Claims for Patent: 7,332,481

Summary for Patent: 7,332,481

Title:	Thrombopoietin mimetics
Abstract:	Invented are non-peptide TPO mimetics. Also invented are novel processes and intermediates used in the preparation of the presently invented compounds. Also invented is a method of treating thrombocytopenia, in a mammal, including a human, in need thereof which comprises administering to such mammal an effective amount of a selected hydroxy-1-azobenzene derivative.
Inventor(s):	Duffy; Kevin J. (Collegeville, PA), Erickson-Miller; Connie (Collegeville, PA), Jenkins; Julian (Collegeville, PA), Luengo; Juan (Collegeville, PA), Price; Alan T. (Collegeville, PA), Shaw; Antony N. (Collegeville, PA), Visonneau; Sophie (San Diego, PA), Wiggall; Kenneth (Collegeville, PA)
Assignee:	SmithKline Beecham Corporation (Philadelphia, PA)
Application Number:	11/620,260
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,332,481
Patent Claims:	1. A method of treating thrombocytopenia in a human in need thereof which comprises administering to such human a therapeutically effective amount of a compound of Formula (I): ##STR00013## wherein: R, R.sup.1, R.sup.2 and R.sup.3 are each independently selected from hydrogen, C.sub.1-6alkyl, --(CH.sub.2).sub.pOR.sup.4, --C(O)OR.sup.4, formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, --S(O).sub.nR.sup.4, cycloalkyl, --NR.sup.5R.sup.6, protected --OH, --CONR.sup.5R.sup.6, phosphonic acid, sulfonic acid, phosphinic acid, --SO.sub.2NR.sup.5R.sup.6, and a heterocyclic methylene substituent as represented by Formula (III), ##STR00014## where, p is 0-6, n is 0-2, V, W, X and Z are each independently selected from O, S and NR.sup.16, where R.sup.16 is selected from: hydrogen, alkyl, cycloalkyl, C.sub.1-C.sub.12aryl, substituted alkyl, substituted cycloalkyl and substituted C.sub.1-C.sub.12aryl, R.sup.4 is selected from: hydrogen, alkyl, cycloalkyl, C.sub.1-C.sub.12aryl, substituted alkyl, substituted cycloalkyl and substituted C.sub.1-C.sub.12aryl, and R.sup.5 and R.sup.6 are each independently selected from hydrogen, alkyl, substituted alkyl, C.sub.3-6cycloalkyl, and aryl, or R.sup.5 and R.sup.6 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; m is 0-6; and AR is a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and containing from one to three heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, --C(O)OR.sup.4, --C(O)NR.sup.10R.sup.11, --S(O).sub.2NR.sup.10R.sup.11, --S(O).sub.nR.sup.4 and protected --OH, where n is 0-2, R.sup.4 is hydrogen, alkyl, cycloalkyl, C.sub.1-C.sub.12aryl, substituted alkyl, substituted cycloalkyl and substituted C.sub.1-C.sub.12aryl, and R.sup.10 and R.sup.11 are independently hydrogen, cycloalkyl, C.sub.1-C.sub.12aryl, substituted cycloalkyl, substituted C.sub.1-C.sub.12aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, --C(O)OR.sup.4, --S(O).sub.nR.sup.4, --C(O)NR.sup.4R.sup.4, --S(O).sub.2NR.sup.4R.sup.4, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl and protected --OH, or R.sup.10 and R.sup.11 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, where R.sup.4 is as described above and n is 0-2; or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof; provided that at least one of R, R.sup.1, R.sup.2 and R.sup.3 is a substituted aryl group or a heterocyclic methylene substituent as represented in Formula (III). 2. The method to claim 1 wherein, when a single substituent is present on a substituted aryl group defined by any of R, R.sup.1, R.sup.2 and R.sup.3, said substituent is selected from the group consisting of: --CO.sub.2R.sup.20 aryl --C(O)NHS(O).sub.2R.sup.20--NHS(O).sub.2R, hydroxyalkyl, alkoxy, --C(O)NR.sup.21R.sup.22, acyloxy, amino, N-acylamino, hydroxy --(CH.sub.2).sub.gC(O)OR.sup.8--S(O).sub.nR.sup.8, nitro, tetrazole, cyano, oxo, halogen, trifluoromethyl, protected --OH and a heterocyclic methylene substituent as represented by Formula (III), ##STR00015## where g is 0-6; R.sup.8 is hydrogen or alkyl; R.sup.20 is selected form hydrogen, C.sub.1-C.sub.4alkyl, aryl and trifluoromethyl; R.sup.21 and R.sup.22 are independently selected from hydrogen, C.sub.1-C.sub.4alkyl, aryl and trifluoromethyl; V, W, X and Z are each independently selected from O, S, and NR.sup.16, where R.sup.16 is selected from: hydrogen, alkyl, cycloalkyl, C.sub.1-C.sub.12aryl, substituted alkyl, substituted cycloalkyl and substituted C.sub.1-C.sub.12aryl; and n is 0-2. 3. The method of claim 1 wherein the administered compound is a compound of the Formula (II): ##STR00016## wherein: R, R.sup.1, R.sup.2 and R.sup.3 are each independently selected from hydrogen, C.sub.1-6alkyl, --(CH.sub.2).sub.pOR.sup.4, --C(O)OR.sup.4, formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, --S(O).sub.nR.sup.4, cycloalkyl, --NR.sup.5R.sup.6, protected --OH, --CONR.sup.5R.sup.6, phosphonic acid, sulfonic acid, phosphinic acid, --SO.sub.2NR.sup.5R.sup.6, and a heterocyclic methylene substituent as represented by Formula (III), ##STR00017## where p is 0-6, n is 0-2, V, W, X and Z are each independently selected from O, S, and NR.sup.16, where R.sup.16 is selected from: hydrogen, alkyl, cycloalkyl, C.sub.1-C.sub.12aryl, substituted alkyl, substituted cycloalkyl and substituted C.sub.1-C.sub.12aryl, R.sup.4 is hydrogen, alkyl, cycloalkyl, C.sub.1-C.sub.12aryl, substituted alkyl, substituted cycloalkyl and substituted C.sub.1-C.sub.12aryl, and R.sup.5 and R.sup.6 are each independently selected from hydrogen, alkyl, substituted alkyl, C.sub.3-6cycloalkyl, and aryl, or R.sup.5 and R.sup.6 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; R.sup.15 is selected from the group consisting of alkyl, C.sub.1-C.sub.12aryl, hydroxy, alkoxy, substituted alkyl, substituted C.sub.1-C.sub.12aryl and halogen; m is 0-6; and Y is selected from alkyl, substituted alkyl and a cyclic or polycyclic aromatic ring containing from 3 to 14 carbon atoms and optionally containing from one to three heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms and when the number of carbon atoms is 4 the aromatic ring contains at least one heteroatom, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, C.sub.1-C.sub.12aryl, substituted cycloalkyl, substituted C.sub.1-C.sub.12aryl, hydroxy, aryloxy, alkoxy, cycloalkyl, nitro, cyano, halogen and protected --OH; or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof; provided that at least one of R, R.sup.1, R.sup.2 and R.sup.3 is a substituted aryl group or a heterocyclic methylene substituent as represented in Formula (III). 4. The method of claim 3 wherein, when a single substituent is present on a substituted aryl group defined by any of R, R.sup.1, R.sup.2 and R.sup.3, said substituent is selected from the group consisting of: --CO.sub.2R.sup.20, aryl, --C(O)NHS(O).sub.2R.sup.20, --NHS(O).sub.2R.sup.20, hydroxyalkyl, alkoxy, --C(O)NR.sup.21R.sup.22, acyloxy, amino, N-acylamino, hydroxy, --(CH.sub.2).sub.gC(O)OR.sup.8, --S(O).sub.nR.sup.8, nitro, tetrazole, cyano, oxo, halogen, trifluoromethyl, protected --OH and a heterocyclic methylene substituent as represented by Formula (III), ##STR00018## where g is 0-6; R.sup.8 is hydrogen or alkyl; R.sup.20 is selected form hydrogen, C.sub.1-C.sub.4alkyl, aryl and trifluoromethyl; R.sup.21 and R.sup.22 are independently selected from hydrogen, C.sub.1-C.sub.4alkyl, aryl and trifluoromethyl; V, W, X and Z are each independently selected from O, S, and NR.sup.16, where R.sup.16 is selected from: hydrogen, alkyl, cycloakyl, C.sub.1-C.sub.12aryl, substituted alkyl substituted cycloalkyl and substituted C.sub.1-C.sub.12aryl; and n is 0-2. 5. The method of claim 3 wherein the compound administered is a compound represented by Formula (II) wherein: either: R is a substituted aryl; and R.sup.1 is hydrogen; or: R is hydrogen; and R.sup.1 is a substituted aryl; and in either case: R.sup.2 and R.sup.3 are each independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, cycloalkyl, phosphonic acid, phosphinic acid and sulfonic acid; R.sup.15 is selected from the group consisting of alkyl, substituted alkyl, C.sub.1-C.sub.12aryl, alkoxy and halogen; m is 0-4; and Y is selected from, phenyl, pyridinyl and pyrimidinyl, where the phenyl, pyridinyl and pyrimidinyl are optionally substituted with from one to three substituents selected from the group consisting of: alkyl, substituted alkyl, C.sub.1-C.sub.12aryl, substituted C.sub.1-C.sub.12aryl, alkoxy and halogen; or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof. 6. The method of claim 5 wherein, when a single substituent is present on a substituted aryl group defined by any of R, R.sup.1, R.sup.2 and R.sup.3, said substituent is selected from the group consisting of: --CO.sub.2R.sup.20, aryl, --C(O)NHS(O).sub.2R.sup.20, --NHS(O).sub.2R.sup.2, hydroxyalkyl, alkoxy, --C(O)NR.sup.21R.sup.22, acyloxy, amino, N-acylamino, hydroxy --(CH.sub.2).sub.gC(O)OR.sup.8, --S(O).sub.nR.sup.8, nitro, tetrazole, cyano, oxo, halogen, trifluoromethyl protected --OH and a heterocyclic methylene substituent as represented by Formula (III), ##STR00019## where g is 0-6; R.sup.8 is hydrogen or alkyl: R.sup.20 is selected form hydrogen, C.sub.1-C.sub.4alkyl, aryl and trifluoromethyl; R.sup.21 and R.sup.22 are independently selected from hydrogen, C.sub.1-C.sub.4alkyl, aryl and trifluoromethyl; V, W, X and Z are each independently selected from O, S, and NR.sup.16, where R.sup.16 is selected from: hydrogen, alkyl, cycloalkyl, C.sub.1-C.sub.12aryl, substituted alkyl substituted cycloalkyl and substituted C.sub.1-C.sub.12ary; and n is 0-2. 7. The method of claim 1 wherein the compound is selected from the group consisting of: 4'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-3'-hydroxybiphenyl-3-carboxylic acid; 2-Aza-3'-{N'-[1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-5'-chloro-2'-hydroxybiphenyl-3-carboxylic acid; 2-Aza-3'-{N'-[1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 2-Aza-5'-chloro-3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro- pyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 2-Aza-3'-{N'-[1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid; 2-Aza-3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid; 3'-{N'-[1-(4-tert-Butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid; 7-({N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2-hydroxyphenyl)quinolin-4[1H]-one-3-carboxylic acid; 7-({N'-[1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2-hydroxyphenyl)quinolin-4[1H]-one-3-carboxylic acid; 3-Aza-3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxybiphenyl-5-carboxylic acid; 3-Aza-3'-(N'-[1-{3-methyl-[4-(1-methylethyl)phenyl]-5-oxo-1,5-dihydropyra- zol-4-ylidene}hydrazino)-2'-hydroxybiphenyl-5-carboxylic acid; 3-Aza-3'-{N'-[1-(4-tertbutylphenyl-3-methyl-5-oxo-1,5-dihydropyrazol-4-yl- idene]hydrazino}-2'-hydroxybiphenyl-5-carboxylic acid; 5'-Chloro-3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazo- l-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-Dimethylphenyl)-3,5-dioxo-1,5-dihydropyrazol-4-ylidene]hyd- razino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(2-Ethoxy-2-oxoethyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylide- ne]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene- ]hydrazino}-2-hydroxy-4'-(tetrazol-5-yl)biphenyl; 3'-(N'-{1-[2-(N-tert-butyl)amino-2-oxoethyl]-3-methyl-5-oxo-1,5-dihydropy- razol-4-ylidene} hydrazino)-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-Chloro-1-(3,4-dimethylphenyl)-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 5-chloro-3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-- 4-ylidene]hydrazino}-2-hydroxy-4'-(tetrazol-5-yl)biphenyl; 3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3,5-dicarboxylic acid; 3-Aza-3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxy-5'-methylbiphenyl-5-carboxylic acid; 3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-4-carboxylic acid; 3'-{N'-[1-(3,4-Dimethylphenyl)-3-methoxy-5-oxo-1,5-dihydropyrazol-4-ylide- ne]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(4-methoxyphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]h- ydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; (3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2-hydroxy-3'-biphenyl)-1,1,1,-trifluoromethanesulfonamide; 3'-{N'-[1-(3,4-Dichlorophenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-methyl-5-oxo-1-(3-trifluoromethylphenyl)-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 8-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene- ]hydrazino} quinolin-4[1H]-one-3-carboxylic acid; 3'-{N'-[3-methyl-5-oxo-1-(4-trifluoromethylphenyl)-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-methyl-5-oxo-1-(4-N-methylcarboxamidolphenyl)-1,5-dihydropyrazo- l-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; N-[1-(3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxybiphenyl-3-yl)methanoyl]methanesulfonamide; 3'-{N'-[3-methyl-5-oxo-1-phenyl-1,5-dihydropyrazol-4-ylidene]hydrazino}-2- '-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-methyl-1-(4-methylphenyl)-5-oxo-1,5-dihydropyrazol-4-ylidene]hy- drazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(4-chlorophenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hy- drazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(4-fluorophenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hy- drazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-methyl-5-oxo-1-(4-trifluoromethoxyphenyl)-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-ethoxy-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-{1-(3,4-dimethylphenyl)-3-(1-methylethoxy)-5-oxo-1,5-dihydropyrazo- l-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-tert-butyl-1-(3,4-dimethylphenyl)-5-oxo-1,5-dihydropyrazol-4-yl- idene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-methyl-1-(4-methyl-2,3,5,6-tetrafluorophenyl)-5-oxo-1,5-dihydro- pyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(4-fluoro-3-methylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-phenyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3,4-dimethylphenyl)-5-oxo-3-phenyl-1,5-dihydropyrazol-4-ylidene- ]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[1-(3,4-dimethylphenyl)-3-methoxy-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[1-(3,4-dimethylphenyl)-3-ethoxy-5-oxo-1,5-dihydropyrazol-4-ylidene- ]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[1-(3,4-dimethylphenyl)-3-(1-methylethoxy)-5-oxo-1,5-dihydropyrazol- -4-ylidene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[1-(4-fluorophenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hyd- razino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[1-(4-fluoro-3-methylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yl- idene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[3-methyl-5-oxo-1-(4-trifluoromethylphenyl)-1,5-dihydropyrazol-4-yl- idene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3'-{N'-[1-(3,4-dimethylphenyl)-3-(pyridin-4-yl-5-oxo-1,5-dihydropyrazol-4- -ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3,4-dimethylphenyl)-3-pyridin-4-yl-5-oxo-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[1-(3,4-dimethylphenyl)-3-pyridin-2-yl-5-oxo-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3'-{N'-[1-(3,4-dimethylphenyl)-3-(pyridin-2-yl-5-oxo-1,5-dihydropyrazol-4- -ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3-fluoro-4-methylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yl- idene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3'-{N'-[1-(3-fluoro-4-methylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-methyl-5-oxo-1-(4-trifluoromethylpyrimidin-2-yl)-1,5-dihydropyr- azol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-N-tert-butoxycarbonylamino-3-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-ox- o-1,5-dihydropyrazol-4-ylidene]hydrazino}-2-hydroxybiphenyl; 3'-amino-3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-- 4-ylidene]hydrazino}-2-hydroxybiphenyl; 3-{N'-[1-(3-fluorophenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hyd- razino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3'-{N'-[1-(3-fluorophenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hy- drazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[3-methyl-5-oxo-1-(2,3,4,5,6-pentafluorophenyl)-1,5-dihydropyrazol-- 4-ylidene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3'-{N'-[3-methyl-5-oxo-1-(2,3,4,5,6-pentafluorophenyl)-1,5-dihydropyrazol- -4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-difluorophenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-methoxymethyl-5-oxo-1,5-dihydropyrazol-4- -ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3,4-dimethylphenyl)-3-methoxymethyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[1-(3,4-difluorophenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene- ]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3'-{N'-[1-(3,4-dimethylphenyl)-5-oxo-3-trifluoromethyl-1,5-dihydropyrazol- -4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-6-fluoro-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-5-oxo-3-propyl-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3,4-dimethylphenyl)-5-oxo-3-propyl-1,5-dihydropyrazol-4-ylidene- ]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3'-{N'-[1-(3,4-dimethylphenyl)-3-(1-methyl-1 H-pyrrol-3-yl)-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazino}-2'-hydroxybi- phenyl-3-carboxylic acid; 3-{N'-[1-(3,4-dimethylphenyl)-3-(1-methyl-1H-pyrrol-3-yl)-5-oxo-1,5-dihyd- ropyrazol-4-ylidene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3'-{N'-[1-(3,4-dimethylphenyl)-3-furan-2-yl-5-oxo-1,5-dihydropyrazol-4-yl- idene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3,4-dimethylphenyl)-3-furan-2-yl-5-oxo-1,5-dihydropyrazol-4-yli- dene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; N-(2'-hydroxy-3'-{N'-[3-methyl-5-oxo-1-(4-trifluoromethyl-phenyl)-1,5-dih- ydro-pyrazol-4-ylidene]hydrazino}biphenyl-3-yl)-1,1,1-trifluoromethanesulf- onamide; N-(2'-hydroxy-3'-{N'-[1-(3-fluoro-4-methylphenyl)-3-methyl-5-oxo-- 1,5-dihydro-pyrazol-4-ylidene]hydrazino}biphenyl-3-yl)-1,1,1-trifluorometh- anesulfonamide; N-(2'-hydroxy-3'-{N'-[1-(4-fluoro-3-methylphenyl)-3-methyl-5-oxo-1,5-dihy- dro-pyrazol-4-ylidene]hydrazino} biphenyl-3-yl)-1,1,1-trifluoromethanesulfonamide; N-(2'-hydroxy-3'-{N'-[1-(3,4-difluorophenyl)-3-methyl-5-oxo-1,5-dihydro-p- yrazol-4-ylidene]hydrazino} biphenyl-3-yl)-1,1,1-trifluoromethanesulfonamide; N-(3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylid- ene]hydrazino}-2'-hydroxybiphenyl-3-yl)guanidine; 3'-{N'-[1-(3,4-dimethylphenyl)-3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene- ]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3,4-dimethylphenyl)-3-ethyl-5-oxo-1,5-dihydropyrazol-4-ylidene]- hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3'-{N'-[1-(3,4-dimethylphenyl)-5-oxo-3-thien-2-yl-1,5-dihydropyrazol-4-yl- idene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-cyclopropyl-1-(3,4-dimethylphenyl)-5-oxo-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-5-oxo-3-thiazol-2-yl-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-5-oxo-1,5-dihydropyrazol-4-ylidene]hydrazi- no}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-(1-methylethyl)-5-oxo-1,5-dihydropyrazol- -4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-(benzyloxymethyl)-1-(3,4-dimethylphenyl)-5-oxo-1,5-dihydropyraz- ol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-ethyl-5-oxo-1-(4-trifluoromethylphenyl)-1,5-dihydropyrazol-4-yl- idene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[5-oxo-1-(4-trifluoromethylphenyl)-1,5-dihydropyrazol-4-ylidene]hy- drazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[-1-(3,4-dimethylphenyl)-3-hydroxymethyl-5-oxo-1,5-dihydropyrazol-- 4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-benzyloxymethyl-5-oxo-1-(4-trifluoromethylphenyl)-1,5-dihydropy- razol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[-1-(3,4-dimethylphenyl)-3-methylsulfanylmethyl-5-oxo-1,5-dihydrop- yrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[-1-(3,4-dimethylphenyl)-5-oxo-3-thiophen-3-yl-1,5-dihydropyrazol-- 4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[5-oxo-1-(4-trifluoromethylphenyl)-3-thiophen-3-yl-1,5-dihydropyra- zol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[5-oxo-1-(4-trifluoromethylphenyl)-3-methylsulfanylmethyl-1,5-dihy- dropyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; N-(3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-yl- idene]hydrazino}-2'-hydroxybiphenyl-3-yl)methanesulfonamide; 3'-[N'-(1-benzo[1,3]dioxol-5-yl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylide- ne)hydrazino]-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,5-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-4'-hydroxybiphenyl-4-carboxylic acid; 3'-{N'-[1-(3-chloro-4-methylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-4'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3-phosphonic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3,4-dicarboxylic acid; 2',6-dihydroxy-3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydrop- yrazol-4-ylidene]hydrazino}biphenyl-3-carboxylic acid; 4-aza-3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxybiphenyl-5-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3-sulfonic acid; and 5-(3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yli- dene]hydrazino}-2'-hydroxybiphenyl-3-ylmethylene)thiazolidine-2,4-dione; and or a pharmaceutically acceptable salt, hydrate, solvaten or esterthereof. 8. The method of claim 1 wherein the compound is administered orally. 9. The method of claim 1 wherein the compound is administered parenterally. 10. A method of claim 1 further comprising co-administering a therapeutically effective amount of an agent selected from the group consisting of: a colony stimulating factor, cytokine, chemokine, and an interleukin or cytokine receptor agonist or antagonists. 11. The method of claim 10 wherein the agent is selected from the group consisting of: G-CSF, GM-CSF, TPO, M-CSF, EPO, Gro-beta, IL-11, SCF, FLT3 ligand, LIF, IL-3, IL-6, IL-1, NESP, SD-01, IL-8, and IL-5. 12. A method of claim 1 wherein said thrombocytopenia is due to myelosuppression caused by chemotherapy or radiation therapy. 13. A method of claim 1 wherein said thrombocytopenia is due to an organ transplant. 14. A method of claim 1 wherein said thrombocytopenia is due to bone marrow, stem cell, or liver transplant. 15. A method of claim 1 wherein said thrombocytopenia is due to idiopathic thrombocytopenia purpura (ITP). 16. A method of claim 1 wherein said thrombocytopenia is due to myelodysplastic syndromes (MDS), aplastic anemia or leukemia. 17. A method of claim 1 wherein said thrombocytopenia is due to viral, fungal, microbial or parasitic infection. 18. A method of claim 1 wherein said thrombocytopenia is due to liver dysfunction. 19. A method of claim 1 wherein said thrombocytopenia is due to surgical procedures. 20. A method of claim 1 wherein said thrombocytopenia is due to treatment with antiviral or antibiotic agents. 21. A method of treating thrombocytopenia in a human in need thereof which comprises administering to such human a therapeutically effective amount of a compound selected from: 4'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-3'-hydroxybiphenyl-3-carboxylic acid; 2-Aza-3'-{N'-[1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-5'-chloro-2'-hydroxybiphenyl-3-carboxylic acid; 2-Aza-3'-{N'-[1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 2-Aza-5'-chloro-3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro- pyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 2-Aza-3'-{N'-[1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid; 2-Aza-3'-{N'-[1-(3,4-dimethylphenyl-3-methyl-5-oxo-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid; 3'-{N'-[1-(4-tert-Butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxy-5'-methylbiphenyl-3-carboxylic acid; 3-{N'-[1-(3,4-dimethylphenyl-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]- hydrazino}-5'-fluoro-2'-hydroxybiphenyl-3-carboxylic acid; 7-({N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2-hydroxyphenyl)quinolin-4[1H]-one-3-carboxylic acid; 7-({N'-[1-(4-tert-butylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2-hydroxyphenyl)quinolin-4[1H]-one-3-carboxylic acid; 3-Aza-3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxybiphenyl-5-carboxylic acid; 3-Aza-3'-(N'-[1-{3-methyl-[4-(1-methylethyl)phenyl]-5-oxo-1,5-dihydropyra- zol-4-ylidene}hydrazino)-2'-hydroxybiphenyl-5-carboxylic acid; 3-Aza-3'-{N'-[1-(4-tertbutylphenyl-3-methyl-5-oxo-1,5-dihydropyrazol-4-yl- idene]hydrazino}-2'-hydroxybiphenyl-5-carboxylic acid; 5'-Chloro-3'-{N'-{[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyraz- ol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-Dimethylphenyl)-3,5-dioxo-1,5-dihydropyrazol-4-ylidene]hyd- razino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(2-Ethoxy-2-oxoethyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylide- ne]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene- ]hydrazino}-2-hydroxy-4'-(tetrazol-5-yl)biphenyl; 3'-{N'-1-[2-(N-tert-butyl)amino-2-oxoethyl]-3-methyl-5-oxo-1,5-dihydropyr- azol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid: and 3'-{N'-[3-Chloro-1-(3,4-dimethylphenyl)-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof. 22. The method of claim 1 wherein R is a phenyl substituted with --(CH.sub.2).sub.gC(O)OR.sup.8, where --(CH.sub.2).sub.g represents a linear or branched, saturated or unsaturated hydrocarbon chain containing 0 to 6 carbons and R.sup.8 is hydrogen or alkyl. 23. A method of treating thrombocytopenia in a human in need thereof which comprises administering to such human a therapeutically effective amount of a compound of Formula (V): ##STR00020## wherein: R, R.sup.1, R.sup.2 and R.sup.3 are each independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy, --(CH.sub.2).sub.pOR.sup.4, --C(O)OR.sup.4, formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted alkyl, --S(O).sub.nR.sup.4, cycloalkyl, --NR.sup.5R.sup.6, protected --OH, --CONR.sup.5R.sup.6, phosphonic acid, sulfonic acid, phosphinic acid and --SO.sub.2NR.sup.5R.sup.6, where, p is 0-6, n is 0-2, R.sup.4 is selected from: hydrogen, alkyl, cycloalkyl, C.sub.1-C.sub.12aryl, substituted alkyl, substituted cycloalkyl and substituted C.sub.1-C.sub.12aryl, and R.sup.5 and R.sup.6 are each independently selected from hydrogen, alkyl, substituted alkyl, C.sub.3-6cycloalkyl, and aryl, or R.sup.5 and R.sup.6 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen; m is 0-6; and AR is a cyclic or polycyclic aromatic ring containing from 3 to 16 carbon atoms and containing one or more heteroatoms, provided that when the number of carbon atoms is 3 the aromatic ring contains at least two heteroatoms, and optionally substituted with one or more substituents selected from the group consisting of: alkyl, substituted alkyl, aryl, substituted cycloalkyl, substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl, acyloxy, amino, N-acylamino, nitro, cyano, halogen, --C(O)OR.sup.4, --C(O)NR.sup.10R.sup.11, --S(O).sub.2NR.sup.10R.sup.11, --S(O).sub.nR.sup.4 and protected --OH, where n is 0-2, R.sup.4 is hydrogen, alkyl, cycloalkyl, C.sub.1-C.sub.12aryl, substituted alkyl, substituted cycloalkyl and substituted C.sub.1-C.sub.12aryl; and R.sup.10 and R.sup.11 are independently hydrogen, cycloalkyl, C.sub.1-C.sub.12aryl, substituted cycloalkyl, substituted C.sub.1-C.sub.12aryl, alkyl or alkyl substituted with one or more substituents selected from the group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino, oxo, hydroxy, --C(O)OR.sup.4, --S(O).sub.nR.sup.4, --C(O)NR.sup.4R.sup.4, --S(O).sub.2NR.sup.4R.sup.4, nitro, cyano, cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl and protected --OH, or R.sup.10 and R.sup.11 taken together with the nitrogen to which they are attached represent a 5 to 6 member saturated ring containing up to one other heteroatom selected from oxygen and nitrogen, where R.sup.4 is as described above and n is 0-2; or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof; provided that at least one of R, R.sup.1, R.sup.2 and R.sup.3 is a substituted aryl group. 24. The method to claim 23 wherein, when a single substituent is present on a substituted aryl group defined by any of R, R.sup.1, R.sup.2 and R.sup.3, said substituent is selected from the group consisting of: --CO.sub.2R.sup.20, aryl, --C(O)NHS(O).sub.2R.sup.20, --NHS(O).sub.2R.sup.20, hydroxyalkyl, alkoxy, --C(O)NR.sup.21R.sup.22, acyloxy, amino, N-acylamino, hydroxy, --(CH.sub.2).sub.gC(O)OR.sup.8, --S(O).sub.nR.sup.8, nitro, tetrazole, cyano, oxo, halogen, trifluoromethyl and protected --OH, where g is 0-6, R.sup.8 is hydrogen or alkyl, R.sup.20 is selected form hydrogen, C.sub.1-C.sub.4alkyl, aryl and trifluoromethyl, and R.sup.21 and R.sup.22 are independently selected form hydrogen, C.sub.1-C.sub.4alkyl, aryl and trifluoromethyl, and n is 0-2. 25. The method of claim 23 wherein R is a phenyl substituted with --(CH.sub.2).sub.gC(O)OR.sup.8, where --(CH.sub.2).sub.g represents a linear or branched, saturated or unsaturated hydrocarbon chain containing 0 to 6 carbons and R.sup.8 is hydrogen or alkyl. 26. The method of claim 1 wherein the compound is selected from: 5-chloro-3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-- 4-ylidene]hydrazino}-2-hydroxy-4'-(tetrazol-5-yl)biphenyl; 3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3,5-dicarboxylic acid; 3-Aza-3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxy-5'-methylbiphenyl-5-carboxylic acid; 3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-4-carboxylic acid; 3'-{N'-[1-(3,4-Dimethylphenyl)-3-methoxy-5-oxo-1,5-dihydropyrazol-4-ylide- ne]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(4-methoxyphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]h- ydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene- ]hydrazino}-2-hydroxy-3'-trifluoromethanesulfonamidobiphenyl; 3'-{N'-[1-(3,4-Dichlorophenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-methyl-5-oxo-1-(3-trifluoromethylphenyl)-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 8-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene- ]hydrazino} quinolin-4[1H]-one-3-carboxylic acid; 3'-{N'-[3-methyl-5-oxo-1-(4-trifluoromethylphenyl)-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-methyl-5-oxo-1-(4-N-methylcarboxamidolphenyl)-1,5-dihydropyrazo- l-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; N-[1-(3'-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxybiphenyl-3-yl)methanoyl]methanesulfonamide; 3'-{N'-[3-methyl-5-oxo-1-phenyl-1,5-dihydropyrazol-4-ylidene]hydrazino}-2- '-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-methyl-1-(4-methylphenyl)-5-oxo-1,5-dihydropyrazol-4-ylidene]hy- drazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(4-chlorophenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hy- drazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(4-fluorophenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hy- drazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-methyl-5-oxo-1-(4-trifluoromethoxyphenyl)-1,5-dihydropyrazol-4-- ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-ethoxy-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-(1-methylethoxy)-5-oxo-1,5-dihydropyrazo- l-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-tert-butyl-1-(3,4-dimethylphenyl)-5-oxo-1,5-dihydropyrazol-4-yl- idene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[3-methyl-1-(4-methyl-2,3,5,6-tetrafluorophenyl)-5-oxo-1,5-dihydro- pyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(4-fluoro-3-methylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3'-{N'-[1-(3,4-dimethylphenyl)-3-phenyl-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3,4-dimethylphenyl)-5-oxo-3-phenyl-1,5-dihydropyrazol-4-ylidene- ]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[1-(3,4-dimethylphenyl)-3-methoxy-5-oxo-1,5-dihydropyrazol-4-yliden- e]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[1-(3,4-dimethylphenyl)-3-ethoxy-5-oxo-1,5-dihydropyrazol-4-ylidene- ]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[1-(3,4-dimethylphenyl)-3-(1-methylethoxy)-5-oxo-1,5-dihydropyrazol- -4-ylidene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[1-(4-fluorophenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene]hyd- razino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[1-(4-fluoro-3-methylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yl- idene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[3-methyl-5-oxo-1-(4-trifluoromethylphenyl)-1,5-dihydropyrazol-4-yl- idene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3'-{N'-[1-(3,4-dimethylphenyl)-3-(pyridin-4-yl-5-oxo-1,5-dihydropyrazol-4- -ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3,4-dimethylphenyl)-3-pyridin-4-yl-5-oxo-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3-{N'-[1-(3,4-dimethylphenyl)-3-pyridin-2-yl-5-oxo-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3'-{N'-[1-(3,4-dimethylphenyl)-3-(pyridin-2-yl-5-oxo-1,5-dihydropyrazol-4- -ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; 3-{N'-[1-(3-fluoro-4-methylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yl- idene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl; 3'-{N'-[1-(3-fluoro-4-methylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-y- lidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; and 3'-{N'-[3-methyl-5-oxo-1-(4-trifluoromethylpyrimidin-2-yl)-1,5-dihydropyr- azol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; or a pharmaceutically acceptable salt, hydrate, solvate or ester thereof.