WO2007062078A2 - Thrombopoietin activity modulating compounds and methods - Google Patents

Thrombopoietin activity modulating compounds and methods Download PDF

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Publication number
WO2007062078A2
WO2007062078A2 PCT/US2006/045129 US2006045129W WO2007062078A2 WO 2007062078 A2 WO2007062078 A2 WO 2007062078A2 US 2006045129 W US2006045129 W US 2006045129W WO 2007062078 A2 WO2007062078 A2 WO 2007062078A2
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Prior art keywords
compound
oxo
optionally substituted
dihydro
hydroxy
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PCT/US2006/045129
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French (fr)
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WO2007062078A3 (en
Inventor
Lin Zhi
Dean P. Phillips
Jackline E. Dalgard
Richard J. Penuliar
Matthew H. Mcneill
Jyun-Hung Chen
Catalina Cuervo
Robert Higuchi
Yongkai Li
Oliver Long
Cornelis Arjan Van Oeveren
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Ligand Pharmaceuticals Inc.
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Priority to BRPI0620532-1A priority Critical patent/BRPI0620532A2/en
Priority to EP06838225A priority patent/EP1951667A2/en
Priority to AU2006318527A priority patent/AU2006318527A1/en
Priority to CA002630234A priority patent/CA2630234A1/en
Priority to JP2008558985A priority patent/JP2009519352A/en
Publication of WO2007062078A2 publication Critical patent/WO2007062078A2/en
Publication of WO2007062078A3 publication Critical patent/WO2007062078A3/en

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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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    • 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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    • 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
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    • 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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    • 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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Definitions

  • 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.
  • Thrombopoietin also referred to as c-Mpl ligand, rnpl ligand, megapoietin, and megakaryocyte growth and development factor
  • TPO Thrombopoietin
  • c-Mpl ligand also referred to as c-Mpl ligand, rnpl ligand, megapoietin, and megakaryocyte growth and development factor
  • 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 :11104-11 108 (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.
  • TPO activity results from binding of TPO to the TPO receptor (also called MPL).
  • 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.
  • 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.
  • patients undergoing certain chemotherapies including but not limited to chemotherapy and/or radiation therapy for the treatment of cancer, may have reduced platelet levels.
  • treating such patients with a selective TPO modulator increases platelet levels.
  • selective TPO modulators stimulate production of glial cells, which may result in repair of damaged nerve cells.
  • the present invention provides a compound of Formula I, II, III, IV, V 3 or VI:
  • R 1 is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NR 14 R 15 , an optionally substituted C]-C 6 alkyl, an optionally substituted Ci-C ⁇ haloalkyl, an optionally substituted C 1 -C 6 heteroalkyl, CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 14 R 15 , 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 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 14 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl;
  • R 7 is selected from CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere; each R 8 and each R 9 is independently selected from hydrogen, OR 16 , NR 16 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 ) m R 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 -Cg ring;
  • R 10 is selected from hydrogen, halogen, oxo, OR 16 , NR 16 R 17 , SR 16 , an optionally substituted Ci-C 6 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 14 , NR 14 R 15 , and SR 14 ; or R 11 and R 4 are linked to form a optionally substituted heterocycle;
  • R 12 is selected from hydrogen, halogen, Ci-C 6 alkyl, Cj-C 6 haloalkyl, Cj- C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl;
  • R 13 is selected from hydrogen, halogen, CN, NO 2 , CO 2 R 14 , S(O)JR. 14 , Ci- C 4 alkyl, C 1 -C 4 haloalkyl, Ci-C 4 heteroalkyl, and Ci-C 4 haloheteroalkyl;
  • R 14 is selected from hydrogen, Ci-C ⁇ alkyl, CpC 6 haloalkyl, C]-C 6 heteroalkyl, and Cj-C 6 heterohaloalkyl;
  • R 15 is selected from hydrogen, SO 2 R 19 , Cj-C 6 alkyl, C 1 -C 5 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 Cj-C 6 haloalkyl, an optionally substituted Cj-C 6 heteroalkyl, and (CH 2 )HiR 18 ; 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 16 and R 17 are linked to form an optionally substituted C 3 -Cs ring;
  • 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 19 is selected from hydrogen, C 1 -C 3 alkyl, C 1 -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 Cj-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 -CiO 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 -CiO 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,
  • D is not naphthyl if X is N and W is NH
  • D is not phenyl if X is CH, W is NH, Z is phenyl, and R 10 or R 11 is -(CH 2 ) O-6 OH,
  • R i i — D-R 10 (iii) I is not pyrazolyl or optionally substituted 5- hydroxypyrazolyl, and
  • 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 !0 , and R l ! do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
  • the present invention provides a compound of Formula I, II, or III as described above:
  • R 1 is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NR 14 R 15 , an optionally substituted Ci-Cg alkyl, an optionally substituted Cj-Ce haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , S ⁇ 2NR 14 R !5 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 14 R 15 , an optionally substituted Cj-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 Cj-C 6 alkyl, an optionally substituted Cj-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R 5 is selected from hydrogen, halogen, OR 14 , Ci-C 6 alkyl, C]-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Cj-C 6 haloheteroalkyl;
  • R 7 is selected from CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere; each R 8 and each R 9 is independently selected from hydrogen, OR 16 , NR 16 R 17 , an optionally substituted Cj-C 6 alkyl, an optionally substituted Cj-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, (CH 2 ) m R 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 10 is selected from hydrogen, halogen, oxo, OR 16 , NR 16 R 17 , SR 16 , an optionally substituted C]-C 6 alkyl, an optionally substituted Cj-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R" is selected from hydrogen, halogen, OR 14 , NR 14 R 15 , and SR 14 ; or R ⁇ and R 4 are linked to form a optionally substituted heterocycle;
  • R 12 is selected from hydrogen, halogen, Cj-C 6 alkyl, Cj-C 6 haloalkyl, Cj- C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl;
  • R 14 is selected from hydrogen, CpC 6 alkyl, Ci-Ce haloalkyl, CpC 6 heteroalkyl, and Ci-C 6 heterohaloalkyl;
  • R 15 is selected from hydrogen, SO 2 R 19 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, Cj-C 6 heteroalkyl, and Cj-C 6 heterohaloalkyl;
  • R 16 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 C,-C 6 heteroalkyl, and (CH 2 )JR.
  • 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 16 and R are linked to form an optionally substituted C 3 -C 8 ring;
  • 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 19 is selected from hydrogen, C1-C 3 alkyl, C 1 -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-Ce 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 -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 Cj-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 aryU 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, ary
  • D is not naphthyl if X is N and W is NH 5
  • D is not phenyl if X is CH, W is NH, Z is phenyl, and R 10 or R u is -(CH 2 ) O-6 OH 5
  • R 11 — D— R 10 (iii) I is not pyrazolyl or optionally substituted 5- hydroxypyrazolyl, and
  • 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 10 , and R 11 do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
  • the present invention provides a compound of Formula I 5 II, or III as described above; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
  • R 1 is selected from a halogen, OR 14 , NO 2 , CN, NR 14 R 15 , C 1 -C 4 alkyl, Ci- C 4 haloalkyl, an optionally substituted C r C 4 heteroalkyl, CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere selected from tetrazole,
  • A, B 5 and C are each independently selected from O, S, and NR 20 ; each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 14 R 15 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, Ci-C 4 heteroalkyl, and C 1 -C 4 heterohaloalkyl;
  • R 3 and R 4 are independently selected from hydrogen, Ci-C 4 alkyl, C]-C 4 haloalkyl, and an optionally substituted Ci -C 4 heteroalkyl;
  • R 5 is selected from hydrogen, OR 14 , Ci-C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 heteroalkyl, and Ci-C 4 haloheteroalkyl;
  • R 7 is selected from CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2 R 19 , OC(S)NR 14 R 15 , SC(O)NR 14 R 15 , and
  • 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 , NR 16 R 17 , Ci-C 4 alkyl, Cj-C 4 haloalkyl, an optionally substituted C r C 4 heteroalkyl, (CH 2 ) m R 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 10 is selected from hydrogen, halogen, oxo, Ci-C 4 alkyl, Cj -C 4 haloalkyl, and an optionally substituted Ci-C 4 heteroalkyl;
  • R" is selected from hydrogen, halogen, OR 14 , NR 14 R 15 , and SR 14 ; or R 11 and R 4 are linked to form a optionally substituted heterocycle;
  • R 12 is selected from hydrogen, halogen, C]-C 4 alkyl, Ci-C 4 haloalkyl, Ci- C 4 heteroalkyl, and Ci -C 4 haloheteroalkyl;
  • R 13 is selected from hydrogen, halogen, CN 3 NO 2 , CO 2 R 14 , S(O) m R 14 , Cr C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 heteroalkyl, and Ci-C 4 haloheteroalkyl;
  • R 14 is selected from hydrogen, C 1 -C4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 heteroalkyl, and Ci-C 4 heterohaloalkyl;
  • R 15 is selected from hydrogen, SO 2 R 19 , Ci-C 4 alkyl, Ci-C 4 haloalkyl, and C 1 -C4 heteroalkyl;
  • R 16 and R 17 are each independently selected from hydrogen, Ci-C 4 alkyl, C J -C 4 haloalkyl, an optionally substituted C)-C 4 heteroalkyl, and (CH 2 ) m R 18 ; or one of R 16 and R 17 is 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 4 -C 7 ring;
  • R 19 is selected from hydrogen, C1-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, NR 14 , and CR 14 R 15 ;
  • 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:
  • Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C 6 -CiO 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 Ci-C 6 alkyl, an optionally substituted Cj-C 6 heteroalkyl, and an optionally substituted Cj-C 6 haloalkyl, each optionally fused with an optionally substituted C 6 -C 1O aryl; m is 0, I 5 2, or 3; and n is 0 or 1; provided that if Y is R oriented in compounds of Formulas I or II to form a dihydropyrazolylene, then:
  • D is not naphthyl if X is N and W is NH 3
  • D is not phenyl if X is CH 5 W is NH, Z is phenyl, and R 10 or R 11 is -(CH 2 ) O-6 OH,
  • R 11 — D-R 10 (iii) I is not pyrazolyl or optionally substituted 5- hydroxypyrazolyl ?
  • 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 10 , and R 11 do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
  • the present invention provides a compound of Formula IV, V, or VI as described above:
  • R 1 is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NR 14 R 15 , an optionally substituted Ci-Ce alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted C 1 -C 6 heteroalkyl, CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 14 R 15 , 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 Cj-C 6 alkyl, an optionally substituted Cj-C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R 5 is selected from hydrogen, halogen, OR 14 , Ci-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl;
  • R 7 is selected from CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere; each R 8 and each R 9 is independently selected from hydrogen, OR 16 , NR 16 R 17 , an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted CpCe heteroalkyl, (CH 2 ) m R 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 -Cs ring;
  • R 10 is selected from hydrogen, halogen, oxo, OR 16 , NR 16 R 17 , SR 16 , an optionally substituted Ci-C 6 alkyl, an optionally substituted C t -C 6 haloalkyl, and an optionally substituted Ci-C 6 heteroalkyl;
  • R n is selected from hydrogen, halogen, OR 14 , NR 14 R 15 , and SR 14 ; or R ⁇ and R 4 are linked to form a optionally substituted heterocycle;
  • R 12 is selected from hydrogen, halogen, Ci-C 6 alkyl, Cj-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 14 , S(O) m R 14 , C 1 - C 4 alkyl. C 1 -C 4 haloalkyl, Cj -C 4 heteroalkyl, and C 1 -C 4 haloheteroalkyl;
  • R 14 is selected from hydrogen, C]-C 6 alkyl, Ci-C 6 haloalkyl, Cj-C 6 heteroalkyl, and C]-C 6 heterohaloalkyl;
  • R 15 is selected from hydrogen, SO 2 R 19 , C r C 6 alkyl, Cj-C 6 haloalkyl, C]-C 6 heteroalkyl, and Ci-C 6 heterohaloalkyl;
  • R 16 and R 17 are each independently selected from hydrogen, an optionally substituted Cj-C 6 alkyl, an optionally substituted Ci-Ce haloalkyl, an optionally substituted Cj-C 6 heteroalkyl, and (CH 2 ) m R 18 ; 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 16 and R 1 are linked to form an optionally substituted C 3 -C 8 ring; R 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 19 is selected from hydrogen, C 1 -C 3 alkyl, Cj-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 ⁇ -Cio aryl and an optionally substituted Ci-Ce 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, 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
  • the present invention provides a compound of Formula IV, V, or VI or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
  • R 1 is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NR 14 R 15 , an optionally substituted Ci-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2 R 19 ,
  • A, B, and C are each independently selected from O, S, and N;
  • R 2 is selected from hydrogen, halogen, OR 14 , NR 14 R 15 , an optionally substituted Ci-C ⁇ alkyl, an optionally substituted Ci-Ce haloalkyl, and an optionally substituted Ci-Cg heteroalkyl;
  • R 7 is selected from CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere selected from tetrazole, NHSO 2 R 19 , OC(S)NR 14 R 15 , SC(O)NR 14 R 15 , and
  • the present invention provides a compound of Formula I, II, III, IV, V, or VI: or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
  • R 1 is selected from hydrogen, halogen, OR 14 , NO 2 , CN, NR 14 R 15 , an optionally substituted Cj-C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere; each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 14 R 15 , 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 Cj-C 6 haloalkyl, and an optionally substituted Cj-C 6 heteroalkyl;
  • R 5 is selected from hydrogen, halogen, OR 14 , C]-C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl;
  • R 10 is selected from hydrogen, halogen, oxo, OR 16 , NR 16 R 17 , SR 16 , an optionally substituted C 1 -C 6 alkyl, an optionally substituted Ci-C 6 haloalkyl, and an optionally substituted Ci -C O heteroalkyl;
  • R 11 is selected from hydrogen, halogen, OR 14 , NR 14 R 15 , and SR 14 ; or R 1 1 and R 4 are linked to form a optionally substituted heterocycle;
  • R 12 is selected from hydrogen, halogen, CpC 6 alkyl, Ci-C 6 haloalkyl, Q- C 6 heteroalkyl, and C]-C 6 haloheteroalkyl;
  • R 13 is selected from hydrogen, halogen, CN, NO 2 , CO 2 R 14 , S(O) m R 14 , C,- C 4 alkyl, Ci-C 4 haloalkyl, Ci-C 4 heteroalkyl, and Ci-C 4 haloheteroalkyl;
  • R 14 is selected from hydrogen, C]-C 6 alkyl, C r C 6 haloalkyl, Ci-C 6 heteroalkyl, and C]-C 6 heterohaloalkyl;
  • R 15 is selected from hydrogen, SO 2 R 19 , CpC 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 Ci-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, and (CH 2 ) m R 18 ; 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 16 and R 17 are linked to form an optionally substituted C 3 -Cs ring;
  • 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 19 is selected from hydrogen, Cj-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 3 NR 4 , CR 3 R 4 , CO 3 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 I -C O alkyl, an optionally substituted Ci-C 6 heteroalkyl, an optionally substituted phenyl, and an optionally substituted heteroaryl;
  • R 20 is selected from hydrogen, a substituted alkyl, a substituted aryl, and a substituted heteroaryl;
  • R 21 and R 22 are each independently selected from hydrogen, alkyl, and aryl; or R 21 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;
  • the invention provides a compound selected from:
  • the invention provides a compound selected from:
  • a compound of Formula I, II, III, IV, V, or VI is a selective TPO modulator.
  • a compound Formula I 5 II, III, IV, V 5 or VI is a TPO mimic.
  • 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.
  • 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.
  • the cell expresses a TPO receptor.
  • the invention provides methods of treating a patient comprising administering to the patient a compound of the present invention.
  • a patient suffers from thrombocytopenia.
  • 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.
  • one or more compounds of the invention are administered to a patient suffering from aplastic anemia, bone marrow failure, and/or idiopathic thrombocytopenia.
  • one or more compounds of the present invention are administered to a patient suffering from a disease of the nervous system.
  • 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 invention are administered to a patient with a nerve injury, including, but not limited to, a spinal cord injury.
  • 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.
  • 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.
  • 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., electroporation, Hpofection).
  • 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.
  • selective binding compound refers to a compound that selectively binds to any portion of one or more target.
  • selective TPO receptor binding compound refers to a compound that selectively binds to any portion of a TPO receptor.
  • selective binding 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.
  • 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.
  • target receptor refers to a receptor or a portion of a receptor capable of being bound by a selective binding compound.
  • a target receptor is a TPO receptor.
  • modulator refers to a compound that alters an activity.
  • 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.
  • a modulator is an inhibitor, which decreases the magnitude of one or more activities.
  • an inhibitor completely prevents one or more biological activities.
  • a modulator is an activator, which increases the magnitude of at least one activity.
  • the presence of a modulator results in a activity that does not occur in the absence of the modulator.
  • selective modulator refers to a compound that selectively modulates a target activity.
  • selective TPO modulator refers to a compound that selectively modulates at least one TPO activity.
  • selective TPO modulator 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 01/21 180, both of which are incorporated herein by reference in their entirety.
  • selective 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • receptor mediated activity refers to any biological activity that results, either directly or indirectly, from binding of a ligand to a receptor.
  • 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.
  • 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.
  • 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.
  • 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 "alkyl” also includes instances where no numerical range of carbon atoms is designated).
  • lower alkyl refers to an alkyl comprising 1 to 5 carbon atoms.
  • intermediate alkyl refers to an alkyl comprising 5 to 10 carbon atoms.
  • An alkyl may be designated as "Cj-C 4 alkyl” or similar designations.
  • 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.
  • alkenyl refers to an alkyl group comprising at least one carbon-carbon double bond.
  • alkynyl refers to an alkyl group comprising at least one carbon-carbon triple bond.
  • 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.
  • straight-chain alkoxy refers to a group comprising the formula: -CCH 2 ) P O- wherein p is any integer.
  • Straight-chain alkoxy does not include substituted or branched alkoxy groups.
  • non-straight-chain-alkoxy-heteroalkyl refers to any heteroalkyl that is not a straight-chain alkoxy heteroalkyl.
  • 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.
  • heterohaloalkyl refers to a heteroalkyl in which at least one hydrogen atom is replaced with a halogen atom.
  • 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.
  • 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.
  • binding for benzo-fused derivatives may be via a carbon of the benzenoid ring.
  • heterocycles include, but are not limited to the following:
  • 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.
  • 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.
  • aromatic refers to a group comprising a covalently closed ring having a delocalized ⁇ -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.
  • 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 Ci -6 alkoxy, a Ci ⁇ alkyl, a Ci -6 hydroxyalkyl, a Ci- 6 aminoalkyl, a Ci_ 6 alkylamino, an alkylsulfenyl, an alkylsulf ⁇ nyl, an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl.
  • an aromatic group is substituted at one or more of the para, meta, and/or ortho positions.
  • aromatic groups comprising substitutions include, but are not limited to, phenyl, 3-halophenyl, 4- halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3- methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4- trifluoromethoxypheny], 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4- morpholin-4-ylphenyl, 4-pyrrolidin-l-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin- 1 -yl)pheny
  • 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.
  • 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.
  • heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci- 6 -alkoxy, Ci-6-alkyl, Ci-6- hydroxyalkyl, Ci ⁇ -aminoalkyl, Ci -6 -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl.
  • substituents independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci- 6 -alkoxy, Ci-6-alkyl, Ci-6- hydroxyalkyl, Ci ⁇ -aminoalkyl, Ci -6 -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamo
  • 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, phthal
  • non-aromatic ring refers to a group comprising a covalently closed ring that does not have a delocalized ⁇ -electron system.
  • 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 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.
  • cycloalkyls include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, and cycloheptene.
  • 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.
  • non-aromatic heterocycles comprise one or more carbonyl or thiocarbonyl groups such as, for example, oxo- and thio-containing groups.
  • non-aromatic heterocycles include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyran, 4/f-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-l,4-thiazine, 2/f-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, cycl
  • arylalkyl refers to a group comprising an aryl group bound to an alkyl group.
  • 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.
  • 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. [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.
  • carboxylic acid bioisostere refers to a group that is biologically equivalent to a carboxylic acid.
  • carboxylic acid bioisosteres include, but are not limited to, tetrazole, NHSO 2 R 15 , OC(S)NR 10 R 11 , SC(O)NR 10 R 11 , thiazolidinedione, oxazolidinedione, and l-oxa-2,4-d ⁇ azolidine-3 5 5-dione.
  • a carboxylic acid bioisoster comprises the following structure:
  • A, B, and C are each independently selected from O, S, and N.
  • 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.
  • spacers are provided.
  • 1 atom spacers include, but are not limited to, the following:
  • a and B represent groups which are separated by the desired number of atoms.
  • 2 atom spacers include, but are not limited to, the following:
  • a and B represent groups which are separated by the desired number of atoms.
  • Examples of 3 atom spacers include, but arc not limited to, the following: 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.
  • 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.
  • 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"
  • 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.
  • resulting structures include, but are not limited to:
  • the two substituents that together form a ring are not immediately bound to the same atom.
  • 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:
  • 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:
  • 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:
  • nuclear refers to a group being absent from a structure.
  • R V 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.
  • R refers to a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and non-aromatic heterocycle (bonded through a ring carbon).
  • C-carboxy refers to a group of formula -C(O)OR.
  • cyano refers to a group of formula -CN.
  • isocyanato refers to a group of formula -NCO.
  • thiocyanato refers to a group of formula -CNS.
  • isothiocyanato refers to a group of formula -NCS.
  • trimethanesulfonamido refers to a group of formula
  • dihydropyrazolylene refers to a di-radical of an optionally substituted dihydropyrazole ring, wherein the dihydropyrazole ring has the structure:
  • pyrazolyl refers to a radical of a pyrzole ring, wherein the pyrzole ring has the structure:
  • esters 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.
  • amide refers to a chemical moiety with formula -(R) n -C(O)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.
  • 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.
  • an amide may be an amino acid or a peptide.
  • amine 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.
  • 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,
  • carrier refers to a compound that facilitates the incorporation of another compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • pharmaceutical agent refers to a chemical compound or composition capable of inducing a desired therapeutic effect in a patient.
  • a pharmaceutical agent comprises an active agent, which is the agent that induces the desired therapeutic effect.
  • a pharmaceutical agent comprises a prodrug.
  • a pharmaceutical agent comprises inactive ingredients such as carriers, excipients, and the like.
  • terapéuticaally effective amount refers to an amount of a pharmaceutical agent sufficient to achieve a desired therapeutic effect.
  • prodrug refers to an pharmaceutical agent that is converted from a less active form into a corresponding more active form in vivo.
  • 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.
  • co-administer refers to administering more than one pharmaceutical agent to a patient.
  • co-administered pharmaceutical agents are administered together in a single dosage unit.
  • co-administered pharmaceutical agents are administered separately.
  • co-administered pharmaceutical agents are administered at the same time.
  • co-administered pharmaceutical agents are administered at different times.
  • patient includes human and animal subjects.
  • 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).
  • 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.
  • a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all species present in the composition.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • cell proliferation refers to the rate at which cells divide.
  • cells are in situ in an organism.
  • 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.
  • 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 [0111] Certain compounds that modulate one or more TPO activity and/or 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.
  • the present invention provides selective TPO modulators.
  • the invention provides selective TPO receptor binding agents.
  • the invention provides methods of making and methods of using selective TPO modulators and/or selective TPO receptor binding agents.
  • selective TPO modulators are agonists, partial agonists, and/or antagonists for the TPO receptor.
  • the present invention relates to compounds of Formula I, IL III, IV, V, or VI:
  • R 1 is selected from hydrogen, halogen, OR 14 ,
  • carboxylic acid bioisostere is selected from tetrazole, NHSO 2 R 19 , OC(S)NR 14 R 15 , SC(O)NR 14 R 15 , and wherein A, B, and C are each independently selected from O, S, and N.
  • each R 2 is independently selected from hydrogen, halogen, OR 14 , NR 14 R 15 , 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 a group of hydrogen, halogen, OR 14 , Cj-C 6 alkyl, Ci-C 6 haloalkyl, C 1 -C 6 heteroalkyl, and Ci-C 6 haloheteroalkyl.
  • R 6 is selected from an optionally substituted Ci-Cio alkyl, an optionally substituted C]-Ci 0 haloalkyl, or an optionally substituted Q- CiQ heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R 6 is (CH 2 ) rn R 18 or C(O)NHR 18 .
  • R 7 is selected from CO 2 R 14 , CONR 14 R 15 , SO 3 R 14 , SO 2 NR 14 R 15 and a carboxylic acid bioisostere.
  • the carboxylic bioisostere is selected from tetrazole, NHSO 2 R 19 , OC(S)NR 14 R 15 , SC(O)NR 14 R 15 , and
  • each R 8 and each R 9 is independently selected from hydrogen, OR 16 , NR 16 R 17 , an optionally substituted Ci-C 6 alky], an optionally substituted Ci-C 6 haloalkyl, an optionally substituted Cj-C 6 heteroalkyl, (CH 2 ) m R l s , 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 10 is selected from hydrogen, halogen, oxo, OR 16 , NR 16 R 17 , SR 16 , an optionally substituted Ci-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, OR 14 , NR 14 R 15 , and SR 14 .
  • R 1 1 and R 4 are linked to form a optionally substituted heterocycle.
  • R 12 is selected from hydrogen, halogen, C r 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 14 , S(O) 1n R 14 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 heteroalkyl, and C 1 -C 4 haloheteroalkyl.
  • R 14 is selected from hydrogen, CpC 6 alkyl, C]-Ce haloalkyl, Ci-C 6 heteroalkyl, and Ci-C 6 heterohaloalkyl.
  • R 15 is selected from hydrogen, SO 2 R 19 , C 1 -C 6 alkyl, Ci-C 6 haloalkyl, Ci-C 6 heteroalkyl, and C 1 -C 6 heterohaloalkyl.
  • R 16 and R 17 are each independently selected from hydrogen, an optionally substituted Cj-C 6 alkyl, an optionally substituted C]-C 6 haloalkyl, an optionally substituted Ci-C 6 heteroalkyl, and (CH 2 ) m R 18 .
  • 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.
  • R 16 and R 17 are linked to form an optionally substituted C 3 -C 8 ring.
  • 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 ]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 19 is selected from hydrogen, C1-C 3 alkyl, C 1 -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 5 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-Ce alkyl, an optionally substituted Ci -Ce heteroalkyl, an optionally substituted phenyl, and an optionally substituted
  • 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.
  • Z is selected from null, a 2-5 atom spacer selected from an optionally substituted C 6 -C I O aryl and an optionally substituted Ci-C 8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycie or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted Ci-Qs alkyl, an optionally substituted CrC 6 heteroalkyl, and an optionally substituted Cj-C 6 haloalkyl, each optionally fused with an optionally substituted Ce-C io aryl.
  • n is 0, 1, or 2. In certain embodiments, m is 0, 1 , 2, or 3.
  • n is 0 or 1.
  • R 6 , R 10 , and R 11 do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
  • the identities of those two or more particular groups are selected independently and, thus, may be the same or different from one another.
  • 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.
  • those R 14 groups are all the same as one another; in certain embodiments, those R 14 groups are all different from one another; and in certain embodiments, some of those R 14 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.
  • a compound of Formula I, II, III, IV, V, or VI is a selective TPO modulator.
  • a compound of Formula I, II, III, IV, V, or VI is a selective TPO receptor agonist. In certain embodiments, a compound of Formula I, II, III, 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, HI, 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.
  • the invention provides compounds selected from:
  • 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 racem ⁇ c 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.
  • Scheme IH 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.
  • U 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 VIII is a multi-step synthetic sequence that commences with enamine or enol ether formation of an iV-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.
  • the invention provides a salt corresponding to a selective TPO modulator.
  • the invention provides a salt corresponding to a selective TPO receptor binding agent.
  • 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.
  • 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)rnethylarnine, 4-(2- hydroxyethyl)-morpholine, l-(2-hydroxyethyl)-pyrrolidine, ethanolamine and salts with amino acids such as arginine, lysine, and the like.
  • 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)
  • 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 b ⁇ s-sodium, bis- ethanolamine, and the like.
  • 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
  • one or more carbon atoms of a compound of the present invention are replaced with silicon. See e.g., WO 03/037905 Al; 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.
  • 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.
  • assays may be used to determine the level of TPO modulating activity of the compounds of the present invention.
  • 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.
  • 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.
  • 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.
  • a pharmaceutical agent comprising one or more compounds of the present invention is a liquid (e.g., a suspension, elixir and/or solution).
  • 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.
  • a pharmaceutical agent comprising one or more compounds of the present invention is a solid (e.g., a powder, tablet, and/or capsule).
  • 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.
  • 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.
  • such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • 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.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises a delivery system.
  • 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.
  • certain organic solvents such as dimethyl sulfoxide are used.
  • 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.
  • pharmaceutical agents include liposomes coated with a tissue-specific antibody.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises a co-solvent system.
  • co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water- miscible organic polymer, and an aqueous phase.
  • co- solvent systems are used for hydrophobic compounds.
  • VPD co-solvent system is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM , and 65% w/v polyethylene glycol 300.
  • co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.
  • identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80TM; 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.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises a sustained-release system.
  • a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers.
  • sustained-release systems may, depending on their chemical nature, release compounds over a period of hours, days, weeks or months.
  • 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 acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.
  • a pharmaceutical agent comprising one or more compounds of the present invention comprises an active ingredient in a therapeutically effective amount.
  • 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.
  • a pharmaceutical agent comprising one or more compounds of the present invention is formulated as a prodrug.
  • prodrugs are useful because they are easier to administer than the corresponding active form.
  • a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form.
  • a prodrug may have improved solubility compared to the corresponding active form.
  • a prodrug is an ester.
  • such prodrugs are less water soluble than the corresponding active form.
  • such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility.
  • the ester in such prodrugs is metabolically hydrolyzed to carboxylic acid.
  • the carboxylic acid containing compound is the corresponding active form.
  • a prodrug comprises a short peptide (polyaminoacid) bound to an acid group.
  • the peptide is metabolized to form the corresponding active form.
  • 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).
  • pharmaceutical intrathecals are administered to achieve local rather than systemic exposures.
  • pharmaceutical agents may be injected directly in the area of desired effect (e.g., in the renal or cardiac area).
  • 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.).
  • dosage units comprise a selective TPO modulator in a dose from about 1 ⁇ g/kg of body weight to about 50 mg/kg of body weight.
  • dosage units comprise a selective TPO modulator in a dose from about 2 ⁇ g/kg of body weight to about 25 mg/kg of body weight.
  • such dosage units comprise a selective TPO modulator in a dose from about 10 ⁇ g/kg of body weight to about 5 mg/kg of body weight.
  • 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.
  • a pharmaceutical agent comprising a compound of the present invention is prepared for oral administration.
  • a pharmaceutical agent is formulated by combining one or more compounds of the present invention with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable 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.
  • 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).
  • PVP polyvinylpyrrolidone
  • such a mixture is optionally ground and auxiliaries are optionally added.
  • pharmaceutical agents are formed to obtain tablets or dragee cores.
  • disintegrating agents ⁇ e.g., cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate) are added.
  • dragee cores are provided with coatings.
  • 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.
  • pharmaceutical agents for oral administration are push-fit capsules made of gelatin.
  • 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.
  • pharmaceutical agents for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • 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.
  • stabilizers may be added.
  • pharmaceutical agents are prepared for buccal administration. Certain of such pharmaceutical agents are tablets or lozenges formulated in conventional manner.
  • a pharmaceutical agent is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
  • 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.
  • other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
  • 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.
  • 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.
  • a pharmaceutical agent is prepared for transmucosal administration.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • 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.
  • the dosage unit may be determined with a valve that delivers a metered amount.
  • 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.
  • 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.
  • a pharmaceutical agent is prepared for topical administration.
  • Certain of such pharmaceutical agents comprise bland moisturizing bases, such as ointments or creams.
  • 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).
  • 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 at 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1 , which is incorporated herein by reference in its entirety).
  • a pharmaceutical agent is administered as a single dose.
  • a pharmaceutical agent is administered as a series of two or more doses administered over one or more days.
  • 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.
  • a suitable human dosage may be inferred from ED 5 O or ID50 values, or other appropriate values derived from in vitro or in vivo studies.
  • 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.
  • a daily dosage regimen is administered as a single daily dose.
  • a daily dosage regimen is administered as two, three, four, or more than four doses.
  • 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.
  • a pharmaceutical agent of the invention is administered for a period of continuous therapy.
  • a pharmaceutical agent of the present invention may be administered over a period of days, weeks, months, or years.
  • Dosage amount, interval between doses, and duration of treatment may be adjusted to achieve a desired effect.
  • dosage amount and interval between doses are adjusted to maintain a desired concentration on compound in a patient.
  • 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.
  • the plasma concentration is maintained above the minimal effective concentration (MEC).
  • 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 lime, between 30-90% of the time, or between 50-90% of the time.
  • the dosage regimen is adjusted to achieve a desired local concentration of a compound of the present invention.
  • a pharmaceutical agent may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing 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.
  • a pharmaceutical agent is in powder form for constitution with a suitable vehicle, e.g. , sterile pyrogen-free water, before use.
  • one or more pharmaceutical agents of the present invention are co-administered with one or more other pharmaceutical agents.
  • 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.
  • 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.
  • such one or more other pharmaceutical agents are designed to treat an undesired effect of one or more pharmaceutical agents of the present invention.
  • 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.
  • 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.
  • 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 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); antiinflammatory agents, including, but not limited to non-steroidal anti-inflammatory drugs (e.g., ibuprofen, COX-I 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, androg
  • the invention provides methods of treating a patient comprising administering one or more compounds of the present invention.
  • thrombocytopenia results from chemotherapy and/or radiation treatment.
  • thrombocytopenia results bone marrow failure resulting from bone marrow transplantation and/or aplastic anemia.
  • thrombocytopenia is idiopathic.
  • 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.
  • 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.
  • Damage 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.
  • 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.
  • compounds of the present invention are used to treat psychological disorders, including, but not limited to, cognitive disorders.

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Abstract

Disclosed herein are amide containing heterocyclic compounds, pharmaceutical compositions comprising the compounds, methods of modulating the activity a thrombopoietin receptor using the compounds, methods of identifying compounds as thrombopoietin receptor modulators, and methods of treating disease by administering the compounds to a patient in need thereof.

Description

THROMBOPOIETIN ACTIVITY MODULATING COMPOUNDS AND
METHODS
FIELD OF THE INVENTION
[0001] 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, rnpl 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 DJ. 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 :11104-11 108 (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.
[0003] 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.
[0004] 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. SUMMARY OF THE INVENTION
[0005] In certain embodiments, the present invention provides a compound of Formula I, II, III, IV, V3 or VI:
Figure imgf000003_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted C]-C6 alkyl, an optionally substituted Ci-Cβ haloalkyl, an optionally substituted C1-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R2 is independently selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R3 and R4 are independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R5 is selected from hydrogen, halogen, OR14, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R is selected from an optionally substituted Ci-Ci0 alkyl, an optionally substituted C1-C10 haloalkyl, and an optionally substituted Ci-Cχ> heteroalkyl, each optionally fused with a substituted aiyl or a substituted heteroaryl, or R6 is selected from (CH2)mR18, C(O)NHR18, C≡CR18, CR3=CR4R18, and CR3=R18;
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R8 and each R9 is independently selected from hydrogen, OR16, NR16R17, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, (CH2)mR18, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-Cg ring;
R10 is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted Ci-C6 alkyl, an optionally substituted C]-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R1 1 is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or R11 and R4 are linked to form a optionally substituted heterocycle;
R12 is selected from hydrogen, halogen, Ci-C6 alkyl, Cj-C6 haloalkyl, Cj- C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R13 is selected from hydrogen, halogen, CN, NO2, CO2R14, S(O)JR.14, Ci- C4 alkyl, C1-C4 haloalkyl, Ci-C4 heteroalkyl, and Ci-C4 haloheteroalkyl;
R14 is selected from hydrogen, Ci-Cβ alkyl, CpC6 haloalkyl, C]-C6 heteroalkyl, and Cj-C6 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, Cj-C6 alkyl, C1-C5 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
R16 and R17 are each independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, and (CH2)HiR18; or one of R16 and R17 is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C3-Cs ring;
R18 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 R18 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; R19 is selected from hydrogen, C1-C3 alkyl, C1-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, NR4, CR3R4, CO, and null;
W is selected from O, NR4, CR3R4, CO, and null;
X is N or CR5;
Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Ci-C6 alkyl, an optionally substituted Cj-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-CiO aryl and an optionally substituted C1-C8 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-C6 alkyl, an optionally substituted Ci-C6 heteroalkyl, and an optionally substituted Ci-C6 haloalkyl, each optionally fused with an optionally substituted C6-CiO 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, sily], trihalomethanesulfonyl, =O, =S, amino, and protected derivatives of amino groups;
provided that if Y is R 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 R10 or R11 is -(CH2)O-6OH,
Rii — D-R10 (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 R6, R!0, and Rl ! do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
[0006} In certain embodiments, the present invention provides a compound of Formula I, II, or III as described above:
Figure imgf000006_0001
thereof, wherein:
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted Ci-Cg alkyl, an optionally substituted Cj-Ce haloalkyl, an optionally substituted Ci-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, Sθ2NR14R!5 and a carboxylic acid bioisostere; each R2 is independently selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted Cj-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R3 and R4 are independently selected from hydrogen, an optionally substituted Cj-C6 alkyl, an optionally substituted Cj-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R5 is selected from hydrogen, halogen, OR14, Ci-C6 alkyl, C]-C6 haloalkyl, Ci-C6 heteroalkyl, and Cj-C6 haloheteroalkyl;
R is selected from an optionally substituted C]-C10 alkyl, an optionally substituted Ci-Cio haloalkyl, an optionally substituted Ci-Cio heteroalkyl, (CH2)mR18, C(O)NHR18, C≡CR18, CR3=CR4R18, and CR3=R18;
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R8 and each R9 is independently selected from hydrogen, OR16, NR16R17, an optionally substituted Cj-C6 alkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, (CH2)mR18 > and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-C8 ring;
R10 is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted C]-C6 alkyl, an optionally substituted Cj-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R" is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or Rπ and R4 are linked to form a optionally substituted heterocycle;
R12 is selected from hydrogen, halogen, Cj-C6 alkyl, Cj-C6 haloalkyl, Cj- C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R14 is selected from hydrogen, CpC6 alkyl, Ci-Ce haloalkyl, CpC6 heteroalkyl, and Ci-C6 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, Ci-C6 alkyl, Ci-C6 haloalkyl, Cj-C6 heteroalkyl, and Cj-C6 heterohaloalkyl;
R16 and R17 are each independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted C,-C6 heteroalkyl, and (CH2)JR.18; or one of R16 and R17 is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R are linked to form an optionally substituted C3-C8 ring; R18 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 R18 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;
R19 is selected from hydrogen, C1-C3 alkyl, C1-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, NR4, CR3R4, CO, and null;
W is selected from O, NR4, CR3R4, CO, and null;
X is N or CR5;
Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Ci-Ce 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-Ci0 aryl and an optionally substituted Ci-C8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycle or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted Cj-C6 alkyl, an optionally substituted Ci-C6 heteroalkyl, and an optionally substituted Ci-C6 haloalkyl, each optionally fused with an optionally substituted C6-Ci0 aryU 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;
provided that if Y is
Figure imgf000009_0001
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 NH5
(ii) D is not phenyl if X is CH, W is NH, Z is phenyl, and R10 or Ru is -(CH2)O-6OH5
R11— D— R10 (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 R6, R10, and R11 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 I5 II, or III as described above; or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from a halogen, OR14, NO2, CN, NR14R15, C1-C4 alkyl, Ci- C4 haloalkyl, an optionally substituted CrC4 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere selected from tetrazole,
NHSO2R19, OC(S)NR14R15, SC(O)NR14R15, and
Figure imgf000009_0002
wherein A, B5 and C are each independently selected from O, S, and NR20; each R2 is independently selected from hydrogen, halogen, OR14, NR14R15, C1-C4 alkyl, C1-C4 haloalkyl, Ci-C4 heteroalkyl, and C1-C4 heterohaloalkyl;
R3 and R4 are independently selected from hydrogen, Ci-C4 alkyl, C]-C4 haloalkyl, and an optionally substituted Ci -C4 heteroalkyl;
R5 is selected from hydrogen, OR14, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 heteroalkyl, and Ci-C4 haloheteroalkyl;
R6 is selected from CI-CJO alkyl, Ci-C]0 haloalkyl, an optionally substituted Ci-C10 heteroalkyl, (CH2)mR18, C(O)NHR18, C≡CR18, CR3=CR4R18, and CR3=R' 8;
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere selected from tetrazole, NHSO2R19, OC(S)NR14R15, SC(O)NR14R15, and
Figure imgf000010_0001
wherein A, B, and C are each independently selected from O, S, and N; each R8 and each R9 is independently selected from hydrogen, OR , NR16R17, Ci-C4 alkyl, Cj-C4 haloalkyl, an optionally substituted CrC4 heteroalkyl, (CH2)mR18, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-C8 ring;
R10 is selected from hydrogen, halogen, oxo, Ci-C4 alkyl, Cj -C4 haloalkyl, and an optionally substituted Ci-C4 heteroalkyl;
R" is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or R11 and R4 are linked to form a optionally substituted heterocycle;
R12 is selected from hydrogen, halogen, C]-C4 alkyl, Ci-C4 haloalkyl, Ci- C4 heteroalkyl, and Ci -C4 haloheteroalkyl;
R13 is selected from hydrogen, halogen, CN3 NO2, CO2R14, S(O)mR14, Cr C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, and Ci-C4 haloheteroalkyl;
R14 is selected from hydrogen, C1-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 heteroalkyl, and Ci-C4 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, Ci-C4 alkyl, Ci-C4 haloalkyl, and C1-C4 heteroalkyl; R16 and R17 are each independently selected from hydrogen, Ci-C4 alkyl, CJ-C4 haloalkyl, an optionally substituted C)-C4 heteroalkyl, and (CH2)mR18; or one of R16 and R17 is C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C4-C7 ring;
R19 is selected from hydrogen, C1-C3 alkyl, Ci-C3 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 NR14;
J is selected from O, S, NR14, and CR14R15;
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, NR4, CR3R4, CO, and null;
W is selected from O, NR4, CR3R4, CO, and null;
X is N or CR5;
Y is selected from:
Figure imgf000011_0001
Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C6-CiO 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 Ci-C6 alkyl, an optionally substituted Cj-C6 heteroalkyl, and an optionally substituted Cj-C6 haloalkyl, each optionally fused with an optionally substituted C6-C1O aryl; m is 0, I 5 2, or 3; and n is 0 or 1; provided that if Y is R 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 NH3
(ii) D is not phenyl if X is CH5 W is NH, Z is phenyl, and R10 or R11 is -(CH2)O-6OH,
R11— D-R10 (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 R6, R10, and R11 do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
[0008] In certain embodiments, the present invention provides a compound of Formula IV, V, or VI as described above:
Figure imgf000012_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted Ci-Ce alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R2 is independently selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl; R3 and R4 are independently selected from hydrogen, an optionally substituted Cj-C6 alkyl, an optionally substituted Cj-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R5 is selected from hydrogen, halogen, OR14, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R6 is selected from an optionally substituted Ci-C]0 alkyl, an optionally substituted Cj-Cio haloalkyl, an optionally substituted C]-CiO heteroalkyl, (CH2VR18, C(O)NHR18, C≡CR18, CR3=CR4R18, and CR3=R18;
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R8 and each R9 is independently selected from hydrogen, OR16, NR16R17, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted CpCe heteroalkyl, (CH2)mR18, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-Cs ring;
R10 is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted Ci-C6 alkyl, an optionally substituted Ct-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
Rn is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or Rπ and R4 are linked to form a optionally substituted heterocycle;
R12 is selected from hydrogen, halogen, Ci-C6 alkyl, Cj-C6 haloalkyl, Ci- C6 heteroalkyl, and C1-C6 haloheteroalkyl;
R13 is selected from hydrogen, halogen, CN, NO2, CO2R14, S(O)mR14, C1- C4 alkyl. C1-C4 haloalkyl, Cj -C4 heteroalkyl, and C1-C4 haloheteroalkyl;
R14 is selected from hydrogen, C]-C6 alkyl, Ci-C6 haloalkyl, Cj-C6 heteroalkyl, and C]-C6 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, CrC6 alkyl, Cj-C6 haloalkyl, C]-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
R16 and R17 are each independently selected from hydrogen, an optionally substituted Cj-C6 alkyl, an optionally substituted Ci-Ce haloalkyl, an optionally substituted Cj-C6 heteroalkyl, and (CH2)mR18; or one of R16 and R17 is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R1 are linked to form an optionally substituted C3-C8 ring; R 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 R18 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;
R19 is selected from hydrogen, C1-C3 alkyl, Cj-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, NR4, CR3R4, CO, and null;
W is selected from O, NR4, CR3R4, CO, and null;
X is N or CR5;
Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted Cβ-Cio aryl and an optionally substituted Ci-Ce 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-C6 alkyl, an optionally substituted Ci-C6 heteroalkyl, and an optionally substituted Ci-C6 haloalkyl, each optionally fused with an optionally substituted C6-Ci0 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-sulfonamido5 N-sulfonamido, C-carboxy, O-carboxy, isQcyanato, 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 R6, R10, and R11 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:
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere selected from tetrazole, NHSO2R19,
OC(S)NR14R15, SC(O)NR14R15, and
Figure imgf000015_0001
wherein A, B, and C are each independently selected from O, S, and N;
R2 is selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted Ci-Cβ alkyl, an optionally substituted Ci-Ce haloalkyl, and an optionally substituted Ci-Cg heteroalkyl;
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere selected from tetrazole, NHSO2R19, OC(S)NR14R15, SC(O)NR14R15, and
Figure imgf000015_0002
wherein A, B, and C are each independently selected from O, S, and N. [0010] In certain embodiments, the present invention provides a compound of Formula I, II, III, IV, V, or VI:
Figure imgf000016_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted Cj-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R2 is independently selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted C]-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R3 and R4 are independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Cj-C6 haloalkyl, and an optionally substituted Cj-C6 heteroalkyl;
R5 is selected from hydrogen, halogen, OR14, C]-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R6 is selected from an optionally substituted Ci-Cio alkyl, an optionally substituted Ci-Cio haloalkyl, and an optionally substituted Cj-Cio heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R is selected from (CH2)Jl1 \ C(O)NHR18, C≡CR18, CR3=CR4R18, and CR3=R18; R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R8 and each R9 is independently selected from hydrogen, OR16, NR16R17, an optionally substituted CI-C6 alkyl, an optionally substituted Ci-Ce haloalkyl, an optionally substituted Ci -C6 heteroalkyl, (CH2)HiR18, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-C8 ring;
R10 is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted C1-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci -CO heteroalkyl;
R11 is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or R1 1 and R4 are linked to form a optionally substituted heterocycle;
R12 is selected from hydrogen, halogen, CpC6 alkyl, Ci-C6 haloalkyl, Q- C6 heteroalkyl, and C]-C6 haloheteroalkyl;
R13 is selected from hydrogen, halogen, CN, NO2, CO2R14, S(O)mR14, C,- C4 alkyl, Ci-C4 haloalkyl, Ci-C4 heteroalkyl, and Ci-C4 haloheteroalkyl;
R14 is selected from hydrogen, C]-C6 alkyl, CrC6 haloalkyl, Ci-C6 heteroalkyl, and C]-C6 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, CpC6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
R16 and R17 are each independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, and (CH2)mR18; or one of R16 and R17 is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C3-Cs ring;
R18 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 R18 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;
R19 is selected from hydrogen, Cj-C3 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, NR4, CR3R4, CO, and null;
W is selected from O3 NR4, CR3R4, CO3 and null;
X is N or CR5;
Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted CI-CO alkyl, an optionally substituted Ci-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-C io aryl and an optionally substituted Cj -C8 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-C6 alkyl, an optionally substituted Ci-C6 heteroalkyl, and an optionally substituted CpC6 haloalkyl, each optionally fused with an optionally substituted Ce-Cio aryl; m is O3 1, 2, or 3; and n is 0 or 1; provided that, if X is N, W is NH, and Y is not -N=CR12- orientated to form a dihydropyrazole, and Z or R6 are not an optionally substituted nonaromatic ring fused with an optionally substituted aromatic ring; or if X is N, W is NH5 R6 is alkoxy, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, Y is -N=CR12- 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 NH5 and Y is -N=CR12- orientated to form a dihydropyrazole, then D is not a naphthyl; provided that, if U is NH; or if D and one of R10 and R11 form a 5- hydroxypyrazole, X is N, and W is NH; or if E and one of R10 and R11 form a 5- hydroxypyrazole and X is N, and W is NH; or if E is phenyl, one of R10 or R1 ' is — (CH2)o-6OH, X is C, W is NH, R6 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 R10 or R11 is -(CH2)O-6OH, X is N3 W is NH5 Z is null, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, and R6 is Cj-C6 alkyl, C]-Cg alkoxy, -(CH2)o-6θR20, an optionally substituted aryl, an optionally substituted heteroaryl., NR21R22 or a heterocyclic methylene substituent as represented by formula VII; or if D is phenyl, one of R10 or R11 is -(CH2VeOH, X is C, W is NH, Z is aromatic, and R6 is alkoxy, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; then Y is not -N=CR12- orientated to form a dihydropyrazole;
R20 is selected from hydrogen, a substituted alkyl, a substituted aryl, and a substituted heteroaryl;
R21 and R22 are each independently selected from hydrogen, alkyl, and aryl; or R21 and R22 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;
Figure imgf000019_0001
(VII) wherein A, B, C, and V are each independently selected from O, S, and NR20.
[0011] In certain embodiments, the invention provides a compound selected from:
3'-{[l-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l ,2-dihydroindol-3- ylidenemethyl]amino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 101); 2,4-Dihydroxybenzoic acid N'-{ l-[l-(3,5-dirnethylphenyl)-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-l-yl}benzoic acid (Compound 103);
3 - { 3-[(2-Hydroxy-3 ',5 ' -dimethylbiphenyl-3 -yl)hydrazono]-2-oxo-2,3 - dihydroindol-l-yl}benzoic acid (Compound 104);
3'-{[l-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l,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'-{[l-(3,4-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l,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-l-yl}benzoic acid (Compound 108);
3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-yl} benzoic acid (Compound 109);
3-{3-[(2-Hydroxy-3',5r-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-yl}benzoic acid methyl ester (Compound HO);
3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3- dihydroindol-l-yl}benzoic acid methyl ester (Compound 111);
3-{3-[(5-Fluoro-2-hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo- 2,3-dihydroindol-l-yl}benzoic acid (Compound 112);
3-{3-[l-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l,2-dihydroindol- 3-ylideneamino]-2-oxo-2,3-dihydrobenzooxazol-7-yI}benzoic acid (Compound 113);
3-{3-[(2-Hydroxy-5,3',4'-trimethylbiphenyl-3-yl)hydrazono]-2-oxo-253- dihydroindol-1-yl} benzoic acid (Compound 1 14);
3-Hydroxybenzoic acid 7V-{l-[l-(335-dimethylphenyl)-2-oxo-6- trifluoromethyl-l,2-dihydroindol-3-ylidene]ethyl}hydrazide (Compound 115); l-(3,5-Dimethylphenyl)-3-{l-[2-(4-hydroxyphenyl)-2-oxo- ethylamino]ethylidene}-6-tπfluoromethyl-l)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-l-yl}benzoic acid (Compound 117);
3 - { 3 - [(2-Hydroxy-3',4'-dimethy lbipheny 1-3 -yl)hydrazono] -2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-yl}benzoic acid (Compound 1 18);
3-{3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3- dihydroindol-1-yl} benzoic acid (Compound 1 19);
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-l-yl}butyric acid (Compound 121);
2-Chloro-3-(4-{[l-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-l,2- dihydroindol-3-ylidenemethyl]amino}-3-hydroxyphenyl)acrylic acid (Compound 122);
4-Hydroxybenzoic acid N-{ l-[l-(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-l-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-l-yl}benzoic acid (Compound 126);
4-Aminobenzoic acid ^-{ ^[ (S^-dimethylphenyO^-oxo-ό- trifluoromethyl-1 ,2-dihydroindol-3-ylidene]ethyl}hydrazide (Compound 127);
3-(7-{N'-[l-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l,2- dihydroindol-3 -ylidene]hydrazino} - 1 H-indol-3 -yl)propionic acid (Compound 128);
4-{3-[N'-(4-Methylbenzoyl)hydrazinoniethylidene]-2-oxo-2,3- dihydroindol-l-yl}benzoic acid (Compound 129;)
3-{2-Oxo-6-txifluoromethyl-3-[4-(3-trifluoromethylphenyl)-lH-pyrrol-2- ylmethylidene]-2,3-dihydroindol-l-yl}benzoic acid (Compound 130); 3-(7-{N'-[l-(3,4-Dimethylphenyl)-3-methyl-5-oxo-l,5-dihydropyrazol-4- ylidene]hydrazino}-lH-indol-3-yI)propionic acid (Compound 131);
3-(3-{[4-(3,4-Dimethy]phenyl)thiazol-2-ylamino]methyltdene}-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-yl)benzoic acid (Compound 132);
3-(3-{[4-(4-Methoxyphenyl)thiazol-2-ylamino]methylene}-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-yl)benzoic acid (Compound 133);
3 - {3 -[(2 -Hydroxy-3 ',5 '-dimethyl biphenyl-3-ylamino)methylene]-2 -oxo-6- trifluoromethyl-2,3-dihydroindol-l -yl}benzoic acid (Compound 134);
3-{3-[(4-(4-Methylphenyl)-2-thiazolylamino)methylene]-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-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 -Chlorobenzoylhydr azino)methy lidene] -2-oxo-6-trifluoromethy 1 - 2,3-dihydroindol-l-yl}berizoic acid (Compound 137);
3-{3-[(4-Methoxybenzoylhydrazino)methylidene]-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-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-Dimethy lphenyl)-3 -[ 1 -(2,4- dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 140); l-(3,4-DimethyIphenyl)-3-[l-(4-hydroxybenzoyIhydrazino)ethylidene]-2- oxo-2,3-dihydroindoIe (Compound 141);
1 -(3,4-Dimethylphenyl)-3-[(2,4- dihydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound H2);
1 -(3,5-Dimethylphenyl)-3-[l -(2,4- dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 143); l-(3,5-Dimethylρhenyl)-3-[l-(4-hydroxybenzoylhydrazino)ethylidene]-2- oxo-2,3-dihydroindole (Compound 144); l-(3,5-Dimethylphenyl)-3-[(2,4- dihydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 145); l-(335-Dimethylphenyl)-3-[(4-hydroxybenzoylhydrazino)methylidene]-2- oxo-2,3-dihydroindole (Compound 146);
3-(3-[l-(3,4-Dihydroxybenzoylhydrazino)ethylidene]-2-oxo-6-chloro-2,3- dihydroindol-l-yl)benzoic acid (Compound 147); l-(3,4-Dimethylphenyl)-3-[(4-hydroxybenzoylhydrazino)methylidene]-2- oxo-2,3-dihydroindole (Compound 148); l-(3,4-Dimethylphenyl)-3-[(3,5-diisoproρyl-2- hydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 149); l-(3,5-Dimethylphenyl)-3-[l-(3,4- dihydτoxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 150); l-(3,4-Dimethylphenyl)-3-[l -(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-l-yl)benzoic acid (Compound 152); l-(3,4-Dimethylphenyl)-3-[l-(2,5- dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 153); l-(3,4-Dimethylphenyl)-3-[l-(3-nitro-4- hydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 154); l-(3,4-Dimethylphenyl)-3-[l-(3-aminosulfonyl-4- chlorobenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 155); l-(334-DimethyIphenyl)-3-[l-(3-amino-4~ hydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 156); l-(3,4-Dimethylphenyl)-3-[l-(4-methoxy-2- hydroxybenzoylhydrazino)ethylidene]-2-oxo-2>3-dihydroindole (Compound 157);
3-{3-(l-(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-l-indolyl}benzoic acid (Compound 159); 3-{3-(l-(3,4-Dimethylphenyl)-2-oxo-2,3-dihydro-3- indolidene)methylamino-2-hydroxyphenyl} benzoic acid (Compound 160);
4-{l-(6-Fluoro-2-oxo-2,3-dihydro-3-(2-(3,5-dimethylphenyl)- aminocarbonylphenyl)aminomethylidene)indolyl}butanoic acid (Compound 161);
4-{l-(6-Chloro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl)- phenyl)aminomethylidene)indolyl}butanoic acid (Compound 162);
3-{l-(6-Chloro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl)- phenyl)aminomethylidene)indolyl}benzoic acid (Compound 163);
4-{l-(5-Fluoro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl)- phenyl)aminomethylidene)indolyl}butanoic acid (Compound 164);
3-{3-(l-(l-(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-Dϊmethylphenyl)-6-trifluoromethy l-2-oxo-2,3 -dihydro-3 - indolidene)ethylamino)-2-hydroxyphenyl}benzoic acid (Compound 166);
3-{l-(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(5-chloro-2-hydroxy-3- cyclohexylphenyl)hydrazono)indolyl} benzoic acid (Compound 167);
3-{l-(5-Fluoro-2-oxo-2,3-dihydro-3-(l -(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-l-(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-253-dihydro-l-(3,5-dimethylphenyl)-3- indolylidene)methylamino)indolyl}propanoic acid (Compound 172);
3-{3-(7-(6-Trifluoromethyl-2-oxo-2,3-dihydro-l-(3,4-dimethylphenyl)-3- indolylidene)methylamino)indolyl} propanoic acid (Compound 173);
4-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolylidcne)methylaminophenyl}butanoic acid (Compound 174); 2-Chloro-3-{3-hydroxy-4-(2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolylidene)methylarainophenyl } propenoic acid (Compound 175);
2-Chloro-3-{3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,4- dimethylphenyl)indolylidene)methylaminophenyl } propenoic acid (Compound 176);
2-Ethyl-3-{3-hydroxy-4-(6-trifluoromethyI-2-oxo-2,3-dihydro-l-(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-l-(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-{ l-(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2- hydroxypheny)aminomethylidene)pyrrolidinyl}butanoic acid (Compound 182);
(Z)-3-{l-(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2- hydroxypheny)aminomethylidene)pyrrolidinyl}benzoic acid (Compound 183);
(E)-3-{l-(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 -dimethylpheny l)-2~ hydroxypheny)hydrozono)thiazolidinyl}butanoic acid (Compound 185);
3-{2-(3-(l-(3.5-Dimethylphenyl)-6-chloro-2-oxo-2,3- dihydroindolidene)methylamino)phenylamino}benzoic acid (Compound 186);
3-{2-(3-(l-(355-Dimethylphenyl)-6-trifluorometriyl-2-oxo-2,3- dihydroindolidene)methylamino)phenylamino}benzoic acid (Compound 187);
3-{2-(4-(2-(355-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-l- (3,5-dimethylphenyl)indolylidene)methylamino)phenyl}pentanoic acid
(Compound 189);
(±)-3-{ l-(6-Chloro-2-oxo-2,3-dihydro-3-(3-(l-(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-253-dihydro-l- (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-l - (3 ,5 -dimethylphenyl)indolidene)methylamino)pyridinyl } benzoic acid (Compound 192);
3-{4-(3-Hydroxy-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(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-l-(3,5- dimethylphenyl)indolylidene)methy lamino)phenyl }benzoic acid (Compound 199);
3-{ l-(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-l-(334- dimethylphenyl)indolidene)methylamino)-l -pyrazolyl)acetic acid (Compound 202);
(3-(5-Fluoro-2-hydroxy-3-(3-(2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolidene)methylamino)-l -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-(l- 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-{ l-(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-l-(3,5- dimethylphenyl)indolidene)methylamino}benzoic acid (Compound 212);
2-Hydroxy-3-{3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolidene)methylamino} benzoic acid (Compound 213);
4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(3-methyl-l- 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-{l-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5- dimethylphenyl)phenyl)hydrazono)indolyl}acetic acid (Compound 219);
2-{l-(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-l-(3,4- dimethylphenyl)indolylidene)methylamino)thiazolyl} benzoic acid (Compound 221);
3-{ 1 -(5-Nitro-2"θxo-2,3-dihydro-3-(2-hydroxy-5-methyl-3-(l- 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.
[0012] In certain embodiments, the invention provides a compound selected from:
4-{2-(5-MethyI-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(l-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-pheny])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- phenylpheny I)-ethy I)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)pheny l)aminomethylidene)pyrazolyl } butanoic acid
(Compound 233);
4-{2-(5-Methyl-3-oxo-354-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(2)-(2-hydroxy-3-(2-(2,6- dimethyl-pheny l)ethyl)phenyl)aminornethylidene)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)pyrazoly I } 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)aminornethylidene)pyrazolyl } benzoic acid
(Compound 241);
3-{2-(5-Methyl-3-oxo-3ϊ4-dihydro-4(Z)-(2-hydroxy-3-(2-(2- methylphenyl)-ethyl)phenyl)aminomethylidene)pyrazolyl}benzoic acid
(Compound 242);
4-{2-(5-Methyl-3-oxo-2s3-dihydro-4(Z)-(2-hydroxy-3-(2-(2- fluorophenyl)-ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 243);
4-{2-(5-Methyl-3-oxo-253-dihydro-4-(2-hydroxy-3-(2-(3,4- dimethylphenyl)-ethyl)phenyl)hydrazono)pyrazolyl }butanoic acid (Compound 244);
4-{2-(5-Methyl-3-oxo-253-dihydro-4-(2-hydroxy-3-(2-(4-phenylphenyl)- ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 245);
4-{2-(5-Methyl-3-oxo-253-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-2J3-dihydro-4-(2-hydroxy-3-(2-(2s6- 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-methylpheny])ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid
(Compound 255);
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indanyI)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-(l- indanylmethyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 258);
(±)-3 - {2-(5-Methyl-3 -oxo-2,3 -dihydro-4-(2-hy droxy-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);
(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-dmydro-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)pyτazolyl} benzoic acid (Compound 272);
3-{l-(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-253-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-l- 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-chIoro-2-hydroxy-3- cyclohexylρhenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 291);
3-{2-(5-Methyl-3-oxo-2s3-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-MethyI-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);
(±)-3-{ 1 -(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(l ,2-dihydro-l - methyl-2-indolylphenyl)aminomethylideπe)indolyl}benzoic acid (Compound 303);
4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2- methylpheny lcarbonyl-amino)phenyl)hydrazono)pyrazolyl } butanoic acid
(Compound 304);
4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(5-chloro-2-hydroxy-3-(2- methylpheny 1 -carbonyl amino)pheny l)hy drazono)pyrazoly 1 } butanoic acid
(Compound 305);
3-{2-Hydroxy-3-(2-oxo-2,3-dϊhydro-l-(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-253-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-l-(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-l-(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}butεmoic acid (Compound 315);
3-{3-Hydroxy-2-(5-methyl-3-oxo-2,3-dihydro-2-(3,4-dimethylpher>yl)-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- diisopropylpheny l)-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-(253-dihydro-l- methyl-2-oxo-3-indolyl)methyl)phenyl)hydrazono)pyrazolyl}butanoic acid
(Compound 320); 3-{l-(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- dimethylpheny l)-ethyl)pheny l)hydrazono)ρyrazolyl } benzoic acid (Compound 322);
(±)-3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2,3-dihydro-l- methy l-2-oxo-3-indolyl)methyl)phenyl)hydrazono)pyrazoIyl } benzoic acid
(Compound 323);
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(l,2-dihydro-l-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-253-dihydro-4-(2-hydroxy~3- raethylphenyl)hydrazono)-pyrazolyl} benzoic acid (Compound 327);
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy~3-(l,2-dihydro-l-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-(256- 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)hy drazono)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)ρhenyl)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-23-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)ρhenyl)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-(l-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);
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-l-(2-(2- methylphenyl)-ethy l)-3 (Z)-indolylidene)methylaminophenyl } benzoic acid
(Compound 350);
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-6-trifluoromethyl-l-(2-indenyl)-3(Z)- indolylidene)methylaminophenyl}benzoic acid (Compound 351);
(±)4-{2-(5-MethyI-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(l,2,3,4- tetrahydro)-naphthyl)phenyl)hydrazono)pyτazolyl } 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)-(l-indanylidene)- methy]phenyl)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 35S); 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-MethyI-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)-(l-(l,2,3,4- tetrahydro)-naphthy lidene)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-MethyI-3-oxo-2s3-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-l-(2(E)-(2-methylphenyl)ethenyl)- 3(Z)-indolylidene)methylaminophenyl}benzoic acid (Compound 368);
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(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); 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-253-dihydro-4-(2-hydroxy-3(E)-(2-(4-fluoro-2- methy lphenyl)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)pyrazo IyI } 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)etheny l)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<256- 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)pyrazoly 1 } 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)pyrazo]yl}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-MethyI-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-253-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-253-dihydro-4-(2-hydroxy-3-(2-(3,4-dihydro-6- fluoro)-naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 396); 4-{2-(54v4ethyl-3-oxo-2,3-dihydro-4-(24iydroxy-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)-naphthy])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 I5 II, III, IV, V5 or VI is a TPO mimic.
[0014] 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 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.
[0018J 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
[0019] 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., electroporation, Hpofection). 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.
[0029] The term "selective TPO modulator" refers to a compound that selectively modulates at least one TPO activity. The term selective TPO modulator 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 01/21 180, both of which are incorporated herein by reference in their entirety.
[0030] 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.
[0033] 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.
[0034] 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.
[0036] 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. [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 "alkyl" 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 "Cj-C4 alkyl" or similar designations. By way of example only, "C1-C4 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.
[0041] The term "alkenyl" refers to an alkyl group comprising at least one carbon-carbon double bond.
[0042] The term "alkynyl" refers to an alkyl group comprising at least one carbon-carbon triple bond.
[0043] 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 limited to, CH3CC=O)CH2-, CH3CC=O)CH2CH2-, CH3CH2CC=O)CH2CH2-, CH3CC=O)CH2CH2CH2-, CH3OCH2CH2-, CH3NHCH2-, and the like.
[0045] The term "straight-chain alkoxy" refers to a group comprising the formula: -CCH2)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:
Figure imgf000048_0001
Figure imgf000049_0001
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 π-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 Ci-6 alkoxy, a Ci^ alkyl, a Ci-6 hydroxyalkyl, a Ci-6 aminoalkyl, a Ci_6 alkylamino, an alkylsulfenyl, an alkylsulfϊnyl, 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- halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3- methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4- trifluoromethoxypheny], 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4- morpholin-4-ylphenyl, 4-pyrrolidin-l-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.
[0054] 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 C3-8 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, Ci-6-alkyl, Ci-6- hydroxyalkyl, Ci^-aminoalkyl, Ci-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].6-alkyl, Ci-6-alkyl, hydroxy-C^-alkyl, and amino-Ci-6-alkyl.
[0055] The term "non-aromatic ring" refers to a group comprising a covalently closed ring that does not have a delocalized π-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 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.
10057] 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, 4/f-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-l,4-thiazine, 2/f-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidine, 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. [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, NHSO2R15, OC(S)NR10R11, SC(O)NR10R11, thiazolidinedione, oxazolidinedione, and l-oxa-2,4-dϊazolidine-355-dione. In certain embodiments, a carboxylic acid bioisoster comprises the following structure:
Figure imgf000052_0001
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:
Figure imgf000052_0002
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:
Figure imgf000052_0003
where A and B represent groups which are separated by the desired number of atoms.
[0065] Examples of 3 atom spacers include, but arc not limited to, the following:
Figure imgf000053_0001
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"
Figure imgf000053_0002
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:
Figure imgf000053_0003
, 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:
Figure imgf000054_0001
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:
Figure imgf000054_0002
and the like.
[0068] 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:
Figure imgf000054_0003
, 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:
Figure imgf000054_0004
, 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"
Figure imgf000054_0005
the resulting structure is:
Figure imgf000054_0006
[0070] The term "null" refers to a group being absent from a structure. For
RVR" 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.
[0071] The substituent "R" appearing by itself and without a number designation refers to a substituent selected from alkyl, cycloalkyl, aryl, heteroaryl (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)CH3.
[0075] The term "trihalomethanesulfonyl" refers to a group of formula X3CSC=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. [0079] The term "isothiocyanato" refers to a group of formula -NCS. [0080] The term "sulfonyl" refers to a group of formula -S(=O)-R. [0081] The term "S-sulfonamido" refers to a group of formula -S(=O)2NR. [0082] The term "N-sulfonamido" refers to a group of formula RS(=O)2NH-. [0083] The term "trihalomethanesulfonamido" refers to a group of formula
X3CS(=O)2NR-. [0084] 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-. [0088] The term "C-amido" refers to a group of formula -C(=O)-NR2. [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:
Figure imgf000055_0001
and wherein the two radicals may be at any positions on the ring. [0092] The term "pyrazolyl" refers to a radical of a pyrzole ring, wherein the pyrzole ring has the structure:
Figure imgf000055_0002
and wherein the radical may be at any position on the ring. [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(O)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, 3rd 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.
[0097] 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. [0099] 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.
[0102] 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. [0106] 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.
[0107] 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.
[0108] 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 [0111] Certain compounds that modulate one or more TPO activity and/or 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, IL III, IV, V, or VI:
Figure imgf000059_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
[0114] In certain embodiments, R1 is selected from hydrogen, halogen, OR14,
NO2, CN, NR14R15, an optionally substituted Cj-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted CrC6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere. In certain such embodiments, the carboxylic acid bioisostere is selected from tetrazole, NHSO2R19, OC(S)NR14R15, SC(O)NR14R15, and
Figure imgf000060_0001
wherein A, B, and C are each independently selected from O, S, and N.
[01151 In certain embodiments, each R2 is independently selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted C]-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl.
[0116] In certain embodiments, R3 and R4 are independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl.
[01171 In certain embodiments, R5 is selected from a group of hydrogen, halogen, OR14, Cj-C6 alkyl, Ci-C6 haloalkyl, C1-C6 heteroalkyl, and Ci-C6 haloheteroalkyl.
[0118] In certain embodiments, R6 is selected from an optionally substituted Ci-Cio alkyl, an optionally substituted C]-Ci0 haloalkyl, or an optionally substituted Q- CiQ heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R6 is (CH2)rnR18 or C(O)NHR18. In certain embodiments, R6 is selected from an optionally substituted Ci-Cio alkyl, an optionally substituted Ci-Cio haloalkyl, and an optionally substituted Ci-Cio heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R6 is selected from (CH2)mR18, C(O)NHR18, C≡CR18, CR3=CR4R18, and CR3=R18;
[0119] In certain embodiments, R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere. In certain such embodiments, the carboxylic bioisostere is selected from tetrazole, NHSO2R19, OC(S)NR14R15, SC(O)NR14R15, and
B
A
M O 5 wherein A, B, and C are each independently selected from O, S, and N.
[0120] In certain embodiments, each R8 and each R9 is independently selected from hydrogen, OR16, NR16R17, an optionally substituted Ci-C6 alky], an optionally substituted Ci-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, (CH2)mRl s, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-C8 ring. [0121] In certain embodiments, R10 is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci- C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl.
[0122] In certain embodiments, R1 ' is selected from hydrogen, halogen, OR14, NR14R15, and SR14. In certain embodiments, R1 1 and R4 are linked to form a optionally substituted heterocycle.
[0123] In certain embodiments, R12 is selected from hydrogen, halogen, CrC6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and C1-C6 haloheteroalkyl.
[0124] In certain embodiments, R13 is selected from hydrogen, halogen, CN, NO2, CO2R14, S(O)1nR14, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, and C1-C4 haloheteroalkyl.
[0125] In certain embodiments, R14 is selected from hydrogen, CpC6 alkyl, C]-Ce haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl.
[0126] In certain embodiments, R15 is selected from hydrogen, SO2R19, C1-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and C1-C6 heterohaloalkyl.
[0127] In certain embodiments, R16 and R17 are each independently selected from hydrogen, an optionally substituted Cj-C6 alkyl, an optionally substituted C]-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, and (CH2)mR18. In certain embodiments, one of R16 and R17 is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null. In certain embodiments, R16 and R17 are linked to form an optionally substituted C3-C8 ring.
[0128] In certain embodiments, R18 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.
[0129] In certain embodiments, R19 is selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, and an optionally substituted aryl.
[0130] 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.
[0131] 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. [0132] 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.
[0134] In certain embodiments, U is selected from O5 NR4, CR3R4, CO, and null.
[0135] In certain embodiments, W is selected from O, NR4, CR3R4, CO, and null.
[0136] In certain embodiments, X is N or CR5.
[0137] In certain embodiments, Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Ci-Ce alkyl, an optionally substituted Ci -Ce heteroalkyl, an optionally substituted phenyl, and an optionally substituted
heteroaryl. In certain embodiments, if Y is ■"" "R 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 CR W is NH5 Z is phenyl, and R10 or R1 1 is -(CH2)O-6OH3 (iii)
R11 — D-R10
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 C6-CI O aryl and an optionally substituted Ci-C8 heteroaryl, each optionally fused with an optionally substituted nonaromatic heterocycie or carbocycle, and a 1-5 atom spacer of selected from an optionally substituted Ci-Qs alkyl, an optionally substituted CrC6 heteroalkyl, and an optionally substituted Cj-C6 haloalkyl, each optionally fused with an optionally substituted Ce-C io aryl.
[0139] 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.
[0141] In certain embodiments, if X is N and W is NH in compounds of Formulas III or VI, then R6, R10, and R11 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 and, thus, may be the same or different from one another. For example, certain compounds of the invention comprise two or more R14 groups. The identities of those two or more R14 groups are each selected independently. Thus, in certain embodiments, those R14 groups are all the same as one another; in certain embodiments, those R14 groups are all different from one another; and in certain embodiments, some of those R14 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 I, II, III, 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, HI, 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-dihydroindoI-3 - ylidenemethyl]amino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 101);
2,4-Dihydroxybenzoic acid N'-{ l-[l-(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-l-yl}benzoic acid (Compound 103);
3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-253- dihydroindol-1-yl} benzoic acid (Compound 104);
3'-{[l-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l,2-dihydroindol-3- ylidenemethyl]amino}-4-fluoro-2'-hydroxybiphenyl-3-carboxylic acid
(Compound 105);
2-(3 '- { [ 1 -(3 ,5-DimethylphenyI)-2-oxo-6-trifluorornethyl- 1 ,2-dihydroindol - 3-ylidenemethyl]amino}-2'-hydroxybiphenyl-3-yl)-2-methylpropionic acid
(Compound 106);
3'-{ [l-(334-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l,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-l-yl}benzoic acid (Compound 108);
3 - { 3 - [(2-Hydroxy-3 ',5'-dimethylbiphenyl-3 -yl)hydrazono] -2-oxo-6- trifluororaethyl-2,3-dihydroindol-l-yl}benzoic acid (Compound 109);
3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6- trifluoromethyl-2,3-dihydroindoI-l-yl}benzoic acid methyl ester (Compound HO);
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-l-yl}benzoic acid (Compound 1 12);
3 - {3-[l -(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'-trimethy]biphenyl-3-yl)hydrazono]-2-oxo-2,3- dihydroindol-l-yl}benzoic acid (Compound 114);
3 -Hydroxy benzoic acid JV-{ l-[l-(3,5-dimethylphenyl)-2-oxo-6- trifluoromethyl-l,2-dihydroindol-3-ylidene]ethyl}hydrazide (Compound 1 15);
1 -(3,5-Dimethylphenyl)-3-{ 1 -[2-(4-hydroxyphenyl)-2-oxo- ethyIamino]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-l-yl}benzoic acid (Compound 1 17);
3-{3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6- trifIuoromethyl-2,3-dihydroindol-l-yl}benzoic acid (Compound 1 18);
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'-dimethylbiphenyI-3-ylamino)methylidene]-2-oxo- 2,3-dihydroindol-l-yl}benzoic acid (Compound 120);
4-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo- 2,3-dihydroindol-l-yl}butyric acid (Compound 121);
2-Chloro-3-(4-{ [1 -(335-dimethylphenyl)-2-oxo-6-trifluoromethyl-l ,2- dihydroindol-3-ylidenemethyl]amino}-3-hydroxyphenyI)acrylic acid (Compound 122); 4-Hydroxybenzoic acid Λ/1-{ l-[l-(3,5-dimethylpheny])-2-oxo-6- trifluoro methyl- 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-l-yl}benzoic acid (Compound 124);
3-{3-[(2-Hydroxy-3\5'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo- 2,3-dihydroindol-l-yl}benzoic acid (Compound 125);
3-{3-[(2-Hydroxy-5,3'55'-trimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3- dihydroindol-l-yl}benzoic acid (Compound 126);
4-Aminobenzoic acid iV-{l-[l-(3,5-dimethylphenyl)-2-oxo-6- trifluoromethyl-1 ,2-dihydroindol-3-ylidene]ethyl}hydrazide (Compound 127);
3-(7-{N'-[l-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l,2- dihydroindol-3-ylidene]hydrazino}-lH-indol-3-yl)propionic acid (Compound 128);
4- { 3 -[N'-(4-Methy lbenzoyl)hydrazinomethylidene]-2-oxo-2 ,3 - dihydroindol-1-yl} benzoic acid (Compound 129;)
3-{2-Oxo-6-trifluoromethyl-3-[4-(3-trifluoromethylphenyl)-lH-pyrrol-2- ylmethylidene]-2,3-dihydroindol-l-yl}benzoic acid (Compound 130);
3-(7-{N'-[l-(3,4-Dimethylphenyl)-3-methyl-5-oxo-l,5-dihydropyrazol-4- ylidene]hydrazino}-lH-indol-3-yl)propionic acid (Compound 131);
3-(3-{[4-(3,4-Dimethylphenyl)thiazol-2-ylamino]methylidene}-2-oxo-6- trifluoromethyl-2,3-dihydτoindol-l-yl)benzoic acid (Compound 132);
3-(3-{[4-(4-Methoxyphenyl)thiazol-2-ylamino]methylene}-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-yl)benzoic acid (Compound 133);
3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylene]-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-y]} benzoic acid (Compound 134);
3-{3-[(4-(4-Methylphenyl)-2-thiazolylamino)methylene]-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l -yl}benzoic acid (Compound 135);
3-{3-[(3,4-Dimethylbenzoylhydrazino)methylidene]-2-oxo-6- trifluoromethyl-2,3-dϊhydroindol-l-yl}benzoic acid (Compound 136);
3-{3-[(4-Chlorobenzoylhydrazino)methylidene]-2-oxo-6-trifluoromethyl- 2,3-dihydroindol-l-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-233- dihydroindol-1-yl} benzoic acid (Compound 139);
1 -(3,4-Dimethylphenyl)-3-[l -(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- dihydroxybenzoylhydrazϊno)methylidene]-2-oxo-2,3-dihydroindole (Compound 142);
1 -(3,5-Dimethylphenyl)-3-[l -(2,4- dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 143); l-(3,5-Dimethylphenyl)-3-[l-(4-hydroxybenzoylhydrazino)ethylideneJ-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)methy Iidenej-2- oxo-2,3-dihydroindole (Compound 146);
3-(3-[l-(3,4-Dihydroxybenzoylhydrazino)ethylidene]-2-oxo-6-chloro-2,3- dihydroindol-l-yl)benzoic acid (Compound 147); l-(3,4-Dimethylphenyl)-3-[(4-hydroxybenzoylhydrazino)methylidene]-2- oxo-2,3-dihydro indole (Compound 148); l-(3,4-Dimethylphenyl)-3-[(3,5-diisopropyl-2- hydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 149);
1 -(3,5-DimethylphenyI)-3-[ 1 -(3 ,4- dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 150); l-(3,4-Dimethylphenyl)-3-[l-(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-l-yl)benzoic acid (Compound 152); l-(3,4-Dimethylphenyl)-3-[l-(2,5- dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 153);
1 -(3 ,4-Dimethy lphenyl>3 -[ 1 -(3 -nitro-4- hydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 154);
1 -(3,4-Dimethylphenyl)-3-[l -(3-aminosulfonyI-4- chlorobenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydro indole (Compound 155); l-(3,4-DimethyIphenyl)-3-[l-(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-dihydroindoIe (Compound 157);
3-{3-(l-(3,5-Dimethylphenyl)-2-oxo-2,3-dihydro-3- indolidene)methylamino-2-hydroxyphenyI}benzoic acid (Compound 158);
3-{3-(3-(3,5-Dimethylphenyl)-2-hydroxyphenyl)aminomethylidene)-2- oxo-2,3-dihydro-l-indolyl} benzoic acid (Compound 159);
3 - { 3 -( 1 -(3 ,4-Dimethylpheny l)-2-oxo-2 ,3 -dihy dro-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-253-dihydro-3-(2-hydroxy-3 -(3 ,5-dimethylphenyl)- phenyl)aminomethylidene)indolyl}butanoic acid (Compound 162);
3-{ l-(6-Chloro-2-oxo-253-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl)- phenyl)aminomethylidene)indolyl}benzoic acid (Compound 163);
4-{ l-(5-FJuoro-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-trifluoromethy l-2-oxo-2,3-dihydro-3 - indoIiden.e)ethylamino)-2-hydroxyphenyl} benzoic acid (Compound 165);
3-{3-(l-(l-(354-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-3- indolidene)ethylamino)-2-hydroxyphenyl}benzoic acid (Compound 166);
3-{ l-(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(5-chIoro-2-hydroxy-3- cyclohexylphenyl)hydrazono)indolyl}benzoic acid (Compound 167); 3-{l-(5-Fluoro-2-oxo-2,3-dihydro-3-(l-(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-trifluoromethy l-2-oxo-233-dihydro- 1 -(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:i3-dihydro-l-(3;,5-dimethylphenyl)-3- indolylidene)methylamino)indolyl}propanoic acid (Compound 172);
3-{3-(7-(6-Trifluoromethyl-2-oxo-2,3-dihydro-l-(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-l-(3,5- dimethylphenyl)indolylidene)methylaminophenyl} propenoic acid (Compound 175);
2-Chloro-3-{3-hydroxy-4-(6-trifluoromethyI-2-oxo-2,3-dihydro- l-(3,4- dimethylphenyl)indolylidene)methylaminophenyl}propenoic acid (Compound 176);
2-Ethyl-3-{3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,4- dimethylphenyl)indolylidene)methylaminophenyl}propenoic acid (Compound 177);
2-Ethyl-3-{3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolylidene)methylaminophenyl } propenoic acid (Compound 178);
2-Ethyl-3-{3-hydroxy-4-(2-oxo-2,3-dihydro-l-(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-{l-(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-{l-(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-(l-(3,5-Dimethylphenyl)-6-chloro-2-oxo-2,3- dihydroindolidene)methylamino)phenylamino}benzoic acid (Compound 186);
3-{2-(3-(l-(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-334- dihydropyrazolidene)methylamino)phenylamino} benzoic acid (Compound 188);
(±)-3-Methyl-5-{2-hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l - (3,5-dimethylphenyl)indolylidene)methylamino)phenyl}pentanoic acid
(Compound 189);
(±)-3-{ l-(6-Chloro-2-oxo-2,3-dihydro-3-(3-(l-(3,5-dimethylphenyl)-2- oxo-2,3-dihydro)indolyl)aminomethylidene)indolyI} benzoic acid (Compound 190);
3-{4-(3-Hydroxy-6-methyl-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l- (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-l- (3,5-dimethylphenyl)indolidene)methylamino)pyridinyl}benzoic acid (Compound 192);
3-{4-(3-Hydroxy-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5- dimethy lphenyl)indolidene)methylamino)pyridiny 1 } benzoic acid (Compound 193);
3-{4-(3-Hydroxy-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolyl)hydrazono)pyridinyl} benzoic acid (Compound 194); 3-{5-(4-Hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(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-l-(3,5- dimethylphenyl)indolylidene)methylamino)ρhenyl } benzoic acid (Compound 199);
3-{ l-(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-l-(3,4- dimethylphenyl)indolidene)methylamino)-l -pyrazolyl)acetic acid (Compound 202);
(3-(5-Fluoro-2-hydroxy-3-(3-(2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolidene)methylamino)- 1 -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-(l- naphthyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 209);
3-{ 1 -(5-Nitro-2-oxo-2,3-dihydro-3-(2~hydroxy-3-(3,5- dimethy Ipheny l)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 21 1 );
2-Hydroxy-3-{3-(2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolidene)methylamino} benzoic acid (Compound 212);
2-Hydroxy-3-{3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l -(3,5- dimethylphenyl)indolidene)methylamino} benzoic acid (Compound 213);
4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(3-methyl-l- 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-{l-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2- methyl)phenyl)ethylphenyl)hydrazono)indolyl} butanoic acid (Compound 218);
2-{ l-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5- dimethy Ipheny l)phenyl)hydrazono)indo Iy 1} 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-l -(3,4- dimethylphenyl)indolylidene)methylamino)thiazolyl}benzoic acid (Compound 221); 3-{ l-(5-Nitro-2-oxo-2,3-dihydro-3-(2-hydroxy-5-methyl-3-(l- adamantane)phenyl)aminomethylidene)indolyl} benzoic acid (Compound 222);
3-{ 1 -(6-Trifluoromethyl-2-oxo-2,3-dihydro-3~(4-hydroxy-5-(3,4- dimethy lphenyl)pyridinyl)hydrazono)indo IyI } benzoic acid (Compound 223);
4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2-(2-raethyl)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-354-dihydro-4(Z)-(2-hydroxy-3-(2-(l-naphthyl)- ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 226);
4-{2-(5-Methyl-3-oxo-334-dihydro-4(Z)-(2-hydroxy-3-(2-(355- 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)ethy l)phenyl)amϊnomethylidene)pyrazolyl } butanoic acid
(Compound 230);
4-{2-(5-Methyl-3-oxo-3.4-dihydro-4(Z)-(2-hydroxy-3-(2-(4- ρhenylphenyl)-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-TrifluoromethyI-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- dimethy 1-pheny l)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- dimethy 1-pheny l)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- methy lphenyl)-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-hy droxy-3 -(2-(3 A- 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);
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)pyrazoly 1 } butanoi c 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-(l- indanylmethyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 258);
(±)-3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(l- indanylmethyl)phenyl)-hydrazoπo)pyrazolyl}benzoic acid (Compound 259);
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2- methylρhenyl)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)-elhyl)phenyl)hydrazoπo)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-MethyI-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-indanyI)phenyI)- hydrazono)pyrazolyl} benzoic acid (Compound 266);
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indenyl)phenyl)- hydrazono)pyτazolyl} 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-methyI-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- di methylphenyl)-(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-MethyI-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-Methy]-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-(355- 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);
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)indo IyI } propionic acid (Compound 299);
3-{l-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-benzylphenyl)hydrazono)- indolyl} benzoic acid (Compound 300);
3-{l-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2- methylphenyl)ethyl)phenyl)-hydrazono)indolyl}propionic acid (Compound 301);
3-{l-(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(3-(3- methylphenyl)propyl)-phenyl)aminomethylidene)indolyl}benzoic acid
(Compound 302); (±)-3-{l-(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(l,2-dihydro-l- methyl-2-indolylpheny l)aminomethylidene)indolyl } benzoic acid (Compound 303);
4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2- methylphenylcarbonyl-amino)phenyl)hydra2ono)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);
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(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-l-(3,5-dimethylphenyl)-3- indolylidene-hydrazino)-4-pyridyl} benzoic acid (Compound 310);
3-{ l-(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-2s3-dihydro-l-(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-dimethyIphenyI)-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- diisopropylph6nyl)-carbonylhydrazinomethylidene)pyrazolyl}butanoic acid
(Compound 318);
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(3,5- dimethylρhenyl)phenyl)-aminomethylidene)pyrazolyl}butanoic acid (Compound 319);
(±)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2,3-dihydro-l- methyl-2-oxo-3-indolyl)methyl)phenyl)hydrazono)pyrazolyl}butanoic acid
(Compound 320);
3-{l-(2-Oxo-2,3-dihydro-5-fluoro-3-(2-hydroxy-3-(2-(2- methylphenyl)ethyl)phenyl)-hydrazono)indolyl}proρionic 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-2J3-dihydro-4-(2-hydroxy-3-(253-dihydro-l- 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-(ls2-dihydro-l-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-253-dihydro-4-(2-hydroxy-3-(l ,2-dihydro-l-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)pyrazoly 1 } 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-hy droxy-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)pyrazoly 1 } 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- triffuoromethylphenyl)-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-pheny I)ethenyl)pheny l)hydrazono)pyrazolyl } butanoic acid
(Compound 344);
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- indeny l)phenyl)hydrazono)pyrazoly I } 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-trifluoromethy 1- 1 -(2-(2- methylphenyl)-ethyl)-3(Z)-indo Iy Ii dene)methylaminophenyl} benzoic acid
(Compound 350);
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-6-trifluoromethyI-l-(2-indenyl)-3(Z)- indolylidene)methylaminophenyl}benzoic acid (Compound 351);
(±)4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(l,2,3,4- tetrahydro)-naphthyl)pheny l)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)pyrazoly]} butanoic acid (Compound 353);
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(l-indanylidene)- methylphenyl)hydrazono)pyrazolyl}butanoic acid (Compound 354); 4-{2-(5-Methyl-3-oxo-253-dihydro-4-(2-hydroxy-3(E)-(2-(5-fluoro-2- trifluoromethylphenyl)ethenyl)pheny l)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- methylpheny l)ethenyl)phenyl)hydrazono)pyrazoly 1 } 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-dmydro-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)-etheny l)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)pyrazoly 1 } butanoic acid (Compound 363);
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(l -(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-2s3-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- isoχazolyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 367);
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(2(E)-(2-methylphenyl)ethenyl)- 3 (Z)-indolylidene)methylaminophenyl) benzoic acid (Compound 368);
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(2(E)-(2J4-difluorophenyl)ethenyl)- 3(Z)-indolylidene)methylaminophenyl}benzoic acid (Compound 369);
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(2-indenyi)-3(Z)- indolylidene)methyl-aminophenyl}benzoic acid (Compound 370);
3-{2-(5-Methyl-3-oxo-2,3-dmydro-4-(2-hydroxy-3(E)-(2-(5-fluoro-2- methylphenyl)ethenyl)phenyl)hy.drazono)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); 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}biutanoic 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-MethyI-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- fluoropheny l)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-f]uorophenyl)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- dichloroρhenyl)-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-fluoropheny l)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-Memyl-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-dmydro-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 racemϊc 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
Figure imgf000086_0001
[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
Figure imgf000087_0001
[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 jV-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
Figure imgf000088_0001
X = OEt, or N(CH3)2
Figure imgf000088_0002
[0149] The process of Scheme IH 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. UR" 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
Figure imgf000088_0003
[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 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
Figure imgf000089_0001
[0151] The process in Scheme V is a single synthetic step which reaction 14 with 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
Figure imgf000089_0002
Rx = R6 Or R7
[0152] 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
Figure imgf000090_0001
[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
,Λ-<
Figure imgf000091_0001
Q = R6 or -Z-R7 or V = OEt, or N(CH3J2 27 25 MeC(OEt)3 26
[0154] The process of Scheme VIII is a multi-step synthetic sequence that commences with enamine or enol ether formation of an iV-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
Figure imgf000092_0001
X1' X2, X3 = 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)rnethylarnine, 4-(2- hydroxyethyl)-morpholine, l-(2-hydroxyethyl)-pyrrolidine, ethanolamine and salts with 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 bϊs-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.
[0159] In certain embodiments, one or more carbon atoms of a compound of the present invention are replaced with silicon. See e.g., WO 03/037905 Al; 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
[0160] 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.
[0161] 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. 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.
[0165] 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.
[0166] 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 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 dimethyl sulfoxide 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.
[0169] 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 80™ , 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 80™; 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.
[0171] 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 acids, including but not 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. Jn 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 selective TPO modulator in a dose from about 1 μg/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 μg/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 μg/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.
[0176] 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. [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.
[0179] In certain embodiments, pharmaceutical agents are prepared for buccal administration. Certain of such pharmaceutical agents are tablets or lozenges formulated in conventional manner.
[0180] 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.
[0181] In certain embodiments, a pharmaceutical agent is prepared for transmucosal administration. In certain of such embodiments penetrants appropriate to 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.
[0183] 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 Eucerin™, available from Beiersdorf (Cincinnati, Ohio). Exemplary suitable cream bases include, but are not limited to, Nivea™ Cream, available from Beiersdorf (Cincinnati, Ohio), cold cream (USP), Purpose Cream™, available from Johnson & Johnson (New Brunswick, New Jersey), hydrophilic ointment (USP) and Lubriderm™, 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 at 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 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. [0186] 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 ED5O or ID50 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 lime, between 30-90% of the time, or between 50-90% of the time.
[0191] 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.
[0192] 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 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 J 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 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); antiinflammatory agents, including, but not limited to non-steroidal anti-inflammatory drugs (e.g., ibuprofen, COX-I 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. 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
Figure imgf000103_0001
3'-{[l-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l,2-dihydroindol-3(Z)- ylidenemethyl]amino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 101)
[0199] This compound was prepared as described in Scheme VIII. 1H NMR (500 MHz, DMSO-^6) 13.05 (s, IH), 11.35 (d, J = 13.3 Hz, IH), 9.40 (s, IH), 8.12 (t, J = 1.6 Hz5 IH), 7.97 (d, J = 7.9 Hz3 IH), 7.95 (ddd, J = 7.7,1.6, 1.3 Hz, IH), 7.81-7.78 (m, 2H), 7.60 (t, J= 7.7 Hz, IH), 7.44 (dq, J = 7.9, 0.9 Hz, IH), 7.14 (t, J = 7.8 Hz, IH), 7.12 (s, IH), 7.11 (m, 2H), 7.07 (dd, J= 7.8, 1.5 Hz, IH), 6.94 (q, J = 0.9 Hz, IH), 2.36(s, 6H). Example 2
Figure imgf000103_0002
2,4-Dihydroxybenzoic acid N'-{l-[l-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-l ,2- dihydroindol-3(2)-ylidene]ethyl}hydrazide (Compound 102)
[0200] This compound was prepared as described in Scheme VIII. 1H NMR (500 MHz3 CD3OD) δ 8.49 (s, IH)3 7.71 (m, IH), 7.67 (m, IH), 7.34 (m, IH), 7.16 (s, IH), 7.04 (s, 2H), 6.93 (s, IH), 6.39 (m, IH), 6.34 (s, IH), 2.64 (s, 3H), 2.41 (s, 6H). Example 3
Figure imgf000104_0001
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. 1H NMR (500MHz3 DMSO- d6) δ 13.29 (s, IH), 12.95 (s, IH)9 9.36 (s, IH)5 8.08 (t, J = 1.7 Hz, IH), 8.04 (ddd, J= 7.7, 1.7, 1.2 Hz, IH), 7.82 (m, 2H), 7.74 (t, J= 7.7 Hz, IH), 7.65 (d, J = 2.6 Hz, IH), 7.34 (m, IH), 7.33 (td, J= 7.6, 1.3 Hz, IH), 7.27 (dd, J= 8.0, 1.8 Hz, IH), 7.23 (d, J= 8.0 Hz, IH), 7.22 (td, J= 7.6, 0.9 Hz, IH), 6.94 (dm, J= 7.6 Hz, IH), 6.93 (d, J= 2.6 Hz, IH), 2.28 (s, 3H), 2.27 (s, 3H). Example 4
Figure imgf000104_0002
3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3-dihydroindol-l- yl}benzoic acid (Compound 104)
[0202] This compound was prepared as described in Scheme II. 1H NMR (500MHz, DMSO- d6\ 13.29 (s, IH), 13.04 (s, IH), 9.11 (s, IH), 8.08 (t, J = J = 1.8 Hz, IH), 8.04 (ddd, J = J = 7.7, 1.8, 1.2 Hz, IH), 7.83 (ddd, J = 7.7, 1.8, 1.2 Hz, IH), 7.75 (m, IH), 7.74 (t, J = 7.7 Hz, IH), 7.69 (dd, J = 7.7, 1.6 Hz, IH), 7.31 (td, J = 7.6, 1.3 Hz, IH)5 7.22 (td, J = 7.6, 0.9 Hz, IH), 7.15 (m, 2H), 7.06 (t, J = 7.7 Hz, IH), 7.00 (m, IH), 6.95 (m, IH), 6.94 (dd, J = 7.7, 1.6 Hz, IH), 2.33 (s, 6H). Example 5
Figure imgf000105_0001
S'-ftl-CS^-DimethylphenyO-l-oxo-β-trifluoromethyl-l^-dihydroindol-SCZ)- ylidenemethyl]amino}-4-fluoro-2'-hydroxybiphenyl-3-carboxylic acid (Compound 105)
[0203] This compound was prepared as described in Scheme VIII. 1H NMR (500 MHz, OMSO-d6) 513.35 (s, IH)5 1 1.34 (d, J = 13.3 Hz, IH), 9.41 (s, IH), 9.08 (d, J = 13.3 Hz, IH), 8.01 (dd, J - 7.2, 2.3 Hz, IH), 7.96 (d, J = 7.9 Hz, IH), 7.79 (dd, J = 7.9, 1.5 Hz, IH)5 7.78 (ddd, J = 8.4, 4.4, 2.3 Hz, IH), 7.44 (dq, J = 7.9, 0.9 Hz5 IH), 7.42 (dd, J = 10.6, 8.4 Hz, IH), 7.13 (t, J = 7.9 Hz5 IH)5 7.12 (m, IH)5 7.10 (m, 2H), 7.06 (dd, J = 7.9, 1.5 Hz, IH), 6.94 (m, IH), 2.36 (s, 6H). Example 6
Figure imgf000105_0002
2-(3 '- { [1 -(355-Dimethylphenyl)-2-oxo-6-trifluoromethyl- 1 ,2-dihydroindol-3 (Z)- ylidenemethyl] amino } -2 ' -hydroxybiphenyl-3 -yl)-2-methy lpropionic acid (Compound 106)
[0204] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-tftf) 512.39 (s, IH), 11.36 (d, J = 13.3 Hz, IH), 9.32 (s, IH)5 9.08 (d, J = 13.3 Hz, IH), 7.97 (d, J = 7.9 Hz, IH), 7.76 (dd, J = 7.9, 1.5 Hz5 IH), 7.54 (m, IH), 7.45-7.42 (m, 3H)5 7.35 (m5 IH)5 7.12 (t, J = 7.9 Hz5 IH)5 7.12 (m, IH)5 7.11 (m, 2H), 7.02 (dd, J = 7.9, 1.5 Hz5 IH), 6.95 (q, J = 0.8 Hz, IH), 2.37 (s, 6H), 1.52 (s, 6H). Example 7
Figure imgf000106_0001
3'-{ [1 -(3,4-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l ,2-dihydroindol-3(Z)- ylidenemethyl]amino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 107)
[0205] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-^) δ 13.03 (s, IH), 1 1.31 (d, J= 13.7 Hz, IH), 9.38 (s, IH), 9.06 (d, J = 13.7 Hz, IH), 8.09 (t, J= 1.5 Hz5 IH), 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, IH), 7.34 (d, J = 7.8 Hz, IH), 7.26 (d, J = 2.0 Hz, IH), 7.19 (dd, J = 7.8, 2.0 Hz, IH), 7.1 1 (t, J = 7.8 Hz, IH)5 7.04 (dd, J = 7.8, 1.5 Hz, IH), 6.90 (d, J= 1.5 Hz, IH)5 2.29 (s, 3H), 2.28 (s, 3H). Example 8
Figure imgf000106_0002
4-{3-[(2-Hydroxy-3',5'-dimethylbiphenyI-3-yl)hydrazono]-2-oxo-2,3-dihydroindol-l- yl}benzoic acid (Compound 108)
[0206] This compound was prepared as described in Scheme II. 1H NMR
(500MHz, DMSO- d6) δ 13.18 (s, IH), 13.05 (s, IH), 9.13 (s, IH), 8.14 (d, J = 8.5 Hz, 2H), 7.75 (m, IH), 7.70 (m, 2H), 7.69 (dd, J = 7.8, 1.6 Hz, IH), 7.32 (td, J = 7.6, 1.2 Hz, IH), 7.23 (td, J = 7.6, 0.7 Hz, IH), 7.15 (s, 2H), 7.06 (t, J = 7.8 Hz, IH), , 7.03 (m, IH), 7.00 (s, IH), 6.94 (dd, J = 7.8, 1.6 Hz, IH), 2.33 (s, 6H). Example 9
Figure imgf000107_0001
3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6-trifluoromethyl-2,3- dihydroindol-1-yl} benzoic acid (Compound 109)
[0207} This compound was prepared as described in Scheme II. 1H NMR
(500MHz5 DMSO- d6) 613.30 (s, IH), 13.20 (s, IH), 9.27 (s, IH), 8.11 (t, J = 1.8 Hz, IH), 8.07 (ddd, J = 7.8, 1.8, 1.2 Hz, IH), 7.94 (d, J = 7.9 Hz, IH), 7.86 (ddd5 J = 7.8, 1.8, 1.2 Hz, IH), 7.77 (t, J = 7.8 Hz, IH), 7.74 (dd, J = 7.8, 1.6 Hz, IH), 7.56 (dq, J = 7.9, 0.7 Hz, IH), 7.15 (m, 2H), 7.09 (t, J = 7.8 Hz, IH), 7.08 (m, IH), 7.01 (m, IH), 6.99 (dd, J = 7.8, 1.6 Hz, IH), 2.33 (s, 6H). Example 10
Figure imgf000107_0002
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)
[0208] This compound was prepared as described in Scheme II. 1H NMR
(500MHz, DMSO- d6) δ. 13.20 (s, IH), 9.27 (s, IH)3 8.15 (dd, J = 2.1, 1.6 Hz, IH), 8.10 (ddd, J = 7.9, 1.6, 1.1 Hz, IH), 7.94 (d, J = 7.9 Hz, IH), 7.90 (ddd, J = 7.9, 2.1, 1.1 Hz, IH), 7.80 (t, J = 7.9 Hz, IH), 7.74 (dd, J = 7.9, 1.6 Hz, IH), 7.57 (dq, J = 7.9, 0.8 Hz, IH), 7.15 (m, 2H), 7.09 (t, J = 7.9 Hz, IH), 7.08 (m, IH), 7.01 (m, IH), 7.00 (dd, J = 7.9, 1.6 Hz, IH), 3.90 (s, 3H), 2.33 (s, 6H). Example 11
Figure imgf000108_0001
3-{3-[(2-Hydroxy-3'35'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3-dihydroindol-l- yl}benzoic acid methyl ester (Compound 11 1)
[0209] This compound was prepared as described in Scheme II. 1H NMR
(500MHz, DMSO- d6) δ 13.04 (s, IH)5 9.11 (s, IH), 8.12 (m, IH), 8.06 (ddd, J = 7.8, 1.6, 1.2 Hz, IH), 7.87 (ddd, J = 7.8, 2.2, 1.2 Hz, IH), 7.77 (t, J = 7.8 Hz5 IH), 7.75 (m, IH), 7.69 (dd, J = 7.8, 1.6 Hz, IH), 7.31 (td, J = 7.6, 1.2 Hz, IH), 7.22 (td, J = 7.6, 0.9 Hz, IH)3 7.15 (m, 2H), 7.06 (t, J = 7.8 Hz, IH), 7.00 (m, IH), 6.95 (m, IH), 6.94 (dd, J = 7.8, 1.6 Hz, IH)3 3.90 (s, 3H)3 2.33 (s, 6H). Example 12
Figure imgf000108_0002
3-{3-[(5-Fluoro-2-hydroxy-3\5'-dimethylbiphenyI-3-yl)hydrazono]-2-oxo-2,3- dihydroindol-l-yl}benzoic acid (Compound 112)
[0210] This compound was prepared as described in Scheme II. 1H NMR
(500MHz,
Figure imgf000108_0003
δ 13.29 (s, IH), 12.97 (s, IH), 9.06 (s, IH)3 8.08 (m, IH), 8.04 (ddd, J= 7.8, 2.2, 1.1 Hz, IH), 7.83 (m, IH), 7.81 (d, J= 7.6 Hz, IH), 7.74 (t, J - 7.8 Hz, IH), 7.45 (dd, J= 9.5, 3.0 Hz, IH), 7.33 (t, J= 7.6 Hz, IH), 7.22 (t, J= 7.6 Hz, IH)3 7.19 (s, 2H)3 7.02 (s, IH), 6.94 (d, J= 1.6 Hz, IH)5 6.75 (dd, J= 9.5, 3.0 Hz, IH), 2.33 (s, 6H). Example 13
Figure imgf000108_0004
3-{3-[l-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l,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'-[l-(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 HCl. 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. 1H NMR (500 MHz, DMSO-^5) δ 13.25 (s, IH), 8.45 (dd, J = 2.0, 1.5 Hz, IH), 8.09 (ddd, J = 7.8, 2.0, 1.0 Hz, IH), 8.05 (ddd, J= 8.3, 1.5, 1.0 Hz, IH), 7.86 (d, J= 8.1 Hz, IH), 7.73 (dd, J = 7.8, 7.8 Hz, IH), 7.64 (dd, J = 8.0, 1.2 Hz, IH), 7.46 (m, 2H), 7.36 (dd, J = 7.8, 1.2 Hz, IH), 7.21 (s, 3H), 6.86 (d, J= 1.6 Hz, IH), 2.38 (s, 6H). Example 14
Figure imgf000109_0001
3-{3-[(2-Hydroxy-5,3',4'-trimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3- dihydroindol-l-yl}benzoic acid (Compound 114)
[0212] This compound was preapred as described as in Scheme II. 1H NMR
(500 MHz, DMSO-^) δ 13.28 (s, IH), 13.03 (s, IH), 8.81 (s, IH), 8.08 (dd, J= 1.5, 1.0 Hz, IH), 8.04 (ddd, J = 7.8, 1.5, 1.5 Hz, IH), 7.83 (ddd, J = 7.9, 2.2, 1.2 Hz, IH), 7.75 (m, 2H), 7.51 (d, J = 2.1 Hz, IH), 7.30 (m, 2H), 7.23 (m, 3H)5 6.94 (d, J = 7.9 Hz, IH), 6.76 (dd, J= 2.1, 0.7 Hz, IH), 2.34 (s, 3H), 2.27 (s, 3H), 2.26 (s, 3H). Example 15
Figure imgf000110_0001
3-Hydroxybenzoic acid Λ/'-{l-[l-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-l,2- dihydroindol-3(Z)-ylidene]ethyl}hydrazide (Compound 115)
[0213] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-^5) δ 1 1.76 (s, IH), 11.08 (s, IH), 9.84 (s, IH), 7.70 (d, J = 8.3 Hz, IH), 7.35 (m, 4H), 7.13 (s, IH), 7.07 (s, 2H), 7.02 (dt, J = 5.2, 3.7 Hz, IH), 6.92 (d, J = 1.5 Hz, IH), 2.58 (s, 3H), 2.36 (s, 6H).
Figure imgf000110_0002
l-(3,5-Dimethylphenyl)-3(2)-{l-[2-(4-hydroxyphenyl)-2-oxo-ethylamino]ethylidene}-6- trifluoromethyl-l,3-dihydroindol-2-one (Compound 116)
[0214] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, Methanol-^) δ 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, 1 H), 6.90 (d, J = 8.3 Hz, 2 H), 5.14 (S5 2 H), 2.67 (s, 3 H), 2.41 (s, 6 H). Example 17
Figure imgf000110_0003
3-{3-[(5-Fluoro-2-hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-yl}benzoic acid (Compound 117) [0215] This compound was prepared as described in Scheme II. 1H NMR (500MHz, DMSO- d6) δ 13.28 (s, IH), 13.09 (s, IH), 9.18 (s, IH)3 8.09 (d, J = 2 Hz, IH),
8.07 (m, IH), 8.0 (d, J = 7.8 Hz, IH), 7.87 (m, IH), 7.77 (t, J = 7.9 Hz, IH), 7.58 (d, J =
7.8 Hz, IH)5 7.52 (dd, J = 9.4, 3.1 Hz, IH), 7.19 (s, 2H), 7.07 (s, IH), 7.03 (s, IH), 6.82 (dd, J= 9.5 Hz, IH), 2.33 (s, 6H).
Example 18
Figure imgf000111_0001
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. 1H NMR
(500MHz, OMSO-d6) δ 13.28 (s, IH), 13.18 (s, IH), 9.23 (s, IH), 8.11 (t, J = 1.7 Hz, IH), 8.07 (dd, J = 7.6, 1.2 Hz, IH), 7.94 (d, J = 7.8 Hz, I H), 7.85 (m, IH), 7.78 (d, J = 8.1 Hz, IH), 7.73 (m, IH), 7.57 (t, J = 8.8 Hz, IH), 7.33 (s, IH), 7.24 (dd, J = 13.9, 4.9 Hz, 2H), 7.09 (m, IH), 6.99 (dd, J = 7.7, 1.6 Hz, IH)3 2.26 (s, 3H), 2.25 (s, 3H). Example 19
Figure imgf000111_0002
3-{3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3-dihydroindol-l- yl} benzoic acid (Compound 1 19)
[0217] This compound was prepared as described in Scheme II. 1H NMR
(500MHz, DMSO-dβ) δ 13.28 (s, IH), 13.04 (s, IH), 9.09 (s, IH), 8.08 (m, IH), 8.04 (dt, J = 7.8, 1.4 Hz, IH)3 7.83 (ddd, J = 8.0, 2.2, 1.2 Hz, IH), 7.74 (t, J = 7.7 Hz, 2H), 7.68 (dd, J = 7.8, 1.5 Hz3 IH), 7.31 (m, 2H), 7.23 (m, 3H), 7.06 (t, J = 7.9 Hz, IH), 6.94 (dt, J = 5.9, 3.9 Hz, 2H), 2.26 (s, 3H), 2.25 (s, 3H). Example 20
Figure imgf000112_0001
3-{3(2)-[(2-Hydroxy-3'>4'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo-2,3- dihydroindol-l-yl}benzoic acid (Compound 120)
[0218] This compound was prepared as described in Scheme III. 1H NMR
(500MHz, DMSO-flfe) δ 13.23 (s, IH)5 11.15 (d, J = 13.2 Hz, IH), 9.08 (s, IH), 8.88 (dd, J - 13.18 Hz, IH), 8.04 (m, IH), 7.99 (m, IH)5 7.81 (m, 2H), 7.70 (m, 2H), 7.33 (s, IH), 7.24 (m, 2H), 7.09 (m, 3H), 6.93 (m, 2H), 2.27 (s, 3H), 2.26 (s, 3H). Example 21
Figure imgf000112_0002
4-{3(Z)-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3-dihydroindol-l - yl}butyric acid (Compound 121)
[0219] This compound was prepared as described in Scheme III. 1H NMR
(500MHz, DMSO-flfe) δ 13.02 (s, IH), 12.14 (s, IH), 9.06 (s, IH), 7.63 (dd, J = 7.8, 1.5 Hz, 2H), 7.33 (td, J = 7.7, 1.1 Hz, IH), 7.21 (t, IH), 7.13 (m, 3H), 7.03 (t, J = 7.8 Hz, IH), 7.00 (S5 IH), 6.91 (m, IH), 3.85 (t, J = 6.8 Hz, 2H), 2.33 (m, 8H), 1.88 (t, J = 6.8 Hz, 2H). Example 22
Figure imgf000112_0003
2-Chloro-3-(4- { [ 1 -(3 ,5-dimethylphenyl)-2-oxo-6-trϊfluoromethyl- 1 ,2-dihydroindol-3 (Z)- ylidenemethyl]amino}-3-hydroxyphenyl)acrylic acid (Compound 122)
- I l l - [02201 This compound was prepared as described in Scheme VIII. 1H NMR (500 MHz, DMSO-^J) δ 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 Hz5 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
Figure imgf000113_0001
4-Hydroxybenzoic acid Λ"-{ l-[l-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-l,2- dihydroindol-3(Z)-ylidene]ethyl}hydrazide (Compound 123)
[0221] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-^6) 12.04 (s, IH), 10.92 (s, IH), 10.11 (s, IH), 7.82 (dt, J = 6.0, 4.8 Hz, 2H), 7.66 (d, J = 8.2 Hz, IH), 7.33 (d, J = 7.8 Hz, IH), 7.12 (s, IH), 7.06 (s, 2H), 6.91 (s, IH), 6.85 (d, J= 8.3 Hz, 2H), 2.60 (s, 3H), 2.36 (s, 6H). Example 24
Figure imgf000113_0002
3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-5-nitro-2-oxo-2,3- dihydroindol-1-yl} benzoic acid (Compound 124)
[0222} This compound was prepared as described in Scheme II. 1H NMR (500
MHz, DMSCW6) δ 13.29 (s, IH), 13.11 (s, IH), 9.29 (s, IH), 8.52 (d, J = 2.4 Hz5 IH), 8.20 (dd, J = 8.8, 2.4 Hz, IH), 8.10 (m, 2H), 7.84 (m, 2H), 7.78 (dd, J = 7.8, 7.8 Hz, IH), 7.15 (d, J = 0.9 Hz5 2H), 7.10 (m, 2H)5 7.01 (dd, J = 7.6, 1.6 Hz, 2H), 2.33 (s, 6H). Example 25
Figure imgf000114_0001
3 - { 3 (Z) - [(2 -Hydroxy-3 ' ,5 '-dimethy lbiphenyl-3 -y lamino)methyl idene] -2-oxo-2 ,3 - dihydroindol-1-yl} benzoic acid (Compound 125)
[0223] This compound was prepared as described in Scheme III. 1H NMR
(500MHz, DMSO-Ci6) & 13.2 (s, IH), 11.17 (d, J = 13.7 Hz5 IH), 9.11 (s, IH), 8.89 (d, J = 13.2 Hz, IH), 8.04 (t, J = 1.8 Hz, IH), 7.99 (m, IH), 7.80 (m, 2H)5 7.71 (m, 2H), 7.14 (m, 2H), 7.10 (m, 2H), 7.06 (m, IH)5 7.00 (s, IH), 6.94 (m, 2H), 2.32 (s, 6H). Example 26
Figure imgf000114_0002
3-{3-[(2-Hydroxy-5)3',5'-trirnethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3-dihydroindol-l- yl} benzoic acid (Compound 126)
[0224] This compound was prepared as described in Scheme II. 1H NMR (500
MHz5
Figure imgf000114_0003
J = 2.0 Hz, IH)5 7.26 (ddd, J = 7.8, 7.3, 1.0 Hz, IH), 7.19 (dd, J = 7.3, 7.3 Hz, IH)5 7.10 (s, 2H), 6.99 (s, IH)5 6.93 (d, J = 7.8 Hz, IH)5 6.74 (d, J= 2.0 Hz, IH), 2.36 (s, 3H), 2.35 (s, 6H). Example 27
Figure imgf000114_0004
4- Aminobenzoic acid JV- { 1 - [ 1 -(3 , 5-di methylphenyl)-2-oxo-6-trifluorornethy 1- 1 ,2- dihydroindol-3(Z)-yIidene]ethyl}hydrazide (Compound 127) [02251 This compound was prepared as described in Scheme VlTl. 1H NMR (500 MHz, DMSO-rf.) δ 11.83 (s, IH), 10.71 (s, IH), 7.67 (m, 3H)5 7.35 (d, J = 7.8 Hz, IH), 7.12 (S3 IH), 7.06 (s, 2H), 6.91 (s, 2H)5 6.60 (d, J = 8.8 Hz, 2H)5 5.84 (s, 2H), 2.57 (s, 3H), 2.36 (s, 6H). Example 28
Figure imgf000115_0001
3-(7-{Nl-[l-(355-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l,2-dihydroindol-3- ylidene]hydrazino}-lH-indol-3-yl)propionic acid (Compound 128)
[0226] This compound was prepared as described in Scheme II. 1H NMR
(500MHz, DMSCM5) δ 13.48 (s, IH)5 12.1 1 (s, IH)5 10.78 (s, IH), 8.39 (d, J = 8.3 Hz, IH)5 7.56 (d, J = 8.1 Hz, IH)5 7.39 (d, J - 7.8 Hz5 IH), 7.27 (d, J = 2.7 Hz, IH)5 7.18 (s, 2H), 7.11 (m, IH), 7.05 (t, J - 7.7 Hz, IH)5 7.00 (s, IH), 2.98 (t, J = 7.32 Hz5 2H)5 2.63 (t, J = 7.8Hz, 2H)5 2.37 (s, 6H). Example 29
Figure imgf000115_0002
4-{3(Z)-[Nt-(4-Methylbenzoyl)hydrazinomethylidene]-2-oxo-2,3-dihydroindol-l- yl}benzoic acid (Compound 129)
[0227] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz5 DMSO-J6) δ 13.8 (s, 1 H)5 8.17 (d, J= 8.3 Hz, 2 H)5 7.82 (d, J= 7.8 Hz, 2 H)5 7.78 (d, J = 7.8 Hz, 1 H)5 7.70 (J= 8.3 Hz5 2 H), 7.46 (dd, J= 7.8, 7.8 Hz, 1 H), 7.43 (d, J = 8.3 Hz, 2 H), 7.28 (dd, J= 7.8, 7.8 Hz, 1 H)5 7.00 (d, J= 7.8 Hz, 1 H), 2.40 (s, 3 H). Example 30
Figure imgf000116_0001
3-{2-Oxo-6-trifluoromethy]-3(Z)-[4-(3-trϊfluoromethylphenyl)-lH-pyrrol-2- ylmethylidene]-2,3-dihydroindol-l-yl}benzoic acid (Compound 130)
[0228] This compound was prepared as described in Scheme IV. 1H NMR
(500MHz, Acetone-tftf) δ 13.70 (s, IH), 8.27 (s, IH), 8.2 (d, J = 7.8Hz, IH)3 7.91 (m, 5H), 7.82 (m, 5H), 7.59 (s, IH), 7.47 (d, J = 7.8Hz, IH), 7.13 (s, IH), 6.74 (m, IH). Example 31
Figure imgf000116_0002
3 -(7- {N'-[ 1 -(3 ,4-Dimethy lpheny l)-3 -methyl-5-oxo- 1 ,5-dihydropyrazol-4- ylidene]hydrazino}-lH-indol-3-yl)propionic acid (Compound 131)
[0229] This compound was prepared as described in Scheme II. 1H NMR
(500MHz, DMSO- d6) δ 12.10 (s, IH), 10.62 (s, IH), 7.75 (s, IH)5 7.67 (d, J = 8.1 Hz, IH), 7.49 (d, J = 7.8 Hz, IH), 7.27 (d, J = 6.8 Hz, IH), 7.22 (d, J = 8.3 Hz, IH), 7.09 (t, J = 7.8 Hz5 IH), 2.97 (I, J = 7.4 Hz, IH), 2.62 (t, J = 7.8Hz, IH), 2.43 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H).
Example 32
Figure imgf000116_0003
3-(3(Z)-{[4-(3,4-Dimethylphenyl)thiazol-2-ylamino]methylidene}-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-yl)benzoic acid (Compound 132) [0230] This compound was prepared as described in Scheme III. 1H NMR (500 MHz3 acetone-^) δ 8.98 (s, IH), 8.24 (s, IH)5 8.16 (d, J- 7.8 Hz, IH), 7.99 (d, J = 7.8 Hz, IH)5 7.88 (d, J= 8.5 Hz, IH)3 7.79 (m, 2H), 7.74 (d, J = 7.8 Hz, IH)5 7.48 (s, I H)5 7.47 (d, J= 9.0 Hz, IH)5 7.21 (m, 2H), 2.33 (s, 3H)5 2.29 (s, 3H). Example 33
Figure imgf000117_0001
3-(3(Z)- { [4-(4-Methoxyphenyl)thiazol-2-ylamino]methylene} -2-oxo-6-trifluoroτnethyl- 2,3-dihydroindol-l-yl)benzoic acid (Compound 133)
[0231] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz, acetone-^) δ 8.98 (s, IH), 8.24 (s, IH), 8.16 (dt, J = 7.8, 1.2 Hz, IH), 8.00 (d, J = 8.1 Hz, IH), 7.96 (d, J = 9.3 Hz, 2H)5 7.88 (d, J = 7.8 Hz, IH), 7.79 (t, J = 7.8 Hz, IH), 7.46 (d, J= 7.3 Hz, IH)5 7.41 (s, IH), 7.19 (s, IH), 7.01 (d, J= 8.8 Hz5 2H)5 3.85 (s, 3H). Example 34
Figure imgf000117_0002
3-{3(Z)-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylainino)methylene]-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-yl} benzoic acid (Compound 134)
[0232] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz, DMSO-^6) δ 1 1.35 (d, J = 13.4 Hz, IH)5 9.24 (s, IH), 9.10 (d, J = 13.2 Hz5 IH)5 8.00 (m, 2H), 7.99 (d, J = 8.3 Hz, IH), 7.74 (m, 2H), 7.68 (t, J = 7.6 Hz, IH), 7.46 (d, J= 7.3 Hz, IH), 7.14 (s, 2H), 7.08 (t, J= 7.9 Hz, IH), 7.03 (s, IH)5 6.99 (m, 2H), 2.32 (s, 6H).
Example 35
Figure imgf000118_0001
3-{3(Z)-[(4-(4-Methylphenyl)-2-thiazolylamino)methylene]-2-oxo-6-trifluoromethyl-2,3- dihydroindol-1-yl} benzoic acid (Compound 135)
[0233] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz, DMSO-*) 13.25 (s, 2H), 11.81 (d, J = 12.1, IH), 11.41 (d, J= 13.0, IH), 8.96 Qi, J= 12.1, IH), 8.59 (d, J = 13.0, IH), 8.35 (m, IH), 8.1 1-8.00 (m, 5H), 7.93 (d, J = 8.2, 2H), 7.84 (d, J = 8.2, 2H), 7.84 (m, IH), 7.81-7.72 (m, 3H), 7.67 (m, IH), 7.65 (s, IH), 7.55 (m, IH)5 7.47 (dq, J = 7.9, 0.7, IH), 7.27 (d, J = 8.1 , 4H), 7.04 (s, IH), 6.98 (s, IH), 2.35 (s, 3H), 2.34 (s, 3H). Example 36
Figure imgf000118_0002
3 - {3 (Z)-[(3 ,4-Dimethylbenzoylhydrazino)methylidene]-2-oxo-6-trifluoromethyl-2,3 - dihydroindol-l-yl}benzoic acid (Compound 136)
[0234] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz, OMSO-Ci6) 13.24 (br s, IH), 1 1.30 (d, J = 13.0, IH), 10.28 (d, J = 13.0, IH), 8.42 (br s, IH), 8.10-7.96 (m5 2H)5 7.82-7.64 (m, 4H), 7.38 (d, J = 8.1, IH), 7.31 (d, J = 7.6, IH), 7.01 (s, IH)5 6.95 (br s, IH), 2.31 (s, 6H~). Example 37
Figure imgf000119_0001
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. 1H NMR
(500 MHz, DMSO-ύk) 15.42 (s, IH), 13.24 (s, IH), 1 1.47 (s, IH), 8.43 (s, IH), 8.10-7.89 (m, 4H)5 7.84-7.70 (m, 3H), 7.65 (d, J = 8.4, 2H), 7.38 (d, J = 7.7, IH), 7.01 (s, 1 H). Example 38
Figure imgf000119_0002
3 - { 3 (Z)- [(4-Methoxybenzoylhy drazino)methy 1 idene] -2-oxo-6-trifluoromethy 1-2 ,3 - dihydroindol-l-yl}benzoic acid (Compound 138)
[0236] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz, DMSO-^15) 1 1.32 (s, IH), 11.30 (d, J = 12.2, IH), 10.27 (d, J = 12.2, IH), 8.43 (s, IH), 8.11-7.65 (m, 7H), 7.38 (d, J = 8.1 , IH), 7.09 (d, J = 8.5, 2H), 7.01 (s, IH), 3.85 (s, 3H). Example 39
Figure imgf000119_0003
3-{3(Z)-[(3,4-Dimethylbenzoylhydrazino)methylidene]-2-oxo-6-chloro-2,3-dihydroindol- l-yl}benzoic acid (Compound 139) [0237] This compound was prepared as described in Scheme III. 1H NMR (500 MHz, DMSO-fik) 13.22 (s, IH), 11.20 (br, 2H), 8.25 (s, IH), 8.05-7.93 (m, 4H), 7.88 (m, IH), 7.78 (m, IH), 7.74-7.69 (m, 5H), 7.68-7.64 (m, 3H), 7.60 (m, 2H), 7.54 (s, IH), 7.32-7.29 (m, 2H)5 7.14 (m, IH), 7.07 (dd, J = 8.2, 1.9, IH), 6.83 (d, J = 1.9, IH), 6.78 (m, IH), 2.30 (s, 12H). Example 40
Figure imgf000120_0001
l-(3,4-Dimethylphenyl)-3(Z)-[l-(254-dϊhydroxybenzoylhydrazino)ethylidene]-2-oxo-2!,3- dihydroindole (Compound 140)
[0238] This compound was prepared as described in Scheme VIII. 1H NMR
(300 MHz, DMSO-^6) 1 1.76 (s, IH), 11.43 (s, IH), 10.73 (s, IH), 10.25 (s, IH), 7.73 (d, J = 8.6, IH), 7.51 (m, IH), 7.32 (d, J = 8.1, IH), 7.21 (d, J = 2.0, IH), 7.14 (dd, J = 8.1 , 2.0, IH), 7.07-6.99 (m, 2H)3 6.79 (m, IH), 6.38 (dd, J = 8.6, 2.4, IH), 6.34 (d, J = 2.4, IH), 2.47 (S3 3H), 2.30 (s, 3H), 2.29 (s, 3H). Example 41
Figure imgf000120_0002
l-(3,4-Dimethylphenyl)-3(2)-[l-(4-hydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3- dihydroindole (Compound 141)
[0239] This compound was prepared as described in Scheme VIII. 1H NMR
(300 MHz, DMSO-έfc) 1 1.44 (s, IH), 10.75 (s, IH), 10.21 (s, IH), 7.81 (d, J = 8.8, 2H), 7.51 (m, IH), 7.32 (d, J = 8.2, IH), 7.21 (d, J = 2.0, IH), 7.14 (dd, J = 8.2, 2.0, IH), 7.07-6.99 (m, 2H), 6.88 (d, J = 8.8, 2H)5 6.79 (m, IH), 2.47 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H). Example 42
Figure imgf000121_0001
l-(334-Dimethylphenyl)-3(2)-[(2,4-dihydroxybenzoylhydrazino)methylidene]-2-oxo-2,3- dihydroindole (Compound 142)
[0240] This compound was prepared as described in Scheme VIII. 1H NMR
(300 MHz, DMSO-J(j) 12.04 (s, IH), 11.94 (s, IH)5 1 1.02 (s, IH), 10.28 (s, IH), 10.25 (s, IH), 9.64 (d, J = 1 1.5, IH), 8.11 (s, IH), 7.80 (m, IH), 7.76-7.70 (m, 2H), 7.58 (d, J = 10.4, IH)5 7.55-7.50 (m, 2H), 7.42 (d, J = 1 1.5, IH)5 7.34-7.27 (m, 2H), 7.23 (d, J = 1.6, IH), 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
Figure imgf000121_0002
l-(3,5-Dimethylphenyl)-3(2)-[l-(2,4-dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3- dihydroindole (Compound 143)
[0241] This compound was prepared as described in Scheme VIII. 1H NMR
(300 MHz, OMSO-d6) 1 1.77 (s, IH), 11.44 (s, IH), 10.73 (s, IH), 10.26 (s, IH), 7.73 (d, J = 8.8, IH), 7.51 (m, IH), 7.09-7.01 (m, 5H), 6.82 (m, IH), 6.38 (dd, J = 8.8, 2.3, IH), 6.34 (d, J = 2.3, IH), 2.47 (s, 3H), 2.35 (s, 6H). Example 44
Figure imgf000122_0001
1 -(3 ,5 -Dimethylpheny I)- 3 (Z)- [ 1 -(4-hy droxybenzoylhy drazino)ethy 1 idene] -2-oxo-2 ,3 - dihydroindole (Compound 144)
[0242] This compound was prepared as described in Scheme VIII. 1H NMR
(300 MHz, DMSO-ctø 1 1.45 (s, IH), 10.76 (s, IH), 10.22 (s, IH), 7.81 (d, J = 8.8, 2H), 7.51 (m, IH), 7.09-6.97 (m, 5H), 6.88 (d, J= 8.8, 2H)5 6.82 (m, IH), 2.48 (s, 3H)5 2.35 (s, 6H). Example 45
Figure imgf000122_0002
l-(3,5-DϊmethyIphenyl)-3(2)-[(2,4-dihydroxybenzoylhydrazino)methylidene]-2-oxo-2,3- dihydroindole (Compound 145)
[0243] This compound was prepared as described in Scheme VIII. 1H NMR
(300 MHz, DMSO-^6) 11.98 (m, 2H), 11.02 (s, 2H), 10.28 (s, IH), 10.26 (s, IH), 9.65 (d, J = 11.6, IH), 8.12 (s, IH), 7.80 (m, IH), 7.77-7.70 (m, 2H), 7.56-7.50 (m, 2H), 7.42 (d, J = 11.6, IH), 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
Figure imgf000123_0001
l-(3,5-Dimethylphenyl)-3(Z)-[(4-hydroxybenzoylhydrazino)methylidene]-2-oxo-2,3- dihydroindole (Compound 146)
[0244] This compound was prepared as described in Scheme VIII. 1H NMR
(300 MHz, DMSO-rftf) 11.00 (s, 2H), 10.20 (s, IH), 10.19 (s, IH), 9.65 (m, IH), 8.10 (s, IH), 7.84-7.74 (m, 5H), 7.54 (m, IH), 7.40 (d, J = 10.3, IH), 7.10-6.95 (m, 10H), 6.91- 6.84 (m, 4H), 6.78 (m, IH), 3.18 (s, IH), 3.16 (s, IH), 2.35 (s, 6H), 2.33 (s, 6H). Example 47
Figure imgf000123_0002
3-(3(Z)-[I -(3,4-Dihydroxybenzoylhydrazino)ethylidene]-2-oxo-6-chloro-2,3- dihydroindol- 1 -yl)benzoic acid (Compound 147)
[0245] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz, DMSO-d«j) H -55 (s, IH), 8.02 (dt, J = 7.6, 1.5, IH), 7.98 (t, J = 1.5, IH), 7.78-7.65 (m, 4H), 7.53 (d, J = 8.2, IH), 7.30 (d, J = 8.2, IH), 7.10 (dd, J = 8.2, 2.0, IH), 6.84 (d, J = 2.0, IH), 2.52 (s, 3H), 2.30 (s, 6H). Example 48
Figure imgf000123_0003
l-CS^-DimethylphenyO-SCZJ-^-hydroxybenzoylhydrazino^ethylideneJ^-oxo^^- dihydroindole (Compound 148)
[0246] This compound was prepared as described in Scheme VIII. 1H NMR (500 MHz, DMSO-Gf6) 10.99 (s, 2H), 10.19 (s, IH), 10.18 (s, IH), 9.64 (d, J = 12.0, IH), 8.09 (s, IH), 7.83-7.74 (m, 5H)5 7.54 (m, IH), 7.40 (m, IH), 7.31 (d, J = 8.0, IH)5 7.29 (d, J = 8.0, IH)5 7.23 (m5 IH)3 7.18-7.14 (m, 2H), 7.10 (dd, J = 8.0, 2.0, IH), 7.07-7.02 (m, 2H), 7.00-6.97 (m, 3H), 6.89-6.84 (m, 4H), 6.77 (m, IH), 6.73 (m, IH), 2.30 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H), 2.27 (s, 3H). Example 49
Figure imgf000124_0001
l-(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. 1H NMR
(500 MHz, DMSO-^6) 12.29 (s, IH), 12.22 (s, IH)5 11.52 (s, 2H)5 9.71 (d, J = 10.6, IH), 8.14 (s, IH), 7.82 (m, IH)5 7.68-7.58 (m, 2H), 7.54-7.48 (m, 2H), 7.34-7.23 (m, 5H), 7.19-7.16 (m, 2H), 7.13-6.96 (m, 5H), 6.78 (m, IH), 6.74 (m, IH), 3.27 (m, 2H)5 2.86 (m, 2H)3 2.31 (S3 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
Figure imgf000124_0002
l-(3,5-Dimethylphenyl)-3(Z)-[l-(3,4-dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3- dihydroindole (Compound 150) [0248] This compound was prepared as described in Scheme VIII. 1H NMR (500 MHz, DMSO-£k) 1 1.47 (s, IH), 7.51 (m, IH), 7.35 (d, J - 1.5, IH), 7.30 (dd, J = 8.3, 1.5, IH)3 7.10-7.01 (m, 5H), 6.86-6.80 (m, 2H), 2.47 (s, 3H), 2.35 (s, 6H). Example 51
Figure imgf000125_0001
l-(3,4-Dimethylphenyl)-3(Z)-[l-(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, OMSO-Cl6) 1 1.47 (br s, IH), 10.68 (br s, IH), 9.70 (br s, IH), 9.31 (br s, IH), 7.50 (m, IH), 7.36-7.27 (m, 3H), 7.21 (s, IH), 7.14 (m, IH), 7.06-6.99 (m, 2H), 6.83 (m, IH), 6.79 (m, IH), 2.47 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H). Example 52
Figure imgf000125_0002
3-(6-Chloro-3(2)-[(2-hydroxy-3,5-diisopropylbenzoylhydrazino)methylidene]-2-oxo-2,3- dihydroindol-l-yl)benzoic acid (Compound 152)
[0250] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz, DMSO-^) 13.22 (s, 2H), 12.25 (s, IH), 12.16 (s, IH), 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, IH), 6.79 (d, J = 1.6, IH), 3.26 (m, 2H), 2.86 (m, 2H), 1.23 (d, J = 6.3, 6H)5 1.22 (d, J = 6.3, 6H), 1.20 (d, J = 6.8, 6H)3 1.19 (d, J = 6.8, 6H). Example 53
Figure imgf000126_0001
l-(3,4-Dimethylphenyl)-3(Z)-[l-(2,5-dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3- dihydroindole (Compound 153)
[0251] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-ύk) 11.49 (s, IH), 10.77 (s, IH), 10.72 (s, IH), 9.14 (s, IH), 7.51 (m, IH), 7.32 (d, J = 8.0, IH), 7.23 (d, J = 3.0, IH), 7.21 (d, J = 2.0, IH), 7.14 (dd, J = 8.0, 2.0, IH), 7.06-7.00 (m, 2H), 6.89 (dd, J = 8.8, 3.0, IH), 6.83 (d, J = 8.8, IH), 6.79 (m, IH), 2.48 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H). Example 54
Figure imgf000126_0002
l-(3,4-Dimethylphenyl)-3(Z)-[l-(3-nitro-4-hydroxybenzoylhydrazino)ethylideneJ-2-oxo- 2,3-dihydroindole (Compound 154)
[0252] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, OMSO-d6) 11.30 (s, IH)3 9.84 (s, IH), 8.36 (d, J = 2.3, IH), 7.98 (dd, J = 8.7, 2.3, IH), 7.42 (ddd, J = 7.7, 1.2, 0.5, IH), 7.29 (d, J = 7.9, IH), 7.16 (d, J = 8.7, IH), 7.16 (d, J = 2.1, IH), 7.10 (dd, J = 7.9, 2.1, IH), 6.96 (td, J = 7.7, 1.2, IH), 6.90 (td, J = 7.7, 1.2, IH), 6.76 (ddd, J = 7.7, 1.2, 0.5, IH), 5.05 (br s, IH), 2.60 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H). Example 55
Figure imgf000127_0001
l-(3,4-Dimethylphenyl)-3(Z-[l-(3-aminosulfonyl-4-chlorobenzoylhydrazino)ethylidene]- 2-oxo-2,3-dihydroindole (Compound 155)
[0253] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz3 DMSO-J5) 1 1-48 (s, IH), 11.29 (s, IH)5 8.52 (d, J = 2.2, IH)5 8.13 (dd, J = 8.3, 2.2, IH), 7.86 (d, J = 8.3, IH), 7.79 (s, 2H), 7.52 (m, IH), 7.32 (d, J = 8.0, IH), 7.22 (d, J = 2.2, IH), 7.15 (dd, J = 8.0, 2.2, IH), 7.07-7.01 (m, 2H), 6.79 (m, IH), 2.50 (m, 3H), 2.30 (s, 3H), 2.29 (s, 3H). Example 56
Figure imgf000127_0002
l-(3,4-Dimethylphenyl)-3(2)-[l-(3-amino-4-hydroxybenzoylhydrazino)ethylidene]-2- oxo-2,3-dihydroindole (Compound 156)
[0254] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-4?) 7.54-7.42 (m, 3H), 7.31 (m, IH), 7.17 (s, IH), 7.11 (m, IH), 7.08- 7.00 (m, 2H), 6.88 (br s, IH), 6.78 (m, IH), 4.61 (br s, IH), 3.91 (s, 2H)3 2.53 (s, 3H), 2.34 (s, 3H), 2.33 (s, 3H). Example 57
Figure imgf000128_0001
l-(3,4-Dimethylphenyl)-3(Z)-[l-(4-methoxy-2-hydroxybenzoylhydra2ino)ethylidene]-2- oxo-2,3-dihydroindole (Compound 157)
[0255] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSCMJ) 11.91 (s, IH), 11.44 (s, IH), 10.83 (s, IH), 7.83 (d, J = 8.8, IH), 7.51 (m, IH), 7.32 (d, J = 8.0, IH)5 7.21 (d, J = 1.9, IH), 7.14 (dd, J = 8.0, 1.9, IH), 7.06-7.00 (m, 2H), 6.79 (m, IH)5 6.57 (dd, J = 8.8, 2.4, IH), 6.51 (d, J = 2.4, IH), 3.80 (s, 3H), 2.48 (s, 3H), 2.30 (s, 3H), 2.29 (s, 3H). Example 58
Figure imgf000128_0002
3-(3(Z)-(I -(3,5-Dimethylphenyl)-2-oxo-2,3-dihydro-3-indolidene)methylamino-2- hydroxyphenyl) benzoic acid (Compound 158)
[0256] This compound was prepared as described in Scheme VIIL 1H NMR
(500 MHz, DMSO-^) 11.16 (d, J = 13.0, IH)5 9.26 (s, IH), 8.84 (d, J = 13.0, IH), 8.12 (t, ./ = 1.7, IH), 7.94 (ddd, J = 7.7, 1.7, 1.2, IH), 7.81-7.72 (m, 3H), 7.60 (t, J = 7.7, IH)5 7.13-7.05 (m, 6H)5 7.01 (dd, J = 7.7, 1.5, IH), 6.85 (m, IH), 2.35 (s, 6H). Example 59
Figure imgf000129_0001
3-{3(Z)-(3-(3,5-Dimethylphenyl)-2-hydroxyphenyl)aminomethylidene)-2-oxo-2,3- dihydro-1 -indolyl}benzoic acid (Compound 159)
[0257] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz, OMSO-d6) 1 1.20 (d, J = 13.1, IH), 9.17 (br s, IH), 8.95 (d, J = 13.1, IH), 8.02 (s, IH), 7.97 (d, J = 7.7, IH), 7.76-1.66 (m, 4H), 7.14 (s, 2H), 7.07 (t, J = 7.7, IH), 7.00 (s, IH), 6.97 (d, J = 7.7, IH), 6.90-6.86 (m, 2H)5 2.32 (s, 6H). Example 60
Figure imgf000129_0002
3-{3(Z)-(l-(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. 1H NMR
(500 MHz, OMSO-d6) 13.03 (s, IH), 11.14 (d, J = 13.0, IH)3 9.25 (s, IH), 8.83 (d, J = 13.0, IH), 8.1 1 Ct, J = 1.7, IH), 7.94 (ddd, J = 7.7, 1.7, 1.1, IH), 7.80-7.75 (m, 2H), 7.73 (dd, J = 7.8, 1.5, IH), 7.59 (t, J = 7.7, IH), 7.32 (d, J = 8.0, IH), 7.25 (d, J = 2.1, IH), 7.18 (dd, J = 8.0, 2.1, IH), 7.10 (t, J = 7.8, IH), 7.07-7.03 (m, 2H), 7.00 (dd, J = 7.8, 1.5, IH), 6.81 (m, IH), 2.30 (s, 3H), 2.30 (s, 3H). Example 61
Figure imgf000129_0003
4-{ l-(6-Fluoro-2-oxo-2,3-dihydro-3(Z)-(2-(3,5-dimethylphenyl)- aminocarbonylphenyl)aminomethylidene)indolyl}butanoic acid (Compound 161)
[0259] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz, DMSO-flfc) 12.11 (s, IH), 12.00 (d, J = 12.8, IH), 10.32 (s, IH), 8.67 (d, J = 12.8, IH)5 7.84 (d, J = 8.2, IH), 7.80 (dd, J = 7.9, 1.5, IH), 7.63 (m, IH), 7.60 (dd, J = 9.3, 2.6, IH), 7.35 (s, 2H), 7.23 (m, IH), 7.01 (dd, J = 8.5, 4.3, IH), 6.91 (ddd, J = 9.5, 8.5, 2.6, IH), 6.79 (s, IH), 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
Figure imgf000130_0001
4-{l-(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(3,5-dimethylphenyl)- phenyl)aminomethylidene)indolyl}butanoic acid (Compound 162)
[0260] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz, DMSO-rfs) 11.25 {ά, J = 12.9, IH), 10.68 (s, IH), 8.65 (d, J = 12.9, IH), 8.05 (s, IH), 7.60 (d, J = 8.0, IH), 7.57 (dd, J = 7.9, 1.3, IH), 7.16 (d, J = 1.8, IH), 7.1 1 (m, 2H), 7.02 (dd, J = 7.9, 7.7, IH), 7.02 (m, IH), 7.00 (dd, J = 8.0, 1.8, IH), 6.94 (dd, J = 7.7, 1.3, IH), 3.94 (t, J = 7.2, 2H), 2.43 (t, J = 7.2, 2H)5 2.35 (m, 6H), 2.01 (qn, J = 7.2, 2H). Example 63
Figure imgf000130_0002
3-{l-(6-Chloro-2-oxo-2,3-dihydro-3(2)-(2-hydroxy-3-(3,5-dimethylphenyl)- phenyl)arninomethylidene)indolyl}benzoic acid (Compound 163)
[0261] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz, OMSOd6) 13.25 (s, IH)5 11.17 (d, J = 13.3, IH)5 9.15 (s, IH), 8.94 (d, J = 13.3, IH)5 8.03-7.99 (m, 2H), 7.80 (m5 IH), 7.80 (d, J = 8.1, IH)5 7.72 (t, J = 7.8, IH), 7.70 (d, J = 7.8, IH), 7.16 (dd, J = 8.13 1.9, IH), 7.14 (s, 2H), 7.06 (t, J = 7.8, IH), 7.00 (s, IH), 6.97 (dd, J = 7.8, 1.2, IH), 6.88 (d, J = 1.9, IH), 2.32 (s, 6H). Example 64
Figure imgf000131_0001
4-{l-(5-Fluoro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(3,5-dimethylphenyl)- phenyl)aminomethylidene)indolyl}butanoic acid (Compound 164)
[0262] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz, DMSO-4?) 11.30 (d, J = 12.8, IH), 10.69 (s, IH), 8.69 (d, J = 12.8, IH), 8.06 (s, IH), 7.58 (dd, J = 8.2, 1.4, IH), 7.45 (dd, J = 9.3, 2.6, IH), 7.11 (m, 2H), 7.07-7.01 (m, 3H), 6.94 (dd, J = 7.7, 1.5, IH), 6.86 (ddd, J = 9.7, 8.2, 2.6, IH), 3.92 (t, J = 7.2, 2H)3 2.41 (t, J = 7.2, 2H), 2.35 (m, 6H), 2.00 (qn, J = 7.2, 2H). Example 65
Figure imgf000131_0002
3-{3-(l-(l-(3,5-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-3(Z)- indolidene)ethylamino)-2-hydroxyphenyl}benzoic acid (Compound 165)
[0263] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-ύfe) 11.86 (s, IH), 8.31 (t, J = 1.5, IH), 8.06 (d, J = 7.8, IH), 7.77 (d, J = 7.8, IH), 7.53 (t, J = 7.8, IH), 7.46 (d, J = 8.1 , IH), 7.33 (dq, J = 8.1, 0.9, IH), 7.30 (dd, J = 7.7, 1.3, IH), 7.13 (dd, J = 7.7, 1.3, IH), 7.06 (s, 2H), 7.02 (t, J = 7.7, IH), 6.99- 6.97 (m, 2H), 2.42 (s, 3H), 2.37 (s, 6H). Example 66
Figure imgf000132_0001
3-{3-(l-(l-(3,4-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-3(Z)- indolidene)ethylamino)-2-hydroxyphenyl}benzoic acid (Compound 166)
[0264] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz3 DMSO-ύfe) H.91 (s, IH), 8.32 (br s, IH), 8.06 (d, J = 7.8, IH), 7.76 (d, J = 7.8, IH), 7.54 (t, J = 7.8, IH), 7.48 (d, J = 8.1, IH), 7.35-7.28 (m, 3H), 7.18 (s, IH), 7.16-7.10 (m, 2H), 7.08 (s, IH), 7.04 (t, J = 7.6, IH), 2.49 (s, 3H), 2.33 (s, 3H), 2.32 (s, 3H). Example 67
Figure imgf000132_0002
3-{ l-(6-TrifluoromethyI-2-oxo-2,3-dihydro-3-(5-chloro-2-hydroxy-3- cyclohexylphenyl)hydrazono)indolyl}benzoic acid (Compound 167)
[0265] This compound was prepared as described in Scheme II. 1H NMR (500
MHz, OMSO-dβ) 13.30 (s, IH), 13.03 (s, IH), 9.44 (s, IH)5 8.11 (dd, J = 2.1, 1.7, IH), 8.08 (ddd, J = 7.8, 1.7, 1.2, IH), 7.99 (d, J = 8.0, IH), 7.85 (ddd, J = 7.8, 2.1, 1.2, IH), 7.77 (t, J = 7.8, IH), 7.56 (d, J = 2.5, IH), 7.54 (dq, J = 8.0, 0.8, IH), 7.04 (m, IH), 6.92 (d, J = 2.5, IH), 2.97 (m, IH), 1.81-1.67 (m, 5H), 1.44-1.31 (m, 4H), 1.25 (m, IH). Example 68
Figure imgf000132_0003
3-{ l-(5-Fluoro-2-oxo-2,3-dihydro-3-(l-(5-chloro-2-hydroxy-3(Z)- cyclohexylphenyl)amino)ethylidene)indolyl}benzoic acid (Compound 168) [0266] This compound was prepared as described in Scheme III. 1H NMR (500 MHz5 OMSO-d6) 11.93 (s, IH), 8.00-7.97 (m, 2H), 7.72-7.66 (m, 2H), 7.34 (dd, J = 10.1, 1.8, IH), 7.23 (d, J = 2.5, IH), 7.12 (d, J = 2.5, IH), 6.91-6.84 (m, 2H), 2.95 (m, IH), 2.49 (s, 3H), 1.82-1.67 (m, 5H), 1.43-1.32 (m, 4H), 1.29-1.20 (m, IH). Example 69
Figure imgf000133_0001
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. 1H NMR
(500 MHz5 DMSO-rftf) 1 1.09 (d, J = 13.2, IH)3 9.38 (br s, IH), 8.91 (d, J = 13.2, IH), 8.02 (t, J = 1.8, IH)5 7.99 (ddd, J = 7.8, 1.8, 1.2, IH), 7.77 (ddd, J = 7.8, 1.8, 1.2, IH), 7.70 (t, J = 7.8, IH), 7.67 (m, IH), 7.66 (d, J = 2.3, IH), 6.90 (d, J = 2.3, IH), 6.90-6.87 (m, 2H), 2.95 (m, IH), 1.81-1.66 (m, 5H), 1.44-1.22 (m, 5H). Example 70
Figure imgf000133_0002
4-{2-Hydroxy-3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5-dimethylphenyl)-3(Z)- indolylidene)methylaminophenyl}butanoic acid (Compound 170)
[0268] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, OMSO-d6) 1 1.27 (d, J = 13.6, IH)5 9.01 (d, J = 13.6, IH), 7.94 (d, J = 8.1, IH), 7.60 (d, J = 7.6, IH), 7.41 (d, J = 8.1, IH), 7.12 (s, IH)3 7.10 (s, 2H), 6.94 (t, J = 7.6, IH), 6.93 (s, IH), 6.88 (d, J = 7.6, I H), 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
Figure imgf000134_0001
4- { 2-Hydroxy-3 -(6-trifluoromethyl-2-oxo-2,3-dihydro- 1 -(3 ,4-dimethylphenyl)- 3 (Z)- indolylidene)methylaminophenyl}butanoic acid (Compound 171)
[0269] This compound was prepared as described in Scheme VIII. 1H NMR
(300 MHz, DMSO-rftf) 8.72 (s, IH), 7.76 (d, J = 7.6, IH), 7.44 (m, IH), 7.38-7.30 (m, 2H), 7.22 (d, J = 1 .7, IH), 7.15 (dd, J = 8.0, 1.7, IH)3 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
Figure imgf000134_0002
3-{3-(7-(6-Trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5-dimethylphenyl)-3(2)- indolylidene)methylamino)indolyl}propanoic acid (Compound 172)
[027Oj This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSCW6) 12.10 (s, IH), 11.32 (m, IH), 10.94 (d, J = 12.8, IH), 8.92 (d, J = 12.8, IH), 7.95 (ά, J = 7.8, IH), 7.43 (d, J = 7.8, IH), 7.40 (m, IH), 7.30 (d, J = 7.8, IH), 7.19 (d, J = 2.4, IH), 7.14 (m, IH), 7.12 (m, 2H), 7.09 (t, J = 7.8, IH), 6.94 (m, IH)5 2.94 (t, J = 7.6, 2H), 2.61 (t, J = 7.6, 2H), 2.37 (s, 6H). Example 73
Figure imgf000135_0001
3-{3-(7-(6-Trifluoromethyl-2-oxo-2,3-dihydro-l-(3,4-dimethylphenyl)-3(Z)- indolylidene)methylamino)indolyl}propanoic acid (Compound 173)
[0271] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMS0-6fc) 12.09 (s, IH), 11.33 (d, J = 2.2, IH), 10.92 (d, J = 12.8, IH), 8.91 (d, J = 12.8, IH), 7.94 (d, J = 8.0, IH), 7.43 (d, J = 8.0, IH), 7.40 (m, IH), 7.37 (d, J = 8.0, IH), 7.30-7.28 (m, 2H)5 7.22 (dd, J - 8.0, 2.0, IH), 7.19 (d, J = 2.2, IH), 7.09 (t, J = 8.0, IH), 6.92 (d, J = 1.6, IH), 2.94 (t, J = 7.7, 2H), 2.60 (t, J = 7.7, 2H), 2.32 (s, 3H), 2.31 (s, 3H). Example 74
Figure imgf000135_0002
4-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(3,5-dimethylphenyl)-3(Z)- indolylidene)methylarninophenyl}butanoic acid (Compound 174)
[02721 This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-J15) 12.07 (s, IH), 11.08 (d, J = 13.0, IH), 8.77 (d, J = 13.0, IH), 7.74 (m, IH), 7.54 (d, J = 7.8, IH), 7.10-7.02 (m, 5H), 6.91 (m, IH), 6.85-6.81 (m, 2H), 2.64 (m, 2H), 2.36 (s, 6H), 2.23 (m, 2H)5 1.77 (m, 2H). Example 75
Figure imgf000136_0001
2-Chloro-3(Z)-{3-hydroxy-4-(2-oxo-2,3-dihydro-l-(3,5-dimethylphenyl)-3(Z)- indolylidene)methylaminophenyl}propenoic acid (Compound 175)
[0273] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSCMJ) 13.48 (br s, IH), 1 1.06 (d, J = 12.6, IH), 10.61 (s, IH), 8.84 (d, J = 12.6, IH)5 7.85 (s, IH), 7.78-7.73 (m, 3H), 7.41 (d, J = 7.4, IH)5 7.10-7.05 (m, 5H), 6.84 (m, IH), 2.36 (s, 6H). Example 76
Figure imgf000136_0002
2-Chloro-3(2)-{3-hydroxy-4-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,4- dimethylphenyl)-3(Z)-indolylidene)methylaminophenyl}propenoic acid (Compound 176) [0274] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-Cf6) 13.53 (s, IH), 1 1.22 (d, J = 13.2, IH), 10.72 (s, IH), 9.08 (d, J = 13.2, IH), 7.95 (d, J = 7.8, IH), 7.87 (s, IH), 7.81 (d, J = 8.5, IH), 7.75 (d, J = 1.8, IH), 7.44 (m, IH)3 7.43 (dd5 J = 8.5, 1.8, IH), 7.36 (d, J = 8.0, IH), 7.28 (d, J = 2.1, IH), 7.21 (dd, J = 8.0, 2.1, IH), 6.92 (m, IH)5 2.32 (s, 3H), 2.31 (s, 3H). Example 77
Figure imgf000137_0001
2-Ethyl-3 (£> { 3 -hydroxy-4-(6-trifluoromethyl-2-oxo-2,3 -dihydro- 1 -(3 ,4- dimethylphenyl)-3(Z)-indolylidene)methylaminophenyl}propenoic acid (Compound 177) [0275] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz5 acetone-^) 1 1.42 (d, J = 12.9, IH), 9.53 (s, IH), 8.93 (d, J = 12.9, IH), 7.87 (d, J = 8.1, IH), 7.73 (d, J = 8.1, IH)5 7.59 (s, IH), 7.38 (m, IH), 7.36 (d, J = 8.1, IH), 7.32 (d, J = 2.1, IH)5 7.25 (dd, J = 8.1, 2.1, IH), 7.22 (d, J = 1.7, IH), 7.11 (dd, J = 8.1, 1.7, IH), 7.06 (m, IH), 2.59 (q, J = 7.4, 2H)5 2.36 (s, 6H), 1.19 (t, J = 7.4, 3H). Example 78
Figure imgf000137_0002
2-Ethyl-3(E)-{3-hydroxy-4-(6-trifluoromethyl-2-oxo-253-dihydro-l-(3,5- dimethylphenyl)-3(Z)-indolylidene)methylaminophenyl}propenoic acid (Compound 178) [0276] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, acetone-^) 1 1.42 (d, J = 12.8, IH), 9.54 (s, IH), 8.94 (d, J = 12.8, IH), 7.87 (d, J = 8.0, IH), 7.74 (d, J = 8.5, IH), 7.59 (s, IH), 7.38 (dq, J = 8.0, 0.9, IH), 7.22 (d, J = 1.7, IH), 7.16 (m, 2H), 7.13 (m, IH), 7.11 (dd, J = 8.5, 1.7, IH), 7.08 (s, IH), 2.59 (q, J = 7.4, 2H), 2.40 (m, 6H), 1.19 (t, J = 7.4, 3H). Example 79
Figure imgf000138_0001
2-Ethyl-3(E)-{3-hydroxy-4-(2-oxo-2,3-dihydro-l-(3,5-dimethylphenyl)-3(Z)- indolylidene)methylaminophenyl}propenoic acid (Compound 179)
[0277] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, acetone-^) 11.24 (d, J = 12.3, IH), 9.40 (br s, IH), 8.71 (d, J = 12.3, IH), 7.70 (m, IH), 7.67 (d, J = 8.4, IH), 7.59 (s, IH), 7.21 (d, J = 1.8, IH), 7.14 (m, 2H)5 7.1 1-7.02 (m, 4H), 6.90 (m, IH), 2.60 (q, J = 7.4, 2H), 2.39 (s, 6H), 1.19 (t, J = 7.4, 3H). Example 80
Figure imgf000138_0002
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. 1H NMR
(500 MHz, methanol-^) 8.46 (s, IH), 7.58 (s, IH), 7.49 (d, J = 8.3, IH)5 7.43 (m, IH), 7.14 (d, J = 8.3, IH), 7.01-6.88 (m, 2H), 6.92 (t, J = 7.3, IH), 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
Figure imgf000138_0003
(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. 1H NMR
(300 MHz, CDClj) 10.08 (d, J = 12.8, IH), 7.30 (dt, J = 12.8, 0.8, IH), 7.06 (s, 3H), 7.03 (dd, J = 7.8, 1.8, IH), 6.95 (t, J = 7.8, IH), 6.89 (dd, J = 7.8, 1.8, IH), 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
Figure imgf000139_0001
(E)-4-{ l-(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. 1H NMR
(500 MHz, CDCl3) 7.91 (dt, J = 13.8, 1.5, IH), 7.13 (dd, J = 7.8, 1.6, IH), 7.06 (s, IH), 7.04 (s, 2H), 6.99 (t, J = 7.8, IH), 6.90 (dd, J = 7.8, 1.6, IH), 6.81 (d, J = 13.8, IH), 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
Figure imgf000139_0002
(Z)-3-{ l-(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. 1H NMR
(300 MHz, acetone-^) 10.28 (d, J = 12.8, IH), 8.15 (m, IH), 8.04 (ddd, J = 7.9, 1.7, 1.2, IH), 7.90 (s, IH), 7.82 (dt, J = 12.8, 1.1, IH), 7.72 (ddd, J = 7.9, 2.1, 1.2, IH), 7.63 (t, J = 7.9, IH), 7.34 (dd, J = 7.8, 1.5, IH), 7.08 (m, 2H), 7.00 (m, IH), 6.98 (t, J = 7.8, IH), 6.86 (dd, J = 7.8, 1.5, IH), 3.54 (d, J = 1.1, 2H), 2.33 (s, 3H), 2.33 (s, 3H). Example 84
Figure imgf000140_0001
(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. 1H NMR
(300 MHz, acetone-^) 8.12 (m, IH), 8.04 (dt, J = 7.8, 1.5, IH), 7.98 (dt, J = 13.6, 1.8, IH), 7.84 (d, J = 13.6, IH), 7.69 (ddd, J = 7.8, 2.0, 1.5, IH), 7.63 (t, J = 7.8, IH), 7.33 (dd, J = 7.8, 1.6, IH), 7.09 (m, 2H), 7.01 (t, J = 7.8, IH), 7.01 (m, IH), 6.92 (dd, J = 7.8, 1.6, IH), 3.57 (d, J = 1.8, 2H)5 2.34 (m, 6H). Example 85
Figure imgf000140_0002
4-{3-(4-Oxo-2-thioxo-5-(3-(3,5-dimethylphenyl)-2- hydroxypheny)hydrozono)thiazolidinyl}butanoic acid (Compound 185)
[0283] This compound was prepared as described in Scheme I. 1H NMR (500
MHz, methanol-^) 8.51 (s, IH)3 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
Figure imgf000140_0003
3-{2-(3(2)-(l-(3.5-Dimethylphenyl)-6-chloro-2-oxo-2,3- dihydroindolidene)methylamino)phenylamino}benzoic acid (Compound 186) [0284] This compound was prepared as described in Scheme VIII. 1H NMR (500 MHz, DMSO-ck) 10.96 (d, J - 13.0, IH), 8.90 (d, J = 13.0, IH), 7.94 (m, IH), 7.82 (m, IH), 7.75 (d, J = 8.2, IH), 7.34-7.28 (m, 2H), 7.27-7.24 (m, 2H), 7.24 (t, J = 7.8, IH), 7.13 <td, J = 7.6, 1.2, IH), 7.10 (dd, J = 8.2, 2.0, IH), 7.07 (m, IH), 6.97 (m, 2H), 6.93 (m, IH), 6.68 (d, J = 2.0, IH), 2.32 (s, 6H). Example 87
Figure imgf000141_0001
3-{2-(3-(l-(3,5-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3- dihydroindolidene)methylamino)phenylamino} benzoic acid (Compound 187)
[0285] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-rfβ) 11.13 (d, J = 13.2, IH), 9.07 (d, J = 13.2, IH), 7.99 (s, IH), 7.95 (d, J = 8.0, IH), 7.88 (m, IH), 7.42 (dd, J = 8.0, 1.0, IH), 7.34 (td, J = 7.5, 1.1, IH), 7.32-7.26 (m, 3H), 7.25 (t, J = 7.6, IH), 7.17 (td, J = 7.5, 1.1, IH), 7.10 (m, I H), 7.00 (m, 2H), 6.95 (m, IH), 6.86 (d, J = 1.0, IH), 2.33 (s, 6H). Example 88
Figure imgf000141_0002
3_{2-(4-(2-(3,5-Dimethylphenyl)-5-methyl-3-oxo-3>4- dihydropyrazolidene)methylamino)phenylamino}benzoic acid (Compound 188)
[0286] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz5
Figure imgf000141_0003
12.0, IH), 8.66 (d, J = 12.0, IH), 8.08 (s, IH), 7.86 (m, IH), 7.67 (d, J = 2.0, IH)3 7.62 (dd, J = 8.3, 2.0, IH), 7.38-7.33 (m, 2H), 7.32-7.29 (m, 2H), 7.30 (t, J = 7.7, IH), 7.23 (td, J = 7.6, 1.3, IH), 7.10 (d, J = 8.3, IH), 7.02 (m, IH), 2.28 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H). Example 89
Figure imgf000142_0001
(±)-3-Methyl-5-{2-hydroxy-3-(3(Z)-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(335- dimethylphenyl)indolylidene)methylamino)phenyl}pentanoϊc acid (Compound 189)
[0287] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-4>) 1 1 -29 (d, J = 13.4, IH), 9.01 (d, J = 13.4, IH)5 7.94 (d, J = 8.0, IH), 7.58 (dd, J = 8.0, 1.5, IH), 7.41 (dq, J = 8.0, 0.7, IH), 7.13 (m, IH), 7.10 (m, 2H), 6.95-6.91 (m, 2H), 6.89 (dd, J = 7.7, 1.5, IH), 2.71-2.58 (m, 2H), 2.37 (s, 6H), 2.31 (dd, J = 15.0, 5.5, IH), 2.04 (dd, J = 15.0, 8.5, IH), 1.87 (m, IH), 1.56 (m, IH), 1.42 (m, IH), 0.95 (d, J = 6.6, 3H). Example 90
Figure imgf000142_0002
(±)-3_{l-(6.Chloro-2-oxo-2,3-dihydro-3-(3(2)-(l-(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. 1H NMR
(500 MHz, DMSO-<fr) 13.20 (s, IH), 7.93 (ddd, J = 7.8, 1.6, 1.1 , IH), 7.73 (m, IH), 7.58 (t, J = 7.8, IH), 7.35 (m, IH), 7.30 (dd, J = 7.8, 1.8, IH), 7.23 (td, J - 7.7, 1.2, IH), 7.14- 7.08 (m, 4H), 7.00 (s, 2H)5 6.89 (t, J = 7.7, IH), 6.67 (d, J = 7.8, IH), 6.63 (d, J = 2.0, IH), 6.31 (m, IH), 2.33 (s, 6H). Example 91
Figure imgf000143_0001
3-{4-(3-Hydroxy-6-methyl-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolyl)hydrazono)pyridinyl}benzoic acid (Compound 191)
[0289] This compound was prepared as described in Scheme IX. 1H NMR
(300 MHz, DMSO-flk) 8.52 (s, IH), 8.16 (m, IH), 7.98 (m, IH), 7.96 (m, IH), 7.60-7.52 (m, 2H), 7.59 (t, J = 7.8, IH), 7.20-7.16 (m, 3H), 6.98 (s, IH), 2.50 (s, 3H), 2.37 (s, 6H). Example 92
Figure imgf000143_0002
3-{4-(3-Hydroxy-6-methyl-2-(3(Z)-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolidene)methylamino)pyridinyl} benzoic acid (Compound 192)
[0290] This compound was prepared as described in Scheme VIIT. 1H NMR
(500 MHz, OMSO-dό) 9.06 (s, IH), 8.55 (s, IH), 8.20 (m, IH), 7.99 (d, J = 7.8, IH), 7.93 (d, J - 7.8, IH)5 7.61 (s, IH), 7.56 (t, J = 7.8, IH), 7.48 (d, J = 7.8, IH), 7.13 (m, IH), 7.11 (m, 2H), 6.94 (m, IH), 2.50 (s, 3H), 2.37 (s, 6H). Example 93
Figure imgf000143_0003
3-{4-(3-Hydroxy-2-(3(Z)-(6-trifluoromethyl~2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indoUdene)methylamino)pyridinyl}benzoic acid (Compound 193) [0291] This compound was prepared as described in Scheme VIII. 1H NMR (500 MHz, OMSO-Cl6) 9.13 (d, J - 12.9, IH), 8.52 (s, IH), 8.24 (m, IH), 8.17 (m, IH), 8.03-7.99 (m, 2H), 7.84 (m, IH), 7.65 (t, J = 7.7, IH)3 7.50 (dq, J = 7.9, 0.6, IH), 7.14 (m, IH), 7.12 (m, 2H), 6.95 (q, J = 0.85 IH), 2.37 (s, 6H). Example 94
Figure imgf000144_0001
3-{4-(3-Hydroxy-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolyl)hydrazono)pyridinyl}benzoic acid (Compound 194)
[0292] This compound was prepared as described in Scheme IX. 1H NMR
(500 MHz, DMSO-J15) 13.22 (s, IH), 8.50 (s, IH), 8.21 (m, IH)3 8.16 (d, J = 7.7, IH), 8.04 (d, J = 7.8, IH), 8.01 (d, J = 7.7, IH), 7.80 (d, J = 5.4, IH), 7.68 (t, J = 7.7, IH), 7.60 (dq, J = 7.8, 0.7, IH), 7.19 (m, IH), 7.17 (m, 2H), 6.98 (m, IH), 2.37 (s, 3H)5 2.37 (s, 3H). Example 95
Figure imgf000144_0002
3-{5-(4-Hydroxy-3-(3(Z)-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolidene)methylamino)pyridinyl}benzoic acid (Compound 195)
[0293] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-^6) 1 1.10 (d, J = 13.8, IH), 8.95 (d, J = 13.8, IH), 8.39 (t, J = 1.7, IH), 8.35 (d, J = 1.3, IH), 8.10 (d, J = 1.3, IH)5 7.98 (ddd, J = 7.7, 1.7, 1.2, IH), 7.88 (ddd, J = 7.7, 1.7, 1.2, IH), 7.86 (d, J = 7.9, IH), 7.53 (t, J = 7.7, IH), 7.43 (dq, J = 7.9, 0.9, IH), 7.12 (m, IH)3 7.10 (m, 2H), 6.94 (m, IH), 2.37 (s3 6H). Example 96
Figure imgf000145_0001
3-{5-(4-Hydroxy-3-(3-(6-trifluorometliyl-2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolyl)hydrazono)pyridinyl} benzoic acid (Compound 196)
[0294] This compound was prepared as described in Scheme IX. 1H NMR
(300 MHz, DMSOrftf) 12.91 (s, IH), 8.39 (t, J - 1.7, IH), 8.17 (d, J = 1.4, IH), 8.06 (d, J = 1.4, IH), 7.99 (m, IH), 7.94-7.86 (m, 2H), 7.53 (m, IH), 7.53 (t, J = 7.7, IH), 7.18- 7.15 (m, 3H), 6.97 (m, IH), 2.37 (s, 6H). Example 97
Figure imgf000145_0002
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. 1H NMR
(500 MHz, DMSO-J15) 13.43 (s, IH)3 12.99 (s, IH), 12.33 (s, IH), 8.40 (t, J = 1.6, IH), 8.16 (s, IH)3 8.10 (s, IH), 7.99 (m, IH), 7.91 (m, IH), 7.71 (m, IH), 7.63 (dd, J = 8.1, 1.9, IH), 7.55 (t, J = 7.7, IH), 7.21 (d, J = 8.1, IH), 2.31 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H). Example 98
Figure imgf000145_0003
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 L 1H NMR (300
MHz3 CDCl3) 13.45 (s, IH), 7.58 (s, IH), 7.47-7.31 (m, 4H), 7.26 (s, IH), 7.22 (d, J = 7.7, IH)5 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)5 2.31 (s, 3H), 2.27 (s, 3H). Example 99
Figure imgf000146_0001
3-{2-Amino-5-methyl-3-(3(Z)-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolylidene)methylamino)phenyl}benzoic acid (Compound 199)
[0297] This compound was prepared as described in Scheme VIII. H NMR
(500 MHz, DMSO-^) 10.91 (d, J = 13.1, IH), 8.94 (d, J = 13.1, IH), 7.98-7.93 (m, 3H), 7.65 (m, IH), 7.62 (t, J = 7.6, IH), 7.43-7.40 (m, 2H), 7.12 (m, IH), 7.09 (m, 2H), 6.93 (d, J = 1.4, IH), 6.81 (m, IH), 4.38 (br s, 2H), 2.36 (s, 6H), 2.33 (s, 3H). Example 100
Figure imgf000146_0002
3-{ l-(5-Fluoro-2-oxo-2,3-dihydro-3(Z)-(3-(3,4- dimethylphenyl)phenyl)arninomethylidene)indolyl} benzoic acid (Compound 200)
[0298] This compound was prepared as described in Scheme III. 1H NMR
(500 MHz, DMSO-^) 13.23 (s, IH), 10.85 (d, J = 12.8, IH), 8.96 (d, J = 12.8, IH), 8.06 (m, IH), 7.99 (m, IH), 7.82-7.78 (m, 2H), 7.74-7.69 (m, 2H), 7.56 (s, IH), 7.51-7.39 (m, 4H), 7.26 (d, J = 7.8, IH), 6.94-6.86 (m, 2H), 2.32 (s, 3H), 2.28 (s, 3H). Example 101
Figure imgf000147_0001
4-{2-(5-Methyl-2-oxo-2,3-dihydro-4(Z)-(3-(3,4- dimethylphenyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 201)
[0299] This compound was prepared as described in Scheme VIIL 1H NMR
(300 MHz, methanol-^) 8.52 (s, IH), 7.63 (s, IH)5 7.49-7.43 (m, 2H), 7.41-7.30 (m, 2H), 7.23-7.09 (m, 2H)5 3.80 (t, J = 6.8, 2H), 2.34 (s, 3H), 2.30 (s, 3H), 2.28 (m, 2H), 2.26 (s, 3H)3 2.01 (qn, J = 6.8, 2H). Example 102
Figure imgf000147_0002
(3-(5-Fluoro-2-hydroxy-3-(3(Z)-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,4- dimethylphenyl)indolidene)methylamino)-l-pyrazolyl)acetic acid (Compound 202)
[0300] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-40 13.26 (s, IH), 1 1.35 (s, IH), 11.26 (d, J = 13.0, IH), 9.06 (d, J = 13.0, IH), 7.97 (d, J = 2.4, IH), 7.93 (d, J = 7.9, IH), 7.71 (dd, J = 10.3, 2.8, IH), 7.46 (dq, J = 7.9, 0.9, IH), 7.42 (dd, J = 9.5, 2.8, IH), 7.36 (d, J = 8.0, IH), 7.29 (d, J = 2.1, IH), 7.22 (dd, J = 8.0, 2.1, IH), 7.03 (d, J = 2.4, IH), 6.94 (m, IH), 5.15 (s, 2H), 2.32 (s, 3H), 2.31 (s, 3H). Example 103
Figure imgf000147_0003
(3-(5-Fluoro-2-hydroxy-3-(3(Z)-(2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolidene)methylamino)-l-pyrazolyl)acetic acid (Compound 203) [0301] This compound was prepared as described in Scheme VIIL 1H NMR (500 MHz,
Figure imgf000148_0001
12.7, IH), 8.83 (d, J = 12.7, IH), 7.96 (d, J = 2.4, IH), 7.75 (m, IH), 7.66 (dd, J = 10.4, 2.8, I H), 7.35 (dd, J = 9.6, 2.8, IH), 7.1 1-7.07 (m, 5H), 7.01 (d, J = 2.4, IH), 6.87 (m, IH), 5.14 (s, 2H), 2.36 (s, 6H). Example 104
Figure imgf000148_0002
4-{2-(5-Methyl-2-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2- phenyl)ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 204)
[0302] This compound was prepared as described in Scheme VIII. 1H NMR
(300 MHz, methanol-^) S.47 (s, IH), 7.42 (m, IH), 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
Figure imgf000148_0003
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. 1H NMR
(300 MHz, methanol-^) 7.54 (m, IH), 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
Figure imgf000149_0001
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)
[0304] This compound was prepared as described in Scheme VII. 1H NMR
(300 MHz, methanol-^) 7.53 (m, IH), 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)5 2.34 (t5 J = 7.3, 2H)5 2.28 (s, 3H), 2.26 (s, 3H), 2.01 (m, 2H). Example 107
Figure imgf000149_0002
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)
[0305] This compound was prepared as described in Scheme VlI. 1H NMR
(300 MHz, methanol-^) 7.53 (m, IH), 7.12 (m, IH), 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
Figure imgf000149_0003
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-^) 7.54 (m, IH), 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 (m, 2H). Example 109
Figure imgf000150_0001
4-{2-(5-Methyl-2-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(l- naphthyl)ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 209)
[0307] This compound was prepared as described in Scheme VII. 1H NMR
(300 MHz5 methanol-^) 8.17 (d, J = 7.9, IH), 7.86 (d, J = 7.9, IH), 7.71 (d, J = 7.9, IH), 7.57-7 '.43 (m, 3H), 7.36 (m, IH), 7.31 (m, IH), 6.91-6.86 (m, 2H), 3.80 (t, J = 6.6, 2H)5 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 1 10
Figure imgf000150_0002
3-{l-(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. 1H NMR
(500 MHz, DMSO-dtø 13.28 (s, IH), 11.26 (d, J = 13.4, IH), 9.29 (d, J = 13.4, IH), 9.26 (s, IH), 8.82 (d, J = 2.4, IH), 8.06-8.03 (m, 2H), 8.02 (dd, J = 8.8, 2.4, IH), 7.82 (ddd, J = 8.1, 2.1, 1.3, IH), 7.79 (m, IH), 7.75 (t, J = 8.1, IH), 7.14 (m, 2H), 7.09 (t, J = 7.7, IH), 7.06 (d, J = 8.8, IH), 7.01 (dd, J = 7.7, 1.5, IH), 7.01 (m, IH), 2.33 (s, 6H). Example 111
Figure imgf000151_0001
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 21 1)
[0309] This compound was prepared as described in Scheme III. 1H NMR
(300 MHz, acetone-^) 1 1.43 (d, J = 13.3, IH), 9.15 (d, J = 13.3, IH)5 8.67 (d, J = 2.3, IH), 8.24 (t, J = 1.7, IH), 8.15 (m, IH), 8.08 (dd, J = 8.8, 2.3, IH), 7.88 (m, IH), 7.78 (t, J = 7.8, IH), 7.66 (dd, J = 10.0, 2.9, IH), 7.14 (m, 2H), 7.14 (d, J = 8.8, IH), 7.04 (m, IH), 6.78 (dd, J = 9.2, 2.9, IH), 2.34 (s, 6H). Example 1 12
Figure imgf000151_0002
2-Hydroxy-3-{3(Z)-(2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolidene)methylamino}benzoic acid (Compound 212)
[0310] This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, DMSO-c/g) 1 1.02 (d, J = 12.8, IH)5 8.84 (d, J = 12.8, IH), 7.96 (dd, J = 8.1, 1.5, IH)5 7.74 (m, IH)5 7.52 (dd, J = 8.1, 1.5, IH), 7.10-7.06 (m, 5H), 7.04 (t, J = 8.1, IH), 6.85 (m, IH), 2.36 (s, 3H), 2.36 (s, 3H). Example 113
Figure imgf000151_0003
2-Hydroxy-3- {3(Z)-(6-trifluoromethyl-2-oxo-253-dihydro- 1 -(3,5- dimethylphenyl)indolideπe)methylamino}benzoic acid (Compound 213) [0311] This compound was prepared as described in Scheme VIII. 1H NMR (500 MHz, DMSO-^) 11.18 (d, J = 12.9, IH), 9.07 (d, J = 12.9, IH), 8.00 (dd, J = 8.0, 1.4, IH)3 7.93 (d, J = 7.8, IH), 7.57 (dd, J = 8.0, 1.4, IH), 7.44 (dq, J = 7.8, 0.9, IH), 7.36 (d, J = 8.1, IH), 7.28 (d, J = 2.1, IH)5 7.21 (dd, J = 8.1, 2.1, IH), 7.06 (t, J = 8.0, IH), 6.92 (m, IH), 2.32 (s, 3H), 2.31 (s, 3H). Example 114
Figure imgf000152_0001
4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3-methyl-l (Z)- butenyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 214)
[0312] This compound was prepared as described in Scheme VIII. 1H NMR
(300 MHz, methanol-^) 8.49 (s, IH), 7.49 (d5 J = 7.6, IH)3 7.02-6.90 (m, 2H), 6.30 (d, J = 11.1, IH), 5.65 (dd, J = 11.1, 10.3, IH), 3.80 (t, J = 6.7, 2H), 2.66 (m, IH), 2.31 (t, J = 7.5, 2H), 2.27 (s, 3H), 2.00 (m, 2H), 1.01 (d, J = 6.7, 6H). Example 115
Figure imgf000152_0002
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-φ) 7.53 (dd, J = 7.6, 1.5, IH), 6.97 (dd, J = 7.6, 1.5, IH), 6.91 (t, J = 7.6, IH)5 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)3 2.01 (m, 2H), 1.60 (m, 2H), 1.42-1.27 (m, 8H), 0.90 (t, J = 6.8, 3H). Example 116
Figure imgf000153_0001
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. 1H NMR
(300 MHz, methanol-^) 7.60 (d, J = 7.9, IH), 7.50-7.41 (m, 4H), 7.21-7.08 (m, 3H), 7.01 (t, J = 7.9, IH), 3.79 (t, J = 6.6, 2H), 2.34 (s, 3H)5 2.34 (t, J = 7.3, 2H), 2.27 (s, 3H), 2.01 (m, 2H).
Figure imgf000153_0002
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)
[0315] This compound was prepared as described in Scheme VII. 1H NMR
(300 MHz, methanol-^) 7.59 (d, J = 7.8, IH), 7.09-6.95 (m, 4H), 6.88 (d, J = 7.8, IH), 6.79 (t, J = 7.8, IH), 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
Figure imgf000153_0003
4-{ l-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2-methyl)phenyl)ethylphenyl) hydrazono)indolyl}butanoic acid (Compound 218)
[0316] This compound was prepared as described in Scheme VII. 1H NMR
(500 MHz, DMSO-ύk) 13.04 (s, IH)3 9.13 (br s, IH), 7.61 (dd, J = 7.7, 0.7, IH), 7.51 (dd, J = 7.7, 1.6, IH), 7.33 (td, J = 7.7, 1.2, IH), 7.23 (m, IH), 7.20 (d, J = 7.7, I H), 7.16- 7.07 (m, 4H), 6.91 (t, J = 7.7, IH)5 6.83 (dd, J = 7.7, 1.5, IH), 3.84 (t, J = 7.1, 2H), 2.89- 2.79 (m, 4H), 2.32 (t, J = 7.1, 2H), 2.29 (s, 3H)5 1.88 (qn, J = 7.1 , 2H). Example 119
Figure imgf000154_0001
2-{ l-(2-Oxo-2s3-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. 1H NMR (500
MHz, methanol-^) 7.66 (dd, J = 7.7, 1.6, IH), 7.65 (m, IH), 7.27 (td, J = 7.7, 1.1 , IH), 7.14-7.10 (m, 3H), 7.01 (m, IH)5 6.99 (t, J = 7.7, IH), 6.95 (d, J = 7.7, IH), 6.89 (dd, J = 7.7, 1.6, IH), 4.55 (s, 2H), 2.36 (s, 6H). Example 120
Figure imgf000154_0002
2-{l-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2-methyl)ρhenyl)ethylphenyl) hydrazono)indolyl} acetic acid (Compound 220)
[0318] This compound was prepared as described in Scheme VII. 1H NMR
(500 MHz, DMSO-^6) 12.95 (s, IH), 9.16 (s, IH)5 7.62 (dd, J = 7.6, 1.0, IH), 7.53 (dd, J = 7.7, 1.6, IH), 7.30 (td, J = 7.6, 1.2, IH), 7.23 (m, IH), 7.16-7.07 (m, 5H)5 6.91 (t, J = 7.7, IH)5 6.84 (dd, J = 7.7, 1.6, IH), 4.59 (s, 2H), 2.89-2.79 (m, 4H)5 2.29 (S5 3H). Example 121
Figure imgf000155_0001
4- { 4-(2-(3 (Z)-(6-Trifluoromethy l-2-oxo-2,3 -dihydro- 1 -(3 ,4-dimethylphenyl) indolylidene)methylamino)thiazolyl}benzoic acid (Compound 221)
[0319J This compound was prepared as described in Scheme VIII. 1H NMR
(500 MHz, OMSO-dβ) 12.99 (s, 2H), 11.83 (d, J = 12.2, IH), 1 1.39 (d, J = 12.2, IH), 8.95 (d, J = 12.2, IH), 8.56 (d, J = 12.2, IH), 8.32 (d, J = 7.8, IH), 8.16 (d, J = 8.5, 2H), 8.08 (d, J = 8.5, 2H)5 8.08 (m, IH), 8.03 (d, J = 8.5, 2H)3 8.02 (d, J = 8.5, 2H), 7.93 (s, IH), 7.91 (s, IH), 7.51 (d, J = 7.8, IH), 7.44 (dq, J = 7.8, 0.9, IH), 7.37 (d, J = 7.9, I H), 7.36 (d, J = 7.9, IH), 7.30 (d, J = 2.1, IH), 7.24 (d, J = 2.1, IH), 7.23 (dd, J = 7.9, 2.1, IH)5 7.18 (dd, J = 7.9, 2.1, IH)5 6.91 (rn, IH), 6.85 (m, IH), 2.32 (s, 3H), 2.31 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H). Example 122
Figure imgf000155_0002
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)
[0320] This compound was prepared as described in Scheme III. 1H NMR
(50O MHZ3 DMSO-^J) 13.28 (S, IH), 11.22 (d, J = 13.7, IH), 9.19 (d, J = 13.7, IH), 8.81 (d, J = 2.4, IH), 8.40 (s, IH), 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, IH)5 7.07 (d, J = 8.8, IH), 6.79 (d, J = 1.5, IH), 2.33 (s, 3H), 2.09-2.06 (m, 6H), 2.05-2.02 (m, 3H), 1.75-1.72 (m5 6H). Example 123
Figure imgf000156_0001
3-{l-(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. 1H NMR (500
MHz, methanol-^) 8.25 (s, IH), 8.1 1 (dt, J = 7.7, 1.6, IH), 8.07 (t, J = 1.6, IH), 7.90 (d, J = 7.8, IH), 7.82 (m, IH)5 7.66 (t, J = 7.7, IH), 7.62 (m, IH), 7.48 (m, IH), 7.42 (m, IH), 7.34 (m, IH), 7.17 (d, J - 7.8, IH), 7.08 (br s, IH), 2.30 (s, 3H), 2.28 (s, 3H). Example 124
Figure imgf000156_0002
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 VIH. 1H NMR
(300 MHz, methanol-^) 8.47 (s, IH), 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
Figure imgf000156_0003
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) [0323] This compound was prepared as described in Scheme VIII. 1H NMR (300 MHz5 methanol-^) 8.47 (s, IH), 7.43 (m, IH), 7.23-7.14 (m, 2H), 7.07-6.97 (m, 2H), 6.90-6.85 (m, 2H), 3.81 (t5 J = 6.S, 2H)3 2.96 (m, 4H), 2.32 (t, J = 7.3, 2H), 2.26 (s, 3H), 2.00 (m, 2H). Example 126
Figure imgf000157_0001
[0324] 4-{2-(5-Methyl-3 -oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(l - naphthyl)ethyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 226)
[0325] This compound was prepared as described in Scheme VIII. 1H NMR (500MHz, DMSO) 8.48 (s, IH), 8.17 (d, J = 8.6 Hz, IH), 7.85 (d, J = 7.4 Hz, IH), 7.71 (d, J= 7.4 Hz, IH), 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, 3H)5 2.01 (m, 2H).
Example 127
Figure imgf000157_0002
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. 1H NMR
(300MHz5 CD3OD) 8.47 (br s, IH), 7.42 (m, IH)5 6.94-6.88 (m, 2H), 6.82-6.79 (m, 3H)5 3.80 (t, J= 6.7 Hz5 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
Figure imgf000158_0001
4-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(2-(2-methoxyphenyl)- ethyl)phenyl)aminomethylidene)pyrazolyl}bυtanoic acid (Compound 228)
[0327] This compound was prepared as described in Scheme VIII. 1H NMR
(300MHz, CD3OD) 8.47 (s, IH)5 7.41 (m, I H), 7.24-7.04 (m, 3H), 6.94-6.78 (m, 4H), 3.82 (s, 3H), 3.81 (m. 2H)3 2.89 (s, 4H), 2.36-2.24 (m, 5H), 2.01 (m; 2H). Example 129
Figure imgf000158_0002
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)
[0328] This compound was prepared as described in Scheme VIII. 1H NMR
(300MHz5 CD3OD) 7.47-7.30 (m, IH), 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
Figure imgf000158_0003
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. 1H NMR
(300MHz, CD3OD) 8.45 (s, IH)3 7.64 (d, J = 7.6 Hz3 IH)3 7.56-7.32 (m3 4H)3 7.16 (m5 IH)3 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
Figure imgf000159_0001
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. 1H NMR
(300MHz, CD3OD) 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)5 6.95-6.91 (m, 2H), 3.81 (t, J = 6.5 Hz5 2H), 3.04-2.92 (m, 4H), 2.32 (t, J = 7.7 Hz, 2H), 2.27 (s, 3H), 2.02 (m, 2H).
Figure imgf000159_0002
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. 1H NMR
(300MHz, CD3OD) 8.45 (s, IH), 7.65 (d, J = 7.5 Hz, IH), 7.55 (t5 J = 7.5 Hz, IH), 7.48- 7.32 (m, 3H), 6.92-6.81 (m, 2H)3 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).
Figure imgf000159_0003
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. 1H NMR
(300MHz5 CD3OD) 8.47 (s, IH), 7.43 (m, IH), 7.35 (m5 IH), 7.24-7.14 (m, 3H), 6.93- 6.85 (m, 2H), 3.81 (t, J= 6.7 Hz5 2H), 3.08-2.94 (m, 4H), 2.32 (t, J= 7.5 Hz, 2H), 2.26 (s, 3H), 2.00 (m, 2H).
Figure imgf000160_0001
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)
[0333] This compound was prepared as described in Scheme VIII. 1H NMR
(300MHz, CD3OD) 8.48 (s, IH), 7.45 (m, IH), 6.98-6.87 (m, 5H), 3.81 (t, J = 6.9 Hz5 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)5 2.00 (m, 2H). Example 135
Figure imgf000160_0002
3-{2-(5-Trifluoromethyi-3-oxo-354-dihydro-4(Z)-(2-hydroxy~3-(2-(2- trifluoromethylphenyl)ethy l)phenyl)aminomethylidene)pyrazolyl } benzoic acid
(Compound 235)
[0334] This compound was prepared as described in Scheme VIII. 1H NMR
(300MHz, DMSO) 8.81 (s, IH), 8.66 (dd, J= 2.2, 1.5 Hz, IH), 8.24 (ddd, J= 8.2, 2.2, 1.1 Hz, I H), 7.84 (ddd,.J= 7.7, 1.5, 1.1 Hz, IH), 7.78 (dd, J= 8.0, 1.6 Hz5 IH), 7.70 (m, IH)5 7.66-7.59 (m, 3H), 7.44 (m, IH), 7.03 (dd, J= 7.7, 1.6 Hz, IH), 6.97 (dd, J = 8.0, 7.7 Hz, IH), 3.05-2.93 (m, 4H). Example 136
Figure imgf000161_0001
3-{2-(5-Tri'fluoromethyl-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 VIIL 1H NMR
(300MHz, DMSO) 9.84 (s, IH)5 8.79 (s, IH)5 8.65 (dd5 J = 2.2, 1.6 Hz3 IH), 8.23 (ddd, J = 8.2, 2.2, 1.1 Hz, IH), 7.84 (ddd, J = 7.8, 1.6, 1.1 Hz3 IH), 7.75 (m, lH), 7.62 (dd, J = 8.2, 7.8 Hz, IH), 7.33 (m, IH)5 7.25 (m, IH), 7.18-7.09 (m, 2H)5 7.01 (dd, J= 7.8, 1.5 Hz, IH), 6.93 (t, J= 7.8 Hz, IH), 3.00-2.85 (m, 4H).
Figure imgf000161_0002
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
(300MHz3 DMSO) 9.80 (s, IH), 8.80 (m, IH), 8.65 (dd, J= 2.2, 1.5 Hz5 IH), 8.23 (ddd, J = 8.2, 2.2, 1.1 Hz, IH), 7.84 (ddd, J = 7.8, 1.5, 1.1 Hz, IH), 7.77 (m, IH), 7.63 (dd, J = 8.2, 7.8 Hz, IH), 7.22 (m, IH), 7.17-7.05 (m, 4H), 6.96 (t, J= 7.8 Hz, IH), 2.90 (m, 2H), 2.82 (m, 2H), 2.29 (s, 3H). Example 138
Figure imgf000161_0003
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) [0337] This compound was prepared as described in Scheme VIII. 1H NMR (300MHz, CD3OD) 8.65 (dd, J = 2.2, 1.6 Hz, IH)3 8.60 (s, IH), 8.23 (ddd, J = 8.1, 2.2, 1.0 Hz, IH), 7.92 (ddd, J= 7.8, 1.6, 1.0 Hz, IH), 7.56 (dd, J= 8.1, 7.8 Hz, IH), 7.47 (m, IH), 7.00-6.86 (m, 5H), 2.93 (m, 2H), 2.85 (m, 2H), 2.25 (s, 3H), 2.24 (s, 3H). Example 139
Figure imgf000162_0001
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. 1H NMR
(300MHz, CD3OD) 8.66 (dd, J = 2.1, 1.6 Hz, IH), 8.60 (s, IH), 8.25 (ddd, J = 8.1, 2.1, 1.0 Hz, IH), 7.92 (ddd, J = 7.7, 1.6, 1.0 Hz, IH), 7.57 (dd, J = 8.1, 7.7 Hz, IH), 7.48 (m, IH), 6.99-6.94 (m, 5H), 2.95 (m, 2H), 2.85 (m, 2H)5 2.31 (s, 6H). Example 140
Figure imgf000162_0002
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. 1H NMR
(300MHz, DMSO) 8.79 (dd, J = 2.1 , 1.6 Hz, IH), 8.69 (br s, IH), 8.36 (ddd, J = 8.2, 2.1, 1.1 Hz, IH), 7.94-7.89 (m, 2H), 7.78 (ddd, J = 7.8, 1.6, 1.1 Hz, IH), 7.67-7.51 (m, 5H), 7.08-7.00 (m, 3H), 6.96-6.88 (m, 2H), 2.87 (m5 2H), 2.77 (m, 2H), 2.25 (s, 6H). Example 141
Figure imgf000163_0001
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. 1H NMR
(300MHz, CD3OD) 8.65 (dd, J = 2.1, 1.7 Hz, IH)3 8.58 (s, IH), 8.25 (m, IH)5 7.83 (m, IH), 7.50 (t, J= 7.9 Hz5 IH), 7.36 (m, IH), 6.99-6.84 (m, 5H), 2.95-2.80 (m, 4H), 2.24 (s, 3H)5 2.23 (s, 3H), 1.47 (s, 9H). Example 142
Figure imgf000163_0002
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. 1H NMR
(500MHz, DMSO) 11.86 (d, J = 13.6 Hz, IH), 9.50 (br s, IH), 8.71 (d, J = 13.6 Hz, IH), 8.66 (dd, J = 2.1, 1.6 Hz, IH), 8.26 (ddd, J = 8.1, 2.1, 1.1 Hz, IH), 7.71 (ddd, J= 7.7, 1.6, 1.1 Hz, IH), 7.64 (dd, J= 8.0, 1.5 Hz, IH), 7.53 (dd, J= 8.2, 7.7 Hz, IH), 7.22 (m, IH), 7.16-7.07 (m, 3H), 6.98 (dd, J = 7.6, 1.5 Hz, IH), 6.94 (m, IH), 2.88 (m, 2H), 2.82 (m, 2H), 2.32 (s, 3H), 2.29 (s, 3H). Example 143
Figure imgf000163_0003
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) [0342] This compound was prepared as described in Scheme VII. 1H NMR (300MHz, CD3OD) 7.53 (m, IH), 7.23-7.15 (m, 2H), 7.07-6.97 (m, 2H), 6.91-6.83 (m, 2H)3 3.79 (t, J= 6.6 Hz, 2H), 2.95 (s, 4H)5 2.34 (t, J= 7.3 Hz, 2H), 2.26 (s, 3H)3 2.01 (m3 2H).
Figure imgf000164_0001
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. 1H NMR
(300MHz5 CD3OD) 7.54 (m, IH), 6.93-6.88 (m, 2H), 6.83-6.79 (m, 3H), 3.79 (t, J= 6.6 Hz, 2H), 2.92 (m, 2H)5 2.80 (m, 2H), 2.34 (t, J = 7.4 Hz, 2H), 2.26 (s, 3H)5 2.25 (s, 6H), 2.01 (m, 2H). Example 145
Figure imgf000164_0002
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. 1H NMR
(300MHz, CD3OD) 7.61-7.49 (m, 5H)5 7.41 (t, J= 7.4 Hz, 2H)5 7.33-7.26 (m5 3H), 6.96- 6.87 (m, 2H)5 3.80 (t5 J= 6.7 Hz5 2H), 3.02-2.94 (m, 4H), 2.33 (t, J= 7.4 Hz, 2H), 2.26 (s, 3H), 2.01 (ra, 2H). Example 146
Figure imgf000165_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methoxyphenyl)- ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 246)
[0345] This compound was prepared as described in Scheme VII. 1H NMR
(300MHz, CD3OD) 7.51 (m, IH), 7.19-7.04 (m, 2H), 6.93-6.78 (m, 4H)3 3.82 (s, 3H), 3.79 (t, J = 6.8 Hz5 2H), 2.88 (s, 4H), 2.34 (t, J = 7.5 Hz, 2H), 2.25 (s, 3H), 2.01 (m, 2H). Example 147
Figure imgf000165_0002
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. 1H NMR
(300MHz, CD3OD) 7.52 (m, IH), 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
Figure imgf000165_0003
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, CD3OD) 7.65 (d, J = 7.6 Hz5 IH), 7.58-7.47 (m, 2H), 7.44-7.32 (m, 2H), 6.96- 6.86 (m, 2H), 3.79 (t, J = 6.6 Hz, 2H), 3.07 (m, 2H), 2.97 (m, 2H), 2.35 (t, J = 7.5 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H). Example 149
Figure imgf000166_0001
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. 1H NMR
(300MHz5 DMSO) 9.60 (s, IH)3 7.78 (d, J= 7.5 Hz, IH), 7.64 (t, J = 7.5 Hz, IH), 7.53- 7.47 (m, 2H), 7.41 (t, J - 7.5 Hz, IH), 6.95-6.84 (m, 2H), 3.69 (t, J= 6.6 Hz5 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
Figure imgf000166_0002
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. 1H NMR
(300MHz, CD3OD) 7.53 (m, IH), 7.35 (m, IH), 7.24-7.14 (m, 3H), 6.92-6.83 (m, 2H), 3.79 (t, J= 6.7 Hz5 2H), 3.08-2.92 (m, 4H), 2.34 (t, J= 7.3 Hz, 2H), 2.26 (s, 3H), 2.01 (m, 2H).
Figure imgf000166_0003
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)
[0350] This compound was prepared as described in Scheme VII. 1H NMR
(300MHz, CD3OD) 7.54 (d, J= 7.6 Hz, IH), 6.97-6.85 (m, 5H), 3.79 (t, J= 6.7 Hz, 2H), 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
Figure imgf000167_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-ethylphenyl)- ethyl)ρhenyl)hydrazono)pyrazolyl}butanoic acid (Compound 252)
[0351] This compound was prepared as described in Scheme VII. 1H NMR
(300MHz, CD3OD) 7.54 (m, IH), 7.19-7.06 (m, 4H), 6.93-6.86 (m, 2H), 3.79 (t, J = 6.7 Hz, 2H)5 2.92 (s, 4H), 2.66 (q, J= 7.5 Hz, 2H)5 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
Figure imgf000167_0002
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. 1H NMR
(300MHz3 DMSO) 13.60 (s, IH), 12.07 (s, IH), 9.43 (s, IH), 7.50-7.43 (m, 3H), 7.27 (m, IH), 6.91 (m, IH), 6.83 (m, IH), 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
Figure imgf000167_0003
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. 1H NMR
(300MHz, CD3OD) 7.54 (m, IH), 7.00-6.95 (m, 2H), 6.92-6.85 (m, 3H), 3.79 (t, J = 6.7 Hz5 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)5 2.01 (m, 2H). Example 155
Figure imgf000168_0001
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. 1H NMR
(300MHz, CD3OD) 7.56 (m, IH), 7.52 (m, IH), 7.47-7.31 (m, 2H)5 6.96-6.87 (m, 2H), 3.80 (t, J= 6.7 Hz, 2H), 3.11 (m, 2H)5 2.95 (m, 2H), 2.34 (t, J= 7.4 Hz, 2H)5 2.26 (s, 3H), 2.01 (m, 2H).
Figure imgf000168_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-indanyl)phenyl)- hydrazono)pyrazolyl}butanoic acid (Compound 256)
[0355] This compound was prepared as described in Scheme VII. 1H NMR
(300MHz3 CD3OD) 7.55 (dd, J= 7.9, 1.5 Hz5 IH), 7.24-7.20 (m, 2H), 7.16-7.12 (m, 2H), 7.06 (dd, J = 7.9, 1.5 Hz, IH), 6.92 (t, J = 7.9 Hz, IH), 4.01 (m, IH), 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 (S5 3H)5 2.01 (m, 2H). Example 157
Figure imgf000169_0001
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. 1H NMR
(500MHz, DMSO) 12.11 (br s, IH), 9.53 (br s, IH), 7.59 (m, IH)3 7.52-7.45 (m, 3H), 7.36 (m, IH), 7.28 (m, IH)9 7.19 (m, IH), 7.10 (m, IH), 3.89 (s, 2H), 3.70 (t, J= 6.7 Hz5 2H)5 2.26 (t5 J= 7.2 Hz, 2H)5 2.21 (s, 3H)5 1.87 (m, 2H). Example 158
Figure imgf000169_0002
(±)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(l-indanylmethyl)phenyl)- hydrazono)pyrazolyl}butanoic acid (Compound 258)
[0357] This compound was prepared as described in Scheme VII. 1H NMR
(300MHz5 CD3OD) 7.58 (dd, J= 7.7, 1.1 Hz, IH)3 7.19 (m, IH), 7.13-7.06 (m, 3H)5 6.98- 6.91 (m, 2H)5 3.79 (t, J= 6.7 Hz5 2H)3 3.51 (m, IH), 3.19 (dd, J= 13.8, 6.1 Hz5 IH)3 2.93 (m5 IH)5 2.78 (m, IH)5 2.72 (dd5 J= 13.8, 9.4 Hz, IH)5 2.34 (t, J= 7.3 Hz, 2H), 2.27 (s, 3H), 2.10 (m5 IH)5 2.01 (m, 2H), 1.78 (m5 IH).
Figure imgf000169_0003
(±)-3- {2-(5 -Methy 1-3 -oxo-2,3 -dihydro-4-(2-hydroxy-3 -( 1 -indany lmethyl)phenyl)- hydrazono)pyrazolyl} benzoic acid (Compound 259)
[0358] This compound was prepared as described in Scheme VII. 1H NMR
(300MHz5 CD3OD) 8.58 (dd, J = 1.9, 1.5 Hz5 IH)5 8.49 (s, IH)3 8.12 (m, IH), 7.83 (ddd, J= 7.8, 1.5, 1.0 Hz, IH)5 7.62 (dd, J= 7.6, 1.7 Hz3 IH), 7.48 (t, J= 7.8 Hz, IH), 7.19 (m, IH)3 7.15-7.07 (m, 3H), 7.00-6.93 (m, 2H)5 3.53 (m, IH)5 3.21 (dd, J= 14.0, 5.8 Hz5 IH), 2.94 (m, IH), 2.80 (m, IH), 2.74 (dd5 J = 14.0, 9.4 Hz, IH), 2.38 (s, 3H), 2.12 (m, IH), 1.80 (m, IH). Example 160
Figure imgf000170_0001
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methylphenyl)ethyl)- phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 260)
[0359] This compound was prepared as described in Scheme VII. 1H NMR
(500MHz, DMSO) 13.78 (s, IH), 9.64 (s, IH)5 8.56 (t, J = 1.6 Hz, IH), 8.20 (m, IH), 7.79 (m, IH), 7.60 (t, J = 7.9 Hz, IH), 7.56 (m, IH), 7.22 (m, IH), 7.16-7.08 (m, 3H), 7.02 (d, J = 7.5 Hz5 IH), 6.97 (t, J = 7.5 Hz, IH), 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
Figure imgf000170_0002
3-{2-(5-Methyl-3-oxo-253-dihydro-4-(2-hydroxy-3-(2-(2-fluoro-3-methylphenyl)- ethyl)phenyl)hydraκono)pyrazolyl} benzoic acid (Compound 261)
[0360] This compound was prepared as described in Scheme VII. 1H NMR
(500MHz, DMSO) 13.75 (br s, IH), 13.15 (br s, IH), 9.66 (br s, IH), 8.55 (dd, J = 2.2, 1.6 Hz, IH), 8.20 (ddd, J= 8.2, 2.2, 1.0 Hz, IH), 7.79 (ddd, J= 7.8, 1.6, 1.0 Hz, IH), 7.60 (dd, J = 8.2, 7.8 Hz, IH), 7.55 (dd, J = 7.4, 2.2 Hz, IH), 7.16-7.10 (m, 2H), 7.01 (t, J = 7.4 Hz, IH), 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
Figure imgf000171_0001
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. 1H NMR
(500MHz3 DMSO) 13.75 (s, IH)5 9.68 (s, IH), 8.55 (t, J = 1.7 Hz, IH), 8.20 (m, IH), 7.78 (m, IH), 7.59 (t, J = 7.9 Hz, IH), 7.55 (m, IH), 7.33 (m, IH), 7.25 (m, IH), 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
Figure imgf000171_0002
3-{2-(5-MethyI-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2,6-dimethylphenyl)- ethyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 263)
[0362] This compound was prepared as described in Scheme VII. H NMR
(500MHz, DMSO) 13.79 (s, IH), 9.55 (s, IH), 8.56 (t, J= 1.7 Hz, IH), 8.20 (ddd, J= 7.9, 1.7, 1.1 Hz, IH), 7.79 (ddd, J= 7.9, 1.7, 1.1 Hz5 IH), 7.60 (t, J = 7.9 Hz3 IH), 7.57 (dd, J = 7.8, 1.6 Hz, IH), 7.05-6.98 (m, 5H), 2.83 (m, 2H), 2.78 (m, 2H), 2.35 (s, 3H), 2.32 (s, 6H). Example 164
Figure imgf000171_0003
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) [0363] This compound was prepared as described in Scheme VII. 1H NMR (500MHz, DMSO) 9.59 (br s, IH), 8.55 (s, IH), 8.20 (d, J= 7.6 Hz, IH), 7.78 (d5 J= 7.6 Hz, IH), 7.64-7.54 (m, 2H), 7.48-7.43 (m, 2H), 7.28 (dd, J= 8.4, 7.5 Hz, IH), 7.00-6.86 (m, 2H)3 3.17 (m, 2H)5 2.93 (m, 2H), 2.35 (s, 3H).
Figure imgf000172_0001
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) [0364] This compound was prepared as described in Scheme VII. !H NMR
(500MHz, DMSO) 9.58 (br s, IH), 8.55 (s, IH), 8.21 (d, J = 7.6 Hz, IH), 7.79 (m, IH), 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
Figure imgf000172_0002
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. 1H NMR
(500MHz, DMSO) 13.78 (br s, IH), 9.67 (br s, IH), 8.56 (s, IH), 8.20 (d, J = 7.9 Hz, IH)5 7.78 (m, IH)5 7.60 (t, J= 7.9 Hz, IH), 7.56 (d, J= 7.7 Hz5 IH)5 7.28-7.12 (m, 5H), 6.98 (t, J= 7.6 Hz, IH), 4.03 (m, IH), 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
Figure imgf000172_0003
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. 1H NMR
(500MHz, DMSO) 8.57 (s, IH), 8.21 (d, J= 8.0 Hz5 IH), 7.79 (m, IH), 7.65 (d, J = 8.0 Hz, IH), 7.60 (t, J= 8.0 Hz, IH), 7.53-7.50 (m, 2H), 7.47 (m, IH)5 7.41 (m, IH), 7.29 (t, J= 7.4 Hz, IH), 7.20 (t, J = 7.4 Hz, IH), 7.13 (t, J = 7.6 Hz, IH), 3.91 (s, 2H), 2.36 (s, 3H). Example 168
Figure imgf000173_0001
(£)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(254-difluorophenyl)- ethenyl)phenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 268)
[0367] This compound was prepared as described in Scheme VIII. 1H NMR
(500MHz, CD3OD) 8.48 (br s, IH), 7.78 (m, IH), 7.57-7.43 (m, 3H), 7.25 (d, J = 15.8 Hz, IH), 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
Figure imgf000173_0002
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. 1H NMR
(500MHz, CD3OD) 8.62 (m, IH), 8.21 (m, IH), 8.03 (m, IH), 7.93-7.87 (m, 2H), 7.61 (m, IH), 7.58-7.53 (m, 2H), 7.37 (m, IH), 2.42 (s, 3H)52.38 (s, 3H), 2.37 (s, 3H). Example 170
Figure imgf000174_0001
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. 1H NMR
(500MHz, CD3OD) 7.66 (s, IH)5 7.55 (s, IH), 7.49 (d, J = 7.1 Hz, IH), 7.33 (d, J= 7.1 Hz5 IH)5 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)5 2.01 (m, 2H). Example 171
Figure imgf000174_0002
3-{2-(5-Memyl-3-oxo-2,3-dihydro-4-(3-hydroxy-2-(3,4-dimethylphenyl)-4- pyridyl)hydrazono)pyrazolyl} benzoic acid (Compound 271)
[0370] This compound was prepared as described in Scheme VII. 1H NMR
(500MHz, CD3OD) 8.62 (s, IH), 8.23-8.12 (m, 2H), 7.97 (m, IH), 7.89 (m, I H), 7.60- 7.51 (m, 3H), 7.41 (m, IH), 2.42 (s, 3H), 2.39 (s, 3H), 2.39 (s, 3H). Example 172
Figure imgf000174_0003
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. 1H NMR
(500MHz, CD3OD) 8.52 (t, J= 1.6 Hz, IH), 8.17 (d, J= 6.3 Hz, IH), 8.14 (m, IH), 7.87 (d, J= 6.3 Hz, IH), 7.81 (d, J = 7.8 Hz, IH), 7.49 (t, J = 7.8 Hz, IH), 7.37 (s, 2H), 7.31 (s, IH), 2.44 (s, 6H), 2.38 (s, 3H). Example 173
Figure imgf000175_0001
3-{ l-(6-Trifluoromethyl-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2-methylphenyl)- ethyl)phenyl)hydrazono)indolyl}benzoic acid (Compound 273)
{0372] This compound was prepared as described in Scheme VII. 1H NMR
(500MHz, DMSO) 13.20 (s, IH), 9.34 (s, IH), 8.11 (dd, J = 2.0, 1.6 Hz, IH), 8.08 (ddd, J = 7.8, 1.6, 1.2 Hz, IH), 7.92 (d, J = 8.0 Hz, IH), 7.86 (ddd, J= 7.8, 2.0, 1.2 Hz, IH) ,7.77 (t, J= 7.8 Hz, IH), 7.62 (dd, J= 7.8, 1.7 Hz, IH), 7.55 (dq, J= 8.0, 0.6 Hz, IH), 7.22 (m, IH), 7.15-7.07 (m, 3H), 7.06 (m, IH), 6.95 (t, J = 7.8 Hz, IH), '6.91 (dd, J= 7.8, 1.7 Hz, IH), 2.88 (m, 2H), 2.82 (m, 2H), 2.28 (s, 3H). Example 174
Figure imgf000175_0002
4-{2-(5-Meihyl-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. 1H NMR
(500MHz, DMSO) 7.49 (d, J = 7.7 Hz, IH), 7.30-7.26 (m, 2H), 7.23-7.16 (m, 3H), 6.92 (t, J = 7.7 Hz, I H), 6.86 (dd, J= 7.7, 1.4 Hz, IH), 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
Figure imgf000175_0003
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. 1H NMR
(500MHz, DMSO) 9.43 (s, IH), 7.47 (d, J = 7.4 Hz, IH), 7.16 (t, J= 7.4 Hz, IH), 7.03- 6.90 (m, 5H), 3.69 (t, J= 6.8 Hz5 2H), 2.67 (t, J= 7.7 Hz5 2H), 2.58 (m, 2H)5 2.27 (s, 3H)5 2.25 (t, J= 7.3 Hz5 2H)5 2.19 (s, 3H)5 1.85 (m, 4H). Example 176
Figure imgf000176_0001
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. 1H NMR
(500MHz5 DMSO) 9.44 (s5 IH)5 7.47 (d, J = 7.4 Hz, IH), 7.28 (t, J = 7.4 Hz, 2H), 7.21 (m, 2H), 7.17 (tt5 J = 7.4, 1.4 Hz, IH), 6.96 (dd, J= 7.4, 1.6 Hz, IH), 6.92 (t, J = 7.4 Hz, IH)5 3.69 (t, J= 6.8 Hz, 2H)5 2.68 (t, J = 7.7 Hz5 2H), 2.62 (m, 2H), 2.25 (t, J = 7.2 Hz, 2H)5 2.19 (s, 3H), 1.86 (t, J= 7.4 Hz, 4H). Example 177
Figure imgf000176_0002
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. 1H NMR
(500MHz5 DMSO) 13.59 (s, IH), 12.09 (s, IH)5 9.45 (s, IH)5 7.48 (dd, J = 7.8, 1.2 Hz, IH), 7.15-7.04 (m, 4H)5 6.98 (dd5 J= 7.8, 1.2 Hz, IH)5 6.93 (t, J= 7.8 Hz5 IH)5 3.69 (t, J = 6.7 Hz5 2H)5 2.72 (t, J= 7.7 Hz, 2H)5 2.60 (t, J= 8.1 Hz5 2H)5 2.25 (t, J = 7.3 Hz, 2H), 2.23 (s, 3H), 2.19 (s, 3H)5 1.86 (m, 2H), 1.78 (m, 2H). Example 178
Figure imgf000176_0003
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydrσxy-3-(2-(2,4-difluorophenyl)- ethyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 278)
[0377] This compound was prepared as described in Scheme VII. 1H NMR
(300MHz, DMSO) 7.48 (m, IH), 7.34 (td, J= 8.5, 6.9 Hz, IH), 7.16 (ddd, J = 10.2, 9.5, 2.4 Hz, IH), 7.01 (tdd, J = 8.5, 2.4, 0.8 Hz, IH), 6.94-6.84 (m, 2H), 3.69 (t, J= 6.7 Hz3 2H), 2.95-2.80 (m, 4H), 2.25 (t, J= 7.2 Hz, 2H), 2.19 (s, 3H), 1.86 (m, 2H).
Figure imgf000177_0001
(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)
[0378] This compound was prepared as described in Scheme VII. 1H NMR
.(500MHz, CD3OD) 8.56 (br s, IH), 8.19 (br s, IH), 7.77 (m, IH), 7.55 (dd, J = 7.8, 1.5 Hz, IH), 7.38-7.28 (m, 2H), 6.98 (dd, J= 7.8, 1.5 Hz, IH), 6.89 (t, J= 7.8 Hz, IH), 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
Figure imgf000177_0002
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. 1H NMR
(300MHz, CD3OD) 7.48 (d, J = 7.0 Hz, IH)5 7.09-6.95 (m, 3H), 6.88 (d, J = 12.1 Hz, IH), 6.70 (d, J= 12.1 Hz, IH), 6.55 (t, J= 7.8 Hz, IH), 6.44 (d, J- 7.8 Hz, IH), 3.79 (t, J = 6.7 Hz5 2H), 2.34 (t, J= 7.5 Hz, 2H), 2.24 (s, 3H), 2.13 (s, 6H), 2.01 (m, 2H). Example 181
Figure imgf000178_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-benzofuranyl)phenyl)- hydrazono)pyrazolyl}butanoic acid (Compound 281)
[0380] This compound was prepared as described in Scheme VII. 1H NMR
(500MHz, DMSO) 7.71 (d, J = 7.4 Hz, IH), 7.69-7.62 (m, 3H), 7.48 (s, IH), 7.34 (t, J = 7.4 Hz, IH), 7.27 (t, J = 7.4 Hz, IH), 7.17 (m, IH), 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
Figure imgf000178_0002
(Z)-4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2 -hydro xy-3-(2-bromoethenyl)phenyl)- hydrazono)pyrazolyl}butanoic acid (Compound 282)
[0381] This compound was prepared as described in Scheme VII. 1H NMR
(300MHz5 CD3OD) 7.71-7.59 (m, 2H), 7.48 (d, J = 7.9 Hz, IH), 7.41 (d, J= 13.8 Hz, IH), 7.25-7.19 (m, 2H), 7.09-6.95 (m, 3H)5 6.71 (d, J = 7.9 Hz, IH), 3.79 (t, J = 6.6 Hz, 4H), 2.34 (t, J = 7.3 Hz, 4H)5 2.26 (s, 6H), 2.01 (m, 4H).
Figure imgf000178_0003
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(2)-(2-hydroxy-3-(3-methyl-l-butenyl)phenyl)- hydrazono)pyrazolyl}butanoic acid (Compound 283)
[0382] This compound was prepared as described in Scheme VII. 1H NMR
(300MHz, CD3OD) 7.60 (dd, J = 7.3, 1.6 Hz, IH), 7.00-6.90 (m, 2H), 6.30 (d, J = 1 1.3 Hz, IH), 5.65 (dd, J= 11.3, 10.4 Hz, IH), 3.79 (t, J= 6.6 Hz, 2H), 2.68 (m, IH), 2.34 (t, J = 7.3 Hz, 2H), 2.26 (s, 3H)S 2.01 (m, 2H), 1.01 (d, J= 6.6 Hz, 6H). Example 184
Figure imgf000179_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2-cyclopropylethenyl)- phenyl)hydrazono)pyrazolyl}butanoic acid (Compovmd 284)
[0383] This compound was prepared as described in Scheme VII. 1H NMR
(300MHz5 CD3OD) 7.59 (d, J= 7.8 Hz, IH), 7.22 (d, J= 7.8 Hz, IH)5 6.95 (t, J = 7.8 Hz, IH), 6.33 (d, J = 11.0 Hz, IH), 5.21 (t, J= 11.0 Hz, IH), 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, IH)5 0.81 (m, 2H)5 0.48 (in, 2H). Example 185
Figure imgf000179_0002
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. 1H NMR
(300MHz, CD3OD) 7.51 (d, J= 7.6 Hz, IH), 6.96 (d, J= 7.6 Hz5 IH), 6.91 (t, J = 7.6 Hz5 IH), 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)5 2.01 (m, 2H)5 1.62 (m, IH)5 1.49 (m5 2H)5 0.97 (d, J= 6.6 Hz, 6H). Example 186
Figure imgf000179_0003
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. 1H NMR
(300MHz, CD3OD) 7.38 (dd, J= 9.4, 3.1 Hz, IH), 7.13 (s, 2H), 7.04 (s, IH), 6.78 (dd, J= 9.2, 3.1 Hz, IH), 3.78 (t, J = 6.1 Hz5 2H)5 2.36 (s, 6H), 2.33 (t, J= 7.3 Hz, 2H)5 2.27 (s, 3H)5 2.00 (m, 2H).
Figure imgf000180_0001
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. 1H NMR
(300MHz, CD3OD) 7.66 (m, IH), 7.28 (s, IH), 7.23-7.20 (m, 2H)5 7.08-6.99 (m, 2H), 3.78 (t, J = 6.7 Hz, 2H)5 2.33 (m, 2H), 2.32 (s, 3H), 2.31 (s, 3H), 2.27 (s, 3H), 2.00 (m, 2H). Example 188
Figure imgf000180_0002
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. 1H NMR
(300MHz, CD3OD) 7.47 (d, J= 2.0 Hz5 IH)5 6.96 (d, J = 2.0 Hz, IH)5 3.78 (t, J= 6.8 Hz5 2H), 2.93 (m, IH), 2.34 (t, J= 7.1 Hz5 2H), 2.26 (s, 3H), 2.00 (m, 2H)5 1.91-1.72 (m, 5H)5 1.58-1.27 (m, 5H). Example 189
Figure imgf000180_0003
4-{2-(5-Methyl-3-oxo-253-dihydro-4-(2-hydroxy-3-(3,5-dimethylphenyl)phenyl)- hydrazono)pyrazolyl}butanoic acid (Compound 289) [0388] This compound was prepared as described in Scheme I. 1H NMR (500MHz3 Acetone-^) 10.58 (br s, IH), 8.28 (br s, IH), 7.70 (dd, J = 7.6, 1.9 Hz, IH), 7.11 (m, 2H), 7.08 (t, J = 7.6 Hz, IH), 7.04 (dd, J= 7.6, 1.9 Hz, IH), 7.03 (m, IH), 3.78 (t, J= 7.0 Hz, 2H), 2.38 (t, J= 7.4 Hz, 2H), 2.34 (m, 6H), 2.23 (s, 3H)5 2.00 (m, 2H). Example 190
Figure imgf000181_0001
3 - { 2-(5-Methyl-3 -oxo-2 ,3-dihydro-4-(2-hydroxy-3 -(3 ,5-dimethylphenyl)phenyl)- hydrazono)pyrazoly]} benzoic acid (Compound 290)
[0389] This compound was prepared as described in Scheme I. 1H NMR
(500MHz3 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 Hz3 IH)3 7.78 (ddd3 J= 8.O3 1.8, 1.0 Hz3 IH)3 7.68 (dd3 J= 5.5, 4.1 Hz, IH), 7.59 (t, J= 8.0 Hz, IH)3 7.17 (m, 2H), 7.11 (d, J = 4.1 Hz, IH), 7.11 (d, J= 5.5 Hz, IH), 7.03 (s, IH), 2.36 (s, 3H), 2.34 (s, 6H). Example 191
Figure imgf000181_0002
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. 1H NMR
(300MHz, DMSO) 8.53 (m, IH), 8.19 (d, J= 7.7 Hz, IH), 7.79 (d, J= 1.1 Hz, IH), 7.59 (t, J= 7.7 Hz, IH), 7.48 (d, J= 2.2 Hz, IH), 7.04 (d, J= 2.2 Hz, IH), 2.97 (m, IH), 2.35 (s, 3H), 1.84-1.67 (m, 6H)5 1.46-1.20 (m, 4H). Example 192
Figure imgf000182_0001
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. 1H NMR
(300MHz, CD3OD) 8.60 (s, IH), 8.17 (d, J- 7.8 Hz, IH), 7.84 (d, J = 7.8 Hz, IH)5 7.71 (m, IH), 7.50 (t, J = 7.8 Hz, IH), 7.30 (m, IH), 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
Figure imgf000182_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3-(2-methylphenyl)propyl)- phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 293)
[0392] This compound was prepared as described in Scheme VII. 1H NMR
(300MHz, DMSO) 13.75 (s, IH), 9.61 (s, IH), 8.55 (t, J = 1.6 Hz, IH), 8.20 (dd, J= 7.9, 1.2 Hz, IH), 7.78 (d, J = 7.9 Hz5 IH)5 7.59 (t, J= 7.9 Hz, IH), 7.55 (dd, J= 7.9, 1.2 Hz5 IH), 7.16-7.03 (m, 5H), 6.97 (t, J = 7.9 Hz, IH), 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
Figure imgf000182_0003
3 - {2-(5-Methy 1 -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. 1H NMR
(500MHz, DMSO) 8.57 (t, J = 1.7 Hz, IH), 8.20 (m, IH), 7.80 (m, IH), 7.75 (m, IH), 7.73 (m, IH), 7.70 (dd, J= 7.9, 1.3 Hz, IH)5 7.65 (d, J= 1.9 Hz, IH), 7.61 (t, J= 7.9 Hz, IH), 7.49 (m, IH), 7.36 (td, J= 7.5, 1.2 Hz, IH), 7.29 (td, J= 7.5, 0.8 Hz, IH), 7.24 (t, J = 7.9 Hz, IH), 2.36 (s, 3H).
Figure imgf000183_0001
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. 1H NMR
(300MHz, DMSO) 13.74 (s, IH), 9.61 (s, IH), 8.55 (t, J = 1.6 Hz, IH), 8.20 (m, IH), 7.78 (m, IH), 7.59 (t, J = 7.9 Hz, IH), 7.54 (m, IH), 7.31 (m, IH)5 7.24 (m, IH), 7.16- 7.1 1 (m, 2H)5 7.02 (m, IH), 6.97 (t, J= 7.7 Hz, IH), 2.72 (t, J= 7.7 Hz, 2H), 2.67 (t, J = 7.7 Hz, 2H)5 2.34 (s, 3H), 1.85 (m, 2H). Example 196
Figure imgf000183_0002
3-{2-(5-Methyl-3-oxo-3,4-dihydro-4(Z)-(2-hydroxy-3-(3,4-dimethylphenyl)- pheπyl)aminomethylidene)pyrazolyl} benzoic acid (Compound 296)
[0395] This compound was prepared as described in Scheme VIII. 1H NMR
(500MHz, DMSO) 1 1.77 (m, IH), 9.37 (s, IH)3 8.73 (m, IH), 8.64 (m, IH), 8.25 (ddd, J = 8.1, 2.2, 1.0 Hz5 IH), 7.76 (m, IH), 7.70 (ddd, J = 7.7, 1.6, 1.0 Hz, IH), 7.52 (dd, J = 8.1, 7.7 Hz5 IH), 7.34 (m, IH), 7.26 (dd, J = 7.8, 1.7 Hz5 IH), 7.23 (d, J = 7.8 Hz, IH), 7.10-7.05 (m, 2H)5 2.33 (s, 3H), 2.29 (s, 3H), 2.27 (s, 3H).
Figure imgf000183_0003
3 - {2-(5-MethyI-3 -oxo-3 ,4-dihy dro-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. 1H NMR
(500MHz5 DMSO) 11.78 (s, IH), 8.74 (br s, IH), 8.65 (m3 IH), 8.24 (m, IH), 7.76 (m, IH), 7.70 (m, IH), 7.52 (t, J = 7.9 Hz, I H), 7.16 (s, 2H), 7.10-7.05 (m, 2H), 7.01 (s, IH), 2.33 (s, 9H).
Figure imgf000184_0001
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. 1H NMR
(500MHz, DMSO) 8.53 (s, IH), 7.64 (m, IH), 7.33 (d, J = 1.6 Hz, IH), 7.25 (dd, J- 7.7, 1.6 Hz, IH), 7.21 (d, J= 7.7 Hz, IH), 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= IA Hz, 2H), 2.18 (s, 3H), 1.82 (m, 2H). Example 199
Figure imgf000184_0002
3-{ l-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl)- phenyl)hydrazono)indolyl} propionic acid (Compound 299)
[0398] This compound was prepared as described in Scheme II. 1H NMR
(500MHz5 CD3OD) 7.63 (dd, J= 7.7, 1.6 Hz, IH), 7.61 (m, IH), 7.27 (td, J = 7.7, 1.2 Hz, IH), 7.12-7.08 (m, 4H), 7.00 (m, IH), 6.98 (t, J= 7.7 Hz, IH), 6.88 (dd, J= 7.7, 1.6 Hz, IH), 4.10 (t, J= 7.2 Hz, 2H), 2.71 (t, J= 7.2 Hz5 2H), 2.36 (s, 6H). Example 200
Figure imgf000185_0001
3-{ l-(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. 1H NMR
(500MHz, DMSO) 13.01 (s, IH), 9.37 (br s, IH)3 8.07 (dd, J = 2.0, 1.7 Hz3 IH), 8.05 (ddd, J = 7.8, 1.7, 1.2 Hz3 IH), 7.82 (ddd, J- 7.8, 2.0, 1.2 Hz, IH), 7.74 (t, J = 7.8 Hz, IH), 7.72 (dd, J= 7.5, 1.0 Hz, IH), 7.57 (dd, J = 8.1, 1.5 Hz, IH), 7.29 (td, J = 7.5, 1.0 Hz3 IH), 7.28 (t, J= 7.1 Hz, 2H)3 7.23 (m, 2H), 7.20 (td, J= 7.5, 1.0 Hz, IH), 7.18 (tt, J = 7.1, 1.5 Hz, IH), 6.94-6.90 (m, 2H), 6.75 (dd, J= 7.7, 1.5 Hz, IH), 4.02 (s, 2H). Example 201
Figure imgf000185_0002
3-{l-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2-methylphenyl)ethyl)phenyl)- hydrazono)indolyl}propionic acid (Compound 301)
[0400] This compound was prepared as described in Scheme VII. 1H NMR
(500MHz3 CD3OD) 7.61 (d, J= 7.6 Hz, I H)3 7.49 (dd, J= 8.O3 1.4 Hz3 IH), 7.29 (td, J = 7.6, 0.9 Hz3 IH), 7.17-7.03 (m, 6H), 6.86 (dd, J = 8.0, 7.5 Hz3 IH), 6.73 (dd, J = 7.5, 1.4 Hz, IH), 4.13 (t, J= 7.3 Hz, 2H), 2.90 (s, 4H), 2.71 (t, J= 7.3 Hz3 2H), 2.30 (s, 3H). Example 202
Figure imgf000185_0003
3-{l-(6-Chloro-2-oxo-233-dihydro-3(Z)-(2-hydroxy-3-(3-(3-methylphenyl)propyl)- phenyl)aminornethylidene)indolyl}benzoic acid (Compound 302)
[0401] This compound was prepared as described in Scheme VIII. 1H NMR
(50OMHz5 DMSO) 11.13 (d, J = 13.4 Hz, IH), 9.17 (br s, IH), 8.89 (d, J= 13.4 Hz3 IH)3 8.03-8.00 (m, 2H), 7.79 (m, IH), 7.78 (d, J = 8.1 Hz, IH), 7.72 (t, J = 7.9 Hz, IH), 7.55 (dd, J = 7.9, 1.5 Hz, IH), 7.15 (t, J = 1.S Hz, IH)5 7.14 (dd, J = 8.1, 2.0 Hz, IH), 7.02- 6.96 (in, 3H), 6.93 (t, J= 7.9 Hz, IH), 6.88 (dd, J= 7.9, 1.5 Hz5 IH), 6.86 (d, J= 2.0 Hz, IH), 2.67 (t, J= 7.7 Hz, 2H), 2.58 (m, 2H), 2.27 (s, 3H), 1.83 (m, 2H). Example 203
Figure imgf000186_0001
(-t)-3-{l-(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(l ,2-dihydro-l-methyl-2- indolylphenyl)aminomethylidene)indolyl}benzoic acid (Compound 303)
[0402] This compound was prepared as described in Scheme VIII. 1H NMR
(500MHz, DMSO) 11.14 (d, J = 13.2 Hz, IH), 9.78 (br s, IH), 8.94 (d, J= 13.2 Hz, IH), 8.03-7.99 (m, 2H), 7.79 (m, IH), 7.79 (d, J = 8.1 Hz, IH), 7.72 (t, J= 7.7 Hz, IH), 7.67 (dd, J = 8.1, 1.2 Hz, IH), 7.16 (dd, J= 8.1, 2.0 Hz, IH), 7.14-7.08 (m, 3H), 7.03 (t, J = 7.8 Hz, IH), 6.87 (d, J= 2.0 Hz5 IH), 6.76-6.70 (m, 2H), 4.65 (dd, J= 11.2, 8.7 Hz, IH), 3.41 (dd, J= 15.6, 8.7 Hz, IH), 2.72 (dd, J= 15.6, 11.2 Hz, IH)32.62 (s, 3H). Example 204
Figure imgf000186_0002
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. 1H NMR
(500MHz, DMSO) 13.57 (br s, IH), 12.12 (br s, I H), 10.50 (s, I H), 10.27 (br s, IH), 7.63 (m, IH), 7.54 (m, IH), 7.45 (m, IH), 7.37-7.32 (m, 2H)5 7.24 (m, IH)5 7.02 (m, IH), 3.70 (t5 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
Figure imgf000187_0001
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. 1H NMR
(500MHz, DMSO) 10.30 (br s, IH), 7.65 (d, J = 7.3 Hz, IH), 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 Hz3 2H), 2.21 (s, 3H), 1.86 (m, 2H). Example 206
Figure imgf000187_0002
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(2-(2-fluorophenyl)ethyl)indolylidene)- hydrazinophenyl} benzoic acid (Compound 306)
[0405] This compound was prepared as described in Scheme IX. 1H NMR
(500MHz3 DMSO) 13.03 (s, IH), 12.97 (s, IH), 9.23 (s, IH), 8.12 (t, J = 1.7 Hz, IH), 7.95 (ddd, J= 7.7, 1.7, 1.2 Hz, IH), 7.79 (ddd, J= 7.7, 1.7, 1.2 Hz, IH), 7.67 (dd, J= 8.1 , 1.6 Hz, IH), 7.62 (m, IH), 7.60 (t, J= 7.7 Hz, IH), 7.34-7.23 (m, 3H), 7.15-7.07 (m, 5H), 6.98 (dd, J= 7.7, 1.6 Hz, IH), 4.04 (dd, J= 7.2, 6.8 Hz, 2H), 3.02 (t, J= 7.2 Hz, 2H). Example 207
Figure imgf000188_0001
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(2-(2-chlorophenyl)ethyl)indolylidene)- hydrazinophenyl} benzoic acid (Compound 307)
[0406] This compound was prepared as described in Scheme IX. 1H NMR
(500MHz5 DMSO) 13.03 (s, IH), 12.97 (s, IH), 9.23 (s, IH), 8.12 (t, J = 1.6 Hz, IH), 7.94 (ddd, J= 7.7, 1.6, 1.2 Hz3 IH)3 7.79 (ddd, J = 7.7, 1.6, 1.2 Hz, IH), 7.68 (dd, J= 7.8, 1.6 Hz3 IH), 7.62 (m, IH), 7.60 (t, J= 7.7 Hz, IH)3 7.41 (m, IH), 7.34 (m, IH), 7.29 (td, J = 7.7, 1.2 Hz3 IH), 7.27-7.22 (m, 2H), 7.13-7.06 (m, 3H), 6.98 (dd, J= 7.8, 1.6 Hz, IH)3 4.05 (t, J= 7.3 Hz, 2H), 3.10 (t, J= 7.3 Hz, 2H). Example 208
Figure imgf000188_0002
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. 1H NMR
(500MHz, DMSO) 8.53 (X, J= 1.6 Hz, IH), 8.20-8.15 (m, 2H), 8.04 (ddd, J= 7.7, 1.6, 1.1 Hz3 IH)3 7.71-7.64 (m3 3H), 7.61 (dd, J= 8.4, 2.3 Hz, IH)3 7.22 (d3 J= 8.4 Hz3 IH), 2.34 (s, 3H)3 2.27 (s, 3H), 2.23 (s, 3H). Example 209
Figure imgf000189_0001
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. 1H NMR
(500MHz, DMSO) 13.75 (s, IH), 9.66 (s, IH), 8.10 (d, J = 8.8 Hz, 2H)5 8.04 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 7.6 Hz5 IH)5 7.22 (dd, J= 7.3, 1.6 Hz, IH), 7.16-7.08 (m, 3H), 7.02 (d5 J = 7.6 Hz, IH), 6.97 (t, J= 7.6 Hz, IH), 2.93-2.87 (m, 2H), 2.86-2.80 (m, 2H), 2.35 (S5 3H), 2.29 (s, 3H). Example 210
Figure imgf000189_0002
3-{3-Hydroxy-2-(2-oxo-2,3-dihydro-l-(3,5-dimethylphenyl)-3-indolylidene-hydrazino)- 4-pyridyl} benzoic acid (Compound 310)
[0409] This compound was prepared as described in Scheme IX. 1H NMR
(500MHz5 DMSO) 13.02 (br s5 IH), 9.68 (br s, IH), 8.52 (br s, IH), 8.25 (br s, IH), 8.16 (br s, IH), 7.96 (d, J= 7.1 Hz, IH), 7.76 (d, J = 7.1 Hz3 IH)5 7.61 (t, J= 7.7 Hz, IH), 7.60 (m, IH), 7.35 (td, J = 7.6, 1.2 Hz, IH), 7.21 (td, J= 7.6, Q.I Hz, IH), 7.16-7.13 (m, 3H), 6.89 (d, J= 7.6 Hz, IH), 2.37 (s, 6H). Example 21 1
Figure imgf000189_0003
3-{l-(2-Oxo-2,3-dihydro-3-(3-hydroxy-6-methyl-4-(3,4-dimethylphenyl)-2- pyridyl)hydrazono)indolyl} benzoic acid (Compound 311)
[0410] This compound was prepared as described in Scheme VlI. 1H NMR
(500MHz3 DMSO) 12.93 (s, IH), 8.07 (t, J = 1.7 Hz, IH), 8.04 (m, IH)3 7.81-7.74 (m, 2H), 7.74-7.60 (m, 3H), 7.42 (s, IH), 7.35 (t, J = 7.6 Hz, IH)3 7.23 (t, J = 7.6 Hz, IH)3 7.20 (d, J = 7.9 Hz3 IH), 6.92 (d, J= 7.6 Hz, IH), 2.47 (s, 3H), 2.28 (s, 3H)3 2.27 (s, 3H). Example 212
3- {2-(5 -Methyl-3 -oxo-2,3 -dihydro-4-(3 -hydroxy-6-methyl-4-(3 ,4-dimethylpheny l)-2- pyridyl)hydrazono)pyrazolyl} benzoic acid (Compound 312)
[0411] This compound was prepared as described in Scheme VII. 1H NMR
(500MHz5 DMSO) 8.50 (dd3 J = 2.1, 1.6 Hz3 IH), 8.15 (ddd, J = 8. I 3 2.1, 1.0 Hz, IH), 7.82 (ddd, J= 7.7, 1.6, 1.0 Hz, IH), 7.71 (s, IH)3 7.62-7.54 (m, 2H), 7.62 (dd, J= 8.I5 7.7 Hz, IH), 7.34 (d, J= 7.8 Hz, IH)5 2.63 (s3 3H), 2.38 (s, 3H), 2.32 (s, 6H). Example 213
Figure imgf000190_0002
3-{3-Hydroxy-4-(2-oxo-2,3-dihydro-l-(3,5-dimethylphenyl)-6-trifluoromethyl-3- indolylidenehydrazino)-2-pyridyl}benzoic acid (Compound 313)
[0412] This compound was prepared as described in Scheme IX. 1H NMR
(500MHz, DMSO) 13.25 (s, IH)5 8.42 (t, J = 1.5 Hz3 IH), 8.32 (d, J = 6.1 Hz, IH), 8.10 (dd, J= 7.8, 1.5 Hz5 IH), 8.10 (m, IH)3 8.03 (d, J= 7.9 Hz, IH), 7.93 (d, J= 6.1 Hz, IH), 7.72 (t, J= 7.8 Hz, IH), 7.61 (dq, J = 7.9, 0.8 Hz, IH), 7.19 (m, IH)3 7.17 (m, 2H), 6.99 (m, IH), 2.37 (s, 6H). Example 214
Figure imgf000191_0001
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. 1H NMR
(500MHz, CD3OD) 7.89 (m, IH), 7.80 (m, IH), 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)5 2.28 (s, 3H), 2.01 (m, 2H). Example 215
Figure imgf000191_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(3-hydroxy-5-phenyl-2-benzothienyl)- hydrazono)ρyrazolyl}butanoic acid (Compound 315)
[0414] This compound was prepared as described in Scheme VI. 1H NMR
(500MHz, DMSO) 12.13 (s, IH), 11.25 (s, IH), 8.04 (d, J = 1.8 Hz, IH), 7.89 (d, J= 8.4 Hz, IH), 7.74 (m, 2H), 7.70 (dd, J = 8.4, 1.8 Hz, IH), 7.51 (t, J= 7.6 Hz, 2H), 7.40 (tt, J = 7.6, 1.0 Hz, IH), 3.85 (t, J= 6.7 Hz, 2H), 2.31-2.23 (m, 5H), 1.92 (m, 2H). Example 216
Figure imgf000191_0003
3-{3-Hydroxy-2-(5-methyl-3-oxo-2,3-dihydro-2-(3,4-dimethylphenyl)-4- pyrazolidene)hydrazino-5-benzothienyl}benzoic acid (Compound 316) [0415] This compound was prepared as described in Scheme VI. 1H NMR (500MHz5 DMSO) 8.29 (t, J = 1.6 Hz, IH), 8.18 (d, J = 1.7 Hz5 IH)5 8.01 (ddd, J= 7.8, 1.6, 0.9 Hz, IH), 7.97 (ddd, J= 7.8, 1.6, 0.9 Hz, IH), 7.96 (d, J= 8.3 Hz, IH), 7.73 (dd, J = 8.3, 1.7 Hz3 IH), 7.69 (d, J= 1.7 Hz, IH), 7.64 (t, J= 7.8 Hz, IH), 7.62 (dd, J= 8.3, 1.7 Hz, IH), 7.22 (d, J= 8.3 Hz3 IH), 2.31 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H). Example 217
Figure imgf000192_0001
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. 1H NMR
(500MHz, DMSO) 12.13 (s, IH), 7.99 (dd, J= 7.6, 1.2 Hz, IH), 7.75 (dd, J= 7.6, 1.2 Hz, IH), 7.71 (t, J= 7.6 Hz, IH), 7.58-7.55 (m, 2H), 7.50 (m, IH), 7.15 (m, IH), 3.86 (s, 3H), 3.69 (t, J= 7.0 Hz, 2H), 3.63 (s, 3H), 2.26 (t, J= 7.0 Hz5 2H), 2.18 (s, 3H), 1.86 (qn, J = 7.0 Hz, 2H).
Example 218
Figure imgf000192_0002
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. 1H NMR
(500MHz, CD3OD) 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 Hz5 2H), 2.20 (s, 3H), 2.03 (m, 2H)5 1.28 (d, J = 7.0 Hz, 6H), 1.23 (d, J= 6.7 Hz, 6H). Example 219
Figure imgf000193_0001
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. 1H NMR
(500MHz5 CD3OD) 8.52 (br s, IH), 7.55 (m, IH), 7.1 1-7.09 (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
Figure imgf000193_0002
(±)-4_{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2,3-dihydro-l-methyl-2-oxo-3- indolyl)methyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 320)
[0419] This compound was prepared as described in Scheme VII. 1H NMR
(300MHz, CD3OD) 7.64 (dd, JM8.0, 1.3 Hz, IH), 7.32 (td, J=7.7, 0.9 Hz, IH), 7.01-6.91 (m, 2H), 6.84 (dd, J=8.0, 7.6 Hz, IH), 6.78 (m, IH), 6.62 (dd, J=7.6, 1.3 Hz, IH), 3.79 (t, J=6.7 Hz5 2H), 3.51 (d, J=14.4 Hz, IH), 3.20 (s, 3H), 2.81 (d, J=I 4.4 Hz, IH), 2.33 (t, J=7.5 Hz, 3H), 2.27 (s, 3H), 2.01 (m, 2H). Example 221
Figure imgf000193_0003
3-{ l-(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. 1H NMR
(500MHz, DMSO) 13.10 (s, IH), 9.24 (s, IH), 8.08 (t, J=I.8 Hz, IH), 8.04 (m, IH), 7.82 (m, IH), 7.74 (t, J=7.7 Hz, IH), 7.61 (dd, J=7.9, 1.6 Hz, IH), 7.55 (dd, J=8.2, 2.6 Hz, IH), 7.22 (m, IH), 7.16-7.07 (m, 4H), 6.96-6.92 (m, 2H), 6.88 (dd, J=7.6, 1.6 Hz, IH), 2.87 (m, 2H), 2.81 (m, 2H), 2.28 (s, 3H). Example 222
Figure imgf000194_0001
3-{2-(5-Methyl-3-oxo-253-dihydro-4-(2-hydroxy-3-(2-(2,5-dimethylphenyl)- ethyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 322)
(0421 J This compound was prepared as described in Scheme VII. 1H NMR
(500MHz, DMSO) 13.77 (s, IH), 9.62 (s, IH), 8.56 (m, IH), 8.21 (m, IH), 7.78 (d, JM7.8 Hz, IH), 7.63-7.53 (m, 2H), 7.08-6.88 (m, 5H)5 2.87 (m, 2H)5 2.77 (m, 2H), 2.35 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H). Example 223
Figure imgf000194_0002
(±)-3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2,3-dihydro-l-methyl-2-oxo-3- indolyl)methyl)phenyl)hydrazono)pyrazolyl}benzoic acid (Compound 323)
[0422] This compound was prepared as described in Scheme VII. !H NMR
(300MHz, CD3OD) 8.59 (dd, J=2.I, 1.6 Hz, IH), 8.19 (ddd, J=8.2, 2.1, 1.0 Hz, IH), 7.82 (ddd, J=7.7, 1.6, 1.0 Hz, IH), 7.60 (dd, J=8.1, 1.4 Hz, IH)5 7.49 (dd, J=8.2, 7.7 Hz3 IH), 7.32 (td, J-7.6, 1.2 Hz, I H), 7.00-6.93 (m, 2H)3 6.83-6.79 (m, 2H), 6.60 (dd, J-7.6, 1.4 Hz, IH), 3.51 (d, J=14.4 Hz, IH), 3.20 (s, 3H), 2.80 (d, J=14.4 Hz, IH), 2.34 (s, 3H). Example 224
Figure imgf000194_0003
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2'hydroxy-3-(l,2-dihydro-l-methyl-2-oxo-3- indolylidene)methyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 324)
[0423] This compound was prepared as described in Scheme VII. 1H NMR
(500MHz, DMSO) 13.65 (br s, IH), 13.16 (br s, IH), 10.54 (s, IH), 8.53 (dd, J=2.1, 1.6 Hz, IH), 8.20 (ddd, J=8.2, 2.1, 1.0 Hz, I H), 7.84-7.76 (m, 3H), 7.59 (dd, J=8.2, 7.9 Hz, IH), 7.46 (m, IH), 7.40 (d, J=7.6 Hz, IH), 7.34 (td, J=7.6, 1.0 Hz, IH), 7.16 (m, IH), 7.07 (d, J=7.6 Hz, IH), 6.93 (td, J=7.6, 1.0 Hz, IH), 3.24 (s, 3H), 2.37 (s, 3H).
Figure imgf000195_0001
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. 1H NMR
(500MHz, DMSO) 13.77 (s, IH), 13.15 (s, IH), 9.66 (s, IH)1 8.55 (dd, J=2.1, 1.6 Hz, IH), 8.20 (ddd, J=8.2, 2.1, 1.0 Hz, IH), 7.79 (ddd, J=7.8, 1.6, 1.1 Hz, IH), 7.60 (dd, J=8.2, 7.8 Hz, IH)3 7.57 (dd, J=7.9, 1.6 Hz, IH), 7.17 (dd, J=8.2, 6.1 Hz, IH), 7.07 (dd, J=10.3, 2.8 Hz, IH), 7.02 (dd, J=7.6, 1.6 Hz, IH), 6.97 (m, IH), 6.92 (ddd, J=8.6, 8.2, 2.8 Hz, IH), 2.90 (m, 2H), 2.83 (m, 2H), 2.35 (s, 3H), 2.25 (s, 3H). Example 226
Figure imgf000195_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(£)-(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. 1H NMR
(300MHz5 DMSO) 7.85 (m, IH), 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
Figure imgf000196_0001
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. 1H NMR
(300MHz, CD3OD) 8.61 (dd, J=2.1, 1.5 Hz, IH), 8.20 (ddd, J=8.1 , 2.1, 1.0 Hz, IH), 7.84 (ddd, J=7.7, 1.5, 1.0 Hz, IH), 7.54 (m, IH), 7.52 (dd, J=8.1, 7.7 Hz, IH), 6.97 (m, IH), 6.88 (t, J=7.8 Hz, IH), 2.36 (s, 3H), 2.28 (s, 3H).
Figure imgf000196_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(l,2-dihydro-l-methyl-2-oxo-3- indolylidene)methyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 328)
[0427] This compound was prepared as described in Scheme VII. 1H NMR
(500MHz, DMSO) 13.54 (s, IH), 10.41 (br s, IH), 8.42 (br, IH), 7.76 (s, IH) ,7.74 (m, IH)5 7.43-7.37 (m, 2H), 7.33 (t, J=7.8 Hz, IH), 7.12 (t, J=7.8 Hz, IH), 7.06 (d, J=7.8 Hz, IH), 6.92 (t, J=7.8 Hz, IH), 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
Figure imgf000196_0003
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. 1H NMR
(300MHz, CD3OD) 7.53 (m, IH), 7.09 (dd, J=8.4, 6.1 Hz, IH), 6.93-6.84 (m, 3H)3 6.78 (td, J=8.4, 2.8 Hz, IH), 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
Figure imgf000197_0001
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)
[0429] This compound was prepared as described in Scheme VII. 1H NMR
(300MHz, CD3OD) 7.53 (m, IH), 7.21 (m, IH), 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)5 2.01 (m, 2H). Example 231
Figure imgf000197_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£r)-(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
Figure imgf000197_0003
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(2-(2-methylphenyl)- ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 332)
[0.431] This compound can be prepared as described in Scheme VII.
Example 233
Figure imgf000198_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(2-(5-fluoro-2- methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 333)
[0432] This compound was prepared as described in Scheme VII. H NMR
(300MHz, CD3OD) 7.63 (d, J = 8.0 Hz, IH)5 7.49-7.29 (m, 4H), 7.18 (dd, J = 8.3, 6.2 Hz, IH), 7.03 (m, IH), 6.89 (td, J = 8.3, 2.3 Hz, IH), 3.79 (t, J = 6.6 Hz, 2H), 2.40 (s, 3H)5 2.34 (t, J = 7.4 Hz, 2H)3 2.26 (s, 3H), 2.01 (m, 2H).
[0433] [0432] This compound can be prepared as described in Scheme VII. Example 234
Figure imgf000198_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(2)-(2-(5-fluoro-2- methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 334) [0434] This compound can be prepared as described in Scheme VII.
Example 235
Figure imgf000198_0003
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) [0435] This compound can be prepared as described in Scheme VII.
Example 236
Figure imgf000199_0001
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
Figure imgf000199_0002
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
Figure imgf000199_0003
4- { 2-(5 -Methy 1-3 -oxo-2 ,3 -dihydro-4-(2 -hydroxy-3 (£)-(2-pheny lethenyl)- phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 338)
[0438] This compound can be prepared as described in Scheme VII.
Example 239
Figure imgf000199_0004
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. Example 240
Figure imgf000200_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(2-methylphenyl)ethynyl)- phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 340)
[0440] This compound can be prepared as described in Scheme VII.
Example 241
Figure imgf000200_0002
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
Figure imgf000200_0003
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
Figure imgf000200_0004
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. Example 244
Figure imgf000201_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(2-(2-trifluoromethyl- phenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 344)
[0444] This compound can be prepared as described in Scheme VII.
Example 245
Figure imgf000201_0002
4- { 2-(5-Methy 1-3 -oxo-2,3-dihydro-4-(2-hydroxy-3 -( 1 -methyl- 1 -indenyl -2-)phenyl)- hydrazono)pyrazolyl}butanoic acid (Compound 345)
This compound can be prepared as described in Scheme VII.
Example 246
Figure imgf000201_0003
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(3,3-dirnethyl-2- indenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 346)
[0445] This compound can be prepared as described in Scheme VII.
Example 247
Figure imgf000201_0004
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-5-methoxy-3-(2-indenyl)- phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 347) [0446] This compound can be prepared as described in Scheme VII.
Example 248
Figure imgf000202_0001
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
Figure imgf000202_0002
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)
[0448] This compound can be prepared as described in Scheme VII.
Example 250
Figure imgf000202_0003
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-6-trifluoromethyl-l-(2-(2-methylphenyl)-ethyl)- 3(Z)-indolylidene)methylaminophenyl}benzoic acid (Compound 350)
[0449] This compound was prepared as described in Scheme VIII. 1H NMR
(500MHz, DMSO) 13.05 (s, IH), 11.29 (d, J = 13.4 Hz5 IH), 9.39 (s, IH), 8.95 (d, J = 13.4 Hz, IH), 8.13 (m, IH), 7.95 (dd, J = 7.8, 1.0 Hz, IH), 7.83 (d, J = 8.1 Hz, IH), 7.80 (m, IH), 7.75 (d, J = 8.1 Hz, IH), 7.61 (t, J = 7.8 Hz, IH), 7.31 (d, J = 7.8 Hz, IH), 7.20 (m, IH), 7.16-7.07 (m, 5H), 7.05 (d, J = 7.8 Hz5 IH)5 4.06 (t, J = 7.4 Hz, 2H)5 2.93 (t, J •■ 7.4 Hz, 2H), 2.32 (s, 3H). Example 251
Figure imgf000203_0001
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-6-trifluoromethyl-l-(2-indenyl)-3(Z)- indolylidene)methylaminophenyl}benzoic acid (Compound 351)
[0450] This compound can be prepared as described in Scheme VIII.
Example 252
Figure imgf000203_0002
(±)4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(l,2,3,4-tetrahydro)- naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 352)
[0451J This compound was prepared as described in Scheme VII. 1H NMR
(500MHz, CD3OD) 7.57 (dd, J = 8.0, 1.6 Hz, IH), 7.1 1-7.04 (m, 5H), 7.00 (t, J = 8.0 Hz, IH), 3.79 (t, J = 6.7 Hz, 2H), 3.39 (m, IH), 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
Figure imgf000203_0003
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
Figure imgf000204_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(l-indanylidene)- methylphenyl)hydrazono)pyrazolyl}butanoic acid (Compound 354)
[0453] This compound can be prepared as described in Scheme VII.
Example 255
Figure imgf000204_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(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
Figure imgf000204_0003
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
Figure imgf000204_0004
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-{2-hydroxy-3(£)-(2-(6-fluoro-2- methylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 357) • [0456] This compound can be prepared as described in Scheme VII.
Example 258
Figure imgf000205_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(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
Figure imgf000205_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(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
Figure imgf000205_0003
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(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
Figure imgf000206_0001
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)
[0460] This compound can be prepared as described in Scheme VII.
Example 262
Figure imgf000206_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(J£}-(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
Figure imgf000206_0003
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
Figure imgf000206_0004
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(l-(l,2,3,4-tetrahydro)- naphthylidene)methylphenyl)hydrazono)pyrazolyl}butanoic acid (Compound 364) [0463] This compound can be prepared as described in Scheme VII. Example 265
Figure imgf000207_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(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
Figure imgf000207_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(F)-(2-(3,5-dimethyl-4- isoxazolyl)ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 366) [0465J This compound can be prepared as described in Scheme VIl.
Example 267
Figure imgf000207_0003
4-{2-(5-Methyl-3-oxo-253-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
Figure imgf000208_0001
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l -(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
Figure imgf000208_0002
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
Figure imgf000208_0003
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(2-indenyl)-3(Z)-indolylidene)methyl- aminophenyl}benzoic acid (Compound 370)
[0469] This compound can be prepared as described in Scheme VIII.
Example 271
Figure imgf000209_0001
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, IH)5 13.13 (br s, IH), 10.23 (s, IH), 8.54 (dd, J = 2.1, 1.6 Hz, IH), 8.21 (ddd, J = 8.0, 2.1, 1.0 Hz, IH), 7.79 (ddd, J = 7.8, 1.6, 1.0 Hz, IH), 7.65 (dd, J = 7.9, 1.3 Hz, IH), 7.60 (dd, J = 8.0, 7.8 Hz, IH), 7.60 (dd, J = 7.9, 1.3 Hz, IH), 7.55 (dd, J = 10.6, 2.8 Hz, IH), 7.50 (d, J = 15.9 Hz, IH), 7.35 (dd, J = 15.9, 1.5 Hz, IH), 7.26 (dd, J = 8.4, 6.2 Hz, IH), 7.07 (t, J = 7.9 Hz, IH), 7.04 (td, J = 8.4, 2.8 Hz, IH)5 2.39 (s, 3H), 2.35 (s, 3H). Example 272
Figure imgf000209_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-methylphenyl)hydrazono)- pyrazolyl}butanoic acid (Compound 372)
[0471] This compound was prepared as described in Scheme VII. 1H NMR
(500MHz, DMSO) 13.57 (br s, IH), 12.11 (br s, IH), 9.45 (br s, IH), 7.46 (d, J = 7.8 Hz, IH)5 6.95 (m, IH), 6.89 (t, J = 7.8 Hz, IH), 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
Figure imgf000209_0003
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. Example 274
Figure imgf000210_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2- indanylmethyl)pheπyl)hydrazono)pyrazolyl}butanoic acid (Compound 374)
[0473] This compound can be prepared as described in Scheme VII.
Example 275
Figure imgf000210_0002
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(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
Figure imgf000210_0003
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(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
Figure imgf000210_0004
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) [0476] This compound can be prepared as described in Scheme VII.
Example 278
Figure imgf000211_0001
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(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
Figure imgf000211_0002
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(2-(2,3-difluoroρhenyl)- ethenyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 379)
[0478] This compound can be prepared as described in Scheme VII.
Example 280
Figure imgf000211_0003
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(J£)-(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
Figure imgf000212_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(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
Figure imgf000212_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(-£)-(2-(2-chlorophenyl)- ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 382)
[0481] This compound can be prepared as described in Scheme VII.
Example 283
Figure imgf000212_0003
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(iO-(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
Figure imgf000212_0004
4- { 2-(5-Methyl-3 -oxo-2,3-dihydro-4-(2-hydroxy-3 (E)-(2 -(3 -chloropheny I)- ethenyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 384) [0483] This compound can be prepared as described in Scheme VII.
Figure imgf000213_0001
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(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
Figure imgf000213_0002
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(£)-(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
Figure imgf000213_0003
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(^)-(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
Figure imgf000214_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3(jB}-(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
Figure imgf000214_0002
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydτoxy-3(JET)-(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
Figure imgf000214_0003
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3C£)-(2-(2,4- dichloromethylphenyl)ethenyl)phenyl)hydrazono)pyrazolyl }benzoic acid (Compound 390)
[0489] This compound can be prepared as described in Scheme VII.
Example 291
Figure imgf000214_0004
3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(334-dihydro)- naphthyl)phenyl)hydrazono)pyrazolyl} benzoic acid (Compound 353)
[0490J This compound can be prepared as described in Scheme VII.
Example 292
Figure imgf000215_0001
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)
[0491] This compound can be prepared as described in Scheme VII.
Example 293
Figure imgf000215_0002
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
Figure imgf000215_0003
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
Figure imgf000216_0001
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(354-dihydro-7-fluoro)- naphthyl)phenyl)hydrazono)pyrazolyl}butanoic acid (Compound 395)
[0494] This compound can be prepared as described in Scheme VII.
Example 296
Figure imgf000216_0002
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
Figure imgf000216_0003
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
Figure imgf000216_0004
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)
[0497] This compound can be prepared as described in Scheme VII.
Example 299
Figure imgf000217_0001
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)
[0498] This compound can be prepared as described in Scheme VII.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I, II, III, IV, V, or VI:
Figure imgf000218_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted Ci-Cg alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted CrC6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R2 is independently selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted C1-CO heteroalkyl;
R3 and R4 are independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted C1-C6 haloalkyl, and an optionally substituted C]-C6 heteroalkyl;
R5 is selected from hydrogen, halogen, OR14, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R6 is selected from an optionally substituted Ci-Ci0 alkyl, an optionally substituted C]-CiO haloalkyl, and an optionally substituted Ci-Cio heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R6 is selected from (CH2)P1R18, C(O)NHR1 s, C≡CR18, CR3=CR4R18, and CR3=R18; R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NRl4Rls and a carboxylic acid bioisostere; each R8 and each R9 is independently selected from hydrogen, OR16, NR16R17, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted CpC6 heteroalkyl, (CH2)mR18, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-Cs ring;
R10 is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted C)-C6 heteroalkyl;
R11 is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or R11 and R4 are linked to form a optionally substituted heterocycle;
R12 is selected from hydrogen, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci- Ce heteroalkyl, and C)-Ce haloheteroalkyl;
R13 is selected from hydrogen, halogen, CN, NO2, CO2R14, S(O)mR14, C,- C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, and C1-C4 haloheteroalkyl;
R14 is selected from hydrogen, C]-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and CpC6 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
R16 and R17 are each independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted CrC6 heteroalkyl, and (CH2)JR.18; or one of R16 and R17 is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C3-C8 ring;
R18 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 R18 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;
R19 is selected from hydrogen, Ci-C3 alkyl, C1-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 O5 NR4, CR3R4, CO, and null;
W is selected from O, NR4, CR3R4, CO, and null;
X is N or CR5;
Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted C1-C6 alkyl, an optionally substituted Ci-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 CO-C io aryl and an optionally substituted C]-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 Ci-C6 alkyl, an optionally substituted Ci-C6 heteroalkyl, and an optionally substituted Ci-C6 haloalkyl, each optionally fused with an optionally substituted C6-CiO aryl; m is O, 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; provided that if Y is
Figure imgf000221_0001
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 CH3 W is NH, Z is phenyl, and R10 or R1Ms -(CH2)O-6OH,
R11— D— R10 (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 R6, R10, and Ru do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
2. A compound of Formula I, II, or III:
Figure imgf000221_0002
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R2 is independently selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Cj-Cβ haloalkyl, and an optionally substituted Ci-Ce heteroalkyl;
R3 and R4 are independently selected from hydrogen, an optionally substituted Q-CO alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Cj-C6 heteroalkyl; R5 is selected from hydrogen, halogen, OR14, Ci-C6 alkyl, Cj-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R6 is selected from an optionally substituted Ci-C io alkyl, an optionally substituted Ci-Ci0 haloalkyl, an optionally substituted Ci-Cio heteroalkyl, (CH2)mR18, C(O)NHR18, C≡CR18, CR3=CR4R18, and CR3=R18;
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R8 and each R9 is independently selected from hydrogen, OR16, NR16R17, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-Cg haloalkyl, an optionally substituted Ci -C6 heteroalkyl, (CH2)UiR18, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-Cs ring;
R10 is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R1 1 is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or R11 and R4 are linked to form a optionally substituted heterocycle;
R12 is selected from hydrogen, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Cj- C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R14 is selected from hydrogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci -C6 heterohaloalkyl;
R16 and R17 are each independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci -C6 heteroalkyl, and (CH2)JR.18; or one of R16 and R17 is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C3-Cs ring;
R18 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 R18 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; R19 is selected from hydrogen, Ci-C3 alkyl, C1-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, NR4, CR3R4, CO, and null;
W is selected from O, NR4, CR3R4, CO, and null;
X is N or CR5;
Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Cj-Cg alkyl, an optionally substituted Cj-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-CiO aryl and an optionally substituted Cj-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 Cj-C6 alkyl, an optionally substituted Ci-C6 heteroalkyl, and an optionally substituted Cj-C6 haloalkyl, each optionally fused with an optionally substituted C6-CjO aryl; m is O, 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, =0, =S, amino, and protected derivatives of amino groups;
provided that if Y is R12 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 R10 or Rn is -(CH2)o-6θH,
R11— D— R10 (iii) I is not pyrazolyl or optionally substituted 5- hydroxypyrazolyl, and
(iv) U is not NH; provided further that if X is TSI and W is NH3 then D is not phenyl; and provided further that if X is N and W is NH in compound of Formula III, then R6, R10, and R1 1 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, OR14, NO2, CN, NR14R15, C-C4 alkyl, Ci-
C4 haloalkyl, an optionally substituted Ci-Q heteroalkyl, CO2R14, CONRI4R1S,
SO3R14, SO2NR14R15 and a carboxylic acid bioisostere selected from tetrazole,
NHSO2R19, OC(S)NR14R15, SC(O)NR14R15, and
Figure imgf000224_0001
wherein A5 B, and C are each independently selected from O, S, and NR20; each R2 is independently selected from hydrogen, halogen, OR14, NR14R15, C1-C4 alkyl, Cj-C4 haloalkyl, Ci-C4 heteroalkyl, and Ci-C4 heterohaloalkyl;
R3 and R4 are independently selected from hydrogen, C1-C4 alkyl, Ci-C4 haloalkyl, and an optionally substituted Ci-C4 heteroalkyl;
R5 is selected from hydrogen, OR14, Ci-C4 alkyl, Q-C4 haloalkyl, C1-C4 heteroalkyl, and Ci-C4 haloheteroalkyl;
R6 is selected from C1-C10 alkyl, Cj-Cio haloalkyl, an optionally substituted Ci-C10 heteroalkyl, (CH2)mR18, C(O)NHR18, C≡CR18, CR3=CR4R18, and CR3=R18; R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere selected from tetrazole, NHSO2R19, OC(S)NR14R15, SC(O)NR14R15, and
Figure imgf000225_0001
wherein A, B5 and C are each independently selected from O, S, and N; each R8 and each R9 is independently selected from hydrogen, OR16, NR16R17, Ci-C4 alkyl, Ci-C4 haloalkyl, an optionally substituted Ci-C4 heteroalkyl, (CH2)JnR18, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-Cs ring;
R10 is selected from hydrogen, halogen, oxo, C1-C4 alkyl, C1-C4 haloalkyl, and an optionally substituted Ci-C4 heteroalkyl;
R11 is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or R11 and R4 are linked to form a optionally substituted heterocycle;
R12 is selected from hydrogen, halogen, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci- C4 heteroalkyl, and Ci-C4 haloheteroalkyl;
R13 is selected from hydrogen, halogen, CN, NO2, CO2R14, S(O)JR.'4, Ci- C4 alkyl, C1-C4 haloalkyl, Ci-C4 heteroalkyl, and C]-C4 haloheteroalkyl;
R14 is selected from hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 heteroalkyl, and Ci-C4 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, Ci-C4 alkyl, CrC4 haloalkyl, and Ci -C4 heteroalkyl;
R16 and R17 are each independently selected from hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, an optionally substituted Ci-C4 heteroalkyl, and (CH2)mR18; or one of R16 and R17 is C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C4-C7 ring;
R19 is selected from hydrogen, Ci-C3 alkyl, C1-C3 haloalkyl, and aryl;
G is selected from O, S, and NR14;
J is selected from O5 S, NR14, and CR14R15;
K is O or S;
Y is selected from:
Figure imgf000226_0001
4. A compound of Formula IV, V, or VI:
Figure imgf000226_0002
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein*.
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted Ci-C6 alky I, an optionally substituted Q-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R2 is independently selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted Ci-Cβ alkyl, an optionally substituted C)-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R3 and R4 are independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-Ce heteroalkyl;
R5 is selected from hydrogen, halogen, OR14, Ci-C6 alkyl, C1-C6 haloalkyl, C]-C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R6 is selected from an optionally substituted Ci-Cio alkyl, an optionally substituted Ci-Cio haloalkyl, an optionally substituted Ci-Cio heteroalkyl, (CH2)JR.18, C(O)NHR18, C≡CR18, CR3=CR4R18, and CR3=R18;
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R8 and each R9 is independently selected from hydrogen, OR16, NR16R17, an optionally substituted Ci-Ce alkyl, an optionally substituted C]-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, (CH2)O1R18, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-Cg ring;
R10 is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-Ce heteroalkyl;
R11 is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or R11 and R4 are linked to form a optionally substituted heterocycle;
R12 is selected from hydrogen, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci- C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R13 is selected from hydrogen, halogen, CN, NO2, CO2R14, S(O)mR14, Ci- C4 alkyl, Ci-C4 haloalkyl, C1-C4 heteroalkyl, and Ci-C4 haloheteroalkyl;
R14 is selected from hydrogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Cj-C6 heteroalkyl, and C1-C6 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, C1-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
R16 and R17 are each independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Q-C6 heteroalkyl, and (CH2)mR18; or one of R16 and Rπ is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C3-Cs ring;
R18 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 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;
R19 is selected from hydrogen, Ci-C3 alkyl, C1-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, NR4, CR3R4, CO, and null;
W is selected from O, NR4, CR3R4, CO, and null;
X is N or CR5;
Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C6-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-C6 alkyl, an optionally substituted Ci-C6 heteroalkyl, and an optionally substituted CrC6 haloalkyl, each optionally fused with an optionally substituted C6-CiO 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; 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 R6, R10, and R11 do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
5. The compound of claim 4, wherein:
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted Ci-C(J alkyl, an optionally substituted C]-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere selected from tetrazole, NHSO2R19, OC(S)NR14R15, SC(O)NR14R15, and
Figure imgf000229_0001
wherein A, B, and C are each independently selected from O, S, and N; and
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere selected from tetrazole, NHSO2R19, OC(S)NR14R15, SC(O)NR14R15, and
Figure imgf000229_0002
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:
Figure imgf000229_0003
(IV) (V) (VI) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from hydrogen, halogen, OR14, NO2, CN5 NR14R15, an optionally substituted Cj-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R2 is independently selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R3 and R4 are independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R5 is selected from hydrogen, halogen, OR14, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R6 is selected from an optionally substituted Ci-C10 alkyl, an optionally substituted Ci-Ci0 haloalkyl, and an optionally substituted Ci-Cio heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R6 is selected from (CH2)mR18, C(O)NHR18, C≡CR18, CR3^CR4R18, and CR3=R18;
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere; each R8 and each R9 is independently selected from hydrogen, OR16, NR16R17, an optionally substituted Ci-C6 alkyl, an optionally substituted CrC6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, (CH2)mR18, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-C8 ring;
R10 is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted C1-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
Ru is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or R1 1 and R4 are linked to form a optionally substituted heterocycle;
R12 is selected from hydrogen, halogen, C)-C6 alkyl, Cj-C6 haloalkyl, C1- C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R13 is selected from hydrogen, halogen, CN, NO2, CO2R14, S(O)mR14, C1- C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, and C]-C4 haloheteroalkyl;
R14 is selected from hydrogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Cj-C6 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, Ci-C6 alkyl, Ci-C6 haloalkyl, CrC6 heteroalkyl, and Ci-C6. heterohaloalkyl; ;
R16 and R17 are each independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted C]-C6 haloalkyl, an optionally substituted CrC6 heteroalkyl, and (CH2)mR18; or one of R16 and R17 is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C3-Cs ring;
R18 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 R18 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;
R19 is selected from hydrogen, C1-C3 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, NR4, CR3R4, CO, and null;
W is selected from O, NR4, CR3R4, CO, and null;
X is N or CR5;
Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-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-Ci0 aryl and an optionally substituted Cj-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 Cj-C6 alkyl, an optionally substituted CrC6 heteroalkyl, and an optionally substituted Ci-C6 haloalkyl, each optionally fused with an optionally substituted C6-CiO aryU 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=CR12- orientated to form a dihydropyrazole, and Z or R6 are not an optionally substituted non- aromatic ring fused with an optionally substituted aromatic ring; or if X is N, W is NH, R6 is alkoxy , an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, Y is -N=CR12- 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 N5 W is NH, and Y is -N=CR12- orientated to form a dihydropyrazole, then D is not a naphthyl; provided that, if U is NH; or if D and one of R10 and R11 form a 5- hydroxypyrazole, X is N, and W is NH; or if E and one of R10 and R1 1 form a 5- hydroxypyrazole and X is N, and W is NH; or if E is phenyl, one of R10 or Rπ is — (CH2)o-βOH, X is C, W is NH, R6 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 R10 or R11 is -(CH2)0-6θH, X is N, W is NH3 Z is null, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, and R is Cj-C6 alkyl, Ci-Ce alkoxy,
Figure imgf000232_0001
an optionally substituted aryl, an optionally substituted heteroaryl, NR21R22 or a heterocyclic methylene substituent as represented by formula VII; or if D is phenyl, one of R10 or R11 is -(CH2)O-OOH, X is C, W is NH, Z is aromatic, and R6 is alkoxy, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; then Y is not -N=CR12- orientated to form a dihydropyrazole;
R20 is selected from hydrogen, a substituted alkyl, a substituted aryl, and a substituted heteroaryl;
R21 and R22 are each independently selected from hydrogen, alkyl, and aryl; or R21 and R22 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;
Figure imgf000233_0001
(VII) wherein A, B, C, and V are each independently selected from O, S, and NR20.
7. A compound of Formula I, II, III, IV, V3 or VI:
Figure imgf000233_0002
wherein:
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted CI-CO haloalkyl, an optionally substituted C1-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere;
R2 is selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted Cj-C6 alkyl, an optionally substituted Ci-Ce haloalkyl, and an optionally substituted Cj-C6 heteroalkyl;
R3 and R4 are independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl; Rs is selected from hydrogen, halogen, OR14, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R6 is selected from an optionally substituted Ci-Ci0 alkyl, an optionally substituted Ci-Cio haloalkyl, or an optionally substituted Ci-Ci0 heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R6 is (CH2)H1R18 or C(O)NHR18;
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere;
R8 and R9 are each independently selected from hydrogen, OR16, NR16R17, an optionally substituted Ci-C6 alkyl, an optionally substituted C]-Ce haloalkyl, an optionally substituted Ci-C6 heteroalkyl, (CH2)mR18, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-C8 ring;
R10 is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R" is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or R1 1 and R are linked to form a optionally substituted heterocycle;
R!2 is selected from hydrogen, halogen, Cj-C6 alkyl, Ci-C6 haloalkyl, Ci- C6 heteroalkyl, and Ci-Ce haloheteroalkyl;
R13 is selected from hydrogen, halogen, CN, NO2, CO2R14, S(O)mR14, Ci- C4 alkyl, Ci-C4 haloalkyl, Ci-C4 heteroalkyl, and C1-C4 haloheteroalkyl;
R14 is selected from hydrogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, Ci-C6 alkyl, Ci-C6 haloalkyl, CrC6 heteroalkyl, and Cj-C6 heterohaloalkyl;
R16 and R17 are each independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, and (CH2)mR18; or one of R16 and R17 is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C3-C8 ring;
R18 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; R19 is selected from hydrogen, C1-C3 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, NR4, CR3R4, CO, and null;
W is selected from O, NR4, CR3R4, CO, and null;
X is N or CR5;
Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-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-CiO aryl and an optionally substituted C]-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 Ci-Ce alkyl, an optionally substituted Ci-C6 heteroalkyl, and an optionally substituted C1-C6 haloalkyl, each optionally fused with an optionally substituted C6-CiO 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-suIfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, =O, =S, amino, and protected derivatives of amino groups;
provided that if Y is
Figure imgf000236_0001
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 R10 or R" is -(CH2)o-6OH,
R11— D — R10 (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 R6, R10, and Rn do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
8. A compound of Formula I, II, or III:
Figure imgf000236_0002
(D (H) (III) wherein:
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted C]-C6 alkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere;
R2 is selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Cj-C6 heteroalkyl; R3 and R4 are independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R5 is selected from hydrogen, halogen, OR14, Ci-C6 alkyl, Cj-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R6 is selected from an optionally substituted Ci-Cio alkyl, an optionally substituted Ci-C10 haloalkyl, an optionally substituted C]-Ci0 heteroalkyl, (CH2)mR18, and C(O)NHR18;
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere;
Rs and R9 are each independently selected from hydrogen, OR16, NR16R17, an optionally substituted Ci-C6 alkyl, an optionally substituted C]-C6 haloalkyl, an optionally substituted Ci-Cs heteroalkyl, (CH2)mRl8 } and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-Cg ring;
R10 is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted C]-C6 heteroalkyl;
R" is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or R1 1 and R4 are linked to form a optionally substituted heterocycle;
R12 is selected from hydrogen, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci- C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R14 is selected from hydrogen, Ci-C6 alkyl, Cj-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, C,-C6 alkyl, C]-C6 haloalkyl, C1-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
R16 and R17 are each independently selected from hydrogen, an optionally substituted Cj-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, an optionally substituted C-C6 heteroalkyl, and (CH2)mR18; or one of R16 and R17 is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C3-Cs ring;
R18 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; R19 is selected from hydrogen, C1-C3 alkyl, C1-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, NR4, CR3R4, CO, and null;
W is selected from O, NR4, CR3R4, CO, and null;
X is N or CR5;
Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted Ci-Cg alkyl, an optionally substituted C]-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-CiO 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 Ci-C6 alkyl, an optionally substituted Ci-Cβ heteroalkyl, and an optionally substituted Ci-C6 haloalkyl, each optionally fused with an optionally substituted Cβ-Cio aryl; m is 0, 1, or 2; and n is 0 or 1 ;
provided that if Y is R12 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 R10 or R11 Is -(CH2)O-6OH,
R1 1 — D — R10 (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 NH5 then D is not phenyl; and provided further that if X is N and W is NH in compound of Formula III, then R6, R10, and R11 do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
9. The compound of claim 2, wherein:
R1 is selected from a halogen, OR14, NO2, CN, NR14R15, Ci-C4 alkyl, C,-
C4 haloalkyl, an optionally substituted Ci-C4 heteroalkyl, CO2R14, CONR14R15,
SO3R14, SO2NR14R15 and a carboxylic acid bioisosteres selected from tetrazole,
NHSO2R19, OC(S)NR14R15, SC(O)NR14R15, and
Figure imgf000239_0001
wherein A, B, and C are each independently selected from O, S, and NR20;
R2 is selected from hydrogen, halogen, OR14, NR14R15, Ci-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, and C1-C4 heterohaloalkyl;
R3 and R4 are independently selected from hydrogen, Cj-C4 alkyl, Ci-C4 haloalkyl, and an optionally substituted Ci-C4 heteroalkyl;.
R5 is selected from hydrogen, OR14, C]-C4 alkyl, Ci-C4 haloalkyl, C ,-C4 heteroalkyl, and Cj-C4 haloheteroalkyl;
R6 is selected from CI-CJO alkyl, CI-CJO haloalkyl, an optionally substituted Ci-Cj0 heteroalkyl, (CH2)mR18, and C(O)NHR18;
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere selected from tetrazole, NHSO2R19, OC(S)NR14R15, SC(O)NR14R15, and
Figure imgf000239_0002
wherein A3 B, and C are each independently selected from O, S, and N; R8 and R9 are each independently selected from hydrogen, OR16, NR16R17, C1-C4 alkyl, Ci-C4 haloalkyl, an optionally substituted Ci-C4 heteroalkyl, (CH2)InR18 5 and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-Cg ring;
R10 is selected from hydrogen, halogen, oxo, Ci-C4 alkyl, C1-C4 haloalkyl, and an optionally substituted Cj-C4 heteroalkyl;
R12 is selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, Ci- C4 heteroalkyl, and Ci -C4 haloheteroalkyl;
R13 is selected from hydrogen, halogen, CN, NO2, CO2R14, S(O)mR!4, Cr C4 alkyl, C1-C4 haloalkyl, Ci-C4 heteroalkyl, and C]-C4 haloheteroalkyl;
R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 heteroalkyl, and Ci-C4 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, Ci-C4 alkyl, C]-C4 haloalkyl, and C1-C4 heteroalkyl;
R16 and R17 are each independently selected from hydrogen, Ci-C4 alkyl, Ci-C4 haloalkyl, an optionally substituted Ci-C4 heteroalkyl, and (CH2)mR18; or one of R16 and R17 is C2-C5 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C4-C7 ring;
R19 is selected from hydrogen, Ci-C3 alkyl, C1-C3 haloalkyl, and aryl;
G is selected from O, S, and NR14;
J is selected from O, S, NR14, and CR14R15;
K is O or S;
L is NH or null; and
Y is selected from:
Figure imgf000240_0001
10. A compound of Formula IV, V, or VI:
Figure imgf000241_0001
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof, wherein:
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere;
R2 is selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Cj-C6 heteroalkyl;
R3 and R4 are independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R5 is selected from hydrogen, halogen, OR14, Ci-C6 alkyl, C)-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R6 is selected from an optionally substituted Ci-Cio alkyl, an optionally substituted Ci-Cio haloalkyl, an optionally substituted Ci-Cio heteroalkyl, (CH2)mR18, and C(O)NHR18;
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere;
R8 and R9 are each independently selected from hydrogen, OR16, NR16R17, an optionally substituted Ci-C6 alkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, (CH2)mRi 8, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-C8 ring;
Riυ is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted Ci -CO alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl; R1 1 is selected from hydrogen, halogen, OR14, NRI4R1S, and SR14; or R11 and R4 are linked to form a optionally substituted heterocycle;
R12 is selected from hydrogen, halogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci- C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R13 is selected from hydrogen, halogen, CN, NO2, CO2R14, S(O)mR14, Ci- C4 alkyl, Ci-C4 haloalkyl, Ci-C4 heteroalkyl, and C1-C4 haloheteroalkyl;
R14 is selected from hydrogen, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and C]-C6 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
R16 and R17 are each independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted C)-C6 haloalkyl, an optionally substituted CrC6 heteroalkyl, and (CH2)mR18; or one of R16 and R17 is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C3-Cs ring;
R18 is selected from an optionally substituted monocyclic or bi cyclic aromatic ring system optionally containing one or more heteroatoms and optionally fused with a non-aromatic heterocycle or carbocycle;
R19 is selected from hydrogen, Cj-C3 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, NR4, CR3R4, CO, and null;
W is selected from O5 NR4, CR3R4, CO, and null;
X is N or CR5;
Z is selected from: null, a 2-5 atom spacer selected from an optionally substituted C6-CiO 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 Ci-C6 alkyl, an optionally substituted Ci-Ce heteroalkyl, and an optionally substituted C]-C6 haloalkyl, each optionally fused with an optionally substituted C6-C io 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 R6, R10, and Ru do not contain a carboxylic, amido, ester, or sulfurate functionality or a carboxylic acid bioisostere.
11. The compound of claim 4, wherein:
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted Ci-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere selected from tetrazole, NHSO2R19, OC(S)NR14R15, SC(O)NR14R15, and
Figure imgf000243_0001
wherein A, B, and C are each independently selected from O, S5 and N; and
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere selected from tetrazole, NHSO2R19, OC(S)NR14R15, SC(O)NR14R15, and
Figure imgf000243_0002
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:
Figure imgf000244_0001
wherein:
R1 is selected from hydrogen, halogen, OR14, NO2, CN, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Cj-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, CO2R14, CONR14R15, SO3R14, SO2NR14R15 and a carboxylic acid bioisostere;
R2 is selected from hydrogen, halogen, OR14, NR14R15, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R3 and R4 are independently selected from hydrogen, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R5 is selected from hydrogen, halogen, OR14, Ci-C6 alkyl, C)-C6 haloalkyl, Ci-C6 heteroalkyl, and Ci-C6 haloheteroalkyl;
R6 is selected from an optionally substituted CI-CJ O alkyl, an optionally substituted Ci-Cio haloalkyl, or an optionally substituted Q-Cio heteroalkyl, each optionally fused with a substituted aryl or a substituted heteroaryl, or R6 is (CH2)mR18 or C(O)NHR18;
R7 is selected from CO2R14, CONR14R15, SO3R14, SO2NRI4R1S and a carboxylic acid bioisostere; R8 and R9 are each independently selected from hydrogen, OR16, NR16R17, an optionally substituted Ci-C6 alkyl, an optionally substituted CrC6 haloalkyl, an optionally substituted Cj-C6 heteroalkyl, (CH2)mR18, and null; or R8 and R9 taken together form an optionally substituted olefin; or R8 and R9 are linked to form an optionally substituted C3-C8 ring;
R10 is selected from hydrogen, halogen, oxo, OR16, NR16R17, SR16, an optionally substituted Ci-C6 alkyl, an optionally substituted Ci-C6 haloalkyl, and an optionally substituted Ci-C6 heteroalkyl;
R1 1 is selected from hydrogen, halogen, OR14, NR14R15, and SR14; or R1 1 and R4 are linked to form a optionally substituted heterocycle;
R12 is selected from hydrogen, halogen, Cj-C6 alkyl, Ci-C6 haloalkyl, Ci- C6 heteroalkyl, and Cj-C6 haloheteroalkyl;
R13 is selected from hydrogen, halogen, CN, NO2, CO2R14, S(O)mR14, Ci- C4 alkyl, C1-C4 haloalkyl, Cj-C4 heteroalkyl, and Ci-C4 haloheteroalkyl;
R14 is selected from hydrogen, Cj-C6 alkyl, Ci-C6 haloalkyl, Ci-Q heteroalkyl, and Ci-C6 heterohaloalkyl;
R15 is selected from hydrogen, SO2R19, C)-C6 alkyl, C1-C6 haloalkyl, Cj-C6 heteroalkyl, and Ci-C6 heterohaloalkyl;
R16 and R17 are each independently selected from hydrogen, an optionally substituted Ci-Ce alkyl, an optionally substituted CrC6 haloalkyl, an optionally substituted CrC6 heteroalkyl, and (CH2)mR18; or one of R16 and R17 is an optionally substituted C2-C6 alkyl and the other of R16 and R17 is null; or R16 and R17 are linked to form an optionally substituted C3-Cg ring;
R18 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;
R19 is selected from hydrogen, C1-C3 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 carbo cycle;
U is selected from O, NR4, CR3R4, CO, and null;
W is selected from O, NR4, CR3R4, CO, and null;
X is N or CR5;
Y is a 1-4 atom spacer comprising one or more groups selected from an optionally substituted C1-C6 alkyl, an optionally substituted Ci-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-CiO aryl and an optionally substituted Ci-C8 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-C6 alkyl, an optionally substituted C]-C6 heteroalkyl, and an optionally substituted Ci-C6 haloalkyl, each optionally fused with an optionally substituted C6-CjO aryl; m is O, 1, or 2; and n is 0 or 1 ; provided that, if X is N5 W is NH, and Y is not -N=CR12- orientated to form a dihydropyrazole, and Z or R are not an optionally substituted nonaromatic ring fused with an optionally substituted aromatic ring; or if X is N, W is NH, R6 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=CR12- orientated to form a dihydropyrazole, then D is not a naphthyl; provided that, if U is NH; or if D and one of R10 and Rn form a 5- hydroxypyrazole, X is N5 and W is NH; or if E and one of R10 and R11 form a 5- hydroxypyrazole and X is N3 and W is NH; or if E is phenyl, one of Ri0 or R1 ' is — (CH2)0-6θH, X is C, W is NH, R6 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 R10 or R1 1 is -(CH2)0-6θH, X is N, W is NH, Z is null, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl, and R6 is Ci-C6 alkyl, Ci-Ce alkoxy, -(CH2)O-6OR20, an optionally substituted aryl, an optionally substituted heteroaryl, NR21R22 or a heterocyclic methylene substituent as represented by formula VII; or if D is phenyl, one of R10 or R1 1 is -(CH2)0-6θH, X is C, W is NH, Z is aromatic, and R6 is alkoxy, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heteroaryl; then Y is not -N=CR12- orientated to form a dihydropyrazole;
R20 is selected from hydrogen, a substituted alkyl, a substituted aryl, and a substituted heteroaryl;
R21 and R22 are each independently selected from hydrogen, alkyl, and aryl; or R21 and R22 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;
Figure imgf000247_0001
(VII) wherein A, B, C5 and V are each independently selected from O, S, and NR20.
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-Dimethylphenyi)-2-oxo-6-trifiuoromethyl- 1 ,2-dihydroindol-3- ylidenemethyl]amino}-2'-hydroxybiphenyl-3-carboxylic acid (Compound 101);
2,4-Dihydroxybenzoic acid N'-{ 1 -[I -(3,5-dimethylphenyl)-2-oxo-6- trifluoromethyl-l,2-dihydroindol-3-ylidene]ethyl}hydrazide (Compound 102); 3-{3-[(5-Chloro-2-hydroxy-3',4r-dimethylbiphenyl-3-yl)hydrazono]-2-oxo- 2,3-dihydroindol-l-yl}benzoic acid (Compound 103);
3- { 3 - [(2-Hydroxy-3 ',5 '-dimethylbipheny 1-3 -yl)hydrazono]-2-oxo-2,3 - dihydroindol-l-yl}benzoic acid (Compound 104);
S'-lfl ^^-DimethylphenyO^-oxo-β-trifluoromethyl-l^-dihydroindol-S- y 1 idenemethy 1] amino } -4-fluoro -T -hydroxybiphenyl-3 - carboxy lie acid
(Compound 105);
2-(3'-{[l-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l,2-dihydroindol- 3 -ylidenemethyl]amino } -2 ' -hydroxybiphenyl-3 -yl)-2-methyl propionic acid
(Compound 106);
3'-{[l-(3,4-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l,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-l-yl}benzoic acid (Compound 109);
3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-yl}benzoic acid methyl ester (Compound 110);
3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3- dihydroindol-l-yl}benzoic acid methyl ester (Compound 1 11);
3-{3-[(5-Fluoro-2-hydroxy-3',5'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo- 2,3-dihydroindol-l -yl}benzoic acid (Compound 1 12);
3-{3-[l-(3,5-Dimethylphenyl)-2-oxo-6-trifluoromethyl-l32-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 iV-{l-[l-(335-dimethylphenyl)-2-oxo-6- trifluoromethyl-l,2-dihydroindol-3-ylidene]ethyl}hydrazide (Compound 115); l-(3,5-Dimethylphenyl)-3-{l-[2-(4-hydroxyphenyl)-2-oxo- ethylamino]ethylidene} -6-trifluoromethyl-l ,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-l-yl}benzoic acid (Compound 117);
3-{3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-yl)hydrazono]-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-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 1 19);
3-{3-[(2-Hydroxy-3',4'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo- 2,3-dihydroindol-l-yl}benzoic acid (Compound 120);
4-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylidene]-2-oxo- 2,3-dihydroindol-l-yl} butyric acid (Compound 121);
2-Chloro-3-(4-{[l-(3,5-dimethylphenyl)-2-oxo-6-trifluoromethyl-l,2- dihydroindol-3-ylidenemethyl]amino} -3-hydroxyphenyl)acrylic acid (Compound 122);
4-Hydroxybenzoic acid iV-{ l-[l-(3,5-dimethylphenyl)-2-oxo-6- trifluoromethyl-l,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-l -yl} benzoic acid (Compound 125);
3-{3-[(2-Hydroxy-5,3',5'-trimethylbiphenyl-3-yl)hydrazono]-2-oxo-2,3- dihydroindol-l-yl}benzoic acid (Compound 126);
4-Aminobenzoic acid N-{l-[l-(3,5-dimethylphenyl)-2-oxo-6- trϊfluoromethyl-l,2-dihydroindol-3-ylidene]ethyl}hydrazide (Compound 127);
3 _(7_ {N'-[ 1 -(3 ,5 -Dimethylphenyl)-2-oxo-6-trifluoromethy 1- 1 ,2- dihydroindol-3-ylidene]hydrazino}-lH-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)-lH-pyrrol-2- ylmethylidene]-2,3-dihydroindol-l-yl}benzoic acid (Compound 130);
3-(7-{N'-[l-(3,4-Dimethylphenyl)-3-methyl-5-oxo-l,5-dihydropyrazol-4- ylidene]hydrazino}-lH-indol-3-yl)propionic acid (Compound 131);
3-(3-{[4-(3,4-Dimethylphenyl)thiazol-2-ylamino]methylidene}-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-yl)benzoic acid (Compound 132); 3-(3-{[4-(4-Methoxyphenyl)thiazol-2-ylamino]methylene}-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-yl)benzoic acid (Compound 133);
3-{3-[(2-Hydroxy-3',5'-dimethylbiphenyl-3-ylamino)methylene]-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-yl}benzoic acid (Compound 134);
3-{3-[(4-(4-Methylphenyl)-2-thiazolylamino)methylene]-2-oxo-6- trifluoromethyl-2,3-dihydroindol-l-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-l-yl}benzoic acid (Compound 138);
3-{3-[(3,4-Dimethylbenzoylhydrazino)methylidene]-2-oxo-6-chloro-2,3- dihydroindol-1-yl} benzoic acid (Compound 139); l-(3,4-Dimethylphenyl)-3-[l-(2,4- dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound
140); l-(3,4-Dimethylphenyl)-3-[l-(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); l-(3,5-Dimethylphenyl)-3-[l-(2,4- dihydroxybenzoylhydrazino)ethylidene]-2-oxo-233-dihydroindole (Compound
143);
1 -(3 ,5-Dimethylphenyl)-3-[l -(4-hydroxybenzoylhydrazino)ethylidene]-2- oxo-2,3-dihydroindole (Compound 144); l-(3,5-Dimethylphenyl)-3-[(2,4- dihydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 145); l-(3,5-Dimethylphenyl)-3-[(4-hydroxybenzoylhydrazino)methylidene]-2- oxo-2,3-dihydroindole (Compound 146);
3-(3-[l-(3,4-Dihydroxybenzoylhydrazino)ethylidene]-2-oxo-6-chloro-2,3- dihydroindol-l-yl)benzoic acid (Compound 147); l-(3,4-Dimethylphenyl)-3-[(4-hydroxybenzoylhydrazino)methylidene]-2- oxo-2,3-dihydroindole (Compound 148); l-(3,4-Dimethylphenyl)-3-[(3,5-diisopropyl-2- hydroxybenzoylhydrazino)methylidene]-2-oxo-2,3-dihydroindole (Compound 149); l-(3,5-Dimethylphenyl)-3-[l-(3,4- dihydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 150); l-(3,4-Dimethylphenyl)-3-[l-(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-l-yl)benzoic acid (Compound 152); l-(3,4-Dimethylphenyl)-3-[l-(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-Dimethylpheny l)-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); l-(3,4-Dimethylphenyl)-3-[l-(4-methoxy-2- hydroxybenzoylhydrazino)ethylidene]-2-oxo-2,3-dihydroindole (Compound 157);
3-{3-(l-(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-indo Iy 1} benzoic acid (Compound 159);
3-{3-(l-(3,4-Dimethylphenyl)-2-oxo-2,3-dihydro-3- indolidene)methylamino-2-hydroxyphenyl} benzoic acid (Compound 160);
4-{l-(6-Fluoro-2-oxo-2,3-dihydro-3-(2-(3,5-dimethylphenyl)- aminocarbonylphenyl)aminomethylidene)indolyl}butanoic acid (Compound 161); 4-{l-(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-hy droxy-3 -(3 ,5 -dimethylphenyl)- phenyl)aminomethylidene)indolyl}benzoic acid (Compound 163);
4-{l-(5-Fluoro-2-oxo-2,3-dihydro-3-(2-hydroxy-3-(3,5-dimethylphenyl)- phenyl)aminomethylidene)indolyl}butanoic acid (Compound 164);
3-{3-(l-(l-(3,5-Dimethylphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-3- indolidene)ethylamino)-2-hydroxyphenyl} benzoic acid (Compound 165);
3-{3-(l-(l-(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-{ l-(5-Fluoro-2-oxo-2,3-dihydro-3-(l-(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-l-(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-l-(3,5-dimethylphenyl)-3- indolylidene)methylamino)indolyl} propanoic acid (Compound 172);
3-{3-(7-(6-Trifluoromethyl-2-oxo-2,3-dihydro-l-(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-l-(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-l-(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-l-(3,5- dimethylphenyl)indoly lidene)methylaminopheny 1 } 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)pyrτolidinyl}butanoic acid (Compound 181);
(E)-4-{ 1 -(2,5-Dioxo-3-(3-(3,5-dimethylphenyl)-2- hydτoxypheny)aminomethylidene)pyrrolidinyl}butanoic acid (Compound 182);
(Z)-3-{l-(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-(l-(3,5-Dimethylphenyl)-6-chloro-2-oxo-2,3- dihydroindolidene)methylamino)phenylamino}benzoic acid (Compound 186);
3-{2-(3-(l-(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-l- (3,5-dimethylphenyl)indolylidene)methylamino)phenyl}pentanoic acid
(Compound 189); (±)-3-{l-(6-Chloro-2-oxo-2,3-dihydro-3-(3-(l-(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-l- (3,5-dimethylphenyl)indolidene)methylamino)pyridinyl}benzoic acid (Compound 192);
3-{4-(3-Hydroxy-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolidene)methylamino)pyridinyl}benzoic acid (Compound 193);
3-{4-(3-Hydroxy-2-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolyl)hydrazono)pyridinyl} benzoic acid (Compound 194);
3-{5-(4-Hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolidene)methylamino)pyridinyl} benzoic acid (Compound 195);
3-{5-(4_Hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(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-l-(3,5- dimethylphenyl)indolylidene)methylamino)phenyl } benzoic acid (Compound 199);
3-{ l-(5-Fluoro-2-oxo-2,3-dihydro-3-(3-(3,4- dimethylpheny l)phenyl)aminomethylidene)indolyl }benzoic acid (Compound 200);
4-{2-(5-Methyl-2-oxo-2,3-dihydro-4-(3-(3,4- dimethylpheny l)phenyl)aminomethylidene)pyrazo IyI } butanoic acid (Compound 201);
(3-(5-Fluoro-2-hydroxy-3-(3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,4- dimethylphenyl)indolidene)methylamino)-l -pyrazolyl)acetϊc acid (Compound 202); (3-(5-Fluoro-2-hydroxy-3-(3-(2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolidene)methylamino)-l -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-(l- 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-{ l-(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-l-(3,5- dimethylphenyl)indolidene)methylamino} benzoic acid (Compound 212);
2-Hydroxy-3-{3-(6-trifluoromethyl-2-oxo-2,3-dihydro-l-(3,5- dimethylphenyl)indolidene)methylamino} benzoic acid (Compound 213);
4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(3-methyl-l- butenyl)ρhenyl)aminomethylidene)pyrazolyl}butanoic acid (Compound 214);
4- {2-(5-Methy 1-3 -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-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-l-(3,4- dimethylphenyl)indolylidene)methylamino)thiazolyl }benzoic acid (Compound 221);
3-{ l-(5-Nitro-2-oxo-2,3-dihydro-3-(2-hydroxy-5-methyl-3-(l - 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-methy l)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-(l-naphthyl)- ethyl)phenyl)aminomethylidene)pyrazolyl} butanoic acid (Compound 226);
4- { 2-(5-Methy 1-3 -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-cyanoρhenyl)- 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- fluoropheny l)-ethyl)phenyl)aminomethy lidene)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);
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)-ethy l)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 -Methy 1-3 -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-(l - indanylmethyl)phenyl)-hydrazono)pyrazolyl} butanoic acid (Compound 258);
(±)-3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(l- 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- methy lphenyl)-ethyl)phenyl)hydrazono)pyrazo Iy 1} 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)pheny l)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); (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-dmydro-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-{l-(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- methylpheny l)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-l- butenyl)phenyl)-hydrazono)pyrazolyl}butanoic acid (Compound 283);
4-{2-(5-Methyl-3-oxo-2,3-dihydro-4(Z)-(2-hydroxy-3-(2- cyclopropylethenyO-pheny^hydrazono^lpyrazolyljbutanoic 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); 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}proρionic acid (Compound 299);
3-{l-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-benzylphenyl)hydrazono)- indolyl} benzoic acid (Compound 300);
3-{l-(2-Oxo-2,3-dihydro-3-(2-hydroxy-3-(2-(2- methylphenyl)ethyl)phenyl)-hydrazono)indolyl}propionic acid (Compound 301);
3-{l-(6-ChIoro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(3-(3- methylphenyl)propyl)-phenyl)aminomethylidene)indolyl} benzoic acid
(Compound 302);
(±)-3-{l-(6-Chloro-2-oxo-2,3-dihydro-3(Z)-(2-hydroxy-3-(l ,2-dihydro-l- methyl-2-indolylphenyl)aminomethylidene)indolyl}benEoic acid (Compound 303);
4-{2-(5-Methyl-3-oxo-3,4-dihydro-4-(2-hydroxy-3-(2- methy lpheny Icarbonyl-amino)pheπyl)hydrazono)pyrazol y 1 } 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);
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(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-{ l-(2-Oxo-233-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-l-(3,5-dimethylphenyl)-6- trifluoromethyl-3-indoIylidenehydrazino)-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-methyI-3-oxo-253-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-l- 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); (±)-3-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2,3-dihydro-l- 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-(l,2-dihydro-l-methyi- 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-(l,2-dihydro-l -methyl- 2-oxo-3-indolylidene)methyl)phenyl)hydrazono)pyrazolyl}butanoic acid
(Compound 32S);
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)pyrazoly 1 } 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-Methy l-3-oxo-2,3 -dihydro-4-(2-hydroxy-3 -(2-pheny lethynyl)- 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-23-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-(l-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-niethoxy-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-l-(2-indenyl)-3(Z)- indolylidene)methylaminophenyl}benzoic acid (Compound. 351);
(±)4-{2-(5-Methyl-3-oxo-2,3-dihydro-4-(2-hydroxy-3-(2-(l,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)-(l-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-methylpheny l)ethenyl)pheny l)hydrazono)pyrazolyl } butanoic acid
(Compound 356);
4-{2-(5-Methyl-3-oxo-2,3-dmydro-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-253-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- difluoropheny l)-etheny l)pheny l)hy drazono)pyr azoly 1 } butanoic aci d (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-MethyI-3-oxo-2,3-dihydro-4-(2-hydroxy-3(E)-(l-(l,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-l-(2(E)-(2,4-difluorophenyl)ethenyl)- 3 (Z)-indolylidene)methylaminoρhenyl} benzoic acid (Compound 369);
3-{2-Hydroxy-3-(2-oxo-2,3-dihydro-l-(2-indenyl)-3(Z)- indolylidene)methyl-aminoρhenyl) 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)-ρyrazolyl} 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-2s3-dihydro-4-(2-hydroxy-3(E)-(2-(2,4- difluorophenyl)-ethenyl)pheny I)hydrazono)pyrazolyl } benzoic acid (Compound 375);
3-{2-(5-Methyl-3-oxo-253-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- methy lpheny l)ethenyl)phenyl)hydrazono)pyrazoly 1 } 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-MethyI-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)pyrazoly 1 } 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)pheny l)hydrazono)pyrazoly 1 } 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-fIuorophenyl)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)pyrazoly 1 }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-dmydro-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- f!uoro)-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, 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.
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.
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BRPI0620532A2 (en) 2011-11-16
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EP1951667A2 (en) 2008-08-06
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