionally substituted Cl-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, CO 2 RI 4 , CONR 4 R" 5 , SO 3 R 4 , SO 2 NR' 4 R is 5 and a carboxylic acid bioisostere; R 2 is selected from hydrogen, halogen, ORI 4 , NR 14 R" 5 , an optionally substituted C1-C 6 alkyl, an optionally substituted C,-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R 3 and R 4 are independently selected from hydrogen, an optionally substituted CI-C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, and an optionally substituted C,-C 6 heteroalkyl; R s is selected from hydrogen, halogen, OR 14 , CI-C 6 alkyl, C,-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI-C 6 haloheteroalkyl; R 6 is selected from an optionally substituted CI-Clo alkyl, an optionally substituted CI-Clo haloalkyl, or an optionally substituted Ci-Co heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R 6 is (CH 2 )mR" or C(O)NHR 1 s R 7 is selected from CO 2 RI 4 , CONRI 4 R s ' 5 , SO 3 RI 4 , SO 2 NRI 4 R s and a carboxylic acid bioisostere; - 243 - WO 2007/062078 PCT/US2006/045129 R 8 and R 9 are each independently selected from hydrogen, OR6, NR1 6 R 17 an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, an optionally substituted C,-C 6 heteroalkyl, (CH 2 )mR 18 , and null; or R 8 and R) taken together form an optionally substituted olefin; or R 8 and R 9 are linked to form an optionally substituted C 3 -Cs ring; R1 0 is selected from hydrogen, halogen, oxo, OR' 6 , NR1 6 R 17 , SR16, an optionally substituted C 1 -C 6 alkyl, an optionally substituted CI-C 6 haloalkyl, and an optionally substituted CI-C 6 heteroalkyl; R'" is selected from hydrogen, halogen, OR 14 , NR 14 R' 5 , and SR14; or R" and R 4 are linked to form a optionally substituted heterocycle; R 12 is selected from hydrogen, halogen, CI-C 6 alkyl, CI-C 6 haloalkyl, Cj C 6 heteroalkyl, and CI-C 6 haloheteroalkyl; R 13 is selected from hydrogen, halogen, CN, NO 2 , CO 2 RI 4 , S(O)mRI 4 , C1 C 4 alkyl, CI-C 4 haloalkyl, CI-C 4 heteroalkyl, and CI-C 4 haloheteroalkyl; R 14 is selected from hydrogen, CI-C 6 alkyl, CI-C 6 haloalkyl, CI-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl; R" is selected from hydrogen, SO 2 R 9 , CI-C 6 alkyl, CI-C 6 haloalkyl, C,-C 6 heteroalkyl, and CI-C 6 heterohaloalkyl; R 1 6 and R 17 are each independently selected from hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted CI-C 6 heteroalkyl, and (CH2)mR"; or one of R 16 and R 17 is an optionally substituted C 2 -C 6 alkyl and the other of R' 1 6 and R 17 is null; or R 16 and R' 7 are linked to form an optionally substituted C 3 -C 8 ring; R1 8 is selected from an optionally substituted monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle; R 9 is selected from hydrogen, CI-C 3 alkyl, CI-C 3 haloalkyl, and an optionally substituted aryl; D is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; E is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; - 244 - WO 2007/062078 PCT/US2006/045129 L is NH or null; Q is a monocyclic or bicyclic aromatic ring system optionally containing one or more heteroatoms, and optionally fused with a nonaromatic heterocycle or carbocycle; U is selected from O, NR 4 , CR 3 R 4 , CO, and null; W is selected from O, NR 4 , CR 3 R 4 , CO, and null; X is N or CR 5 ; Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted CI-C 6 alkyl, an optionally substituted CI-C 6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl; Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6 -Co 10 aryl and an optionally substituted C,-C 8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted CI-C 6 alkyl, an optionally substituted C 1 -C 6 heteroalkyl, and an optionally substituted CI-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -C, 0 aryl; m is 0, 1, or 2; and n is 0 or 1; provided that, if X is N, W is NH, and Y is not -N=CR 12 - orientated to form a dihydropyrazole, and Z or R 6 are not an optionally substituted non aromatic ring fused with an optionally substituted aromatic ring; or if X is N, W is NH, R 6 is alkoxy, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, Y is -N=CR - orientated to form a dihydropyrazole, and Z is not an optionally substituted non-aromatic ring fused with an optionally substituted aromatic ring; then D is not a phenyl; provided that, if X is N, W is NH, and Y is -N=CRI 2 - orientated to form a dihydropyrazole, then D is not a naphthyl; provided that, if U is NH; or if D and one of Rio and R" form a 5 hydroxypyrazole, X is N, and W is NH; or if E and one of R"o and R' form a 5 hydroxypyrazole and X is N, and W is NH; orifE is phenyl, one of R 1 0 or R'I is (CH 2 )0-60H, X is C, W is NH, R 6 is an optionally substituted aryl or an optionally substituted heteroaryl, and Z is null, an optionally substituted alkyl, an optionally - 245 - WO 2007/062078 PCT/US2006/045129 substituted aryl, or an optionally substituted heteroaryl; or if E is phenyl, one of R i 'o or R" is -(CH 2 )o- 6 0H, X is N, W is NH, Z is null, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, and R 6 is C,-C 6 alkyl, CI-C 6 alkoxy, -(CH 2 )o.0- 6 0R 20 , an optionally substituted aryl, an optionally substituted heteroaryl, NR 21 R 22 or a heterocyclic methylene substituent as represented by formula VII; or if D is phenyl, one of R i 0 or R" is -(CH 2 ) 0 - 6 0H, X is C, W is NH, Z is aromatic, and R 6 is alkoxy, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; then Y is not -N=CR' 12 - orientated to form a dihydropyrazole; R 20 is selected from hydrogen, a substituted alkyl, a substituted aryl, and a substituted heteroaryl; R 1 and R 2 are each independently selected from hydrogen, alkyl, and aryl; or R 2 1 and R 22 taken together with the nitrogen to which they are attached represent a 5 or 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; B A-C R 20 v (VII) wherein A, B, C, and V are each independently selected from O, S, and NR 20
13. The compound of claim 3, wherein the compound is of Formula I.
14. The compound of claim 3, wherein the compound is of Formula II.
15. The compound of claim 3, wherein the compound is of Formula III.
16. The compound of claim 5, wherein the compound is of Formula IV.
17. The compound of claim 5, wherein the compound is of Formula V.
18. The compound of claim 5, wherein the compound is of Formula VI.
19. The compound of claim 1, selected from: 3'- { [1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3 ylidenemrnethyl]amino } -2'-hydroxybiphenyl-3-carboxylic acid (Compound 101); 2,4-Dihydroxybenzoic acid N'-{ 1-[1 -(3,5-dimethylphenyl)-2-oxo- 6 trifluoromethyl-1,2-dihydroindol-3-ylidenelethyl }hydrazide (Compound 102); - 246 - WO 2007/062078 PCT/US2006/045129 3-{3-[(5-Chloro-2-hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo 2,3-dihydroindol-1-yl}benzoic acid (Compound 103); 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl}benzoic acid (Compound 104); 3'-{[1 -(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3 ylidenemethyl]amino}-4-fluoro-2'-hydroxybiphenyl-3-carboxylic acid (Compound 105); 2-(3'- {[1-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol 3-ylidenemethyl]amino}-2'-hydroxybiphenyl-3-yl)-2-methylpropionic acid (Compound 106); 3'-{[1 -(3,4-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2-dihydroindol-3 ylidenemethyl]amino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 107); 4-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl} benzoic acid (Compound 108); 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazonojl-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1 -yl}benzoic acid (Compound 109); 3 -{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo- 6 trifluoromethyl-2,3-dihydroindol-1-yl}benzoic acid methyl ester (Compound 110); 3- { 3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl } benzoic acid methyl ester (Compound 111); 3-{3-[(5-Fluoro-2-hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo 2,3-dihydroindol-1-yl}benzoic acid (Compound 112); 3- { 3-[1 -(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl- 1,2-dihydroindol 3-ylideneamino]-2-oxo-2,3-dihydrobenzooxazol-7-yl}benzoic acid (Compound 113); 3-{3-[(2-Hydroxy-5,3',4'-trimethylbiphenyl-3-yl)hydrazono]- 2 -oxo- 2 , 3 dihydroindol-1-yl}benzoic acid (Compound 114); 3-Hydroxybcnzoic acid N'- { 1-[1 -(3,5-dimethylphenyl)-2-oxo- 6 trifluoromethyl-1,2-dihydroindol-3-ylidene]ethyl}hydrazide (Compound 115); 1-(3,5-Dimethylphenyl)-3-{ 1-[2-(4-hydroxyphenyl)-2-oxo ethylamino]ethylidene } -6-trifluoromethyl-1,3-dihydroindol-2-one (Compound 116); - 247 - WO 2007/062078 PCT/US2006/045129 3- { 3-[(5-Fluoro-2-hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo 6-trifluoromethyl-2,3-dihydroindol-1-yl } benzoic acid (Compound 117); 3-{3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1l-yl}benzoic acid (Compound 118); 3-{3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1l-yl}benzoic acid (Compound 119); 3-{3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo 2,3-dihydroindol-1l-yl}benzoic acid (Compound 120); 4-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo 2,3-dihydroindol-1-yl } butyric acid (Compound 121); 2-Chloro-3-(4- { [1 -(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2 dihydroindol-3-ylidenemethyl]amino}-3-hydroxyphenyl)acrylic acid (Compound 122); 4-Hydroxybenzoic acid N-{ 1 -[1 -(3,5-dimethylphenyl)-2-oxo-6 trifluoromethyl- 1,2-dihydroindol-3 -ylidene]ethyl }hydrazide (Compound 123); 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-5-nitro-2-oxo 2,3-dihydroindol-1-yl } benzoic acid (Compound 124); 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo 2,3-dihydroindol-1 -yl} benzoic acid (Compound 125); 3- {3-[(2-Hydroxy-5,3',5'-trimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3 dihydroindol-1-yl}benzoic acid (Compound 126); 4-Aminobenzoic acid N'- {1-[1-(3,5-dimethylphenyl)-2-oxo-6 trifluoromethyl- 1,2-dihydroindol-3-ylidene]ethyl } hydrazide (Compound 127); 3-(7- {N'-[ 1 -(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-1,2 dihydroindol-3-ylidene]hydrazino}-1H-indol-3-yl)propionic acid (Compound 128); 4- { 3-[N'-(4-Methylbenzoyl)hydrazinomethylidene]-2-oxo-2,3 dihydroindol-1l-yl}benzoic acid (Compound 129;) 3-{2-Oxo-6-trifluoromethyl-3-[4-(3-trifluoromethylphenyl)-l1H-pyrrol-2 ylmethylidene]-2,3-dihydroindol-1-yl }benzoic acid (Compound 130); 3-(7-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4 ylidene]hydrazino }-1H-indol-3-yl)propionic acid (Compound 131); 3-(3-{ [4-(3,4-Dimethylphenyl)thiazol-2-ylamino]methylidene } -2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl)benzoic acid (Compound 132); -248- WO 2007/062078 PCT/US2006/045129 3-(3- { [4-(4-Methoxyphenyl)thiazol-2-ylamino]methylene} -2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl)benzoic acid (Compound 133); 3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylene]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl}benzoic acid (Compound 134); 3-{3-[(4-(4-Methylphenyl)-2-thiazolylamino)methylene]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl } benzoic acid (Compound 135); 3-{3-[(3,4-Dimethylbenzoylhydrazino)methylidene]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl } benzoic acid (Compound 136); 3- { 3-[(4-Chlorobenzoylhydrazino)methylidene]-2-oxo-6-trifluoromethyl 2,3-dihydroindol-1-yl} benzoic acid (Compound 137); 3- { 3-[(4-Methoxybenzoylhydrazino)methylidene]-2-oxo-6 trifluoromethyl-2,3-dihydroindol-1-yl}benzoic acid (Compound 138); 3- {3-[(3,4-Dimethylbenzoylhydrazino)methylidene]-2-oxo- 6 -chloro- 2 ,3 dihydroindol-1-yl}benzoic acid (Compound 139); 1 -(3,4-Dimethylphenyl)-3-[1 -(2,4 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 140); 1-(3,4-Dimethylphenyl)-3-[1-(4-hydroxybenzoylhydrazino)ethylidene]-2 oxo-2,3-dihydroindole (Compound 141); 1-(3,4-Dimethylphenyl)-3-[(2, 4 dihydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 142); 1-(3,5-Dimethylphenyl)-3-[1 -(2,4 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 143); 1-(3,5-Dimethylphenyl)-3- [1 -(4-hydroxybenzoylhydrazino)ethylidene]-2 oxo-2,3-dihydroindole (Compound 144); 1-(3,5-Dimethylphenyl)-3-[(2, 4 dihydroxybenzoylhydrazino)methylidene]-2-oxo- 2 , 3 -dihydroindole (Compound 145); 1-(3,5-Dimethylphenyl)-3-[(4-hydroxybenzoylhydrazino)methylidene]-2 oxo-2,3-dihydroindole (Compound 146); 3-(3-[1-(3,4-Dihydroxybenzoylhydrazino)ethylidene]-2-oxo-6-chloro- 2 , 3 dihydroindol-1 -yl)benzoic acid (Compound 147); - 249 - WO 2007/062078 PCT/US2006/045129 1-(3,4-Dimethylphenyl)-3-[(4-hydroxybenzoylhydrazino)methylidene]-2 oxo-2,3-dihydroindole (Compound 148); 1-(3,4-Dimethylphenyl)-3-[(3,5-diisopropyl-2 hydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 149); 1-(3,5-Dimethylphenyl)-3-[1-(3,4 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 150); 1-(3,4-Dimethylphenyl)-3-[1-(3,4 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 151); 3-(6-Chloro-3- [(2-hydroxy-3,5 diisopropylbenzoylhydrazino)methylidene]-2-oxo- 2 ,3-dihydroindol- 1 -yl)benzoic acid (Compound 152); 1-(3,4-Dimethylphenyl)-3-[1-(2,5 dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 153); 1-(3,4-Dimethylphenyl)-3-[1-(3-nitro-4 hydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 154); 1-(3,4-Dimethylphenyl)-3-[1-(3-aminosulfonyl-4 chlorobenzoylhydrazino)ethylidene]-2-oxo- 2 , 3 -dihydroindole (Compound 155); 1-(3,4-Dimethylphenyl)-3-[1-(3-amino-4 hydroxybenzoylhydrazino)ethylidene]- 2 -oxo-2,3-dihydroindole (Compound 156); 1-(3,4-Dimethylphenyl)-3-[1 -(4-methoxy-2 hydroxybenzoylhydrazino)ethylidene]-2-oxo- 2 , 3 -dihydroindole (Compound 157); 3-{3-(1 -(3,5-Dimethylphenyl)-2-oxo-2,3-dihydro-3 indolidene)methylamino-2-hydroxyphenyl}benzoic acid (Compound 158); 3- { 3-(3-(3,5-Dimethylphenyl)-2-hydroxyphenyl)aminomethylidene)-2 oxo-2,3-dihydro- 1-indolyl}benzoic acid (Compound 159); 3-{3-(1 -(3,4-Dimethylphenyl)-2-oxo-2,3-dihydro-3 indolidene)methylamino-2-hydroxyphenyl}benzoic acid (Compound 160); 4-{ 1-(6-Fluoro-2-oxo- 2 ,3-dihydro-3-(2-(3,5-dimethylphenyl) aminocarbonylphenyl)aminomethylidene)indolyl } butanoic acid (Compound 161); - 250 - WO 2007/062078 PCT/US2006/045129 4-{1-(6-Chloro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)aminomethylidene)indolyl}butanoic acid (Compound 162); 3-{ 1-(6-Chloro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)aminomethylidene)indolyl}benzoic acid (Compound 163); 4-{ 1-(5-Fluoro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)aminomethylidene)indolyl}butanoic acid (Compound 164); 3-{3-(1-(1-(3,5-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-3 indolidene)ethylamino)-2-hydroxyphenyl}benzoic acid (Compound 165); 3-{3-(1-(1-(3,4-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-3 indolidene)ethylamino)-2-hydroxyphenyl}benzoic acid (Compound 166); 3- { 1-(6-Trifluoromethyl-2-oxo-2,3 -dihydro-3 -(5-chloro-2-hydroxy-3 cyclohexylphenyl)hydrazono)indolyl}benzoic acid (Compound 167); 3- { 1 -(5-Fluoro-2-oxo-2,3-dihydro-3-(1 -(5-chloro-2-hydroxy-3 cyclohexylphenyl)amino)ethylidene)indolyl}benzoic acid (Compound 168); 3-{ 1-(5-Fluoro-2-oxo-2,3-dihydro-3-(5-chloro-2-hydroxy-3 cyclohexylphenyl)aminomethylidene)indolyl}benzoic acid (Compound 169); 4-{2-Hydroxy-3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolylidene)methylaminophenyl } butanoic acid (Compound 170); 4-{2-Hydroxy-3-(6-trifluoromethyl-2-oxo-2, 3 -dihydro-l1-(3,4 dimethylphenyl)indolylidene)methylaminophenyl } butanoic acid (Compound 171); 3-{3-(7-(6-Trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,5-dimethylphenyl)-3 indolylidene)methylamino)indolyl}propanoic acid (Compound 172); 3-{3-(7-(6-Trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,4-dimethylphenyl)-3 indolylidene)methylamino)indolyl}propanoic acid (Compound 173); 4-{2-Hydroxy-3-(2-oxo-2,3-dihydro- 1-(3,5 dimethylphenyl)indolylidene)methylaminophenyl } butanoic acid (Compound 174); 2-Chloro-3- {3-hydroxy-4-(2-oxo-2,3-dihydro-l1-(3,5 dimethylphenyl)indolylidene)methylaminophenyl}propenoic acid (Compound 175); -251 - WO 2007/062078 PCT/US2006/045129 2-Chloro-3-{ 3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro-1 -(3,4 dimethylphenyl)indolylidene)methylaminophenyl}propenoic acid (Compound 176); 2-Ethyl-3- {3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,4 dimethylphenyl)indolylidene)methylaminophenyl}propenoic acid (Compound 177); 2-Ethyl-3- {3-hydroxy-4-(6-trifluoromrnethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolylidene)methylaminophenyl}propenoic acid (Compound 178); 2-Ethyl-3-{3-hydroxy-4-(2-oxo-2,3-dihydro- 1-(3,5 dimethylphenyl)indolylidene)methylaminophenyl } propenoic acid (Compound 179); 4- {2-Hydroxy-3-(4-(2-(3,4-dimethylphenyl)-3-oxo-3,4-dihydro-5 methyl)pyrazolidene)methylaminophenyl}butanoic acid (Compound 180); (Z)-4- { 1-(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl}butanoic acid (Compound 181); (E)-4- { 1 -(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl} butanoic acid (Compound 182); (Z)-3-{1-(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl}benzoic acid (Compound 183); (E)-3-{ 1 -(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2 hydroxypheny)aminomethylidene)pyrrolidinyl}benzoic acid (Compound 184); 4-{3-(4-Oxo-2-thioxo-5-(3-(3,5-dimethylphenyl)-2 hydroxypheny)hydrozono)thiazolidinyl}butanoic acid (Compound 185); 3-{2-(3-(1-(3,5-Dimethylphenyl)-6-chloro-2-oxo-2,3 dihydroindolidene)methylamino)phenylamino}benzoic acid (Compound 186); 3-{2-(3-(1 -(3,5-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3 dihydroindolidene)methylamino)phenylamino}benzoic acid (Compound 187); 3- {2-(4-(2-(3,5-Dimethylphenyl)-5-methyl-3-oxo-3,4 dihydropyrazolidene)methylamino)phenylamino } benzoic acid (Compound 188); (i)-3-Methyl-5-{2-hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-1 (3,5-dimethylphenyl)indolylidene)methylamino)phenyl } pentanoic acid (Compound 189); - 252 - WO 2007/062078 PCT/US2006/045129 (+)-3-{ 1-(6-Chloro-2-oxo-2,3-dihydro-3-(3-(1-(3,5-dimethylphenyl)-2 oxo-2,3-dihydro)indolyl)aminomethylidene)indolyl } benzoic acid (Compound 190); 3- {4-(3-Hydroxy-6-methyl-2-(3-(6-trifluoromethyl-2-oxo-2,3 -dihydro- 1 (3,5-dimethylphenyl)indolyl)hydrazono)pyridinyl}benzoic acid (Compound 191); 3-{4-(3-Hydroxy-6-methyl-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 (3,5-dimethylphenyl)indolidene)methylamino)pyridinyl}benzoic acid (Compound 192); 3-{4-(3-Hydroxy-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,5 dimethylphenyl)indolidene)methylamino)pyridinyl } benzoic acid (Compound 193); 3- {4-(3-Hydroxy-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolyl)hydrazono)pyridinyl}benzoic acid (Compound 194); 3- {5-(4-Hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolidene)methylamino)pyridinyl } benzoic acid (Compound 195); 3- { 5-(4-Hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolyl)hydrazono)pyridinyl } benzoic acid (Compound 196); 3- { 5-(4-Hydroxy-3-(4-(3-oxo-3,4-dihydro-5-methyl-2-(3,4 dimethylphenyl)pyrazolyl)hydrazono)pyridinyl} benzoic acid (Compound 197); 4- {2-(3-oxo-3,4-dihydro-5-methyl-4-(3-(3,4 dimethylphenyl)phenyl)hydrozono)pyrazolyl} butanoic acid (Compound 198); 3- {2-Amino-5 -methyl-3-(3-(6-trifluoromethyl-2-oxo- 2 , 3 -dihydro- 1 -(3,5 dimethylphenyl)indolylidene)methylamino)phenyl } benzoic acid (Compound 199); 3-{ 1-(5-Fluoro-2-oxo-2,3-dihydro-3-(3-(3,4 dimethylphenyl)phenyl)aminomethylidene)indolyl }benzoic acid (Compound 200); 4-{2-(5-Methyl-2-oxo-2,3-dihydro-4-(3-(3,4 dimethylphenyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 201); (3-(5-Fluoro-2-hydroxy-3-(3-(6-trifluoromethyl-2-oxo- 2 , 3 -dihydro- 1 -(3,4 dimethylphenyl)indolidene)methylamino)-l1-pyrazolyl)acetic acid (Compound 202); - 253 - WO 2007/062078 PCT/US2006/045129 (3-(5-Fluoro-2-hydroxy-3-(3-(2-oxo-2,3-dihydro- 1 -(3,5 dimethylphenyl)indolidene)methylamino)-l1-pyrazolyl)acetic acid (Compound 203); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 204); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 phenyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 205); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(4 methyl)phenyl)ethyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 206); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3 methyl)phenyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 207); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 methyl)phenyl)ethyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 208); 4-{2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(1 naphthyl)ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 209); 3- { 1 -(5-Nitro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)aminomethylidene)indolyl } benzoic acid (Compound 210); 3- { 1-(5-Nitro-2-oxo-2,3-dihydro-3-(5-fluoro-2-hydroxy-3-(3,5 dimethylphenyl)phenyl)aminomethylidene)indolyl } benzoic acid (Compound 211); 2-Hydroxy-3- { 3-(2-oxo-2,3-dihydro- 1-(3,5 dimethylphenyl)indolidene)methylamino}benzoic acid (Compound 212); 2-Hydroxy-3-{3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,5 dimethylphenyl)indolidene)methylamino}benzoic acid (Compound 213); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(3-methyl-1 butenyl)phenyl)aminomethylidene)pyrazolyl }butanoic acid (Compound 214); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3 heptanylphenyl)hydrazono)pyrazolyl} butanoic acid (Compound 215); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-(4 methyl)phenyl)ethenylphenyl)hydrazono)pyrazolyl} butanoic acid (Compound 216); - 254 - WO 2007/062078 PCT/US2006/045129 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-(3 methyl)phenyl)ethenylphenyl)hydrazono)pyrazolyl}butanoic acid (Compound 217); 4-{ 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2 methyl)phenyl)ethylphenyl)hydrazono)indolyl } butanoic acid (Compound 218); 2-{ 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)hydrazono)indolyl}acetic acid (Compound 219); 2- { 1 -(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2 methyl)phenyl)ethylphenyl)hydrazono)indolyl } acetic acid (Compound 220); 4- {4-(2-(3-(6-Trifluoromethyl-2-oxo-2,3-dihydro-l1-(3,4 dimethylphenyl)indolylidene)methylamino)thiazolyl}benzoic acid (Compound 221); 3- { 1 -(5-Nitro-2-oxo-2,3-dihydro-3-(2-hydroxy-5-methyl-3-(1 adamantane)phenyl)aminomethylidene)indolyl } benzoic acid (Compound 222); 3-{ 1-(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(4-hydroxy-5-(3,4 dimethylphenyl)pyridinyl)hydrazono)indolyl}benzoic acid (Compound 223); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-(2-methyl)phenyl) ethylphenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 224); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-(2-fluoro)phenyl) ethylphenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 225); and a pharmaceutically acceptable salt, ester, or prodrug of any of those compounds.
20. The compound of claim 1, selected from: 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(1-naphthyl) ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 226); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(3,5 dimethylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 227); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 methoxyphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 228); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-fluoro-3 methyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 229); -255- WO 2007/062078 PCT/US2006/045129 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-fluoro-3 methyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl }butanoic acid (Compound 230); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(4 phenylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 231); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-cyanophenyl) ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 232); 4- { 2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 chlorophenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 233); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 234); 3-{2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 trifluoromethylphenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 235); 3- {2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 fluorophenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 236); 3- {2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 methyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl} benzoic acid (Compound 237); 3- {2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,5 dimethyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 238); 3-{2-(5-Trifluoromethyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,6 dimethyl-phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl } benzoic acid (Compound 239); 3-{2-(5-Phenyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,5 dimethylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl} benzoic acid (Compound 240); - 256 - WO 2007/062078 PCT/US2006/045129 3-{2-(5-tert-Butyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2,5 dimethylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl }benzoic acid (Compound 241); 3-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2 methylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 242); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2-(2 fluorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 243); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 244); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(4-phenylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 245); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methoxyphenyl) ethyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 246); 4- {2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluoro-3 methylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 247); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 trifluoromethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 248); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 cyanophenyl)ethyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 249); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 chlorophenyl)ethyl)-phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 250); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 251); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-ethylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 252); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dichlorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 253); - 257 - WO 2007/062078 PCT/US2006/045129 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,5 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 254); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluoro-6 trifluoro-methylphenyl)ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 255); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indanyl)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 256); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indenyl)phenyl) hydrazono)pyrazolyl}butanoic acid (Compound 257); (+-)-4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1 indanylmethyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 258); (d-)-3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1 indanylmethyl)phenyl)-hydrazono)pyrazolyl } benzoic acid (Compound 259); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 methylphenyl)ethyl)-phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 260); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluoro-3 methylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 261); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-fluorophenyl) -ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 262); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-( 2 , 6 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 263); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dichlorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 264); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methyl-6 trifluoromethylphenyl)ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 265); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indanyl)phenyl) hydrazono)pyrazolyl}benzoic acid (Compound 266); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indenyl)phenyl) hydrazono)pyrazolyl}benzoic acid (Compound 267); -258 - WO 2007/062078 PCT/US2006/045129 (E)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,4 difluorophenyl)-ethenyl)phenyl)aminomethylidene)pyrazolyl } butanoic acid (Compound 268); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-4-(3,4-dimethylphenyl) 2-pyridyl)hydrazono)pyrazolyl}benzoic acid (Compound 269); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-6-methyl-4-(3,4 dimethylphenyl)-2-pyridyl)hydrazono)pyrazolyl } butanoic acid (Compound 270); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-2-(3,4-dimethylphenyl) 4-pyridyl)hydrazono)pyrazolyl}benzoic acid (Compound 271); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-2-(3,5-dimethylphenyl) 4-pyridyl)hydrazono)pyrazolyl} benzoic acid (Compound 272); 3-{ 1-(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2 methylphenyl)-ethyl)phenyl)hydrazono)indolyl} benzoic acid (Compound 273); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 benzylphenyl)hydrazono)-pyrazolyl}butanoic acid (Compound 274); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(3 methylphenyl)propyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 275); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-phenylpropyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 276); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(2 methylphenyl)propyl)-phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 277); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,4 difluorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 278); (E)-4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 pyridyl)ethyl)-phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 279); 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-(Z)-ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 280); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 benzofuranyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 28 1); - 259 - WO 2007/062078 PCT/US2006/045129 (Z)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 bromoethenyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 282); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(3-methyl-1 butenyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 283); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2 cyclopropylethenyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 284); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3 methylbutyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 285); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-5-fluoro-3-(3,5 dimethylphenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 286); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,4 dimethylphenyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 287); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(5-chloro-2-hydroxy-3 cyclohexylphenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 288); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 289); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)-hydrazono)pyrazolyl}benzoic acid (Compound 290); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(5-chloro-2-hydroxy-3 cyclohexylphenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 291); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,4 dimethylphenyl)phenyl)-hydrazono)pyrazolyl} benzoic acid (Compound 292); 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(2 methylphenyl)propyl)-phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 293); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 benzofuranyl)phenyl)-hydrazono)pyrazolyl}benzoic acid (Compound 294); 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(2 fluorophenyl)propyl)-phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 295); 3- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3,4 dimethylphenyl)-phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 296); - 260 - WO 2007/062078 PCT/US2006/045129 3-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3,5 dimethylphenyl)-phenyl)aminomethylidene)pyrazolyl}benzoic acid (Compound 297); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3,4 dimethylphenyl)-phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 298); 3-{ 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl) phenyl)hydrazono)indolyl}propionic acid (Compound 299); 3-{ 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-benzylphenyl)hydrazono) indolyl } benzoic acid (Compound 300); 3- { 1-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2 methylphenyl)ethyl)phenyl)-hydrazono)indolyl}propionic acid (Compound 301); 3- { 1 -(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(3-(3 methylphenyl)propyl)-phenyl)aminomethylidene)indolyl}benzoic acid (Compound 302); (+)-3-{ I1-(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(1,2-dihydro- 1 methyl-2-indolylphenyl)aminomethylidene)indolyl }benzoic acid (Compound 303); 4- {2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2 methylphenylcarbonyl-amino)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 304); 4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(5-chloro-2-hydroxy-3-(2 methylphenyl-carbonylamino)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 305); 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro- 1-(2-(2 fluorophenyl)ethyl)indolylidene)-hydrazinophenyl} benzoic acid (Compound 306); 3-{ 2-Hydroxy-3-(2-oxo-2,3-dihydro- 1 -(2-(2 chlorophenyl)ethyl)indolylidene)-hydrazinophenyl } benzoic acid (Compound 307); 3-{3-Hydroxy-2-(5-methyl-3-oxo-2,3-dihydro-2-(3,4-dimethylphenyl) pyrazolylidene)hydrazino-4-pyridyl}benzoic acid (Compound 308); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methylphenyl) ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 309); -261- WO 2007/062078 PCT/US2006/045129 3-{3-Hydroxy-2-(2-oxo-2,3-dihydro- 1 -(3,5-dimethylphenyl)-3 indolylidene-hydrazino)-4-pyridyl}benzoic acid (Compound 310); 3-{ 1 -(2-Oxo-2,3-dihydro-3-(3-hydroxy-6-methyl-4-(3,4-dimethylphenyl) 2-pyridyl)hydrazono)indolyl } benzoic acid (Compound 311); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-6-methyl-4-(3,4 dimethylphenyl)-2-pyridyl)hydrazono)pyrazolyl } benzoic acid (Compound 312); 3-{3-Hydroxy-4-(2-oxo-2,3-dihydro-l1-(3,5-dimethylphenyl)-6 trifluoromethyl-3-indolylidenehydrazino)-2-pyridyl } benzoic acid (Compound 313); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-2-(3,5-dimethylphenyl) 4-pyridyl)hydrazono)pyrazolyl}butanoic acid (Compound 314); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-5-phenyl-2 benzothienyl)-hydrazono)pyrazolyl}butanoic acid (Compound 315); 3-{3-Hydroxy-2-(5-methyl-3-oxo-2,3-dihydro-2-(3,4-dimethylphenyl)-4 pyrazolidene)hydrazino-5-benzothienyl}benzoic acid (Compound 316); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-(2,3 dimethoxycarbonylphenyl)phenyl)-hydrazono)pyrazolyl } butanoic acid (Compound 317); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3,5 diisopropylphenyl)-carbonylhydrazinomethylidene)pyrazolyl } butanoic acid (Compound 318); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(3,5 dimethylphenyl)phenyl)-aminomethylidene)pyrazolyl } butanoic acid (Compound 319); (:)-4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2,3-dihydro- 1 methyl-2-oxo-3-indolyl)methyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 320); 3-{ 1-(2-Oxo-2,3-dihydro-5-fluoro-3-(2-hydroxy-3-(2-(2 methylphenyl)ethyl)phenyl)-hydrazono)indolyl }propionic acid (Compound 321); 3-{ 2 -(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,5 dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 322); - 262 - WO 2007/062078 PCT/US2006/045129 (±)-3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2,3-dihydro- 1 methyl-2-oxo-3-indolyl)methyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 323); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1,2-dihydro-1-methyl 2 -oxo- 3 -indolylidene)methyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 324); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(5-fluoro-2 methylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 325); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4(E)-(2-hydroxy-3-(2-(2,4 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 326); 3- {2-(5 -Methyl-3 -oxo-2,3-dihydro-4-(2-hydroxy-3 methylphenyl)hydrazono)-pyrazolyl } benzoic acid (Compound 327); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1,2-dihydro- 1-methyl 2 -oxo-3-indolylidene)methyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 328); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(5-fluoro-2 methylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 329); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 difluorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 330); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6 dimethylphenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 331); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 methylphenyl)-ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 332); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(5-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 333); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(Z)-(2-(5-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 334); - 263 - WO 2007/062078 PCT/US2006/045129 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 335); 4- {2-(5-Methyl-3 -oxo-2,3-dihydro-4-(2-hydroxy-3 (E)-(2-(4 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 336); 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 fluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 337); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-phenylethenyl) phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 338); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-phenylethynyl) phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 339); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 methylphenyl)ethynyl)-phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 340); 4-{ 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6 dimethylphenyl)-ethynyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 341); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 fluorophenyl)ethynyl)-phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 342); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2 trifluoromethylphenyl)-ethynyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 343); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 trifluoromethyl-phenyl)ethenyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 344); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(1-methyl-l-indenyl-2 )phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 345); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,3-dimethyl-2 indenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 346); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-5-methoxy-3-(2 indenyl)-phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 347); - 264 - WO 2007/062078 PCT/US2006/045129 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(4,7-dimethyl-2 indenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 348); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(4,7-difluoro-2 indenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 349); 3- {2-Hydroxy-3-(2-oxo-2,3-dihydro-6-trifluoromethyl-l1-(2-(2 methylphenyl)-ethyl)-3(Z)-indolylidene)methylaminophenyl } benzoic acid (Compound 350); 3- {2-Hydroxy-3-(2-oxo-2,3-dihydro-6-trifluoromethyl-l1-(2-indenyl)-3(Z) indolylidene)methylaminophenyl}benzoic acid (Compound 351); (+)4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(1,2,3,4 tetrahydro)-naphthyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 352); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro) naphthyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 353); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(1-indanylidene) methylphenyl)hydrazono)pyrazolyl}butanoic acid (Compound 354); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(5-fluoro-2 trifluoromethylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 355); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(6-fluoro-2 trifluoro-methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 356); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(6-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 357); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(4-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 358); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 359); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 360); - 265 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,5 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 361); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(4-fluoro-2 trifluoro-methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 362); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,4 difluorophenyl)-ethynyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 363); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(1-(1,2,3,4 tetrahydro)-naphthylidene)methylphenyl)hydrazono)pyrazolyl } butanoic acid (Compound 364); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-fluoro-5 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 365); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3,5-dimethyl-4 isoxazolyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 366); 4- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,5-dimethyl-4 isoxazolyl)ethyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 367); 3- { 2-Hydroxy-3-(2-oxo-2,3-dihydro- 1 -(2(E)-(2-methylphenyl)ethenyl) 3(Z)-indolylidene)methylaminophenyl}benzoic acid (Compound 368); 3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l1-(2(E)-(2,4-difluorophenyl)ethenyl) 3(Z)-indolylidene)methylaminophenyl } benzoic acid (Compound 369); 3- {2-Hydroxy-3-(2-oxo-2,3-dihydro- 1-(2-indenyl)-3(Z) indolylidene)methyl-aminophenyl}benzoic acid (Compound 370); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(5-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 371); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3 methylphenyl)hydrazono)-pyrazolyl} butanoic acid (Compound 372); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 indanylidenemethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 373); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2 indanylmethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 374); -266- WO 2007/062078 PCT/US2006/045129 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,4 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 375); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 376); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(4-fluoro-2 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 377); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-fluoro-6 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 378); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,3 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 379); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,3 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 380); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-fluoro-4 methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 381); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 chlorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 382); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,6 dichlorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 383); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(3 chlorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 384); 3- { 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,5 difluorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 385); - 267 - WO 2007/062078 PCT/US2006/045129 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-chloro-4 fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 386); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2 trifluoromethyl-4-fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 387); 4-{ 2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,4 dichlorophenyl)-ethenyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 388); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2-chloromethyl 4-fluorophenyl)ethenyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 389); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(2-(2,4 dichloromethylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl } benzoic acid (Compound 390); 3- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro) naphthyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 353); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-8 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 392); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-8 methyl)-naphthyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 393); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-7 methyl)-naphthyl)phenyl)hydrazono)pyrazolyl } butanoic acid (Compound 394); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-7 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl}.butanoic acid (Compound 395); 4- {2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-6 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl} butanoic acid (Compound 396); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-5 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 397); 4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-8 chloro)-naphthyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 398); 3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-7 fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl }benzoic acid (Compound 399); -268- WO 2007/062078 PCT/US2006/045129 and a pharmaceutically acceptable salt, ester, or prodrug of any of those compounds.
21. A compound of any one of the preceding claims that is a selective TPO modulator.
22. A compound of claim 21 that is a TPO mimic.
23. A compound of claim 21 that is a selective TPO receptor agonist.
24. A compound of claim 21 that is a selective TPO receptor partial agonist.
25. A compound of claim 21 that is a selective TPO receptor antagonist.
26. A compound of any one of the preceding claims that is a selective TPO receptor binding compound.
27. A compound of claim 26, wherein the compound is a tissue-specific modulator.
28. A method for modulating a TPO activity in a cell comprising contacting a cell with a compound of any one of the preceding claims.
29. A method for identifying a compound that modulates a TPO activity, comprising contacting a cell that expresses a TPO receptor with a compound of any one of claims 1-27; and monitoring an effect of the compound on the cell.
30. A method of treating a patient, comprising administering to the patient a compound of any one of claims 1-27.
31. The method of claim 30, wherein the patient suffers form thrombocytopenia.
32. The method of claim 31, wherein the thrombocytopenia results from radiation or chemotherapy.
33. The method of claim 30, further comprising harvesting cells from the patient.
34. The method of claim 30, wherein the treatment is prophylactic.
35. The method of claim 30, wherein the patient suffers from a condition affecting the nervous system.
36. The method of claim 35, wherein the patient suffers from a disease selected from amyotrophic lateral sclerosis, multiple sclerosis, and multiple dystrophy.
37. The method of claim 35, wherein the patient suffers from injury to the nervous system.
38. The method of claim 35, wherein the patient suffers from injury to the spinal cord. - 269 - WO 2007/062078 PCT/US2006/045129
39. A pharmaceutical composition comprising a physiologically acceptable carrier, diluent, or excipient; and a compound of any one of claims 1-27.
40. The pharmaceutical composition of claim 39 for use in treating a condition selected from thrombocytopenia and a condition affecting the nervous system. - 270 -
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