Renal-selective biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonists for treatment of hypertension

Abstract

Renal-selective compounds are described which, in one embodiment, are prodrugs preferentially converted in the kidney to compounds capable of blocking angiotensin II (AII) receptors. These prodrugs are conjugates formed from two components, namely, a first component provided by an AII antagonist compound and a second component which is capable of being cleaved from the first component when both components are chemically linked within the conjugate. The two components are chemically linked by a bond which is cleaved selectively in the kidney, for example, by an enzyme. The liberated AII antagonist compound is then available to block AII receptors within the kidney. Conjugates of particular interest are glutamyl derivatives of biphenylmethyl 1H-substituted-1,2,4-triazole compounds, of which N-acetylglutamic acid, 5-[[4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]]carbonylhydrazide, (shown below) is an example: 1

Description

FIELD OF THE INVENTION

[0002] This invention is in the field of cardiovascular therapeutics and relates to a class of compounds useful in control of hypertension. Of particular interest is a class of prodrugs of angiotensin II antagonists which, when selectively hydrolyzed in the kidney, provide hypertension control.

BACKGROUND OF THE INVENTION

[0003] The renin-angiotensin system is one of the hormonal mechanisms involved in regulation of pressure/volume homeostasis and in expression of hypertension. Activation of the renin-angiotensin cascade begins with renin secretion from the juxtaglomerular apparatus of the kidney and culminates in the formation of angiotensin II, an octapeptide which is the primary active species of this system. Angiotensin II is a potent vasoconstrictor agent and also produces other physiological effects such as promoting aldosterone secretion, promoting sodium and fluid retention, inhibiting renin secretion, increasing sympathetic nervous system activity, increasing vasopressin secretion, causing positive cardiac inotropic effect and modulating other hormonal systems.

[0004] Previous studies have shown that antagonizing angiotensin II at its receptors is a viable approach to inhibit the renin-angiotensin system, given the pivotal role of this octapeptide which mediates the actions of the renin-angiotensin system through interaction with various tissue receptors. There are several known angiotensin II antagonists, most of which are peptidic in nature. Such peptidic compounds are of limited use due to their lack of oral bioavailability or their short duration of action. Also, commercially-available peptidic angiotensin II antagonists (e.g., Saralasin) have a significant residual agonist activity which further limit their therapeutic application.

[0005] Non-peptidic compounds with angiotensin II antagonist properties are known. For example, the sodium salt of 2-n-butyl-4-chloro-1-(2-chlorobenzyl) imidazole-5-acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [P. C. Wong et al, J. Pharmacol. Exp. Ther., 247 (1), 1-7 (1988)]. Also, the sodium salt of 2-butyl-4-choloro-1-(2-nitrobenzyl)imidazole-5-acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [A. T. Chiu et al, European J. Pharmacol., 157, 3121 (1988)]. A family of 1-benzylimidazole-5-acetate derivatives has been shown to have competitive angiotensin II antagonist properties [A. T. Chiu et al, J. Pharmacol. Exp. Ther., 250 (3), 867-874 (1989)]. U.S. Pat. No. 4,816,463 to Blankey et al describes a family of 4,5,6,7-tetrahydro-1H-imidazo(4,5-c)-tetrahydro-pyridine derivatives useful as antihypertensives, some of which are reported to antagonize the binding of labelled angiotensin II to rat adrenal receptor preparation and thus cause a significant decrease in mean arterial blood pressure in conscious hypertensive rats. EP No. 253,310, published Jan. 20, 1988, describes a series of aralkyl imidazole compounds, including in particular a family of biphenylmethyl substituted imidazoles, as antagonists to the angiotensin II receptor. EP No. 323,841, published Jul. 12, 1989, describes four classes of angiotensin II antagonists, namely, biphenylmethylpyrroles, biphenylmethylpyrazoles, biphenylmethyl-1,2,3-triazoles and biphenylmethyl 4-substituted-4H-1,2,4-triazoles, including the compound 3,5-dibutyl-4-[(2′-carboxybiphenyl-4-yl)methyl]-4H-1,2,4-triazole. U.S. Pat. No. 4,880,804 to Carini et al describes a family of biphenylmethylbenzimidazole compounds as angiotensin II receptor blockers for use in treatment of hypertension and congestive heart failure.

[0006] One disadvantage of these angiotensin II antagonist compounds is that the desired hypertension-reducing effect may be offset by hypotension-induced compensatory stimulation of the renin-angiotensin system or stimulation of the sympathetic nervous system, either of which may result in promotion of sodium and water retention. Also, some angiotensin II antagonists may have toxicological effects systemically which preclude their use at doses necessary to be effective in reducing blood pressure.

[0007] To avoid such systemic side effects, drugs may be targetted to the kidney by creating a conjugate compound that would be a renal-specific prodrug containing the targetted drug modified with a chemical carrier moiety. Cleavage of the drug from the carrier moiety by enzymes predominantly localized in the kidney releases the drug in the kidney. Gamma glutamyl transpeptidase and acylase are examples of such cleaving enzymes found in the kidney which have been used to cleave a targetted drug from its prodrug carrier within the kidney.

[0008] Renal targetted prodrugs are known for delivery of a drug selectively to the kidney. For example, the compound L-γ-glutamyl amide of dopamine when administered to dogs was reported to generate dopamine in vivo by specific enzymatic cleavage by γ-glutamyl transpeptidase [J. J. Kyncl et al, Adv. Biosc., 20, 369-380 (1979)]. In another study, γ-glutamyl and N-acyl-γ-glutamyl derivatives of the anti-bacterial compound sulfamethoxazole were shown to deliver relatively high concentrations of sulfame-thoxazole to the kidney which involved enzymatic cleavage of the prodrug by acylamino acid deacylase and γ-glutamyl transpeptidase [M. Orlowski et al, J. Pharmacol. Exp.Ther., 212, 167-172 (1980)]. The N-γ-glutamyl derivatives of 2-, 3-, or 4-aminophenol and p-fluoro-L-phenylalanine have been found to be readily solvolyzed in vitro by γ-glutamyl transpeptidase [S. D. J. Magnan et al, J. Med. Chem., 25, 1018-1021 (1982)]. The hydralazine-like vasodilator 2-hydrazino-5-γ-butylpyridine (which stimulates guanylate cyclase activity) when substituted with the N-acetyl-γ-glutamyl residue resulted in a prodrug which provided selective renal vasodilation [K. G. Hofbauer et al, J. Pharmacol. Exp. Ther., 212, 838-844 (1985)]. The dopamine prodrug γ-L-glutamyl-L-dopa (“gludopa”) has been shown to be relatively specific for the kidney and to increase renal blood flow, glomerular filtration and urinary sodium excretion in normal subjects [D. P. Worth et al, Clin. Sci., 69, 207-214 (1985)]. In another study, gludopa was reported to be an effective renal dopamine prodrug whose activity can be blocked by the dopa-decarboxylase inhibitor carbidopa [R. F. Jeffrey et al, Br. J. Clin. Pharmac., 25, 195-201 (1988)]. A class of 4-ureido derivatives of isoquinolin-3-ol has been investigated for renal specific effects, such as increases in renal vasodilation and renal blood flow [R. M. Kanojia et al, J. Med. Chem., 32, 990-997 (1989)].

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0009] FIG. 1 is a graph showing reduction in mean arterial pressure by intravenous administration of a conjugate of the invention to rats over a period of four days.

[0010] FIG. 2 is a graph showing angiotensin II pressor response by intravenous administration of a conjugate of the invention to rats over a period of four days.

[0011] FIG. 3 is a graph showing change in heart rate upon intravenous administration of a conjugate of the invention to rats over a period of four days.

DESCRIPTION OF THE INVENTION

[0012] Treatment of circulatory disorders, which include cardiovascular disorders, such as chronic hypertension, sodium-retaining disorders, congestive heart failure, cirrhosis and nephrosis, may be accomplished by administering to a susceptible or afflicted subject a therapeutically-effective amount of a renal-selective prodrug capable of causing blood-pressure reducing effects by selective action in the kidney. An advantage of such renal-selective prodrug therapy resides in reduction or avoidance of adverse side effects associated with systemically-acting drugs.

[0013] Advantages of a renal-selective antihypertensive compound are several. First, the renal-selective compound is targetted at those pathophysiological mechanisms which occur primarily in the kidney. Second, the regulation of other organ systems is unaffected; thus, normal physiological regulation of other organ systems is maintained. Third, fewer side-effects may be anticipated, since the compound remains inactive until cleaved in the kidneys. Similarly, fewer negative drug-drug interactions may be anticipated. Finally, since a renal-selective accumulation of active compound may occur, which is not dependent on plasma levels of the parent compound, lower doses of the renal-selective compound compared to active parent compound may be used.

[0014] A renal-selective prodrug is provided by a conjugate comprising a residue of an angiotensin II antagonist compound, which conjugate is renal selective. The conjugate will typically comprise a first component and a second component connected together by a cleavable or hydrolyzable bond. The term “renal-selective”, as used to characterize a conjugate of the invention, embraces any of the following four pharmacological events: (1) the conjugate is selectively taken up by the kidney and is selectively cleaved in the kidney; (2) the conjugate is not taken up selectively by the kidney, but is selectively cleaved in the kidney; (3) the conjugate is selectively taken up by the kidney and then cleaved in the kidney; or (4) where the conjugate itself is active as an angiotensin II antagonist, the conjugate is selectively taken up by the kidney without cleavage of the hydrolyzable bond.

[0015] The first component of a conjugate of the invention is a residue derived from an antagonist compound capable of inhibiting angiotensin II (AII) receptors, especially those AII receptors located in the kidney. The second residue is capable of being cleaved from the first residue preferential-ly. Cleaving of the first and second residues may be accomplished by a variety of mechanisms. For example, the bond may be cleaved by an enzyme in the kidney.

[0016] The residue providing the first component may be characterized as the “AII antagonist active” residue. Such “active” residue may be provided by a compound having AII antagonist activity or by a metabolite of such compound having AII antagonist activity. The residue providing the second component may be characterized in being capable of forming a cleavable bond connecting the “active” first residue and the second residue. Such bond is cleavable by an enzyme located in the kidney. In a preferred embodiment, this cleavable bond is typically a hydrolyzable amide bond, that is, a bond between a carbonyl-terminated moiety and an reactive nitrogen-terminated moiety, such as an amino-terminated moiety, which may be cleaved by enzyme found in the kidney, but which is not cleaved substantially by enzymes located in other organs or tissues of the body. Preferred bond-cleaving enzymes would be found predominantly in the kidney.

[0017] The conjugate containing the residue of an AII antagonist compound and containing the cleavable fragment or residue may possess AII antagonist activity comparable to, or more than, or less than, the AII antagonist compound which forms the conjugate. In one embodiment of the invention, the conjugate will have AII receptor blocking activity comparable to the AII antagonist component forming the conjugate. In another embodiment of the invention, the conjugate will have AII receptor blocking activity less than the AII receptor blocking activity forming the conjugate. One advantage of such differential activity between the conjugate and the AII antagonist component is that certain side effects associated with non-renal, systemic AII receptor blocking may be avoided or reduced. For example, at least one conjugate of the invention has been found to have very large differential in AII receptor blocking activities between the conjugate and the AII antagonist component forming the conjugate. Such differential activity is advantageous in that therapeutically-effective antihypertensive doses of the conjugate may be administered to give renal-selective AII receptor blocking action resulting from kidney-specific enzyme hydrolysis or metabolism of the conjugate to free the active AII receptor blocker within the kidney. Inasmuch as this renal-selective conjugate has relatively low AII receptor blocking activity, compared to the AII receptor compound forming the conjugate, this conjugate will have fewer adverse side effects associated with unwanted systemic interaction with non-renal AII receptors such as found in the vascular bed.

DETAILED DESCRIPTION OF THE INVENTION

[0018] The first residue of the conjugate may be selected from any class of compounds, or metabolites thereof, having angiotensin II antagonist activity. An example of one such class of angiotensin II antagonist compounds is provided by a class of biphenylalkyl 1H-substituted-1,2,4-triazole compounds defined by Formula I: 2

[0019] wherein m is a number selected from one to four, inclusive;

[0020] wherein each of R1 through R11 is independently selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, alkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- and cyclohetero-containing groups has one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula 3

[0021] wherein X is oxygen atom or sulfur atom;

[0022] wherein each n is a number independently selected from zero to six, inclusive;

[0023] wherein each of R12 through R24 is independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R12 and R13 taken together, R14 and R15 taken together, R16 and R17 taken together, R19 and R20 taken together and R21 and R22 taken together may each form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein R12 and R13 taken together, R14 and R15 taken together, R19 and R20 taken together and R21 and R22 taken together may each form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms;

[0024] and wherein each of R3 through R11 may be further independently selected from hydroxy and from acidic moieties of the formula

—YnA

[0025] wherein n is a number selected from zero through three, inclusive, and wherein A is an acidic group selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms;

[0026] and wherein any of the foregoing R1 through R24, Y and A groups having a substitutable position may be substituted with one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, trifluoromethyl, difluoroalkyl, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula 4

[0027] wherein X is selected from oxygen atom and sulfur atom; wherein each of R25, R26, R27, R28 and R29 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR30 and 5

[0028] wherein D is selected from oxygen atom and sulfur atom and R30 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R25, R26, R27, R28, R29, R31 and R32 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R25, R26, R27, R28, R29, R31 and R32 is further independently selected from amino and amido radicals of the formula 6

[0029] wherein X is oxygen atom or sulfur atom;

[0030] wherein each of R33, R34, R35, R36, R37 and R38 is independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein R26 and R27 taken together and R28 and R29 taken together may each form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein R26 and R27 taken together and R31 and R32 taken together may each form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms;

[0031] with the proviso that at least one of said R1 through R24, Y and A substituents contains a terminal primary or secondary amino moiety or a moiety convertible to a primary or secondary amino moiety.

[0032] or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

[0033] Conjugates of the invention are therapeutically effective in treatment of cardiovascular disorders by acting directly on, or by providing cleavable components selected from Formula I compounds which act directly on, or as antagonists to, or as blockers of, the angiotensin II (AII) receptor. Thus, conjugates of Formula I would be therapeutically effective in treatment of cardiovascular disorders or would be precursors to, or prodrugs of, therapeutically-effective compounds.

[0034] Preferred compounds of Formula I, from which a cleavable component may be selected, are all characterized in having a substituent, other than hydrido, at each of the three- and five-positions of the triazole ring. Such substituents are selected from the aforementioned R1 and R2 groups. Also especially useful are compounds having one of the R1 and R2 substituents selected from alkylcarbonyl, monoalkoxyalkyl, dialkoxyalkyl and difluoroalkyl groups. When the selected substituent for R1 and R2 is difluoroalkyl, then it is particularly useful for both of the fluoro atoms of the difluoroalkyl group to be substituted on the difluoroalkyl group carbon atom attached at the R1 or R2 positions of the triazole ring. Such difluoroalkyl group may be characterized as an “alpha-carbon difluoro-substituted difluoroalkyl group”, or as an “alpha, alpha-difluoro-substituted alkyl group”. When the selected substituent for R1 or R2 is monoalkoxyalkyl or dialkoxyalkyl, then it is particularly useful for the single alkoxy group or the two alkoxy groups, respectively, to be substituted on the carbon atom of the selected substituent which is attached at the R1 or R2 positions of the triazole ring. Such alkoxyalkyl groups may be characterized as “alpha-carbon monoalkoxy- or dialkoxy-substituted alkoxyalkyl groups”, respectively, or “alpha-monoalkoxy-substituted or alpha, alpha-dialkoxy-substituted alkyl groups”, respectively. When the selected substituent is alkylcarbonyl, then it is particularly useful for the carbonyl group to be attached at the R1 or R2 positions of the triazole ring. Such alkylcarbonyl group may be characterized as an “alpha-oxo-substituted alkyl group”, and may be exemplified by the substituents 1-oxoethyl, 1-oxopropyl and 1-oxobutyl. Where compounds of Formula I contain any of these above-mentioned particularly-useful alpha-carbon substituted R1 or R2 groups at the triazole ring three- or five-position, it is preferred that such particularly-useful group be attached at the three-position, that is, as an R1 substituent.

[0035] The phrase “acidic group selected to contain at least one acidic hydrogen atom”, as used to define the —YnA moiety, is intended to embrace chemical groups which, when attached to any of the R3 through R11 positions of Formula I, confers acidic character to the compound of Formula I. “Acidic character” means proton-donor capability, that is, the capacity of the compound of Formula I to be a proton donor in the presence of a proton-receiving substance such as water. Typically, the acidic group should be selected to have proton-donor capability such that the product compound of Formula I has a pKa in a range from about one to about twelve. More typically, the Formula I compound would have a pKa in a range from about two to about seven. An example of an acidic group containing at least one acidic hydrogen atom is carboxyl group (—COOH). Where n is zero and A is —COOH, in the —YnA moiety, such carboxyl group would be attached directly to one of the R3 through R11 positions. The Formula I compound may have one —YnA moiety attached at one of the R3 through R11 positions, or may have a plurality of such —YnA moieties attached at more than one of the R3 through R11 positions, up to a maximum of nine such —YnA moieties. There are many examples of acidic groups other than carboxyl group, selectable to contain at least one acidic hydrogen atom. Such other acidic groups may be collectively referred to as “bioisosteres of carboxylic acid” or referred to as “acidic bioisosteres”. Specific examples of such acidic bioisosteres are described hereinafter. Compounds of Formula I having the —YnA moiety attached at one of positions R5, R6, R8 and R9 would be expected to have preferred properties, while attachment at R5 or R9 would be more preferred.

[0036] A preferred class of compounds within the sub-class defined by Formula I consists of those compounds wherein m is one; wherein each of R1 through R11 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkyithiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula 7

[0037] wherein X is selected from oxygen atom or sulfur atom;

[0038] wherein each n is a number independently selected from zero to six, inclusive;

[0039] wherein each of R12 through R24 is independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl;

[0040] and wherein each of R3 through R11 may be further independently selected from hydroxy and from acidic moieties of the formula

—YnA

[0041] wherein n is a number selected from zero through three, inclusive; wherein A is an acidic group selected from acids containing one or more atoms selected from oxygen, sulfur, phosphorus and nitrogen atoms, and wherein said acidic group is selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms;

[0042] and wherein any of the foregoing R1 through R24, Y and A groups having a substitutable position may be substituted with one or more groups selected from alkyl, alkenyl, aralkyl, hydroxyalkyl, trifluoromethyl, difluoroalkyl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercaptocarbonyl, alkylthio, alkylthiocarbonyl, and amino and amido radicals of the formula 8

[0043] wherein X is selected from oxygen atom and sulfur atom; wherein each of R25, R26, R27, R28 and R29 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and DR30 and 9

[0044] wherein D is selected from oxygen atom and sulfur atom, and R30 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R25, R26, R27, R28, R29, R31 and R32 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R25, R26, R27, R28, R29, R31 and R32 is further independently selected from amino and amido radicals of the formula 10

[0045] wherein X is selected from oxygen atom or sulfur atom;

[0046] wherein each of R33 through R38 is independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl;

[0047] with the proviso that at least one of said R1 through R24, Y and A substituents contains a terminal primary or secondary amino moiety or a moiety convertible to a primary or secondary amino moiety;

[0048] or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

[0049] A more preferred class of compounds within the sub-class defined by Formula I consists of those compounds wherein m is one; wherein each of R1 through R11 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, alkylthio, cycloalkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalklylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula 11

[0050] wherein X is selected from oxygen atom or sulfur atom;

[0051] wherein each n is a number independently selected from zero to six, inclusive;

[0052] wherein each of R12 through R24 is independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl;

[0053] and wherein each of R3 through R11 may be an further independently selected from hydroxy and from acidic moieties of the formula

—YnA

[0054] wherein n is a number selected from zero through three, inclusive;

[0055] wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from 12

[0056] wherein each W is independently selected from oxygen atom, sulfur atom and NR43; wherein each of R39, R40, R41, R42 and R43 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R39, R40, R41 and R42 may be further independently selected from amino radical of the formula 13

[0057] wherein each of R44 and R45 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R44 and R45 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein R44 and R45 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; wherein each of R44 and R45 may be further independently selected from hydroxy, alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and aralkoxy; and the amide, ester and salt derivatives of said acidic groups;

[0058] wherein said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which heterocyclic ring contains at least one hetero atom selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R3 through R11 or may be attached at any two adjacent positions selected from R3 through R11 so as to form a fused-ring system with one of the phenyl rings of the biphenyl moiety of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups;

[0059] wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl;

[0060] and wherein any of the foregoing R1 through R24, Y and A groups having a substitutable position may be substituted by one or more groups selected from alkyl, difluoroalkyl, alkenyl, aralkyl, hydroxyalkyl, trifluoromethyl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercaptocarbonyl, alkylthio, alkylthiocarbonyl, and amino and amido radicals of the formula 14

[0061] wherein X is selected from oxygen atom and sulfur atom; wherein each of R25, R26, R27, R28 and R29 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl and DR30 and 15

[0062] wherein D is selected from oxygen atom and sulfur atom, wherein R30 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl;

[0063] wherein each of R25, R26, R27, R28, R29, R31 and R32 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl;

[0064] with the proviso that at least one of said R1 through R24, Y and A substituents contains a terminal primary or secondary amino moiety or a moiety convertible to a primary or secondary amino moiety;

[0065] or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

[0066] An even more preferred class of compounds within the sub-class defined by Formula I consists of those compounds wherein m is one; wherein each of R1 and R2 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula 16

[0067] wherein X is selected from oxygen atom and sulfur atom;

[0068] wherein each n is a number independently selected from zero to six, inclusive;

[0069] wherein each of R12 through R24 is independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl;

[0070] wherein each of R3 through R11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylthio, aralkylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms;

[0071] and wherein each of R3 through R11 may be an acidic moiety further independently selected from acidic moieties of the formula

—YnA

[0072] wherein n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from 17

[0073] wherein each W is independently selected from oxygen atom, sulfur atom and NR43; wherein each of R39, R42 and R43 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R39 and R42 may be further independently selected from amino radical of the formula 18

[0074] wherein each of R44 and R45 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R44 and R45 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms, and which heterocyclic group may be saturated or partially unsaturated; wherein R44 and R45 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R3 through R11 or may be attached at any two adjacent positions selected from R3 through R11 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups;

[0075] wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl;

[0076] wherein each of R1 through R11, Y and A independently may be substituted at any substitutable position with one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, oxo, trifluoromethyl, difluoroalkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy;

[0077] with the proviso that at least one of said R1 through R24, Y and A substituents contains a terminal primary or secondary amino moiety or a moiety convertible to a primary or secondary amino moiety;

[0078] or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

[0079] A highly preferred class of compounds within the sub-class defined by Formula I consists of those compounds wherein m is one; wherein each of R1 and R2 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, benzoyl, phenoxy, phenoxyalkyl, phenalkyloxy, phenylthio, phenalkylthio, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula 19

[0080] wherein X is selected from oxygen atom and sulfur atom;

[0081] wherein each n is a number independently selected from zero to six, inclusive;

[0082] wherein each of R12 through R24 is independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl and phenyl;

[0083] wherein each of R3 through R11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio, mercapto and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms;

[0084] and wherein each of R3 through R11 may be an acidic moiety further independently selected from acidic moieties of the formula

—YnA

[0085] wherein n is a number selected from zero through two, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from 20

[0086] wherein each W is independently selected from oxygen atom, sulfur atom and NR43; wherein each of R39, R42 and R43 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benzyl; wherein each of R39 and R42 may be further independently selected from amino radical of the formula 21

[0087] wherein each of R44 and R45 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, benzyl and phenyl; and the amide, ester and salt derivatives of said acidic groups;

[0088] wherein said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R3 through R11 or may be attached at any two adjacent positions selected from R3 through R11 so as to form a fused-ring system with one of the phenyl rings of the biphenyl moiety of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups;

[0089] wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenalkyl and aralkyl;

[0090] wherein each of R1 through R11, Y and A and independently may be substituted at any substitutable position with one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, oxo, trifluoromethyl, difluoroalkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy;

[0091] with the proviso that at least one of said R1 through R24, Y and A substituents contains a terminal primary or secondary amino moiety or a moiety convertible to a primary or secondary amino moiety;

[0092] or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

[0093] An even more highly preferred class of compounds within Formula I consists of those compounds wherein m is one; wherein each of R1 and R2 is independently selected from alkyl, aminoalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, benzoyl, phenoxy, phenoxyalkyl, phenalkyloxy, phenylthio, phenalkylthio, aralkoxy, alkoxyalkyl, acetyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, mercaptoalkyl, mercaptocarbonyl, alkoxycarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, phthalimido, phthalimidoalkyl, imidazoalkyl, tetrazole, tetrazolealkyl, alkylthio, cycloalkylthio, and amino and amido radicals of the formula 22

[0094] wherein X is selected from oxygen atom and sulfur atom;

[0095] wherein each n is a number independently selected from zero to six, inclusive;

[0096] wherein each of R12 through R24 is independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl and phenyl;

[0097] wherein each of R3 through R11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, acetyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto;

[0098] and wherein each of R3 through R11 may be an acidic moiety further independently selected from acidic moieties consisting of CO2H, CO2CH3, SH, CH2SH, C2H4SH, PO3H2, NHSO2CF3, NHSO2C6F5, SO3H, CONHNH2, CONHNHSO2CF3, CONHOCH3, CONHOC2H5, CONHCF3, OH, CH2OH, C2H4OH, OPO3H2, OSO3H, 23

[0099] wherein each of R46, R47 and R48 is independently selected from H, Cl, CN, NO2, CF3, C2F5, C3F7, CHF2, CH2F, CO2CH3, CO2C2H5, SO2CH3, SO2CF3 and SO2C6F5; wherein Z is selected from O, S, NR49 and CH2; wherein R49 is selected from hydrido, CH3 and CH2C6H5; and wherein said acidic moiety may be a heterocyclic acidic group attached at any two adjacent positions of R3 through R11 so as to form a fused ring system so as to include one of the phenyl rings of the biphenyl moiety of Formula I, said biphenyl fused ring system selected from 24

[0100]  and the esters, amides and salts of said acidic moieties;

[0101] with the proviso that at least one of said R1 through R24 substituents contains a terminal primary or secondary amino moiety or a moiety convertible to a primary or secondary amino moiety;

[0102] or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

[0103] A class of compounds of particular interest within the sub-class defined by Formula I consists of those compounds wherein m is one; wherein each of R1 and R2 is independently selected from amino, aminomethyl, aminoethyl, aminopropyl, CH2OH, CH2OCOCH3, CH2Cl, Cl, CH2OCH3, CH2OCH(CH3)2, I, CHO, CH2CO2H, CH(CH3)CO2H, NO2, Cl, 2526

[0104] —CO2CH3, —CONH2, —CONHCH3, CON(CH3)2, —CH2—NHCO2C2H5, 27

[0105]  —CH2NHCO2CH3, —CH2NHCO2C3H7, —CH2NHCO2CH2(CH3)2, —CH2NHCO2C4H9, CH2NHCO2-adamantyl, —CH2NHCO2-(1-napthyl), —CH2NHCONHCH3, —CH2NHCONHC2H5, —CH2NHCONHC3H7, —CH2NHCONHC4H9, —CH2NHCONHCH(CH3)2, —CH2NHCONH(1-napthyl), —CH2NHCONH(1-adamantyl), CO2H, 28

[0106]  —CH2CH2CH2CO2H, —CH2CH2F, —CH2OCONHCH3, —CH2OCSNHCH3, —CH2NHCSOC3H7, —CH2CH2CH2F, —CH2ONO2, 29

[0107]  —CH2SH, 30

[0108]  H, Cl, NO2, CF3, CH2OH, Br, F, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, halo, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein each of R3 through 11 is hydrido, with the proviso that at least one of R5, R6, R8 and R9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, 31

[0109] wherein each of R46 and R47 is independently selected from Cl, CN, NO2, CF3, CO2CH3 and SO2CF3;

[0110] with the proviso that at least one of said R1 through R11 substituents contains a terminal primary or secondary amino moiety or a moiety convertible to a primary or secondary amino moiety;

[0111] or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

[0112] A class of compounds of more particular interest within the sub-class defined by Formula I consists of those compounds wherein m is one; wherein R1 is selected from amino, aminomethyl, aminoethyl, aminopropyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, halo, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein R2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl and neopentyl; wherein each of R3, R4, R6, R7, R8, R10, and R11 is hydrido; wherein one of R5 and R9 is hydrido and the other of R5 and R9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, 32

[0113] wherein each of R46 and R47 is independently selected from Cl, CN, NO2, CF3, CO2CH3 and SO2CF3;

[0114] with the proviso that at least one of said R1 through R11 substituents contains a terminal primary or secondary amino moiety or a moiety convertible to a primary or secondary amino moiety;

[0115] or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

[0116] The second component of a conjugate of the invention is provided by a residue which forms a kidney-enzyme-cleavable amide bond with the residue of the first-component AII antagonist compound. Such residue is preferably selected from a class of compounds of Formula II: 33

[0117] wherein each of R50 and R51 may be independently selected from hydrido, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein G is selected from hydroxyl, halo, mercapto, —OR52, —SR53 and 34

[0118] with each of R52, R53 and R54 independently selected from alkyl; and wherein R54 may be further selected from hydrido; with the proviso that said cleavable bond is within an amide group formed between said first and second residues, wherein said first residue has a terminal primary or second amino moiety provided by one of said R1 through R11 substituents of said Formula I compound or provided by a linker group attached to one of said R1-R11 substituents of said Formula I, and wherein said second residue has a carbonyl moiety attached at the gamma-position carbon of said Formula II compound, whereby said amide bond is formed from said first residue amino moiety and said second residue carbonyl moiety.

[0119] More preferred are compounds of Formula II wherein each G is hydroxy.

[0120] A more highly preferred class of compounds within Formula II consists of those compounds wherein each G is hydroxy; wherein R50 is hydrido; and wherein R51 is selected from 35

[0121] wherein R55 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and chloromethyl.

[0122] A most highly preferred compound of Formula II is N-acetyl-γ-glutamic acid which provides a residue for the second component of a conjugate of the invention as shown below: 36

[0123] The phrase “terminal primary or secondary amino moiety or a moiety convertible to a primary or secondary amino terminal moiety” characterizes a structural requirement for selection of a suitable angiotensin II antagonist compound as the “active” first residue of a conjugate of the invention. Such terminal amino moiety must be available to react with a terminal carboxylic moiety of the cleavable second residue to form a kidney-enzyme-specific hydrolyzable bond.

[0124] In one embodiment of the invention, the first component used to form a conjugate of the invention provides a first residue derived from an AII antagonist compound containing a terminal primary or secondary amino moiety. Examples of such terminal amino moiety are amino and linear or branched aminoalkyl moieties containing linear or branched alkyl groups such as aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminosecbutyl, aminoisobutyl, aminotertbutyl, aminopentyl, aminoisopentyl and aminoneopentyl.

[0125] In another embodiment of the invention, the first component used to form the conjugate of the invention provides a first residue derived from an AII antagonist compound containing a moiety convertible to a primary or secondary amino terminal moiety. An example of a moiety convertible to an amino terminal moiety is a carboxylic acid group reacted with hydrazine so as to convert the acid moiety to carboxylic acid hydrazide. The hydrazide moiety thus contains the terminal amino moiety which may then be further reacted with the carboxylic acid containing residue of the second component to form a hydrolyzable amide bond. Such hydrazide moiety thus constitutes a “linker” group between the first and second components of a conjugate of the invention.

[0126] Suitable linker groups may be provided by a class of diamino-terminated linker groups based on hydrazine as defined by Formula III: 37

[0127] wherein each of R200 and R201 may be independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, haloalkyl, amino, monoalkylamino, dialkylamino, cyanoamino, carboxyalkyl, alkylsulfino, alkylsulfonyl, arylsulfinyl and arylsulfonyl; and wherein n is zero or a number selected from three through seven, inclusive. In Table I there is shown a class of specific examples of diamino-terminated linker groups within Formula III, identified as Linker Nos. 1-73. These linker groups would be suitable to form a conjugate between a carbonyl moiety of an AII antagonist (designated as “I”) and a carbonyl moiety of a carbonyl terminated second residue such as the carbonyl moiety attached to the gamma carbon of a glutamyl residue (designated as “T”).

TABLE I
38
I = inhibitor
T = acetyl-γ-glutamyl
	LINKER
	NO.	n	R200	R201
	1	0	H	H
	2	0	CH3	H
	3	0	C2H5	H
	4	0	C3H7	H
	5	0	CH(CH3)2	H
	6	0	C4H9	H
	7	0	CH(CH3)CH2CH3	H
	8	0	C(CH3)3	H
	9	0	C5H9	H
	10	0	C6H11(cyclo)	H
	11	0	C6H5	H
	12	0	CH2C6H5	H
	13	0	H	CH3
	14	0	H	C2H5
	15	0	H	C3H7
	16	0	H	CH(CH3)2
	17	0	H	C4H9
	18	0	H	CH(CH3)CH2CH3
	19	0	H	C(CH3)3
	20	0	H	C5H9
	21	0	H	C6H13
	22	0	H	C6H5
	23	0	H	CH2C6H5
	24	0	H	C6H11(cyclo)
	25	0	C6H13	H
	26	0	CH3	CH3
	27	0	C2H5	C2H5
	28	0	C3H7	C3H7
	29	0	CH(CH3)2	CH(CH3)2
	30	0	C4H9	C4H9
	31	0	CH(CH3)CH2CH3	CH(CH3)CH2CH3
	32	0	C(CH3)3	C(OH3)3
	33	0	C5H9	C5H9
	34	0	C6H13	C6H13
	35	0	C6H11(cyclo)	C6H5(cyclo)
	36	0	C6H5	C6H5
	37	0	CH2C6H5	CH2C6H5
	38	3	H	H
	39	3	CH3	H
	40	3	H	CH3
	41	3	C6H5	H
	42	3	H	C6H5
	43	3	CH3	C6H5
	44	3	C6H5	CH3
	45	3	CH2C6H5	H
	46	3	H	CH2C6H5
	47	4	H	H
	48	4	CH3	H
	49	4	H	CH3
	50	4	C6H5	H
	51	4	H	C6H5
	52	4	CH3	C6H5
	53	4	C6H5	CH3
	54	4	CH2C6H5	H
	55	4	H	CH2C6H5
	56	5	H	H
	57	5	CH3	H
	58	5	H	CH3
	59	5	C6H5	H
	60	5	H	C6H5
	61	5	CH3	C6H5
	62	5	C6H5	CH3
	63	5	CH2C6H5	H
	64	5	H	CH2C6H5
	65	6	H	H
	66	6	CH3	H
	67	6	H	CH3
	68	6	C6H5	H
	69	6	H	C6H5
	70	6	CH3	C6H5
	71	6	C6H5	CH3
	72	6	CH2C6H5	H
	73	6	H	CH2C6H5

[0128] Another class of suitable diamino terminal linker groups is defined by Formula IV: 39

[0129] wherein each of Q and T is one or more groups independently selected from 40

[0130] wherein each of R202 through R205 is independently selected from hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl.

[0131] A preferred class of linker groups within Formula IV is defined by Formula V: 41

[0132] wherein each of R202 and R203 is independently selected from hydrido, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number independently selected from one through six, inclusive; with the proviso that when each of R202 and R203 is selected from halo, hydroxy, amino, monoalkylamino and dialkylamino, then the carbon to which R202 or R203 is attached in Formula V is not adjacent to a nitrogen atom of Formula V.

[0133] A more preferred class of linker groups of Formula V consists of divalent radicals wherein each of R202 and R203 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number independently selected from two through four, inclusive. Even more preferred are linker groups wherein each of R202 and R203 is independently selected from hydrido, amino, monoalkylamino and carboxyl; and wherein each of p and q is independently selected from the numbers two and three. Most preferred is a linker group wherein each of R202 and R203 is hydrido; and wherein each of p and q is two; such most preferred linker group is derived from a piperazinyl group and has the structure 42

[0134] In Table II there is shown a class of specific examples of cyclized, diamino-terminated linker groups within Formula V. These linker groups, identified as Linker Nos. 74-95, would be suitable to form a conjugate between a carbonyl moiety of an AII antagonist (designated as “I”) and a carbonyl moiety of carbonyl terminated second residue such as the carbonyl moiety attached to the gamma carbon of a glutamyl residue (designated as “T”).

TABLE II
43
I = inhibitor
T = acetyl-γ-glutamyl
LINKLER
NO.	R206	R207	R208	R209	R210	R211	R212	R213
74	H	H	H	H	H	H	H	H
75	CH3	H	H	H	H	H	H	H
76	H	H	H	H	CH3	H	H	H
77	CH3	H	H	H	CH3	H	H	H
78	CH3	H	CH3	H	H	H	H	H
79	CH3	H	H	H	H	H	CH3	H
80	CH3	CH3	H	H	H	H	H	H
81	H	H	H	H	CH3	CH3	H	H
82	CH3	CH3	H	H	CH3	CH3	H	H
83	CH3	CH3	CH3	CH3	H	H	H	H
84	CH3	CH3	H	H	H	H	CH3	CH3
85	H	H	H	H	CH3	CH3	CH3	CH3
86	C6H5	H	H	H	H	H	H	H
87	H	H	H	H	C6H5	H	H	H
88	C6H5	H	H	H	C6H5	H	H	H
89	C6H5	H	H	H	H	H	C6H5	H
90	C6H5	H	C6H5	H	H	H	H	H
91	CH2C6H5	H	H	H	H	H	H	H
92	H	H	H	H	CH2C6H5	H	H	H
93	CH2C6H5	H	H	H	CH2C6H5	H	H	H
94	CH2C6H5	H	H	H	H	H	CH2C6H5	H
95	CH2C6H5	H	CH2C6H5	H	H	H	H	H

[0135] Another class of suitable diamino terminal linker groups is defined by Formula VI: 44

[0136] wherein each of R214 through R217 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, aryl, haloalkyl, amino, monoalkylamino, dialkylamino, cyanoamino, carboxyalkyl, alkylsulfino, alkylsulfonyl, arylsulfinyl and arylsulfonyl; and wherein p is a number selected from one through six inclusive.

[0137] A preferred class of linker groups within Formula VI consists of divalent radicals wherein each of R214 and R215 is hydrido; wherein each of R62 and R63 is independently selected from hydrido, alkyl, phenalkyl, phenyl, alkoxyalkyl, hydroxyalkyl, haloalkyl and carboxyalkyl; and wherein p is two or three. A more preferred class of linker groups within Formula VI consists of divalent radicals wherein each of R214 and R215 is hydrido; wherein each of R216 and R217 is independently selected from hydrido and alkyl; and wherein p is two. A specific example of a more preferred linker within Formula VI is the divalent radical ethylenediamino. In Table III there is shown a class of specific examples of diamino- terminated linker gorups within Formula VI. These linker groups, identified as Linker Nos. 96-134, would be suitable to form a conjugate between a carbonyl moiety of an AII antagonist (designated as “I”) and a carbonyl moiety of carbonyl terminated second residue such as the carbonyl moiety attached to the gamma carbon of a glutamyl residue (designated as “T”).

TABLE III
45
I = inhibitor
G = acetyl-γ-glutamyl
LINKER
NO.	R218	R219	R220	R221	R222	R223
96	H	H	H	H	H	H
97	H	H	H	H	H	CH3
98	H	H	H	CH3	H	H
99	H	H	H	CH3	H	CH3
100	CH3	H	H	H	H	H
101	H	CH3	H	H	H	H
102	H	H	H	H	CH3	CH3
103	H	H	CH3	CH3	H	H
104	CH3	CH3	H	H	H	H
105	H	H	H	H	H	C6H5
106	H	H	H	C6H5	H	H
107	H	H	H	C6H5	H	C6H5
108	C6H5	H	H	H	H	H
109	H	C6H5	H	H	H	H
110	H	H	H	H	C6H5	C6H5
111	H	H	C6H5	C6H5	H	H
112	C6H5	C6H5	H	H	H	H
113	H	H	H	H	H	C2H5
114	H	H	H	C2H5	H	H
115	H	H	H	C2H5	H	C2H5
116	C2H5	H	H	H	H	H
117	H	C2H5	H	H	H	H
118	H	H	H	H	C2H5	C2H5
119	H	H	C2H5	C2H5	H	H
120	C2H5	C2H5	H	H	H	H
121	CH3	H	C6H5	H	H	H
122	CH3	H	H	H	C6H5	H
123	H	CH3	C6H5	H	H	H
124	H	CH3	H	H	C6H5	H
125	CH3	CH3	H	C6H5	H	H
126	CH3	CH3	H	H	H	C6H5
127	H	H	H	H	H	CH2C6H5
128	H	H	H	CH2C6H5	H	H
129	CH2C6H5	H	H	H	H	H
130	H	CH2C6H5	H	H	H	H
131	CH3	H	CH2C6H5	H	H	H
132	CH3	H	H	H	CH2C6H5	H
133	H	CH3	CH2C6H5	H	H	H
134	H	CH3	H	H	CH2C6H5	H

[0138] The term “hydrido” denotes a single hydrogen atom (H). This hydrido group may be attached, for example, to a carbon atom to form a 46

[0139] group or attached to an oxygen atom to form a hydroxyl group; or as another example, two hydrido groups may be attached to a carbon atom to form a —CH2— group. Where the term “alkyl” is used, either alone or within other terms such as “haloalkyl” and “hydroxyalkyl”, the term “alkyl” embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about five carbon atomms. The term “cycloalkyl” embraces cyclic radicals having three to about ten ring carbon atoms, preferably three to about six carbon atoms, such as cyclopropyl and cyclobutyl. The term “haloalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo groups, preferably selected from bromo, chloro and fluoro. Specifically embraced by the term “haloalkyl” are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for example, may have either a bromo, a chloro, or a fluoro atom within the group. Dihaloalkyl and polyhaloalkyl groups may be substituted with two or more of the same halo groups, or may have a combination of different halo groups. A dihaloalkyl group, for example, may have two fluoro atoms, such as difluoromethyl and difluorobutyl groups, or two chloro atoms, such as a dichloromethyl group, or one fluoro atom and one chloro atom, such as a fluoro-chloromethyl group. Examples of a polyhaloalkyl are trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl and 2,2,3,3-tetrafluoropropyl groups. The term “difluoroalkyl” embraces alkyl groups having two fluoro atoms substituted on any one or two of the alkyl group carbon atoms. Preferably, when the difluoroalkyl group is attached at the triazole ring R1 and R2 positions of Formula I, the two fluoro atoms are substituted on the carbon atom which is attached directly to the triazole ring. Such preferred difluoroalkyl group may be characterized as an “alpha-carbon difluoro-substituted difluoroalkyl group” The terms “alkylol” and “hydroxyalkyl” embrace linear or branched alkyl groups having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl groups. The term “alkenyl” embraces linear or branched radicals having two to about twenty carbon atoms, preferably three to about ten carbon atoms, and containing at least one carbon-carbon double bond, which carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety. The term “alkynyl” embraces linear or branched radicals having two to about twenty carbon atoms, preferably two to about ten carbon atoms, and containing at least one carbon-carbon triple bond. The term “cycloalkenyl” embraces cyclic radicals having three to about ten ring carbon atoms including one or more double bonds involving adjacent ring carbons. The terms “alkoxy” and “alkoxyalkyl” embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy group. The term “alkoxyalkyl” also embraces alkyl radicals having two or more alkoxy groups attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl groups. The “alkoxy” or “alkoxyalkyl” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or haloalkoxyalkyl groups. The term “alkylthio” embraces radicals containing a linear or branched alkyl group, of one to about ten carbon atoms attached to a divalent sulfur atom, such as a methythio group. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl and biphenyl. Preferred aryl groups are those consisting of one, two, or three benzene rings. The term “aralkyl” embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, phenylbutyl and diphenylethyl. The terms “benzyl” and “phenylmethyl” are interchangeable. The terms “aryloxy” and “arylthio” denote radical respectively, aryl groups having an oxygen or sulfur atom through which the radical is attached to a nucleus, examples of which are phenoxy and phenylthio. The terms “sulfinyl” and “sulfonyl”, whether used alone or linked to other terms, denotes respectively divalent radicals SO and SO2. The term “aralkoxy”, alone or within another term, embraces an aryl group attached to an alkoxy group to form, for example, benzyloxy. The term “acyl” whether used alone, or within a term such as acyloxy, denotes a radical provided by the residue after removal of hydroxyl from an organic acid, examples of such radical being acetyl and benzoyl. The term “heteroaryl” embraces aromatic ring systems containing one or two hetero atoms selected from oxygen, nitrogen and sulfur in a ring system having five or six ring members, examples of which are thienyl, furanyl, pyridinyl, thiazolyl, pyrimidyl and isoxazolyl. Such heteroaryl may be attached as a substituent through a carbon atom of the heteroaryl ring system, or may be attached through a carbon atom of a moiety substituted on a heteroaryl ring-member carbon atom, for example, through the methylene substituent of imidazolemethyl moiety. Also, such heteroaryl may be attached through a ring nitrogen atom as long as aromaticity of the heteroaryl moiety is preserved after attachment. The term “amido” denotes a radical consisting of a nitrogen atom attached to a carbonyl group, which radical may be further substituted in the manner described herein. The amido radical can be attached to the nucleus of a compound of the invention through the carbonyl moiety or the nitrogen atom of the amido radical. The term “alkenylalkyl” denotes a radical having a double-bond unsaturation site between two carbons, and which radical may consist of only two carbons or may be further substituted with alkyl groups which may optionally contain additional double-bond unsaturation. For any of the foregoing defined radicals, preferred radicals are those containing between one and about ten carbon atoms.

[0140] Specific examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, methylbutyl, dimethylbutyl and neopentyl. Typical alkenyl and alkynyl groups may have one unsaturated bond, such as an allyl group, or may have a plurality or unsaturated bonds, with such plurality of bonds either adjacent, such as allene-type structures, or in conjugation, or separated by several saturated carbons.

[0141] Conjugates of the invention formed from compounds of Formula I have been found to inhibit the action of angiotensin II in mammals. Thus, conjugates of Formula I are therapeutically useful in methods for treating hypertension by administering to a hypertensive patient a therapeutically-effective amount of a conjugate containing a compound of Formula I, such that the conjugate is hydrolyzed by an enzyme found predominantly in the kidney so as to release an active angiotensin II antagonist species. The phrase “hypertensive patient” means, in this context, a mammalian subject suffering from the effects of hypertension or susceptible to a hypertensive condition if not treated to prevent or control such hypertension.

[0142] Included within the invention are conjugates of compounds of Formula I which are tautomeric forms of the described compounds, isomeric forms including diastereoisomers, and the pharmaceutically-acceptable salts thereof. The term “pharmaceutically-acceptable salts” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methansulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I. Also, such pharmaceutical salts may be formed with either a compound of Formula I which is contained in the conjugate, or such salts may be formed with the conjugate itself.

[0143] Conjugates of the invention can possess one or more asymmetric carbon atoms and are thus capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed by liberation of the optically active bases from these salts. A different process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available method involves synthesis of covalent diastereoisomeric molecules by reacting conjugates with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active conjugates can likewise be obtained by utilizing optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt.

[0144] The first and second residues are provided by precursor compounds having suitable chemical moieties which react together to form a cleavable bond between the first and second residues. For example, the precursor compound of one of the residues will have a reactable carboxylic acid moiety and the precursor of the other residue will have a reactable amino moiety or a moiety convertible to a reactable amino moiety, so that a cleavable amide bond may be formed between the carboxylic acid moiety and the amino moiety.

[0145] Conjugates of the invention may be prepared using precursors of highly active angiotensin II antagonists of Formula I. Examples of lesser active, suitable precursors are acid chloride, esters and amides of angiotensin II antagonists of Formula I. For example, ester precursors of angiotensin II antagonists may be reacted with hydrazine to provide an amino terminal moiety which then can be reacted with a glutamic acid derivative to form a conjugate of the invention. Such precursors or intermediates themselves may be relatively strong, relatively weak, or inactive as AII antagonists. Also, conjugates of the invention may be prepared using angiotensin II antagonists lacking a reactive terminal amino moiety. Such angiotensin II antagonists may be modified to contain a terminal acid moiety which then may be connected to a glutamyl residue through a diamino-terminated linker group, such as shown in Tables I-III.

[0146] A family of specific angiotensin II antagonist compounds of Formula I, from which a suitable first component of the conjugate may be selected, consists of biphenylmethyl 1H-substituted-1,2,4-triazole compounds listed below having a carboxylic acid terminal moiety or carboxylic acid moiety modified to be a hydrazide terminal moiety. All such compounds are characterized in having such carboxylic acid at one of the R5 through R9 positions of Formula I. Those compounds having a terminal carboxylic moiety may be reacted with one of the aforementioned linker groups, such as a hydrazine or a piperazine linker, to provide an amino terminal moiety which can then be reacted with the carboxylic acid moiety of a second component of the conjugate, such as a glutamic acid residue to form an enzyme-cleavable bond. Specific examples of these compounds are listed below:

[0147] 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid, hydrazide;

[0148] 4′-[(5-butyl-3-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0149] 4′-[(3-butyl-5-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0150] 4′-[(5-butyl-3-ethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0151] 4′-[(5-butyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0152] 4′-[(5-butyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0153] methyl 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylate;

[0154] 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0155] 4′-[(5-butyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0156] 4′-[(5-butyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0157] 4′-[(5-butyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0158] 4′-[(5-butyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0159] 4′-[(5-butyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0160] 4′-[(5-butyl-3-mercapto-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0161] 4′-[(5-butyl-3-thiomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0162] 4′-[(5-butyl-3-thioethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0163] 4′-[(5-butyl-3-thiopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0164] 4′-[(5-butyl-3-hydroxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0165] 4′-[(5-butyl-3-methoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0166] 4′-[(5-butyl-3-ethoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0167] 4′-[(5-butyl-3-propoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0168] 4′-[(5-butyl-3-butoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0169] 4′-[(5-butyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0170] 4′-[(5-butyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0171] 4′-[[5-butyl-3-(2-cyclohexylethyl))-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0172] 4′-[(5-butyl-3-cyclohexanoyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0173] 4′-[[5-butyl-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0174] 4′-[(5-butyl-3-phenyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0175] 4′-[(5-butyl-3-phenylmethyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0176] 4′-[(5-butyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0177] 4′-[(3-butyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0178] 4′-[[5-butyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0179] 4′-[(5-butyl-3-benzoyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0180] 4′-[[5-butyl-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0181] 4′-[[5-butyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0182] 4′-[[5-butyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0183] 4′-[[5-butyl-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0184] 4′-[[5-butyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0185] 4′-[[5-butyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0186] 4′-[[5-butyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0187] 4′-[[5-butyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0188] 4′-[[5-butyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0189] 4′-[[5-butyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0190] 4′-[[3-butyl-5-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0191] 4′-[[5-butyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0192] 4′-[(5-propyl-3-ethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0193] 4′-[(3,5-dipropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0194] 4′-[(3,5-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0195] 4′-[(5-propyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0196] 4′-[(5-propyl-3-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0197] 4′-[(5-propyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0198] 4′-[(5-propyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0199] 4′-[(5-propyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0200] 4′-[(5-propyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0201] 4′-[(5-propyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0202] 4′-[(5-propyl-3-mercapto-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0203] 4′-[(5-propyl-3-thiomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0204] 4′-[(5-propyl-3-thioethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0205] 4′-[(5-propyl-3-thiopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0206] 4′-[(5-propyl-3-hydroxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0207] 4′-[(5-propyl-3-methoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0208] 4′-[(5-propyl-3-ethoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0209] 4′-[(5-propyl-3-propoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0210] 4′-[(5-propyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0211] 4′-[(5-propyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0212] 5-[4′-[[5-propyl-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0213] 4′-[(5-propyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0214] 5-[4′-[[5-propyl-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0215] 4′-[(5-propyl-3-phenyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0216] 4′-[(5-propyl-3-phenylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0217] 4′-[[5-propyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0218] 4′-[(5-propyl-3-benzoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0219] 4′-[[5-propyl-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0220] 4′-[[5-propyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0221] 4′-[[5-propyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0222] 4′-[[5-propyl-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0223] 4′-[[5-propyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0224] 4′-[[5-propyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0225] 4′-[[5-propyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0226] 4′-[[5-propyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0227] 4′-[[3,5-bis(heptafluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0228] 4′-[[5-propyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0229] 4′-[[5-propyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0230] 4′-[[5-propyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0231] 4′-[(3,5-diethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0232] 4′-[(5-ethyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0233] 4′-[(5-ethyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0234] 4′-[(5-ethyl-3-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0235] 4′-[(5-ethyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0236] 4′-[(5-ethyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0237] 4′-[(5-ethyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0238] 4′-[(5-ethyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0239] 4′-[(5-ethyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0240] 4′-[(5-ethyl-3-mercapto-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0241] 4′-[(5-ethyl-3-thiomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0242] 4′-[(5-ethyl-3-thioethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0243] 4′-[(5-ethyl-3-thiopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0244] 4′-[(5-ethyl-3-hydroxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0245] 4′-[(5-ethyl-3-methoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0246] 4′-[(5-ethyl-3-ethoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0247] 4′-[(5-ethyl-3-propoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0248] 4′-[(5-ethyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0249] 4 ′-[(5-ethyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0250] 4′-[[5-ethyl-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0251] 4′-[(5-ethyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0252] 4′-[[5-ethyl-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0253] 4′-[(5-ethyl-3-phenyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0254] 4′-[(5-ethyl-3-phenylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0255] 4′-[[5-ethyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0256] 4′-[(5-ethyl-3-benzoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0257] 4′-[[5-ethyl-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0258] 4′-[[5-ethyl-3-(1,1′-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0259] 4′-[[5-ethyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0260] 4′-[[5-ethyl-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0261] 4′-[[5-ethyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0262] 4′-[[5-ethyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0263] 4′-[[5-ethyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0264] 4′-[[5-ethpyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0265] 4′-[[5-ethyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0266] 4′-[[5-ethyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0267] 4′-[[5-ethyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0268] 4′-[(5-secbutyl-3-ethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0269] 4′-[(5-secbutyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0270] 4′-[(5-secbutyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0271] 4′-[(5-secbutyl-3-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0272] 4′-[(3,5-disecbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0273] 4′-[(5-secbutyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0274] 4′-[(5-secbutyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0275] 4′-[(5-secbutyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0276] 4′-[(5-secbutyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0277] 4′-[(5-secbutyl-3-mercapto-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0278] 4′-[(5-secbutyl-3-thiomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0279] 4′-[(5-secbutyl-3-thioethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0280] 4′-[(5-secbutyl-3-thiopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0281] 4′-[(5-secbutyl-3-hydroxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0282] 4′-[(5-secbutyl-3-methoxy-1H-1,2,4-triazol-1-yl)methyl](1,1′-biphenyl]-2-carboxylic acid;

[0283] 4′-[(5-secbutyl-3-ethoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0284] 4′-[(5-secbutyl-3-propoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0285] 4′-[(5-secbutyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0286] 4′-[(5-secbutyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0287] 4′-[[5-secbutyl-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0288] 4′-[(5-secbutyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0289] 4′-[[5-secbutyl-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0290] 4′-[(5-secbutyl-3-phenyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0291] 4′-[(5-secbutyl-3-phenylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0292] 4′-[[5-secbutyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0293] 4′-[(5-secbutyl-3-benzoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0294] 4′-[[5-secbutyl-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0295] 4′-[[5-secbutyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0296] 4′-[[5-secbutyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0297] 4′-[[5-secbutyl-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0298] 4′-[[5-secbutyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,140 -biphenyl]-2-carboxylic acid;

[0299] 4′-[[5-secbutyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0300] 4′-[[5-secbutyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0301] 4′-[[5-secbutyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0302] 4′-[[5-secbutyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0303] 4′-[[5-secbutyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0304] 4′-[[5-secbutyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0305] 4′-[(5-isobutyl-3-ethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0306] 4′-[(5-isobutyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0307] 4′-[(5-isobutyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0308] 4′-[(5-isobutyl-3-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0309] 4′-[(5-isobutyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0310] 4′-[(3,5-diisobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0311] 4′-[(5-isobutyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0312] 4′-[(5-isobutyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0313] 4′-[(5-isobutyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0314] 4′-[(5-isobutyl-3-mercapto-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0315] 4′-[(5-isobutyl-3-thiomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0316] 4′-[(5-isobutyl-3-thioethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0317] 4′-[(5-isobutyl-3-thiopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0318] 4′-[(5-isobutyl-3-hydroxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0319] 4′-[(5-isobutyl-3-methoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0320] 4′-[(5-isobutyl-3-ethoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0321] 4′-[(5-isobutyl-3-propoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0322] 4′-[(5-isobutyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0323] 4′-[(5-isobutyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0324] 4′-[[5-isobutyl-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0325] 4′-[(5-isobutyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0326] 4′-[[5-isobutyl-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0327] 4′-[(5-isobutyl-3-phenyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0328] 4′-[(5-isobutyl-3-phenylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0329] 4′-[[5-isobutyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0330] 4′-[(5-isobutyl-3-benzoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0331] 4′-[[5-isobutyl-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0332] 4′-[[5-isobutyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0333] 4′-[[5-isobutyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0334] 4′-[[5-isobutyl-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0335] 4′-[[5-isobutyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0336] 4′-[[5-isobutyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0337] 4′-[[5-isobutyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0338] 4′-[[5-isobutyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0339] 4′-[[5-isobutyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0340] 4′-[[5-isobutyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0341] 4′-[[5-isobutyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0342] 4′-[(5-tertbutyl-3-ethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0343] 4′-[(5-tertbutyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0344] 4′-[(5-tertbutyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0345] 4′-[(5-tertbutyl-3-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0346] 4′-[(5-tertbutyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0347] 4′-[(5-tertbutyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0348] 4′-[(3,5-ditertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0349] 4′-[(5-tertbutyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0350] 4′-[(5-tertbutyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0351] 4′-[(5-tertbutyl-3-mercapto-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0352] 4′-[(5-tertbutyl-3-thiomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0353] 4′-[(5-tertbutyl-3-thioethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0354] 4′-[(5-tertbutyl-3-thiopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0355] 4′-[(5-tertbutyl-3-hydroxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0356] 4′-[(5-tertbutyl-3-methoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0357] 4′-[(5-tertbutyl-3-ethoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0358] 4′-[(5-tertbutyl-3-propoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0359] 4′-[(5-tertbutyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl)[1,1′-biphenyl]-2-carboxylic acid;

[0360] 4′-[(5-tertbutyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0361] 4′-[[5-tertbutyl-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0362] 4′-[(5-tertbutyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0363] 4′-[[5-tertbutyl-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0364] 4′-[(5-tertbutyl-3-phenyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0365] 4′-[(5-tertbutyl-3-phenylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0366] 4′-[[5-tertbutyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0367] 4′-[(5-tertbutyl-3-benzoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0368] 4′-[[5-tertbutyl-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0369] 4′-[[5-tertbutyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0370] 4′-[[5-tertbutyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0371] 4′-[[5-tertbutyl-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0372] 4′-[[5-tertbutyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0373] 4′-[[5-tertbutyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0374] 4′-[[5-tertbutyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0375] 4′-[[5-tertbutyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0376] 4′-[[5-tertbutyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0377] 4′-[[5-tertbutyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0378] 4′-[[5-tertbutyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0379] 4′-[(5-pentyl-3-ethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0380] 4′-[(5-pentyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0381] 4′-[(5-pentyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0382] 4′-[(5-pentyl-3-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0383] 4′-[(5-pentyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0384] 4′-[(5-pentyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0385] 4′-[(5-pentyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0386] 4′-[(3,5-dipentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0387] 4′-[(5-pentyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0388] 4′-[(5-pentyl-3-mercapto-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0389] 4′-[(5-pentyl-3-thiomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0390] 4′-[(5-pentyl-3-thioethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0391] 4′-[(5-pentyl-3-thiopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0392] 4′-[(5-pentyl-3-hydroxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0393] 4′-[(5-pentyl-3-methoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0394] 4′-[(5-pentyl-3-ethoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0395] 4′-[(5-pentyl-3-propoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0396] 4′-[(5-pentyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0397] 4′-[(5-pentyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0398] 4′-[[5-pentyl-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0399] 4′-[(5-pentyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0400] 4′-[[5-pentyl-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0401] 4′-[(5-pentyl-3-phenyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0402] 4′-[(5-pentyl-3-phenylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0403] 4′-[[5-pentyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0404] 4′-[(5-pentyl-3-benzoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0405] 4′-[[5-pentyl-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0406] 4′-[[5-pentyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0407] 4′-[[5-pentyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0408] 4′-[[5-pentyl-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0409] 4′-[[5-pentyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0410] 4′-[[5-pentyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0411] 4′-[[5-pentyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0412] 4′-[[5-pentyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0413] 4′-[[5-pentyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0414] 4′-[[5-pentyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0415] 4′-[[5-pentyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0416] 4′-[(5-isopentyl-3-ethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0417] 4′-[(5-isopentyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0418] 4′-[(5-isopentyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0419] 4′-[(5-isopentyl-3-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0420] 4′-[(5-isopentyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0421] 4′-[(5-isopentyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0422] 4′-[(5-isopentyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0423] 4′-[(5-isopentyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0424] 4′-[(3,5-diisopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0425] 4′-[(5-isopentyl-3-mercapto-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0426] 4′-[(5-isopentyl-3-thiomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0427] 4′-[(5-isopentyl-3-thioethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0428] 4′-[(5-isopentyl-3-thiopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0429] 4′-[(5-isopentyl-3-hydroxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0430] 4′-[(5-isopentyl-3-methoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0431] 4′-[(5-isopentyl-3-ethoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0432] 4′-[(5-isopentyl-3-propoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0433] 4′-[(5-isopentyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0434] 4′-[(5-isopentyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0435] 4′-[[5-pentyl-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0436] 4′-[(5-isopentyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0437] 4′-[[5-isopentyl-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0438] 4′-[(5-isopentyl-3-phenyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0439] 4′-[(5-isopentyl-3-phenylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0440] 4′-[[5-isopentyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0441] 4′-[(5-isopentyl-3-benzoyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0442] 4′-[[5-isopentyl-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0443] 4′-[[5-isopentyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0444] 4′-[[5-isopentyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0445] 4′-[[5-isopentyl-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0446] 4′-[[5-isopentyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0447] 4′-[[5-isopentyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0448] 4′-[[5-isopentyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0449] 41-[[5-isopentyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0450] 4′-[[5-isopentyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0451] 4′-[[5-isopentyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0452] 4′-[[5-isopentyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0453] 4′-[[5-(1-butenyl)-3-ethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0454] 4′-[[5-(1-butenyl)-3-propyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0455] 4′-[[5-(1-butenyl)-3-isopropyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0456] 4′-[[5-(1-butenyl)-3-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0457] 4′-[[5-(1-butenyl)-3-secbutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0458] 4′-[[5-(1-butenyl)-3-isobutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0459] 4′-[[5-(1-butenyl)-3-tertbutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0460] 4′-[[5-(1-butenyl)-3-pentyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0461] 4′-[[5-(1-butenyl)-3-isopentyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0462] 4′-[[5-(1-butenyl)-3-mercapto-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0463] 4′-[[5-(1-butenyl)-3-thiomethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0464] 4′-[[5-(1-butenyl)-3-thioethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0465] 4′-[[5-(1-butenyl)-3-thiopropyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0466] 4′-[[5-(1-butenyl)-3-hydroxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0467] 4′-[[5-(1-butenyl)-3-methoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0468] 4′-[[5-(1-butenyl)-3-ethoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0469] 4′-[[5-(1-butenyl)-3-propoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0470] 4′-[[5-(1-butenyl)-3-cyclohexyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0471] 4′-[[5-(1-butenyl)-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0472] 4′-[[5-(1-butenyl)-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0473] 4′-[[5-(1-butenyl)-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0474] 4′-[[5-(1-butenyl)-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0475] 4′-[[5-(1-butenyl)-3-phenyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0476] 4′-[[5-(1-butenyl)-3-phenylmethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0477] 4′-[[5-(1-butenyl)-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0478] 4′-[[5-(1-butenyl)-3-benzoyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0479] 4′-[[5-(1-butenyl)-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0480] 4′-[[5-(1-butenyl)-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0481] 4′-[[5-(1-butenyl)-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0482] 4′-[[5-(1-butenyl)-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0483] 4′-[[5-(1-butenyl)-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0484] 4′-[[5-(1-butenyl)-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0485] 4′-[[5-(1-butenyl)-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0486] 4′-[[5-(1-butenyl)-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0487] 4′-[[5-(1-butenyl)-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0488] 4′-[[5-(1-butenyl)-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0489] 4′-[[5-(1-butenyl)-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0490] 4′-[[5-(2-butenyl)-3-ethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0491] 4′-[[5-(2-butenyl)-3-propyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0492] 4′-[[5-(2-butenyl)-3-isopropyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0493] 4′-[[5-(2-butenyl)-3-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0494] 4′-[[5-(2-butenyl)-3-secbutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0495] 4′-[[5-(2-butenyl)-3-isobutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0496] 4′-[[5-(2-butenyl)-3-tertbutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0497] 4′-[[5-(2-butenyl)-3-pentyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0498] 4′-[[5-(2-butenyl)-3-isopentyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0499] 4′-[[5-(2-butenyl)-3-mercapto-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0500] 4′-[[5-(2-butenyl)-3-thiomethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0501] 4′-[[5-(2-butenyl)-3-thioethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0502] 4′-[[5-(2-butenyl)-3-thiopropyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0503] 4′-[[5-(2-butenyl)-3-hydroxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0504] 4′-[[5-(2-butenyl)-3-methoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0505] 4′-[[5-(2-butenyl)-3-ethoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0506] 4′-[[5-(2-butenyl)-3-propoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0507] 4′-[[5-(2-butenyl)-3-cyclohexyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0508] 4′-[[5-(2-butenyl)-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0509] 4′-[[5-(2-butenyl)-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0510] 4′-[[5-(2-butenyl)-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0511] 4′-[[5-(2-butenyl)-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0512] 4′-[[5-(2-butenyl)-3-phenyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0513] 4′-[[5-(2-butenyl)-3-phenylmethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0514] 4′-[[5-(2-butenyl)-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0515] 4′-[[5-(2-butenyl)-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0516] 4′-[[5-(2-butenyl)-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol -1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0517] 4′-[[5-(2-butenyl)-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0518] 4′-[[5-(2-butenyl)-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0519] 4′-[[5-(2-butenyl)-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0520] 4′-[[5-(2-butenyl)-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0521] 4′-[[5-(2-butenyl)-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0522] 4′-[[5-(2-butenyl)-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0523] 4′-[[5-(2-butenyl)-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0524] 4′-[[5-(2-butenyl)-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0525] 4′-[[5-(3-butenyl)-3-ethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0526] 4′-[[5-(3-butenyl)-3-propyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0527] 4′-[[5-(3-butenyl)-3-isopropyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0528] 4′-[[5-(3-butenyl)-3-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0529] 4′-[[5-(3-butenyl)-3-secbutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0530] 4′-[[5-(3-butenyl)-3-isobutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0531] 4′-[[5-(3-butenyl)-3-tertbutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0532] 4′-[[5-(3-butenyl)-3-pentyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0533] 4′-[[5-(3-butenyl)-3-isopentyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0534] 4 ′-[[5-(3-butenyl)-3-mercapto-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0535] 4′-[[5-(3-butenyl)-3-thiomethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl)-2-carboxylic acid;

[0536] 4′-[[5-(3-butenyl)-3-thioethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0537] 4′-[[5-(3-butenyl)-3-thiopropyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0538] 4′-[[5-(3-butenyl)-3-hydroxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0539] 4′-[[5-(3-butenyl)-3-methoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0540] 4′-[[5-(3-butenyl)-3-ethoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0541] 4′-[[5-(3-butenyl)-3-propoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0542] 4′-[[5-(3-butenyl)-3-cyclohexyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0543] 4′-[[5-(3-butenyl)-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0544] 4′-[[5-(3-butenyl)-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0545] 4′-[[5-(3-butenyl)-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0546] 4′-[[5-(3-butenyl)-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0547] 4′-[[5-(3-butenyl)-3-phenyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0548] 4′-[[5-(3-butenyl)-3-phenylmethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0549] 4′-[[5-(3-butenyl)-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0550] 4′-[[5-(3-butenyl)-3-benzoyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0551] 4′-[[5-(3-butenyl)-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0552] 4′-[[5-(3-butenyl)-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1-biphenyl]-2-carboxylic acid;

[0553] 4 ′-[[5-(3-butenyl)-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0554] 4′-[[5-(3-butenyl)-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0555] 4′-[[5-(3-butenyl)-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0556] 4′-[[5-(3-butenyl)-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0557] 4′-[[5-(3-butenyl)-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0558] 4′-[[5-(3-butenyl)-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0559] 4′-[[5-(3-butenyl)-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0560] 4′-[[5-(3-butenyl)-3-(1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0561] 4′-[[5-(3-butenyl)-3-(1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0562] 4′-[[5-(1-butynyl)-3-ethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0563] 4′-[[5-(1-butynyl)-3-propyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0564] 4′-[[5-(1-butynyl)-3-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0565] 4′-[[5-(1-butynyl)-3-secbutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0566] 4′-[[5-(1-butynyl)-3-isobutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0567] 4′-[[5-(1-butynyl)-3-tertbutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0568] 4′-[[5-(1-butynyl)-3-pentyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0569] 4′-[[5-(1-butynyl)-3-isopentyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0570] 4′-[[5-(1-butynyl)-3-mercapto-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0571] 4′-[[5-(1-butynyl)-3-thiomethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0572] 4′-[[5-(1-butynyl)-3-thioethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0573] 4′-[[5-(1-butynyl)-3-thiopropyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0574] 4′-[[5-(1-butynyl)-3-hydroxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0575] 4′-[[5-(1-butynyl)-3-methoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0576] 4′-[[5-(1-butynyl)-3-ethoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0577] 4′-[[5-(1-butynyl)-3-propoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0578] 4′-[[5-(1-butynyl)-3-cyclohexyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0579] 4′-[[5-(1-butynyl)-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0580] 4′-[[5-(1-butynyl)-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0581] 4′-[[5-(1-butynyl)-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0582] 4′-[[5-(1-butynyl)-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0583] 41′-[[5-(1-butynyl)-3-phenyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0584] 4′-[[5-(1-butynyl)-3-phenylmethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0585] 4′-[[5-(1-butynyl)-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0586] 4′-[[5-(1-butynyl)-3-benzoyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0587] 4′-[[5-(1-butynyl)-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0588] 4′-[[5-(1-butynyl)-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0589] 4′-[[5-(1-butynyl)-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0590] 4′-[[5-(1-butynyl)-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0591] 4′-[[5-(1-butynyl)-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0592] 4′-[[5-(1-butynyl)-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0593] 4′-[[5-(1-butynyl)-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0594] 4′-[[5-(1-butynyl)-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0595] 4′-[[5-(1-butynyl)-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0596] 4′-[[5-(1-butynyl)-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0597] 4′-[[5-(1-butynyl)-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0598] 4′-[[5-(2-butynyl)-3-ethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0599] 4′-[[5-(2-butynyl)-3-propyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0600] 4′-[[5-(2-butynyl)-3-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0601] 4′-[[5-(2-butynyl)-3-secbutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0602] 4′-[[5-(2-butynyl)-3-isobutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0603] 4′-[[5-(2-butynyl)-3-tertbutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0604] 4′-[[5-(2-butynyl)-3-pentyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0605] 4′-[[5-(2-butynyl)-3-isopentyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0606] 4′-[[5-(2-butynyl)-3-mercapto-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0607] 4′-[[5-(2-butynyl)-3-thiomethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0608] 4′-[[5-(2-butynyl)-3-thioethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0609] 4′-[[5-(2-butynyl)-3-thiopropyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0610] 4′-[[5-(2-butynyl)-3-hydroxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0611] 4′-[[5-(2-butynyl)-3-methoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0612] 4′-[[5-(2-butynyl)-3-ethoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0613] 4′-[[5-(2-butynyl)-3-propoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0614] 4′-[[5-(2-butynyl)-3-cyclohexyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0615] 4′-[[5-(2-butynyl)-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0616] 4′-[[5-(2-butynyl)-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0617] 4′-[[5-(2-butynyl)-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0618] 4′-[[5-(2-butynyl)-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0619] 4′-[[5-(2-butynyl)-3-phenyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0620] 4′-[[5-(2-butynyl)-3-phenylmethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0621] 4′-[[5-(2-butynyl)-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0622] 4′-[[5-(2-butynyl)-3-benzoyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0623] 4′-[[5-(2-butynyl)-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0624] 4′-[[5-(2-butynyl)-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0625] 4′-[[5-(2-butynyl)-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0626] 4′-[[5-(2-butynyl)-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0627] 4′-[[5-(2-butynyl)-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0628] 4′-[[5-(2-butynyl)-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0629] 4′-[[5-(2-butynyl)-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0630] 4′-[[5-(2-butynyl)-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0631] 4′-[[5-(2-butynyl)-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0632] 4′-[[5-(2-butynyl)-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0633] 4′-[[5-(2-butynyl)-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0634] 4′-[[5-(3-butynyl)-3-ethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0635] 4′-[[5-(3-butynyl)-3-propyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0636] 4′-[[5-(3-butynyl)-3-isopropyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0637] 4′-[[5-(3-butynyl)-3-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0638] 4′-[[5-(3-butynyl)-3-secbutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0639] 4′-[[5-(3-butynyl)-3-isobutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0640] 4′-[[5-(3-butynyl)-3-tertbutyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0641] 4′-[[5-(3-butynyl)-3-isopentyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0642] 4′-[[5-(3-butynyl)-3-pentyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0643] 4′-[[5-(3-butynyl)-3-mercapto-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0644] 4′-[[5-(3-butynyl)-3-thiomethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0645] 4′-[[5-(3-butynyl)-3-thioethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0646] 4′-[[5-(3-butynyl)-3-thiopropyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0647] 4′-[[5-(3-butynyl)-3-hydroxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0648] 4′-[[5-(3-butynyl)-3-methoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0649] 4′-[[5-(3-butynyl)-3-ethoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0650] 4′-[[5-(3-butynyl)-3-propoxy-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0651] 4′-[[5-(3-butynyl)-3-cyclohexyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0652] 4′-[[5-(3-butynyl)-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0653] 4′-[[5-(3-butynyl)-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0654] 4′-[[5-(3-butynyl)-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0655] 4′-[[5-(3-butynyl)-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0656] 4′-[[5-(3-butynyl)-3-phenyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0657] 4′-[[5-(3-butynyl)-3-phenylmethyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0658] 4′-[[5-(3-butynyl)-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0659] 4′-[[5-(3-butynyl)-3-benzoyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0660] 41-[[5-(3-butynyl)-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0661] 4′-[[5-(3-butynyl)-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0662] 4′-[[5-(3-butynyl)-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0663] 4′-[[5-(3-butynyl)-3-(1,1-dimethoxypentyl)-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0664] 4′-[[5-(3-butynyl)-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0665] 4′-[[5-(3-butynyl)-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0666] 4′-[[5-(3-butynyl)-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0667] 4′-[[5-(3-butynyl)-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0668] 4′-[[5-(3-butynyl)-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0669] 4′-[[5-(3-butynyl)-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0670] 4′-[[5-(3-butynyl)-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0671] 4′-[(3,5-diethoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0672] 4′-[(3,5-dipropoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0673] 4′-[(3,5-diisopropoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0674] 4′-[(3,5-dibutoxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0675] 4′-[(3,5-dithiomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0676] 4′-[(3,5-dithioethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0677] 4′-[(3,5-dithiopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0678] 4′-[(3,5-dithioisopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0679] 4′-[[3,5-di(1-butenyl)-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[0680] 4′-[[3,5-di(2-butenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0681] 4′-[[3,5-di(3-butenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0682] 4′-[[3,5-di(1-butynyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[0683] 4′-[[3,5-di(2-butynyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; and

[0684] 4′-[[3,5-di(3-butynyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid.

[0685] Another family of specific angiotensin II antagonist compounds of Formula I, from which a suitable first component of the conjugate may be selected, consists of biphenylmethyl 1H-substituted-1,2,4-triazole compounds listed below having an amino terminal moiety attached at the R1 or R2 positions of Formula I.. Such amino terminal moiety may be reacted directly with the carboxylic acid moiety of a second component of the conjugate, such as a glutamic acid residue to form an enzyme-cleavable bond. Specific examples of these compounds are listed below:

[0686] 5-[4′-[(5-ethyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0687] 5-[4′-[(5-ethyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0688] 5-[4′-[(5-ethyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0689] 5-[4′-[(5-ethyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0690] 5-[4′-[(5-ethyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0691] 5-[4′-[[3-ethyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0692] 5-[4′-[[3-ethyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0693] 5-[4′-[[3-ethyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0694] 5-[4′-[[3-ethyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0695] 5-[4′-[[3-ethyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0696] 5-[4′-[[3-ethyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0697] 5-[4′-[[3-ethyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0698] 5-[4′-[[3-ethyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0699] 5-[4′-[[3-ethyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0700] 5-[4′-[[3-ethyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0701] 5-[4′-[[3-ethyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0702] 5-[4′-[[3-ethyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1-biphenyl]-2-yl]-1H-tetrazole;

[0703] 5-[4′-[(5-propyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0704] 5-[4′-[(5-propyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl)[1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0705] 5-[4′-[(5-propyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0706] 5-[4′-[(5-propyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0707] 5-[4′-[(5-propyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0708] 5-[4′-[[3-propyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0709] 5-[4′-[[3-propyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0710] 5-[4′-[[3-propyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0711] 5-[4′-[[3-propyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0712] 5-[4′-[[3-propyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0713] 5-[4′-[[3-propyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0714] 5-[4′-[[3-propyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0715] 5-[4′-[[3-propyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0716] 5-[4′-[[3-propyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0717] 5-[4′-[[3-propyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0718] 5-[4′-[[3-propyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0719] 5-[4′-[[3-propyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0720] 5-[4′-[(5-isopropyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0721] 5-[4′-[(5-isopropyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0722] 5-[4′-[(5-isopropyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0723] 5-[4′-[(5-isopropyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0724] 5-[4′-[(5-isopropyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0725] 5-[4′-[[3-isopropyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0726] 5-[4′-[[3-isopropyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0727] 5-[4′-[[3-isopropyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0728] 5-[4′-[[3-isopropyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0729] 5-[4′-[[3-isopropyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1-biphenyl]-2-yl]-1H-tetrazole;

[0730] 5-[4′-[[3-isopropyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0731] 5-[4′-[[3-isopropyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0732] 5-[4′-[[3-isopropyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0733] 5-[4′-[[3-isopropyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0734] 5-[4′-[[3-isopropyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0735] 5-[4′-[[3-isopropyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0736] 5-[4′-[[3-isopropyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0737] 5-[4′-[(5-butyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0738] 5-[4′-[(5-butyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0739] 5-[4′-[(5-butyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0740] 5-[4′-[(5-butyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0741] 5-[4′-[(5-butyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0742] 5-[4′-[[3-butyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0743] 5-[4′-[[3-butyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0744] 5-[4′-[[3-butyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0745] 5-[4′-[[3-butyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0746] 5-[4′-[[3-butyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0747] 5-[4′-[[3-butyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0748] 5-[4′-[[3-butyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0749] 5-[4′-[[3-butyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0750] 5-[4′-[[3-butyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0751] 5-[4′-[[3-butyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0752] 5-[4′-[[3-butyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0753] 5-[4′-[[3-butyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0754] 5-[4′-[(5-secbutyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0755] 5-[4′-[(5-secbutyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl)[1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0756] 5-[4′-[(5-secbutyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0757] 5-[4′-[(5-secbutyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0758] 5-[4′-[(5-secbutyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0759] 5-[4′-[[3-secbutyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0760] 5-[4-[[3-secbutyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0761] 5-[4′-[[3-secbutyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0762] 5-[4′-[[3-secbutyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0763] 5-[4′-[[3-secbutyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0764] 5-[4′-[[3-secbutyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0765] 5-[4′-[[3-secbutyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0766] 5-[4′-[[3-secbutyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0767] 5-[4′-[[3-secbutyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0768] 5-[4′-[[3-secbutyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0769] 5-[4′-[[3-secbutyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0770] 5-[4′-[[3-secbutyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0771] 5-[4′-[(5-isobutyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0772] 5-[4′-[(5-isobutyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0773] 5-[4′-[(5-isobutyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0774] 5-[4′-[(5-isobutyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0775] 5-[4′-[(5-isobutyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0776] 5-[4′-[[3-isobutyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0777] 5-[4′-[[3-isobutyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0778] 5-[4′-[[3-isobutyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0779] 5-[4′-[[3-isobutyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0780] 5-[4′-[[3-isobutyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0781] 5-[4′-[[3-isobutyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0782] 5-[4′-[[3-isobutyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0783] 5-[4′-[[3-isobutyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0784] 5-[4′-[[3-isobutyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0785] 5-[4′-[[3-isobutyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0786] 5-[4′-[[3-isobutyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0787] 5-[4′-[[3-isobutyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0788] 5-[4′-[(5-tertbutyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0789] 5-[4′-[(5-tertbutyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0790] 5-[4′-[(5-tertbutyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0791] 5-[4′-[(5-tertbutyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0792] 5-[4′-[(5-tertbutyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0793] 5-[4′-[[3-tertbutyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0794] 5-[4′-[[3-tertbutyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0795] 5-[4′-[[3-tertbutyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0796] 5-[4′-[[3-tertbutyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0797] 5-[4′-[[3-tertbutyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0798] 5-[4′-[[3-tertbutyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0799] 5-[4′-[[3-tertbutyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0800] 5-[4′-[[3-tertbutyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0801] 5-[4′-[[3-tertbutyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0802] 5-[4′-[[3-tertbutyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0803] 5-[4′-[[3-tertbutyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0804] 5-[4′-[[3-tertbutyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0805] 5-[4′-[(5-pentyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0806] 5-[4′-[(5-pentyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1-biphenyl]-2-yl]-1H-tetrazole;

[0807] 5-[4′-[(5-pentyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0808] 5-[4′-[(5-pentyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0809] 5-[4′-[(5-pentyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0810] 5-[4′-[[3-pentyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0811] 5-[4′-[[3-pentyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0812] 5-[4′-[[3-pentyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1-biphenyl]-2-yl]-1H-tetrazole;

[0813] 5-[4′-[[3-pentyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0814] 5-[4′-[[3-pentyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0815] 5-[4′-[[3-pentyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0816] 5-[4′-[[3-pentyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0817] 5-[4′-[[3-pentyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0818] 5-[4′-[[3-pentyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1-biphenyl]-2-yl]-1H-tetrazole;

[0819] 5-[4′-[[3-pentyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0820] 5-[4′-[[3-pentyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0821] 5-[4′-[[3-pentyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0822] 5-[4′-[(5-isopentyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0823] 5-[4′-[(5-isopentyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0824] 5-[4′-[(5-isopentyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0825] 5-[4′-[(5-isopentyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0826] 5-[4′-[(5-isopentyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0827] 5-[4′-[[3-isopentyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0828] 5-[4′-[[3-isopentyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0829] 5-[4′-[[3-isopentyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0830] 5-[4′-[[3-isopentyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0831] 5-[4′-[[3-isopentyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0832] 5-[4′-[[3-isopentyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0833] 5-[4′-[[3-isopentyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0834] 5-[4′-[[3-isopentyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0835] 5-[4′-[[3-isopentyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0836] 5-[4′-[[3-isopentyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0837] 5-[4′-[[3-isopentyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0838] 5-[4′-[[3-isopentyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0839] 5-[4′-[(5-hexyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1,′-biphenyl]-2-yl]-1H-tetrazole;

[0840] 5-[4′-[(5-hexyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0841] 5-[4′-[(5-hexyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0842] 5-[4′-[(5-hexyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0843] 5-[4′-[(5-hexyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0844] 5-[4′-[[3-hexyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0845] 5-(

[0846] 4′-[[3-hexyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0847] 5-[4′-[[3-hexyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0848] 5-[4′-[[3-hexyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0849] 5-[4′-[[3-hexyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0850] 5-[4′-[[3-hexyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0851] 5-[4′-[[3-hexyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0852] 5-[4′-[(3-hexyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0853] 5-[4′-[[3-hexyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0854] 5-[4′-[[3-hexyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0855] 5-[4′-[[3-hexyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; and

[0856] 5-[4′-[[3-hexyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole.

[0857] Another family of specific angiotensin II antagonist compounds of Formula I, from which a suitable first component of the conjugate may be selected, consists of biphenylmethyl 1H-substituted-1,2,4-triazole compounds listed below having a terminal carboxylic acid moiety attached at the R1 or R2 positions of Formula I.. Those compounds having a terminal carboxylic moiety may be reacted with one of the aforementioned linker groups, such as a hydrazine or a piperazine linker, to provide an amino terminal moiety which can then be reacted with the carboxylic acid moiety of a second component of the conjugate, such as a glutamic acid residue to form an enzyme-cleavable bond. Specific examples of these compounds are listed below:

[0858] 5-[4′-[(5-ethyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0859] 5-[4′-[(5-ethyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0860] 5-[4′-[(5-ethyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0861] 5-[4′-[(5-ethyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0862] 5-[4′-[(5-ethyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0863] 5-[4′-[[3-ethyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0864] 5-[4′-[[3-ethyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0865] 5-[4′-[[3-ethyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0866] 5-[4′-[[3-ethyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0867] 5-[4′-[[3-ethyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0868] 5-[4′-[[3-ethyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0869] 5-[4′-[[3-ethyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0870] 5-[4′-[[3-ethyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0871] 5-[4′-[[3-ethyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0872] 5-[4′-[[3-ethyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0873] 5-[4′-[[3-ethyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0874] 5-(4′-[[3-ethyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0875] 5-[4′-[(5-propyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0876] 5-[4′-[(5-propyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0877] 5-[4′-[(5-propyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0878] 5-[4′-[(5-propyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0879] 5-[4′-[(5-propyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl)-2-yl]-1H-tetrazole;

[0880] 5-[4′-[[3-propyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0881] 5-[4′-[[3-propyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0882] 5-[4′-[[3-propyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0883] 5-[4′-[[3-propyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1-biphenyl]-2-yl]-1H-tetrazole;

[0884] 5-[4′-[[3-propyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0885] 5-[4′-[[3-propyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0886] 5-[4′-[[3-propyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0887] 5-[4′-[[3-propyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0888] 5-[4′-[[3-propyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-H-tetrazole;

[0889] 5-[4′-[[3-propyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0890] 5-[4′-[[3-propyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0891] 5-[4′-[[3-propyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0892] 5-[4′-[(5-isopropyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0893] 5-[4′-[(5-isopropyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0894] 5-[4′-[(5-isopropyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0895] 5-[4′-[(5-isopropyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0896] 5-[4′-[(5-isopropyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl](1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0897] 5-[4′-[[3-isopropyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0898] 5-[4′-[[3-isopropyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0899] 5-[4′-[[3-isopropyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0900] 5-[4′-[[3-isopropyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0901] 5-[4′-[[3-isopropyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0902] 5-[4′-[[3-isopropyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0903] 5-[4′-[[3-isopropyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0904] 5-[4′-[[3-isopropyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0905] 5-[4′-[[3-isopropyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0906] 5-[4′-[[3-isopropyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0907] 5-[4′-[[3-isopropyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0908] 5-[4′-[[3-isopropyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0909] 5-[4′-[(5-butyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0910] 5-[4′-[(5-butyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0911] 5-[4′-[(5-butyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0912] 5-[4′-[(5-butyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0913] 5-[4′-[(5-butyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0914] 5-[4′-[[3-butyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0915] 5-[4′-[[3-butyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0916] 5-[4′-[[3-butyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0917] 5-[4′-[[3-butyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0918] 5-[4′-[[3-butyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0919] 5-[4′-[[3-butyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0920] 5-[4′-[[3-butyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0921] 5-[4′-[[3-butyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0922] 5-[4′-[[3-butyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0923] 5-[4′-[[3-butyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0924] 5-[4′-[[3-butyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0925] 5-[4′-[[3-butyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0926] 5-[4′-[(5-secbutyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0927] 5-[4′-[(5-secbutyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0928] 5-[4′-[(5-secbutyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0929] 5-[4′-[(5-secbutyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0930] 5-[4′-[(5-secbutyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0931] 5-[4′-[[3-secbutyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0932] 5-[4′-[[3-secbutyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0933] 5-[4′-[[3-secbutyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0934] 5-[4′-[[3-secbutyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0935] 5-[4′-[[3-secbutyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0936] 5-[4′-[[3-secbutyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0937] 5-[4′-[[3-secbutyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0938] 5-[4′-[[3-secbutyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0939] 5-[4′-[[3-secbutyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0940] 5-[4′-[[3-secbutyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0941] 5-[4′-[[3-secbutyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0942] 5-[4′-[[3-secbutyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0943] 5-[4′-[(5-isobutyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0944] 5-[4′-[(5-isobutyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0945] 5-[4′-[(5-isobutyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0946] 5-[4′-[(5-isobutyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0947] 5-[4′-[(5-isobutyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0948] 5-[4-[[3-isobutyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0949] 5-[4′-[[3-isobutyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0950] 5-[4′-[[3-isobutyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0951] 5-[4′-[[[3-isobutyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0952] 5-[4′-[[3-isobutyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0953] 5-[4′-[[3-isobutyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0954] 5-[4′-[[3-isobutyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0955] 5-[4′-[[3-isobutyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0956] 5-[4′-[[3-isobutyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0957] 5-[4′-[[3-isobutyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0958] 5-[4′-[[3-isobutyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0959] 5-[4′-[[3-isobutyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0960] 5-[4′-[(5-tertbutyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0961] 5-[4′-[(5-tertbutyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0962] 5-[4′-[(5-tertbutyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0963] 5-[4′-[(5-tertbutyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0964] 5-[4′-[(5-tertbutyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0965] 5-[4′-[[3-tertbutyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0966] 5-[4′-[[3-tertbutyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0967] 5-[41-[[3-tertbutyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl](1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0968] 5-[4′-[[3-tertbutyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0969] 5-[4′-[[3-tertbutyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0970] 5-[4′-[[3-tertbutyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0971] 5-[4′-[[3-tertbutyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0972] 5-[4′-[[3-tertbutyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0973] 5-[4′-[[3-tertbutyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0974] 5-[4′-[[3-tertbutyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0975] 5-[4′-[[3-tertbutyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0976] 5-[4′-[[3-tertbutyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0977] 5-[4′-[(5-pentyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0978] 5-[4′-[(5-pentyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0979] 5-[4′-[(5-pentyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0980] 5-[4′-[(5-pentyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0981] 5-[4′-[(5-pentyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0982] 5-[4′-[[3-pentyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0983] 5-[4′-[[3-pentyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0984] 5-[4′-[[3-pentyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0985] 5-[4′-[[3-pentyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0986] 5-[4′-[[3-pentyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0987] 5-[4′-[[3-pentyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0988] 5-[4′-[[3-pentyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0989] 5-[4′-[[3-pentyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0990] 5-[4′-[[3-pentyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0991] 5-[4′-[[3-pentyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0992] 5-[4′-[[3-pentyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0993] 5-[4′-[[3-pentyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0994] 5-[4′-[(5-isopentyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0995] 5-[4′-[(5-isopentyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0996] 5-[4′-[(5-isopentyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0997] 5-[4′-[(5-isopentyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0998] 5-[4′-[(5-isopentyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[0999] 5-[4′-[[3-isopentyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1000] 5-[4′-[[3-isopentyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1001] 5-[4′-[[3-isopentyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1002] 5-[4′-[[3-isopentyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1003] 5-[4′-[[3-isopentyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1004] 5-[4′-[[3-isopentyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1005] 5-[4′-[[3-isopentyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1006] 5-[4′-[[3-isopentyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1007] 5-[4′-[[3-isopentyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1008] 5-[4′-[[3-isopentyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1009] 5-[4′-[[3-isopentyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1010] 5-[4′-[[3-isopentyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1011] 5-[4′-[(5-hexyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1012] 5-[4′-[(5-hexyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1013] 5-[4′-[(5-hexyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1014] 5-[4′-[(5-hexyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1015] 5-[4′-[(5-hexyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1016] 5-[4′-[[3-hexyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1017] 5-[4′-[[3-hexyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1018] 5-[4′-[[3-hexyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1019] 5-[4′-[[3-hexyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1020] 5-[4′-[[3-hexyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1021] 5-[4′-[[3-hexyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1022] 5-[4′-[[3-hexyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1023] 5-[4′-[[3-hexyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1024] 5-[4′-[[3-hexyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1025] 5-[4′-[[3-hexyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1026] 5-[4′-[[3-hexyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; and

[1027] 5-[4′-[[3-hexyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole.

[1028] A family of specific angiotensin II antagonist compounds of highest interest within Formula I from which a suitable first component of the conjugate may be selected, consists of amino-terminated biphenylmethyl 1H-substituted-1,2,4-triazole compounds as listed below. Such compounds would be suitable to form a conjugate with a carboxylic moiety of a second component of the conjugate, such as a glutamic acid residue, to form an enzyme-cleavable amide bond by direct reaction or by reaction through a diamino-containing linker of the type mentioned above. These Formula I angiotensin II antagonist compounds of highest interest are as follows:

[1029] methyl 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylate;

[1030] 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1031] 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid, hydrazide;

[1032] 4′-[(5-butyl-3-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1033] 4′-[(3-butyl-5-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1034] 4′-[(5-butyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1035] 4′-[(5-butyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1036] 4′-[(5-butyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1037] 4′-[(5-butyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1038] 4′-[(5-butyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1039] 4′-[(5-butyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1040] 4′-[(5-butyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1041] 4′-[(5-butyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1042] 4′-[(5-butyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1043] 4′-[[5-butyl-3-(2-cyclohexylethyl))-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1044] 4′-[(5-butyl-3-cyclohexanoyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1045] 4′-[[5-butyl-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1046] 4′-[(5-butyl-3-phenyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1047] 4′-[(5-butyl-3-phenylmethyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1048] 4′-[[5-butyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1049] 4′-[(5-butyl-3-benzoyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1050] 4′-[[5-butyl-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1051] 4′-[[5-butyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1052] 4′-[[5-butyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1053] 4′-[[5-butyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1054] 4′-[[5-butyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1055] 4′-[[5-butyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1056] 4′-[[5-butyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1057] 4′-[[5-butyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1058] 4′-[[5-butyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1059] 4′-[[3-butyl-5-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1060] 4′-[[5-butyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid;

[1061] 4′-[(3,5-dipropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1062] 4′-[(3,5-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1063] 4′-[(3,5-disecbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1064] 4′-[(3,5-diisobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1065] 4′-[(3,5-ditertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1066] 4′-[(3,5-dipentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1067] 4′-[(3,5-diisopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid;

[1068] 5-[4′-[(5-butyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1069] 5-[4′-[(5-butyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1070] 5-[4′-[(5-butyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1071] 5-[4′-[(5-butyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1072] 5-[4′-[(5-butyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1073] 5-[4′-[[3-butyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1074] 5-[4′-[[3-butyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1075] 5-[4′-[[3-butyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1076] 5-[4′-[[3-butyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1077] 5-[4′-[[3-butyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1078] 5-[4′-[[3-butyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1079] 5-[4′-[[3-butyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1080] 5-[4′-[[3-butyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1081] 5-[4′-[[3-butyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1082] 5-[4′-[[3-butyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1083] 5-[4′-[[3-butyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1084] 5-[4′-[[3-butyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1085] 5-[4′-[(5-butyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1086] 5-[4′-[(5-butyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1087] 5-[4′-[(5-butyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1088] 5-[4′-[(5-butyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1089] 5-[4′-[(5-butyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1090] 5-[4′-[[3-butyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1091] 5-[4′-[[3-butyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1092] 5-[4′-[[3-butyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1093] 5-[4′-[[3-butyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1094] 5-[4′-[[3-butyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1095] 5-[4′-[[3-butyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1096] 5-[4′-[[3-butyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1097] 5-[4′-[[3-butyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1098] 5-[4′-[[3-butyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1099] 5-[4′-[[3-butyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole;

[1100] 5-[4′-[[3-butyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; and

[1101] 5-[4′-[[3-butyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole.

General Synthetic Procedures

[1102] Conjugates of the invention are synthesized by reaction between precursors of the first and second residues. One of such precursors must contain a reactive acid moiety, and the other precursor must contain a reactive amino moiety, so that a conjugate is formed having a cleavable bond. Either precursor of the first and second residues may contain such reactive acid or amino moieties. Preferably, the precursors of the first residue are angiotensin II antagonists and will contain a reactive amino moiety or a moiety convertible to a reactive amino moiety. Inhibitor compounds lacking a reactive amino moiety may be chemically modified to provide such reactive amino moiety. Chemical modification of these inhibitor compounds lacking a reactive amino group may be accomplished by reacting an acid or an ester group on an AII antagonist compound with an amino compound having at least one reactive amino moiety and another reactive hetero atom selected from O, S and N. A suitable amino compound would be a diamino compound such as hydrazine or urea. Hydrazine, for example, may be reacted with a carboxylic acid or ester moiety of an AII antagonist compound to form a hydrazide derivative of such AII antagonist compound.

[1103] The AII antagonist compound 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid may be used as a model compound to illustrate the chemical modification of a carboxylic acid-containing compound to make a reactive amino-containing precursor for synthesizing a conjugate of the invention. In the following General Synthetic Procedures, there are described firstly, in Schemes I-VI, methods for making suitable angiotensin II antagonists of Formula I for selection as the first component of the conjugate. Then, in Schemes VII-XII, there are described general methods for making a conjugate by reacting a first component AII antagonist of Formula I with a cleavable second component represented by N-acetyl-γ-glutamic acid.

[1104] Conjugates of the invention may be prepared using precursors of highly active angiotensin II antagonists of Formula I. Examples of lesser active, suitable precursors are acid chloride, esters and amides of angiotensin II antagonists of Formula I. For example, ester precursors of more active angiotensin II antagonists, such as ester-type AII antagonists of Example Nos. 1, 34, 35, 67 and 68, as well as AII antagonists containing carboxylic acid terminal moieties, of Example Nos. 2, 6, 8, 18-20, 36, 52, 63, 64, 71-72 and 75-78, may be reacted with hydrazine to provide an intermediate bearing an amino terminal moiety which then can be reacted with a glutamic acid derivative to form a conjugate of the invention. Such precursors or intermediates themselves may be relatively strong, relatively weak, or inactive as AII antagonists. Also, conjugates of the invention may be prepared using angiotensin II antagonists lacking a reactive terminal acidic or amino moiety. Such angiotensin II antagonists, as shown in Example Nos. 3, 5, 7, 9-16, 21-33, 37-40, 42-51, 53-62, 65, 66, 69-70, 73 and 74, lack a terminal amino moiety. These AII antagonist compounds may be modified to contain a terminal amino moiety which then may be connected to a glutamyl residue through a diamino-terminated linker group, such as shown in Tables I-III. 47

[1105] Synthetic Scheme I shows the preparation of 1H-1,2,4-triazoles 1 from ethyl iminoesters 2 and the corresponding hydrazide 3 via the general proceure outlined by H. Paul, G. Hilgetog and G. Jahnchen, Chem. Ber., 101, 2033 (1968). The free, iminoesters 2 can be prepared from the corresponding iminoester hydrochlorides 4, which in turn can be prepared from the corresponding nitrile 5; the procedures for the preparation of 2 and 4 from 5 are outlined by P. Reynaud and R. D. Moreau, Bull. Soc. Chim. France, 2997 (1964). The hydrazides 3 can be either purchased or prepared from the corresponding alkyl esters 6 or lactones 6a and hydrazine. 48

[1106] Synthetic Scheme II shows the preparation of the alkylating agent 7 from the corresponding precursor 8. When R5 equals CO2CH3, 8 was purchased from Chemo Dynamics Inc. 49

[1107] Synthetic Scheme III shows the preparation of the alkylating agent precursor 8 where R5 equal CN4C(C6H5)3 from the corresponding methyl ester 8 (R5═CO2CH3). In step 1, the methyl ester is converted to the corresponding acid (R5═CO2H) by the action of sodium hydroxide/hydrochloric acid. In step 2, the acid is converted to the corresponding acid chloride (R5═COCl) by the action of oxalyl chloride. In step 3, the acid chloride is converted to the corresponding primary amide (R5═CONH2) by the action of ammonia. In step 4, the amide is converted to the corresponding nitrile 9 by the action of thionyl chloride at reflux. The nitrile 9 is reacted with trimethyltinazide in toluene at reflux to give the corresponding trimethytin protected tetrazole 10; deprotection with acetic acid/water and reprotection with triphenylmethyl chloride/triethylamine gives the N-trityl tetrazole 8 (R5═CN4C(C6H5)3). 50

[1108] Synthetic Scheme IV shows the coupling reaction of the 1H-1,2,4-triazole 1 with the appropriate alkylating reagent 7. In the first step, 1 is treated with a base, such as sodium hydride, to generate the corresponding anion 11. Anion 11 is reacted with an alkylating agent 7 to give a mixture of regioisomers 12a and 12b. The isomer mixture may be converted to mixtures of the corresponding acids 13a and 13b or tetrazoles 14a and 14b by treatment with the appropriate reagent. Or, the isomers 12a and 12a may be separated by chromatographic methods, and each isomer may be reacted with the appropriate reagent to provide the acid- or tetrazole-substituted end product. 51

[1109] Synthetic Scheme V shows the regioselective synthesis of isomer 13a or 14a from Scheme IV. In the first step of the reaction, an alkylating agent 7 is reacted with an appropriate hydrazide 3 to provide substituted hydrazide 15. An imidate 2 is reacted with hydrazide 15 to provide intermediate 16 which cyclizes upon heating to provide the corresponding product compound 13a or 14a. 52

[1110] Synthetic Scheme VI shows the regioselective synthesis of isomer 13b or 14b from Scheme IV. In the first step of the reaction, imidate 2 is reacted with hydrazine to give amidazone 17. This intermediate is reacted with alkylating agent 7 to give intermediate 18 which is then cyclized in the presence of heat and an appropriate orthoester 19 to yield the corresponding product compound 13b or 14b. 53

[1111] Synthetic Scheme VII shows the preparation of renal-selective angiotensin II antagonists by coupling γ-glutamic acid with an angiotensin II antagonist; the biphenyl R5 acid moiety of the AII antagonist is coupled to the γ-acid moiety of glutamic acid via an hydrazine linker. In step 1, the methyl ester of the AII antagonist 12b is converted to the hydrazide 20 by the action of hydrazine. In step 2, the hydrazide 20 is first reacted with the symmetrical anhydride of the protected γ-glutamic acid 21 and subsequently reacted with trifluoroacetic acid (TFA) to give the deprotected coupled material 22. In step 3, the free amino group of 22 is acetylated with acetic anhydride in the presence of base to give the renal-selective angiotensin II antagonists 23. 54

[1112] Synthetic Scheme VIII shows the preparation of angiotensin II antagonists 24 which have an amino moiety incorporated in R1. In step 1, a protected amino acid 6 is first reacted with dicyclohexylcarbodiimide (DCC) and subsequently reacted with hydrazine to give the hydrazide 3. In step 2, the hydrazide 3 is reacted with the iminoester 2 and subsequently cyclized to the corresponding 1H-1,2,4-triazole 1. In step 3, the anion of 1 is reacted with the appropriate alkylating agent 7 to give a mixture of regioisomers 12a and 12b which can be separated by chromatography. In step 4, the desired isomer 12b is deprotected with TFA to give the free amino AII antagonist 24. 55

[1113] Synthetic Scheme IX shows the preparation of angiotensin II antagonists 25 and 26 which have a carbomethoxy moiety and an amino moiety, respectively, incorporated in R1. In step 1, the dialkylacetal alkyl ester 6 is reacted with hydrazine to give the hydrazide 3. In step 2, the hydrazide 3 is reacted with the iminoester 2 and subsequently cyclized to the corresponding 1H-1,2,4-triazole 1. In step 3, the anion of 1 is reacted with the apropriate alkylating agent 7 to give a mixture of regioisomers which can be separated by chromatography prior to the generation of the free aldehyde 12b with aqueous acid. In step 4, the aldehyde 12b is oxidized to the corresponding acid with KMnO4 and subsequently converted to the methyl ester 25 by SOCl2/CH3OH at −10° or reduced to the corresponding aminomethyl analog 26 (homolog of 24) by NH4OAc/NaBH3CN. 56

[1114] Synthetic Scheme X shows an alternate preparation of angiotensin II antagonists 25 which have a carbomethoxy moiety incorporated in R1. In step 1, the lactone 6a is reacted with hydrazine to give the hydrazide 3. In step 2, the hydrazide 3 is reacted with the iminoester 2 and subsequently cyclized to the corresponding 1H-1,2,4-triazole 1. In step 3, the anion of 1 is reacted with the appropriate alkylating agent 7 to give a mixture of regioisomers which can be separated by chromatography to give 12b. In step 4, the primary alcohol 12b is oxidized to the corresponding acid with KMnO4 and subsequently converted to the methyl ester 25 by SOCl2/CH3OH at −10°. 57

[1115] Synthetic Scheme XI shows the preparation of renal-selective angiotensin II antagonists by coupling amino containing AII antagonists 24 with γ-glutamic acid. In step 1, the AII antagonist is reacted with the symmetrical anhydride of the protected γ-glutamic acid 21 to give 27. In step 2, the protected material 27 is reacted with TFA to give the deprotected coupled material 28. In step 3, the free amino compound 28 is acetylated with acetic anhydride in the presence of base to give the renal-selective angiotensin II antagonists 29. 58

[1116] Synthetic Scheme XII shows the preparation of renal-selective angiotensin II antagonists by coupling γ-glutamic acid with an angiotensin II antagonist; the triazole R1 acid moiety of the AII antagonist is coupled to the γ-acid moiety of glutamic acid via an hydrazine linker. In step 1, the methyl ester of the AII antagonist 25 is converted to the hydrazide 30 by the action of the hydrazine. In step 2, the hydrazide 30 is first reacted with the symmetrical anhydride of the protected γ-glutamic acid 21 and subsequently reacted with TFA to give the deprotected coupled material 31. In step 3, the free amino group of 31 is acetylated with acetic anhydride in the presence of base to give the renal-selective angiotensin II antagonists 32.

[1117] The following Examples 1-78 are detailed descriptions of the methods of preparation of specific angiotensin II antagonist compounds within Formula I. These detailed preparations fall within the scope of, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention. These Examples #1-#78, as well as methods described in other preparatory examples which follow, are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are given in centigrade degrees, unless otherwise indicated.

EXAMPLE 1

[1118] 59

methyl 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylate

[1119] Step 1: Preparation of 4-bromomethyl-2′-methoxycarbonylbiphenyl.

[1120] A 47.46 g (210 mmol) sample of methyl 2-(p-tolyl)benzoate (Chemo Dynamics Inc.) was dissolved in 3 L of carbon tetrachloride and treated with 37.33 g (209 mmol) of N-bromosuccinimide (NBS) and 1.17 g (7.13 mmol) of azobisisobutyronitrile (AIBN) at reflux under nitrogen for 24 hours. The reaction mixture was treated again with 1.0 g (6.1 mmol) of AIBN and stirred at reflux for an additional 24 hours. The reaction was filtered and the solvent removed in m vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (5:95) as eluent provided 50.0 g (78%) of a colorless solid: mp 48-51° C.; NMR (CDCl3) δ3.64 (s, 3H), 4.54 (s, 2H), 7.23-7.63 (m, 7H), 7.81-7.89 (m, 1H). NMR indicated that this material was only 91% pure; it contained 9% of the corresponding dibromocompound (δ6.70); however, no further attempts at purification were made and this mixture was used in all subsequent alkylation reactions.

[1121] Step 2: Preparation of 3,5-dibutyl-1H-1,2,4-triazole.

[1122] A solution of 64.5 g (0.50 mol) of ethyl iminovalerate [P. Reynaud and R. C. Moreau, Bull. Soc. Chim. France, 2997 (1964)] in 100 mL of methanol was added slowly to 58.0 g (0.50 mol) of valeric acid hydrazide (Lancaster Synthesis) in 400 mL of methanol at 0° C. under a nitrogen atmosphere. After the addition was complete, the reaction was allowed to warm to ambient temperature and then stir at reflux for 2 days. The solvent was removed in vacuo; purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (80:20) gave 78.9 g (93%) of a colorless solid: mp 50.5-51.5° C.; NMR (CDCl3) δ0.88 (t, J=7 Hz, 6H), 1.28-1.33 (m, 4H), 1.63-1.77 (m, 4H), 2.72 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 183 (12%), 182 (100), 181 (3), 180 (6), 152 (8), 139 (4); HRMS. Calcd for M+H: 182.1657. Found: 182.1661.

[1123] Step 3: Preparation of methyl 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylate.

[1124] Under a static nitrogen atmosphere, 2.01 g (11.0 mmol) of solid 3,5-dibutyl-1H-1,2,4-triazole was added in small portions to 12 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution had ceased. The anion solution was cooled to −100° C. (ice/methanol) and treated with a solution of 3.37 g (11.0 mmol) of 4-bromomethyl-2′-methoxycarbonyl-biphenyl in 20 ml of dry DMF. The reaction was allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) was added to destroy any unreacted sodium hydride and the DMF was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and dried (MgSO4). Silica gel chromatography (Waters Prep-500A) using 40% ethyl acetate/hexane gave 2.0 g (41%) of compound as an oil: NMR (CDCl3) δ0.90 (t, J=7 HZ, 3H), 0.94 (t, J=7 Hz, 3H), 1.28-1.47 (m, 4H), 1.62-1.80 (m, 4H), 2.63-2.75 (m, 4H), 3.63 (s, 3H), 5.27 (s, 2H), 7.13-7.18 (m, 2H), 7.25-7.35 (m, 3H), 7.37-7.44 (m, 1H), 7.48-7.55 (m, 1H), 7.80-7.85 (m, 1H).

EXAMPLE 2

[1125] 60

4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid

[1126] A 2.0 g (4.9 mmol) sample of the methyl ester product compound from Example 1 was dissolved in 80 ml of ethanol and treated with 80 ml of 10% NaOH at ambient temperature for 3 days. The ethanol was removed in vacuo and the aqueous phase acidified to pH 1 with hydrochloric acid which caused the product to precipitate; filtration and drying in vacuo gave 1.65 g (86%) of colorless compound: mp 134-135° C.; NMR (DMSO-d6) δ0.85 (t, J=7 Hz, 3H), 0.90 (t, J=7 Hz, 3H), 1.23-1.39 (m, 4H), 1.53-1.68 (m, 4H), 2.59 (t, J=7 Hz, 2H), 2.78 (t, J=7 Hz, 2H), 5.37 (s, 2H), 5.37 (s, 2H), 7.18-7.26 (m, 2H), 7.28-7.37 (m, 3H), 7.42-7.48 (m, 1H), 7.53-7.60 (m, 1H), 7.70-7.75 (m, 1H).

EXAMPLE 3

[1127] 61

5-[4′-[(3-aminomethyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1128] Step 1: Preparation of N-Triphenylmethyl-5-[2-(4′-bromomethylbiphen-2-yl]tetrazole.

[1129] A 542.5 g (2.4 mol) sample of methyl 2-(p-tolyl)benzoate (Chemo Dynamics Inc.) was dissolved in 5.5 L of ethanol and treated with 3 L (7.5 mol) of 2.5 N sodium hydroxide. The reaction was stirred overnight at ambient temperature and treated with an additional 480 ml (6.0 mol) of sodium hydroxide; stirring was continued for an additional 24 h and the ethanol removed in vacuo. The remaining solution was cooled in ice and acidified to pH 1 with hydrochloric acid which caused the product to precipitate; filtration and drying in vacuo gave 510 g (100%) of crude 2-(p-tolyl)benzoic acid: mp 145.0-147.5° C.; NMR (CDCl3) δ2.40 (s, 3H), 7.17-7.28 (m, 4H), 7.35-7.45 (m, 2H), 7.51-7.59 (m, 1H), 7.90-7.97 (m, 1H). The crude acid was suspended in 1 L of toluene and slowly treated with 400 g (3.15 mol) of oxalyl chloride under nitrogen. The reaction was allowed to stir at ambient temperature for 4.5 h and concentrated in vacuo to remove excess oxalyl chloride. The residue was redissolved in 2 L of toluene and treated with 92.8 g (5.46 mol) of anhydrous ammonia. The reaction was filtered and the filtrate concentrated in vacuo producing 424 g (84%) of crude 2-(p-tolyl)benzamide: mp 128-130° C.; NMR (CDCl3) δ2.40 (s, 3H), 5.28 (br s, 1H), 5.77 (br s, 1H), 7.21-7.53 (m, 7H), 7.76-7.83 (m, 1H). The crude amide was treated with 1420 ml (19.5 mol) of thionyl chloride at reflux for 3.5 h. The reaction was filtered and the thionyl chloride removed in vacuo. The residue was dissolved in 800 ml of toluene and reconcentrated in vacuo. On standing overnight, the residue crystallized. The crystals were collected and washed with hexane to give 296 g (64%) of 2-(p-tolyl)benzonitrile: mp 50.5-52.0° C.; NMR (CDCl3) δ2.42 (s, 3H), 7.22-7.34 (m, 2H), 7.37-7.52 (m, 3H), 7.58-7.66 (m, 1H), 7.72-7.78 (m, 1H). A 286 g (1.48 mol) sample of the crude nitrile was dissolved in 1630 mL to toluene and treated with 377 g (1.8 mol) of trimethyltinazide at reflux for 24 h. The reaction was cooled; filtration gave 600 g of crude N-trimethylstannyl-5-[2-(4′-methylbiphen-2-yl]tetrazole: mp 271-272° C. (dec.); NMR (DMSO-d6) δ0.36 (br t, J=34 Hz, 9H), 2.24 (s, 3H), 6.89-7.06 (m, 4H), 7.35-7.55 (m, 4H). The crude N-trimethylstannyl tetrazole was suspended in 4270 mL of toluene and 287 mL of anhydrous tetrahydrofuran (THF) and treated with 63.4 g (173 mol) of anhydrous hydrogen chloride at ambient temperature under nitrogen with stirring. The reaction was allowed to stand overnight and filtered; recrystallization from toluene gave 217 g (62%) of 5-[2-(4′methylbiphen-2-yl)]tetrazole as a solid: mp 149-152° C.; NMR (DMSO-d6) δ2.28 (s, 3H), 6.94-7.02 (m, 2H), 7.08-7.15 (m, 2H), 7.50-7.59 (m, 2H), 7.62-7.72 (m, 2H). A 200 g (0.85 mol) sample of the tetrazole was suspended in 3.3 L of dichloromethane and treated with 262 g (0.91 mol) of triphenylmethyl chloride and 141 mL (1.0 mol) of anhydrous triethylamine. The reaction was stirred at reflux for 3 h under nitrogen, washed with water, dried (MgSO4), and concentrated in vacuo. Recrystallization gave 338 g (83%) of N-triphenylmethyl-5-[2-(4′-methylbiphen-2-yl)]tetrazole as a colorless solid: mp 170-173° C.; NMR (CDCl3) δ2.27 (s, 3H), 6.86-6.96 (m, 8H), 6.98-7.04 (m, 2H), 7.09-7.52 (m, 12H), 7.86-7.94 (m, 1H). The N-triphenylmethyl tetrazole was dissolved in 4260 mL of carbon tetrachloride and treated with 126.4 g (0.71 mol) of N-bromosuccinimide (NBS) and 11.9 g (49 mmol) of benzoyl peroxide at reflux for 3.5 h. The reaction was filtered and the solvent removed in vacuo. Recrystallization from toluene gave 277 g (59%) of N-triphenylmethyl-5-[2-(4′-bromomethylbiphen-2-yl)]tetrazole as a colorless solid: mp 140-142° C.; NMR (CDCl3) δ4.39 (s, 2H), 6.85-6.95 (m, 7H), 7.06-7.15 (m, 4H), 7.22-7.43 (m, 9H), 7.45-7.55 (m, 2H), 7.94-8.01 (m, 1H). NMR indicated that this material was only 85% pure; it contained 7% of corresponding dibromo-compound (δ6.50) and 8% of starting material (δ2.27); however, no further attempts at purification were made and this mixture was used in all subsequent alkylation reactions.

[1130] Step 2: Preparation of 5-butyl-3-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole.

[1131] Under nitrogen, a colution of 5.0 g (15.6 mmol) of anhydrous hydrazine in 100 mL of methanol is cooled to 0° C. and treated with a solution of 25.0 g (13.2 mmol) of N-BOC glycine methyl ester (Chemical Dynamics Corporation) in 50 mL of methanol. The reaction is allowed to warm to ambient temperature and stirred overnight. Concentration in vacuo gives the crude hydrazide which is purified either by recrystallization or by silica gel chromatography (Waters Prep-500A). A 18.9 g (100 mol) sample of hydrazide is dissolved in 100 mL of methanol and is treated with 12.9 g (100 mmol) of ethyl iminovalerate under nitrogen. The reaction is stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives 5-butyl-3-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole.

[1132] Step 3: Preparation of 5-[4′-[(3-aminomethyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole.

[1133] Under a static nitrogen atmosphere, 3.81 g (15.0 mmol) of 3-butyl-5-tert-butoxycarbonylamino-1H-1,2,4-triazole is added slowly to 15 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring is continued until hydrogen evolution has ceased. The anion solution is cooled to −10° C. (ice/methanol) and treated with a solution of 8.45 g (15.0 mmol) of N-triphenylmethyl-5-[2-(4′-bromomethylbiphen-2-yl)]tetrazole in 20 ml of dry DMF. The reaction is allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) is added to destroy any unreacted sodium hydride and the DMF is removed in vacuo. The residue is dissolved in ethyl acetate, washed with water, and dried (MgSO4). Purification by silica gel chromatography gives the desired isomer which is dissolved in 100 mL of TFA and is stored at ambient temperature overnight. The reaction is cooled to 0° C., 50 mL of water is added, and is allowed to stir at ambient temperature overnight. The solvent is removed n vacuo and the residue is dissolved in acetonitrile/water. Purification by reverse phase chromatography (Waters Delta Prep.-3000) provides pure 5-[4′-[(3-aminomethyl-5-butyl-1H-1,2,4-triazol-1-yl][1,1′-biphenyl]-2-yl]-1H-tetrazole as the TFA salt.

EXAMPLE 4

[1134] 62

4′-[(3.5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid, hydrazide

[1135] A 7.10 g (17.5 mmol) sample of the methyl ester product compound of Example 1 was dissolved in 150 ml of methanol and treated with 22 ml (22.2 g 695 mmol) of anhydrous hydrazine under a static nitrogen atmosphere. The reaction was stirred at reflux for 2 days and concentrated in vacuo to give 7.03 g (99%) of compound which was a colorless glass: NMR (CDCl3) δ0.88 (t, J=7 Hz, 3H), 0.94 (t, J=7 Hz, 3H), 1.28-1.47 (m, 4H), 1.62-1.78 (m, 4H), 2.62-2.73 (m, 4H), 3.5-4.1 (br s, 2H), 5.26 (s, 2H), 6.53 (s, 1H), 7.13-7.63 (m, 8H).

EXAMPLE 5

[1136] 63

5-[4′-[[3-(3-aminopropyl)-5-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1137] Step 1: Preparation of 5-butyl-3-(3-tertbutoxycarbonylaminoprioyl)-1H-1,2,4-triazole

[1138] Under nitrogen, 60.0 g (0.30 mol) of N-BOC-γ-aminobutyric acid (BACHEM) is dissolved in 1200 mL of methylene chloride and treated with 30.5 g (0.15 mol) of dicyclohexylcarbodiimide (DCC). The reaction is allowed to stir for 2 hours and filtered under nitrogen. The anhydride solution is then added to a solution of 1.58 g (98.5 mmol) of anhydrous hydrazine in 100 mL of methylene chloride at 0° C. The reaction is allowed to warm to ambient temperature and stirred overnight. Concentration in vacuo gives the crude hydrazide which is purified either by recrystallization or by silica gel chromatography (Waters Prep-500A). A 21.7 g (100 mmol) sample of hydrazide is dissolved in 100 mL of methanol and treated with 12.9 g (100 mmol) of ethyl iminovalerate under nitrogen. The reaction is stirred at reflux overnight and concentrated in invacuo. Purification by silica gel chromatography (Waters Prep-500A) gives 5-butyl-3-(3-tert-butoxycarbonylaminopropyl-1H-1,2,4-triazole.

[1139] Step 2. Preparation of 5-[4′-[[3-(3-aminopropyl)-5-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1140] Under a static nitrogen atmosphere, 14.4 g (46.0 mmol) of 3-(3-N-BOC-aminopropyl)-5-butyl-1H-1,2,4-triazole is added in small portions to 50 mmol of sodium hydride in 250 ml of dimethylformamide (DMF); stirring is continued until hydrogen evolution has ceased. The anion solution is cooled to −10° C. (ice/methanol) and is treated with a solution of 25.5 g (46.0 mmol) of N-triphenylmethyl-5-[2-(4′-bromomethylbiphen-2-yl)]tetrazole (from Step 1 of Example 3) in 100 ml of dry DMF. The reaction is allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) is added to destroy any unreacted sodium hydride and the DMF is removed in vacuo; the residue is dissolved in ethyl acetate, washed with water, and dried (MgSO4). Purification by silica gel chromatography gives the desired isomer which is dissolved in 200 mL of TFA and is stirred at ambient temperature overnight. The reaction is cooled to 0° C., 100 mL of water is added, and is allowed to stir at ambient temperature overnight. The solvent is removed in vacuo and the residue is dissolved in acetonitrile/water. Purification by reverse phase chromatography (Waters Delta Prep-3000) provided pure 5-[4′-[[3-(3-aminopropyl)-5-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as the TFA salt.

EXAMPLE 6

[1141] 64

4′-[(5-butyl-3-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid

[1142] Step 1: Preparation of 3-butyl-5-chloro-1H-1,2,4-triazole.

[1143] A 10.0 g (80 mmol) sample of 3-butyl-1H-1,2,4-triazole [H. Paul, G. Hilgetag, and G. Jahnchen, Chem. Ber., 101, 2033 (1968)] was dissolved in 320 mL of water containing 7.0 g (177 mmol) of sodium hydroxide. With stirring, the solution was cooled to 0° C. and chlorine was introduced over 3 h. The reaction was purged with nitrogen overnight and the solution extracted with chloroform. The extracts were combined, dried (MgSO4), and concentrated in vacuo to give 16.8 g of a colorless oil which was placed in 200 mL of water and treated twice with 8.0 g (80 mmol) of sodium metabisulfite. The pH of the reaction medium was adjusted to 6 with 1M sodium carbonate prior to extraction with chloroform; the extracts were dried (MgSO4) and concentrated in vacuo to give 14.9 g of crude product. Purification by silica gel chromatograph (Waters Prep-500A) using chloroform/methanol (95:5) gave 9.53 g (75%) of a colorless solid: mp 104-105° C.; NMR (CDCl3) δ0.94 (t, J=7 Hz, 3H), 1.33-1.47 (m, 2H), 1.68-1.83 (m, 2H), 2.80 (t, J=7 Hz, 2H); MS (FAB) m/e (rel intensity) 162 (28), 160 (100), 158 (10), 130 (5), 126 (10), 117 (5); HRMS. Calcd for M+H: 160.0642. Found: 160.0651.

[1144] Step 2: Preparation a 4′-[(5-butyl-3-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid.

[1145] Under a static nitrogen atmosphere, 5.0 g (31.3 mmol) of solid 5-butyl-3-chloro-1H-1,2,4-triazole was added in small portions to 32 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution had ceased. The anion solution was cooled to −10° C. (ice/methanol) and treated with a solution of 9.55 g (31.3 mmol) of 4-bromomethyl-2′-methoxycarbonylbiphenyl in 20 ml of dry DMF. The reaction was allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) was added to destroy any unreacted sodium hydride and the DMF was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and dried (MgSO4) to give 12.2 g of crude material was obtained which was a clear golden oil. A 4.81 g sample of this material was dissolved in 250 ml of methanol and treated with 250 ml of 10% NaOH at ambient temperature for 2 days. A portion of the isomer mixture of acids was separated by reverse phase chromatography (Waters Delta Prep-3000) using isocratic 45% acetronitrile/water (0.05% TFA). The faster moving isomer (250 mg) was identified as the 3-chloro isomer: NMR (DMSO-d6) δ0.86 (t, J=7 Hz, 3H), 1.23-1.36 (m, J=7 Hz, 2H), 1.54-1.65 (m, J=7 Hz, 1H), 2.80 (t, J=7 Hz, 2H), 5.40 (s, 2H), 7.23-7.58 (m, 7H), 7.72-7.77 9 m, 1H).

EXAMPLE 7

[1146] 65

5-[4′-[(5-butyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1147] Step 1: Preparation of 5-butyl-3-(2,2-diethoxyethyl)-1H-1,2,4-triazole.

[1148] Under nitrogen, a solution of 38.4 g (1.2 mol) of anhydrous hydrazine in 500 mL of methanol is cooled to 0° C. and treated with a solution of 190.0 g (1.0 mol) of ethyl 3,3-diethoxypropionate (Aldrich) in 200 mL o fmethanol. The reaction is allowed to warm to ambient temperature and is stirred overnight at reflux. Concentration in vacuo gives the crude hydrazide which is purified either by recrystallization or by silica gel chromatography (Waters Prep-500A). A 17.6 g (100 mmol) sample of hydrazide is dissolved in 100 mL of methanol and is treated with 12.9 g (100 mmol) of ethyl iminovalerate under nitrogen. The reaction is stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives 5-butyl-3-(2,2-di-ethoxyethyl)-1H-1,2,4-triazole.

[1149] Step 2: Preparation of 5-[4′-[(5-butyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole.

[1150] Under a static nitrogen atmosphere, 11.1 g (46.0 mmol) of 5-butyl-3-(2,2-diethoxyethyl)-1H-1,2,4-triazole is added in small portions to 50 mmol of sodium hydride in 250 ml of dimethylformamide (DMF); stirring is continued until hydrogen evolution has ceased. The anion solution is cooled to −10° C. (ice/methanol) and is treated with a solution of 25.5 g (9.2 mmol) of N-triphenylmethyl-5-[2-(4′-bromomethylbiphen-2-yl)]tetrazole (from Step 1 of Example 3) in 100 ml of dry DMF. The reaction is allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) is added to destroy any unreacted sodium hydride and the DMF is removed in vacuo; the residue is dissolved in ethyl acetate, washed with water, and dried (MgSO4). Purification by silica gel chromatography gives the desired isomer which is treated with 3N HCl/methanol (1:1) at reflux for 4 hours. The methanol is removed in vacuo and the pH is adjusted to 9 with NaOH. The solution is extracted with ethyl acetate twice to remove triphenylmethanol. The pH is readjusted to 3 with 6N HCl and the solution is extracted 3 times with ethyl acetate, the extracts are combined, washed with water, an dried (MgSO4). Concentration in vacuo gives 5-[4′-[(5-butyl-3-formalmethyl-1H-1,2,4-triazole-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole. A 4.01 g (10.0 mmol) sample of the free aldehyde is dissolved in 500 mL of acetone/water (1:1) and is treated with 1.65 g (10.4 mmol) of solid KMnO4 over 6 hours at ambient temperature. The reaction is allowed to stir overnight and excess KMnO4 is destroyed by the addition of 100 mL of methanol. The reactin is filtered and the acetone is removed in vacuo; the pH is adjusted to 3 with 6N HCl and the product is extracted with ethyl acetate. The extracts are combined, washed with water, and dried (MgSO4). Concentration in vacuo gives the crude product which was dissolved in acetonitrile/water; purification by reverse phase chromatograpphy (Waters Delta Prep-3000) provides pure 5-[4′-[5-butyl-3-caroxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1-biphenyl]-2-yl]-1H-tetrazole.

EXAMPLE 8

[1151] 66

4′-[(3-butyl-5-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid

[1152] The slower moving isomer (120 mg) isolated in Example 6 was identified as the 5-chloro isomer: NMR (DMSO-d6) δ0.88 (t, J=7 Hz, 3H), 1.25-1.35 (m, J=7 Hz, 2H), 1.56-1.67 (m; J=7 Hz, 2H), 2.49 (t, J=7 Hz, 2H), 5.37 (s, 2H), 7.23-7.58 (m, 7H), 7.72-7.77 (m, 1H).

EXAMPLE 9

[1153] 67

5-[4′-[[5-butyl-3-(2-carboxyethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1154] Step 1: Preparation of 5-butyl-3-(3-hydroxypropyl)-1H-1,2,4-triazole.

[1155] Under nitrogen, a solution 38.4 g (1.2 mol) of anhydrous hydrazine in 500 mL of methano is cooled to 0° C. and is treated with a solution of 86.0 g (1.0 mol) of γ-butyrolactone (Aldrich) in 100 mL of methanol. The reaction is allowed to warm to ambient temperature and stir overnight at reflux. Concentration in vacuo gives the crude hydrazide which is purified either by recrystallization or by silica gel chromatography (Waters Prep-500A). A 11.8 g (100 mmol) sample of hydrazide is dissolved in 100 mL of methanol and is treated with 12.9 g (100 mmol) of ethyl iminovalerate under nitrogen. The reaction is stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives 5-butyl-3-(3-hydroxypropyl)-1H-1,2,4-triazole.

[1156] Step 2: Preparation of 5-[4′-[[5-butyl-3-(2-carboxyethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole.

[1157] Under a static nitrogen atmosphere, 8.4 g (46 mmol) of 5-butyl-3-(3-hydroxypropyl)-1H-1,2,4-triazole is added in small portions to 50 mol of sodium hydride in 250 ml of dimethylformamide (DMF); stirring is continued until hydrogen evolution has ceased. The anion solution is cooled to −10° C. (ice/methanol) and treated with a solution of 25.5 g (46 mmol) of N-triphenylmethyl-5-[2-(4′-bromomethylbiphen-2-yl)]tetrazole (from Step 1 of Example 3) in 100 ml of dry DMF. The reaction is allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) is added to destroy any unreacted sodium hydride and the DMF is removed in vacuo; the residue is dissolved in ethyl acetate, washed with water, and dried (MgSO4). Purification by silica gel chromatography gives a mixture of isomers which is treated with 3N HCl/methanol (1:1) at reflux for 4 hours. The methanol is removed in vacuo and the pH is adjusted to 9 with NaOH. The solution is extracted with ethyl acetate twice to remove triphenylmethanol. The pH is readjusted to 3 with 6 N HCl and the solution is extracted 3 times with ethyl acetate; the extracts are combined, washed with water, and dried (MgSO4). Concentration in vacuo gives a mixture of 5-butyl-3-(3-hydroxypropyl)- and 3-butyl-5-(3-hydroxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole isomers. A 4.17 g (10.0 mmol) sample of the isomeric mixture of alcohols is dissolved in 500 mL of acetone/water (1:1) and is treated with 3.30 g (20.8 mmol) of solid KMnO4 over 6 hours at ambient temperature. The reaction is allowed to stir overnight and excess KMnO4 is destroyed by the addition of 100 mL of methanol. The reaction is filtered and the acetone is removed in vacuo; the pH is adjusted to 3 with 6N HCl and the product is extracted with ethyl acetate. The extracts are combined, washed with water, and dried (MgSO4). Concentration in vacuo gives the isomeric mixture of acids; purification by reverse phase chromatography (Waters Delta Prep-3000) provides pure 5-[4′-[[5-butyl-3-(2-carboxyethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole.

EXAMPLE 10

[1158] 68

5-[4′-[[5-butyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid

[1159] Step 1: Preparation of 3-butyl-5-(1,1-difluorobutyl)-1H-1,2,4-triazole.

[1160] Under nitrogen, a stirred solution of 56.9 g (0.65 mol) of N-tert-butyl-N-methylamine (Fluka) and 66.1 g (0.65 mol) of triethylamine in 1 L of methylene chloride was cooled to 0° C. and treated with neat difluoroacetic anhydride [E. Sawicki, J. Org. Chem., 21, 376 (1956)] at such a rate as to maintain the reaction temperature below 10° C. The reaction was allowed to warm to ambient temperature and stir overnight. All volitiles were removed in vacuo (bath temperature<35° C.) and the residue redissolved in methylene chloride; the solution was washed with saturated sodium bicarbonate, dried (MgSO4), and concentrated to give 94 g (89%) of a yellow liquid. Vacuum distillation gave 86 g (81%) of colorless N-tert-butyl-N-methyldifluoroacetamide: bp 87-88° C. (22 mm); 1H NMR (CDCl3) δ1.37 (s, 9H), 2.93 (t, J=3 Hz, 3H), 5.97 (t, J=57 Hz, 1H); 19F NMR (CDCl3) δ−122.20 (d, J=57 Hz, 2F). A 17.0 g (103 mmol) sample of the amide was dissolved in 50 mL of dry THF and added slowly to a solution of 145 mmol of lithium diisopropylamine (LDA) in 450 mL of dry THF at −78° C. The reaction was allowed to stir for 1 h at −78° C. prior to the addition of 17 mL (175 mmol) of 1-iodopropane by syringe. Stirring at −78° C. was continued for 1 hr and then the reaction was allowed to warm to ambient temperature overnight. Methanol (10 mL) was added and the reaction was concentrated in vacuo; the residue was dissolved in methylene chloride and washed with 1N hydrochloric acid, dried (MgSO4) and reconcentrated to give 17.6 g (83%) of crude product. Purification by vacuum distillation gave 13.3 g (62%) of colorless N-tert-butyl-N-methyl-2,2-difluoro-valeramide: bp 125-130° C. (84 mm); 1H NMR (CDCl3) δ0.94 (t, J=7 Hz, 3H), 1.37 (s, 9H), 1.40-1.52 (m, 2H), 1.95-2.15 (m, 2H); 19F NMR (CDCl3) δ−100.29 (t, J=20 Hz, 2F). The difluorovaleramide was dissolved in 30 mL of trifluoroacetic acid (TFA) and stirred at reflux overnight under nitrogen. The solvent was removed in vacuo and the residue dissolved in methylene chloride; the solution was washed with water, dried (MgSO4) and concentrated to give 9.7 g (100%) of crude N-methyl-2,2-difluorovaleramide: 1H NMR (CDCl3) δ0.92 (t, J=7 Hz, 3H), 1.36-1.51 (m, 2H), 1.90-2.11 (m, 2H), 2.84 (d, J=6 Hz, 3H), 6.60-6.85 (br s, 1H); 19F NMR (CDCl3) δ-106.98 (t, J=19 Hz, 2F). The crude N-methyl amide was dissolved in 40 mL of 6N hydrochloric acid and stirred at reflux for 24 hr. The reaction was cooled to ambient temperature and extracted with methylene chloride; the extracts were combined, dried (MgSO4), and concentrated to give 8.0 g (56%) of crude 2,2-difluorovaleric acid: 1H NMR (CDCl3) δ1.00 (t, J=7 Hz, 3H), 1.46-1.63 (m, 2H), 1.97-2.17 (m, 2H); 19F NMR (CDCl3) δ−107.16 (t, J=18 Hz, 2F). A 4.83 g (35 mmol) sample of the crude acid was dissolved in 25 mL (35.2 g, 174 mmol) of phthaloyl chloride in a flask equipped with a reflux condenser and stirred under nitrogen in a 110° C. oil bath for 6 hrs. The condenser was replaced with a distillation head and 3.22 g (60%) of colorless 2,2-difluorovaleryl chloride was collected: bp 96°; 1H NMR (CDCl3) δ1.03 (t, J=7 Hz, 3H), 1.48-1.65 (m, 2H), 2.03-2.23 (m, 2H); 19F NMR (CDCl3) δ−102.41 (t, J=18 Hz, 2F). The 2,2-difluorovaleryl chloride (20.6 mmol) was dissolved in 10 mL of methylene chloride and dropwise to a solution of 135 g (42 mmol) of anhydrous hydrazine in 20 mL of methylene chloride at 0° C. After the addition was complete, the reaction was stirred at ambient temperature for 1 h, washed with water, dried (MgSO4), and concentrated to give 3.12 g (91%) of 2,2-difluorovaleric acid hydrazide: NMR (CDCl3) δ0.96 (t, J=7 Hz, 3H), 1.40-1.56 (m, 2H), 1.96-2.17 (m, 2H), 3.93 (br s, 2H), 7.67 (br s, 1H). A 2.84 g (18.7 mmol) sample of the crude hydrazide was dissolved in 50 mL of methanol and treated with 2.41 g (18.7 mmol) of ethyl iminovalerate. Under nitrogen, the reaction was stirred at reflux for 3 days and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (60:40) gave 3.0 g (74%) of 3-butyl-5-(1,1-difluoro)butyl-1H-1,2,4-triazole as a colorless solid: mp 92-93° C.; 1H NMR (CDCl3) δ0.97 (t, J=Hz, 3H), 0.92 (t, J=7 Hz, 3H), 1.30-1.45 (m, 2H), 1.47-1.62 (m, 2H), 1.66-1.81 (m, 2H), 2.18-2.38 (m, 2H), 2.83 (t, J=7 Hz, 2H); 19F NMR (CDCl3) δ−97.27 (t, J=18 Hz, 2F); MS (FAB) m/e (rel intensity) 218 (100), 198 (8), 188 (5), 178 (8), 170 (5); HRMS. Calcd for M+H: 218.1469. Found: 218.1461.

[1161] Step 2: Preparation of 5-[4′-[[5-butyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid

[1162] Under a static nitrogen atmosphere, 2.0 g (9.2 mmol) of solid 3-butyl-5-(1,1-difluorobutyl)-1H-1,2,4-triazole is added in small portions to 10 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring is continued until hydrogen evolution has ceased. The anion solution is cooled to −10° C. (ice/methanol) and is treated with a solution of 3.0 g (9.2 mmol) of 4-bromomethyl-2′-methoxycarbonylbiphenyl (from Step 1 of Example 1) in 20 ml of dry DMF. The reaction is allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) is added to destroy any unreacted sodium hydride and the DMF is removed in vacuo; the residue is dissolved in ethyl acetate, washed with water, and dried (MgSO4). Silica gel chromatography separates the two isomers; the more abundant isomer is dissolved in 80 ml of ethanol and is treated with 80 ml of 10% NaOH at ambient temperature for 3 days. The ethanol is removed in vacuo and the aqueous phase is acidified to pH 1 with hydrochloric acid which causes the product to precipitate; filtration and drying in vacuo gives 4′-[(5-butyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid.

EXAMPLE 11

[1163] 69

4′-[[3-butyl-5-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid

[1164] The less abundant isomer isolated in Example 10 is dissolved in 40 ml of ethanol and is treated with 40 ml of 10% NaOH at ambient temperature for 3 days. The ethanol is removed in vacuo and the aqueous phase is acidified to pH 1 with hydrochloric acid which causes the product to precipitate; filtration and drying in vacuo gives 4′-[(3-butyl-5-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid.

EXAMPLE 12

[1165] 70

5-[4′-[(3-aminomethyl-5-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1166] Step 1: Preparation of 5-propyl-3-tert-butoxycarbonylamino-methyl-1H-1,2,4-triazole.

[1167] Under nitrogen, a solution of 18.9 g (100 mmol) of N-Boc glycine hydrazide (from step 2 of Example 3) in 100 mL of methanol is treated with 11.5 g (100 mmol) of ethyl iminobutyrate [P. Reynaud and R. C. Moreau, Bull. Soc. Chim. France, 2997 (1964)]. The reaction is stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives 5-propyl-3-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole.

[1168] Step 2: Preparation of 5-[4′-[(3-aminomethyl-5-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole.

[1169] Under a static nitrogen atmosphere, 3.81 g (15.0 mmol) of 3-propyl-5-tert-butoxy-carbonylaminomethyl-1H-1,2,4-triazole is added to 15 mmol of sodium hydride in 50 ML of DMF; stirring is continued until hydrogen evolution has ceased. The anion solution is cooled to −10° C. (ice/methanol) and treated with a solution of 8.45 g (15 mmol) of N-triphenylmethyl-5-[2-(4′-bromomethylbiphen-2-yl)]tetrazole in 20 mL of dry DMF. The reaction is allowed to warm to ambient temperature and stir overnight. Methanol (10 mL) is added to destroy any unreacted sodium hydride and the DMF is removed in vacuo. The residue is dissolved in ethyl acetate, washed with water, and dried (MgSO4). Purification by silica gel chromatography gives the desired isomer which is dissolved in 100 mL of TFA and is stirred at ambient temperature overnight. The reaction is cooled to 0° C., 50 mL of water is added and is allowed to stir at ambient temperature overnight. The solvent is removed in vacuo and the residue is dissolved in acetonitrile/water. Purification by reverse phase chromatography (Waters Delta Prep-3000) provides pure 5-[4′-[(3-aminomethyl-5-propyl-1H-1,2,4-triazole-1-yl][1,1′-biphenyl]-2-yl]-1H-tetrazole as the TFA salt.

EXAMPLE 13

[1170] 71

5-[4′-[(3-aminomethyl-5-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1171] Step 1: Preparation of 5-pentyl-3-tert-butoxycarbonylamino-methyl-1H-1,2,4-triazole.

[1172] Under nitrogen, a solution of 18.9 g (100 mmol) of N-Boc glycine hydrazide (from step 2 of Example 3) in 100 mL of methanol is treated with 14.3 g (100 mmol) of ethyl iminocaproate [P. Reynaud and R. C. Moreau, Bull. Soc. Chim. France, 2997 (1964)]. The reaction is stirred at reflux overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives 5-pentyl-3-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole.

[1173] Step 2: Preparation of 5-[4′-[(3-aminomethyl-5-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl-2-yl]-1H-tetrazole.

[1174] Under a static nitrogen atmosphere, 4.02 g (15.0 mmol) of 3-pentyl-5-tert-butoxy-carbonylaminomethyl-1H-1,2,4-triazole is added to 15 mmol of sodium hydride in 50 mL of DMF; stirring is continued until hydrogen evolution has ceased. The anion solution is cooled to −10° C. (ice/methanol) and treated with a solution of 8.45 g (15 mmol) of N-triphenylmethyl-5-[2-(4′-bromomethylbiphen-2-yl)]tetrazole in 20 mL of dry DMF. The reaction is allowed to warm to ambient temperature and stir overnight. Methanol (10 mL) is added to destroy any unreacted sodium hydride and the DMF is removed in vacuo. The residue is dissolved in ethyl acetate, washed with water, and dried (MgSO4). Purification by silica gel chromatography gives the desired isomer which is dissolved in 100 mL of TFA and is stirred at ambient temperature overnight. The reaction is cooled to 0° C., 50 mL of water is added and is allowed to stir at ambient temperature overnight. The solvent is removed in vacuo and the residue is dissolved in acetonitrile/water. Purification by reverse phase chromatography (Waters Delta Prep-3000) provides pure 5-[4′-[(3-aminomethyl-5-pentyl-1H-1,2,4-triazole-1-yl][1,1′-biphenyl]-2-yl]-1H-tetrazole as the TFA salt.

EXAMPLE 14

[1175] 72

4′-[(5-butyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl]-[1,1-biphenyl]-2-carboxylic acid

[1176] Step 1: Preparation of 5-butyl-3-propyl-1H-1,2,4-triazole.

[1177] A 3.95 g (38.7 mmol) sample of butyric acid hydrazide was dissolved in 30 mL of methanol and treated with 5.0 g (38.8 mmol) of ethyl iminovalerate under nitrogen. The reaction was stirred at reflux for 3 days and concentrated in vacuo. Purification by silica gel chromatography (waters Prep-500A) using ethyl acetate/hexane (80:20) gave 5.51 g (85%) of 5-butyl-3-propyl-1H-1,2,4-triazole as a colorless solid: mp 48.5-50.0° C.; NMR (CDCl3) δ0.92 (t, J=7 Hz, 3H), 0.97 (t, J=7 Hz, 3H), 1.31-1.46 (m, 2H), 1.66-1.84 (m, 4H), 2.72 (t, J=7 Hz, 2H), 2.75 (t, J=7 Hz, 2H); MS (FAB) m/e (rel intensity) 168 (100), 166 (4), 152 (3), 138 (3), 125 (3); HRMS. Calcd for M+H: 168.1501. Found: 168.1534.

[1178] Step 2: Preparation of 4′-[(5-butyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid.

[1179] Under a static nitrogen atmosphere, 2.0 g (12 mmol) of solid 5-butyl-3-propyl-1H-1,2,4-triazole is added in small portions to 12 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring is continued until hydrogen evolution has ceased. The anion solution is cooled to −10° C. (ice/methanol) and treated with a solution of 3.8 g (12 mmol) of 4-bromomethyl-2′-methoxycarbonylbiphenyl (from Step 1 of Example 1) in 20 ml of dry DMF. The reaction is allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) is added to destroy any unreacted sodium hydride and the DMF is removed in vacuo. The residue is dissolved in ethyl acetate, washed with water, and dried (MgSO4). Silica gel chromatography produces a mixture of the two isomers which is dissolved in 80 ml of ethanol and is treated with 80 ml of 10% nAOH at ambient temperature for 3 days. The thanol is removed in vacuo and the aqueous phase is acidified to pH 1 with hydrochloric acid which causes the mixture of product isomers to precipitate. Purification by reverse phase chromatography (Waters Delta Prep-3000) gives the 5-butyl-3-propyl isomer.

EXAMPLE 15

[1180] 73

4′-[(3-butyl-5-propyl-1H-1,2,4-triazol-1-yl)methyl]-[1,1′-biphenyl]-2-carboxylic acid

[1181] The other isomer for Example 14 is isolated in an identical manner and provides the 3-butyl-5-propyl isomer.

EXAMPLE 16

[1182] 74

4′-[(3-butyl-5-isopentyl-1H-1,2,4-triazol-1-yl)methyl]-[1,1′-biphenyl]-2-carboxylic acid

[1183] Step 1: Preparation of 3-butyl-5-isopentyl-1H-1,2,4-triazole.

[1184] Under nitrogen, a solution of 53.8 g (1.68 mol) of anhydrous hydrazine in 300 mL of methanol was cooled to 0° C. and treated with 186 g (1.4 mol) of methyl 4-methylvalerate. The reaction was allowed to warm to ambient temperature and stir overnight prior to stirring at reflux for 4 h. The reaction was concentrated in vacuo giving 166 g (93%) of 4-methylvaleric acid hydrazide as a colorless solid: 49-51° C.; NMR (CDCl3) δ0.89 (d, J=7 Hz, 6H), 1.48-1.64 (m, 3H), 2.15 (t, J=7 Hz, 2H), 3.91 (br s, 2H), 6.94 (br s, 1H). A 7.86 g (60 mmol) sample of the hydrazide was dissolved in 50 mL of methanol and treated with 7.8 g (60 mmol) of ethyl iminovalerate under nitrogen. The reaction was stirred at reflux overnight and concentrated i vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (40:60) gave 9.6 g (82%) of 3-butyl-5-isopentyl-1H-1,2,4-triazole as a colorless solid which melts close to ambient temperature: NMR (CDCl3) δ0.81-0.90 (m, 9H), 1.25-1.40 (m, 2H), 1.47-1.74 (m, 5H), 2.70 (t, J=7 Hz, 4H); MS (FAB) m/e (rel intensity) 196 (100); HRMS. Calcd for M+H: 196.1814. Found: 196.1832.

[1185] Step 2: Preparation of 4′-[(3-butyl-5-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid.

[1186] Under a static nitrogen atmosphere, 2.0 g (10.3 mmol) of solid 3-butyl-5-isopentyl-1H-1,2,4-triazole is added in small portions to 11 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring is continued until hydrogen evolution has ceased. The anion solution is cooled to −10° C. (ice/methanol) and is treated with a solution of 3.27 g (10.2 mmol) of 4-bromomethyl-2′-methoxycarbonylbiphenyl (from Step 1 of Example 1) in 20 ml of dry DMF. The reaction is allowed to warm to ambient temperature and stir overnight. Methanol (10 ml) is added to destroy any unreacted sodium hydride and the DMF is removed in vacuo. The residue is dissolved in ethyl acetate, washed with water, and dried (MgSO4). The crude material is dissolved in 80 ml of ethanol and is treated with 80 ml of 10% NaOH at ambient temperature for 3 days. The ethanol is removed in vacuo and the aqueous phase is acidified to pH 1 with hydrochloric acid which causes the mixture of product isomers to precipitate purification by reverse phase chromatography (Waters Delta Prep-3000) give sthe 3-butyl-5-isopentyl isomer.

EXAMPLE 17

[1187] 75

4′-[(5-butyl-3-isopentyl-1H-1,2,4-triazol-1-yl]methyl)-[1,1′-biphenyl]-2-carboxylic acid

[1188] The other isomer from Example 16 is isolated in an identical manner and provides the 5-butyl-3-isopentyl isomer.

EXAMPLE 18

[1189] 76

4′-[(5-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid

[1190] Following General Procedure A, 5.0 g (39.9 mmol) of 5-butyl-1H-1,2,4-triazole was coupled with 12.2 g (39.9 mmol) of the alkylating reagent prepared in step 1 of Example 1 to give 3.1 g (22%) of a faster moving isomer: NMR (CDCl3) δ0.90 (t, J=8 Hz, 3H), 1.29-1.45 (m, 2H), 1.63-1.76 (m, 2H), 2.71 (t, J=8 Hz, 2H), 3.62 (s, 3H), 5.34 (s, 2H), 7.14-7.20 (m, 2H), 7.24-7.33 (m, 3H), 7.40 (dt, J=8 and 2 Hz, 1H), 7.50 (dt, J=8 and 2 Hz, 1H), 7.82 (dd, J=8 and 2 Hz, 1H), 7.85 (s, 1H) and 3.7 g (26%) of a slower moving isomer: NMR (CDCl3) δ0.92 (t, J=8 Hz, 3H), 1.31-1.46 (m, 2H), 1.66-1.79 (m, 2H), 2.73 (t, J=8 Hz, 2H), 3.62 (s, 3H), 5.28 (s, 2H), 7.21-7.34 (m, 5H), 7.39 (dt, J=8 and 2 Hz, 1H), 7.50 (dt, J=8 and 2 Hz, 1H), 7.83 (dd, J=8 and 2 Hz, 1H), 7.94 (s, 1H). The faster moving isomer was hydrolyzed to give 2.75 g (92%) of 4′-[(5-butyl-1H-1,2,4-triazol-1-yl)methyl]-[1,1′-biphenyl]-2-carboxylic acid as a colorless solid: NMR (DMSO-d6) δ0.85 (t, J=8 Hz, 3H), 1.23-1.38 (m, 2H), 1.52-1.65 (m, 2H), 2.76 (t, J=7 Hz, 2H), 5.41 (s, 2H), 7.16-7.24 (m, 2H), 7.27-7.37 (m, 3H), 7.44 (dt, J=8 and 2 Hz, 1H), 7.56 (dt, J=8 and 2 Hz, 1H), 7.72 (dd, J=8 and 2 Hz, 1H), 7.86 (s, 1H); MS (FAB) m/e (rel intensity) 336 (100), 307 (7), 289 (7), 224 (8), 211 (100), 193 (9).

EXAMPLE 19

[1191] 77

4′-[(3-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid

[1192] The slower moving isomer from Example 18 was hydrolyzed to give 2.3 g (67%) of 4′-[(3-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid as a colorless solid: NMR (DMSO-d6) δ0.87 (t, J=8 Hz, 3H), 1.23-1.38 (m, 2H), 1.54-1.67 (m, 2H), 2.58 (t, J=8 Hz, 2H), 5.36 (s, 2H), 7.23-7.38 (m, 5H), 7.44 (dt, J=8 and 2 Hz, 1H), 7.56 (dt, J=8 and 2 Hz, 1H), 7.72 (dd, J=8 and 2 Hz, 1H), 8.51 (s, 1H); MS (FAB) m/e (rel intensity) 336 (85), 211 (100), 165 (24), 126 (52). 1

EXAMPLE 20

[1193] 78

4′-[3,5-di-perfluoropropyl-1H-1,2,4-triazol-1-yl)methyl][1′-biphenyl]-2-carboxylic acid

[1194] Following General Procedure A, 11.0 g (27.2 mmol) of 3,5-bis(perfluoropropyl)-1H-1,2,4-triazole was coupled with 8.30 g (27.2 mmol) of the alkylating reagent prepared in step 1 of Example 1 to give 8.7 g (51%) of a colorless oil: NMR (CDCl3) δ3.62 (s, 3H), 5.63 (s, 2H), 7.25-7.37 (m, 5H), 7.44 (dt, J=8 and 2 Hz, 1H), 7.54 (dt, J=8 and 2 Hz, 1H), 7.87 (dd, J=8 and 2 Hz, 1H). A 8.5 g (13.5 mmol) sample of this material was hydrolyzed to give 6.91 g (81%) of 4′-[(3,5-bis(1,1,2,2,3,3,3-heptafluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxlic acid as a colorless solid: NMR (CDCl3) δ5.62 (s, 2H), 7.27-7.37 (m, 5H), 7.44 (dt, J=8 and 2 Hz, 1H), 7.58 (dt, J=8 and 2 Hz, 1H), 7.98 (dd, J=8 and 2 Hz, 1H); MS (TSP) M+NH4 (rel intensity) 633 (100), 211 (12); HRMS. Calc'd for M+Li: 622.0788. Found: 622.0759.

EXAMPLE 21

[1195] 79

5-[4′-[(3-phenyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl](1,1′-biphenyl)-2-yl]-1H-tetrazole

[1196] Following General Procedure A, 2.0 g (9.9 mol) of 5-butyl-3-phenyl-1H-1,2,4 triazole was coupled with 5.5 g (9.9 mmol) of the alkylating reagent prepared in step 1 of Example 3 to give 5.2 g (77%) of a faster moving isomer: NMR (CDCl3) δ0.90 (t, J=8 Hz), 1.30-1.44 (m, 2H), 1.63-1.77 (m, 2H), 2.67 (t, J=8 Hz, 2H), 5.24 (s, 2H), 6.88-7.01 (m, 8H), 7.08-7.53 (m, 17H), 7.95 (dd, J=8 and 2 Hz, 1H), 8.12 (dd, J=8 and 2 Hz, 2H) and 420 mg (6.3%) of a slower moving isomer: NMR (CDCl3) δ0.96 (t, J=8 Hz, 3H), 1.38-1.52 (m, 2H), 1.75-1.89 (m, 2H), 2.84 (t, J=8 Hz, 2H), 5.27 (s, 2H), 6.88-6.97 (m, 8H), 7.13 (d, J=8 Hz, 2H), 7.17-7.54 (m, 15H), 7.57 (d, J=8 Hz, 2H), 7.93 (dd, J=8 and 2 Hz, 1H). A 4.8 g (7.1 mmol) sample of the faster moving isomer was deportected to give 1.64 g (53%) of 5-[4′-[(3-phenyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl](1,1′-biphenyl-2-yl]-1H-tetrazole as a colorless solid: mp 113° C. (dec); NMR (CDCl3) δ0.87 (t, J=8 Hz, 3H), 1.24-1.39 (m, 2H),1.55-1.69 (m, 2H), 2.60 (t, J=8 2 Hz, 5.19 (s, 2H), 7.04 (d, J=8 Hz, 2H), 7.11 (d, J=8 Hz, 2H), 7.27-7.39 (m, 4H), 7.47-7.60 (m, 2H), 7.87 (dd, J=8 and 2 Hz, 2H), 7.95 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 436 (100), 393 (8), 207 (60), 192 (20), 178 (13), 165 (8); HRMS. Calc'd for M+H: 436.2249. Found: 436.2240.

EXAMPLE 22

[1197] 80

5-[4′-[(3-butyl-5-phenyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl)-2-yl]-1H-tetrazole

[1198] The slower moving isomer from Example 21 was deprotected to give 251 mg (60%) of 5-[4′-[(3-butyl-5-phenyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: mp 205° C. (dec); NMR (CDCl3) δ0.88 (t, J=8 Hz, 3H), 1.23-1.38 (m, 2H), 1.55-1.68 (m, 2H), 2.52 (t, J=8 Hz, 2H), 5.32 (s, 2H), 6.99 (d, J=8 Hz, 2H), 7.08 (d, J=8 Hz, 2H), 7.31-7.61 (m, 8H), 7.90 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 436 (100), 393 (9), 374 (7), 277 (7), 247 (15), 207 (45); HRMS. Calc'd for M+H: 436.2249. Found: 436.2201.

EXAMPLE 23

[1199] 81

5-[4′-[[3-butyl-5-(dimethoxymethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1200] Following General Procedure A, 2.0 g (10 mmol) of 5-butyl-3-(dimethoxymethyl)-1H-1,2,4-triazole was coupled with 5.6 g (10 mmol) of the alkylating regagent prepared in step 1 of Example 3 to give 1.65 g (24%) of a faster moving isomer: NMR (CDCl3) δ0.92 (t, J=8 Hz, 3H), 1.31-1.45 (m, 2H), 1.66-1.78 (m, 2H), 2.69 (t, J=8 Hz, 2H), 3.33 (s, 6H), 5.30 (s, 2H), 5.42 (s, 1H), 6.90-6.96 (m, 5H), 7.02-7.12 (m, 4H), 7.21-7.38 (m, 11H), 7.41-7.52 (m, 2H), 7.86-7.92 (m, 1H) and 3.65 g (54.0%) of a slower moving isomer: NMR (CDCl3) δ0.85 (t, J=8 Hz, 3H), 1.22-1.36 (m, 2H), 1.57-1.70 (m, 2H), 2.59 (t, J=8 Hz, 2H), 3.45 (s, 6H), 5.20 (s, 2H), 5.55 (s, 1H), 6.89-6.97 (m, 5H), 7.08-7.19 (m, 4H), 7.21-7.37 (m, 11H), 7.41-7.52 (m, 2H), 7.90-7.95 (m, 1H). The faster moving isomer was deprotected to give 737 mg (70%) of 5-[4′-[[3-butyl-5-(dimethoxymethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: mp 152.5-153.5° C.; NMR (CDCl3) δ0.87 (t, J=8 Hz, 3H), 1.20-1.30 (m, 2H), 1.53-1.65 (m, 2H), 2.46 (t, J=8 Hz, 2H), 3.30 (s, 6H), 5.37 (s, 2H), 5.40 (s, 1H), 7.05-8.05 (m, 4H), 7.45 (dd, J=8 and 2 Hz, 1H), 7.51-7.65 (m, 2H), 8.02 (d, J=8 Hz, 1H); MS (FAB) m/e (rel intensity) 434 (65), 402 (40), 370 (11), 342 (46), 249 (85), 235 (18), 207 (100), 192 (89), 168 (70); HRMS. Calc'd for M+H: 434.2304. Found: 434.2332.

EXAMPLE 24

[1201] 82

5-[4′-[(5-butyl-3-dimethoxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl-2-yl]-1H-tetrazole

[1202] A 3.65 g (5.4 mmol) sample of the slower moving isomer from Example 23 was deprotected to give 108 mg of colorless 5-[4′-[[5-butyl-3-(dimethoxymethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole after lyophilization: NMR (CDCl3) δ0.86 (t, J=8 Hz, 3H), 1.24-1.39 (m, 2H), 1.56-1.70 (m, 2H), 2.66 (t, J=8 Hz, 2H), 3.30 (s, 6H), 5.23 (s, 2H), 5.35 (s, 1H), 7.02 (d, J=8 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 7.40 (dd, J=8 and 2 Hz, 1H), 7.51 (dt, J=8 and 2 Hz, 1H), 7.59 (dt, J=8 and 2 Hz, 1H), 7.89 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 434 (10), 402 (40), 249 (100), 207 (36), 192 (54), 168 (12); HRMS. Calc'd for M+H: 434.2304. Found: 434.2271.

EXAMPLE 25

[1203] 83

5-[4′-[(3-butyl-5-phenylethyl-1H-1,2,4-triazol-1-yl)methyl](1,1′-biphenyl-2-yl]-1H-tetrazole

[1204] Following General Procedure A, 2.3 g (10 mmol) of 3-butyl-5-phenethyl-1H-1,2,4-triazole was coupled with 6.6 g (10 mmol) of the alkylating reagent prepared in step 1 of Example 3 to give 2.67 g (38%) of a faster moving isomer: NMR (CDCl3) δ0.97 (t, J=8 Hz, 3H), 1.36-1.50 (m, 2H), 1.71-1.84 (m, 2H), 2.73 (t, J=8 Hz, 2H), 2.78-2.88 (m, 2H), 2.92-3.01 (m, 2H), 4.82 (s, 2H), 6.80-6.95 (m, 9H), 7.02-7.11 (m, 5H), 7.16-7.36 (m, 11H), 7.41-7.52 (m, 2H), 7.91-7.97 (m, 1H) and 2.94 g (42%) of a slower moving isomer: NMR (CDCl3) δ0.88 (t, J=8 Hz, 3H), 1.23-1.38 (m, 2H), 1.57-1.70 (m, 2H), 2.58 (t, J=8 Hz, 2H), 2.97-3.13 (m, 4H), 5.11 (s, 2H), 6.86 (d, J=8 Hz, 2H), 6.89-6.96 (m, 6H), 7.10 (d, J=8 Hz, 2H), 7.14-7.39 (m, 15H), 7.42-7.54 (m, 2H), 7.93 (dd, J=8 and 2 Hz, 1H). The faster moving isomer was deprotected to give 1.6 g (88%) of 5-[4′-[[3-butyl-5-(2-phenylethyl)-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl-2-yl]-1H-tetrazole a colorless solid: NMR (CDCl3) δ0.86 (t, J=8 Hz, 3H), 1.17-1.31 (m, 2H), 1.48-1.51 (m, 2H), 2.42 (t, J=8 Hz, 2H), 2.76 (t, J=8 Hz, 2H), 2.92 (t, J=8 Hz, 2H), 4.80 (s, 2H), 6.83 (d, J=8, 2H), 6.92-7.00 (m, 2H), 7.08 (d, J=8 Hz, 2H), 7.17-7.32 (m, 3H), 7.42 (dd, J=8 and 2 Hz, 1H), 7.51-7.65 (m, 2H), 7.96 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 464 (37), 230 (25), 207 (100), 178 (17); HRMS. Calc'd for M+H: 464.2563. Found: 464.2532.

EXAMPLE 26

[1205] 84

5-[4′[(5-butyl-3-phenylethyl-1H-1,2,4-triazol-1-yl)methyl](1,1′-biphenyl-2-yl]-1H-tetrazole

[1206] The slower moving isomer from Example 25 was deprotected to give 1.5 g (77%) of 5-[4′-[[5-butyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl-2-yl]-1H-tetrazole as a colorless solid: mp 156.0-157.2° C.; NMR (CDCl3) δ0.84 (t, J=8 Hz, 3H), 1.19-1.34 (m, 2H), 1.47-1.61 (m, 2H), 2.52 (t, J=8 Hz, 2H), 2.66-2.77 (m, 2H), 2.85-2.95(m, 2H), 5.15 (s, 2H), 6.88 (d, J=8 Hz, 2H), 7.05-7.11(m, 4H), 7.12-7.28(m, 5H), 7.41 (dd, J=8 and 2 Hz, 1H), 7.50 (dt, J=8 and 2 Hz, 1H), 7.59 (dt, J=8 and 2 Hz, 1H), 7.92 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 464 (83), 230 (22), 207 (92); HRMS. Calc'd for M+H: 464.2563. Found: 464.2560.

EXAMPLE 27

[1207] 85

5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-methanamine

[1208] A 1.5 g (3.5 mmol) sample of the diacetal compound of Example 24 was dissolved in 40 ml of ethanol and 40 ml of 3N HCl. The reaction was stirred at ambient temperature overnight and then at reflux for 50 min, the course of the reaction was followed by analytical reverse phase HPLC. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate and extracted with saturated sodium bicarbonate solution until the water layer stayed basic. The water layer was acidified and extracted with an ethyl acetate/methylene chloride mixture. The organic layer was dried (MgSO4) and removed in vacuo yielding 0.96 g of crude aldehyde: NMR (CDCl3) δ0.66 (t, J=8 Hz, 3H), 1.06-1.20 (m, 2H), 1.42-1.54 (m, 2H), 2.53 (t, J=8 Hz, 2H), 5.17 (s, 2H), 6.80-6.95 (m, 4H), 7.17-7.38 (m, 3H), 7.42-7.48 (m, 1H), 9.70 (s, 1H). Under a static nitrogen atmosphere, 0.91 g (2.3 mmol) of this material was dissolved in 10 ml of methanol and 1.77 g (23 mmol) ammonium acetate was added followed by 0.10 g (1.61 mmol) sodium cyanoborate. After stirring at ambient temperature for 3 days, analytical reverse phase HPLC indicated that the reaction was complete. Purification was accomplished by reverse phase chromatography (Waters Delta Prep 3000) using 25% acetonitrile/water (0.05% TFA). The solvent from the pure fractions was removed in vacuo and the residue dissolved in methanol and 3N HCl. After stirring for 30 min, the solvent was removed in vacuo and the residue lyophilized from acetonitrile/water providing 100 mg (10%) of 5-butyl-1-(2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-methanamine as the colorless hydrochloride salt: NMR (DMSO-d6) δ0.85 (t, J=8 Hz, 3H), 1.22-1.38 (m, 2H), 1.51-1.64 (m, 2H), 2.77 (t, J=8 Hz, 2H), 4.00-4.09 (m, 2H), 5.40 (s, 2H), 7.01-7.25 (m, 4H), 7.39 (s, 1H), 7.48-7.73 (m, 3H); MS (FAB) m/e (rel intensity) 389 (100), 207 (65), 192 (17); HRMS. Calc'd for M+H: 389.2202. Found: 389.2170.

EXAMPLE 28

[1209] 86

5-[4′-[(3-butyl-5-octyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1210] Following General Procedure A, 2.0 g (8.4 mmol) of 3-butyl-5-octyl-1H-1,2,4-triazole was coupled with 5.5 g (8.4 mmol) of the alkylating reagent prepared in step 1 of Example 3. Silica gel chromatography (Waters Prep 500-A) using 25% ethyl acetate/hexane produced 4.5 g (75.4%) of a mixture of the two isomers which was dissolved in 40 ml of 10% water/acetic acid and stirred at ambient temperature overnight. The solvent was removed in vacuo. Purification of a sample of the isomeric product mix by reverse phase chromatography (Waters Delta Prep-3000) using 45% acetonitrile/water (0.05% TFA) for 30 minutes followed by 50% acetonitrile/water (0.05% TFA) provided two isomers. The faster moving isomer compound was dissolved in dilute base, the water was acidified (pH 4-5) with 1N HCl, and the product extracted with ethyl acetate. The ethyl acetate was dried (MgSO4) and removed in vacuo yielding a solid which was recrystallized from acetonitrile providing 92 mg of 5-[4′-[(3-butyl-5-octyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: mp 136.5-138.0° C.; NMR (CDCl3) δ0.82 (t, J=8 Hz, 3H), 0.86 (t, J=8 Hz, 3H), 1.11-1.33 (m, 12H), 1.40-1.60 (m, 4H), 2.27 (t, J=8 Hz, 2H), 2.44 (t, J=8 Hz, 2H), 5.16 (s, 2H), 6.87 (d, J=8 Hz, 2H), 7.07 (d, J=8 Hz, 2H), 7.44 (dd, J=8 and 2 Hz, 1H), 7.50-7.66 (m, 2H), 7.90 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 472 (5), 207 (7); HRMS. Calc'd for M+H: 472.3189. Found: 472.3180.

EXAMPLE 29

[1211] 87

5-[4′-[(5-butyl-3-octyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1212] The slower moving isomer from Example 28 was isolated in an identical manner and the product lyophilized from acetonitrile/water providing 53 mg of 5-[4′-[(5-butyl-3-octyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ0.83 (t, J=8 Hz, 3H), 0.86 (t, J=8 Hz, 3H), 1.12-1.37 (m, 12H), 1.46-1.63 (m, 4H), 2.35 (t, J=8 Hz, 2H), 2.51 (t, J=8 Hz, 2H), 5.19 (s, 2H), 6.92 (d, J=8 Hz, 2H), 7.09 (d, J=8 Hz, 2H), 7.40-7.48 (m, 1H), 7.51-7.66 (m, 2H), 7.91 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 472 (6), 207 (8); HRMS. Calc'd for M+H: 472.3189. Found: 472.3230.

EXAMPLE 30

[1213] 88

1-[[5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-3-yl]methyl]-1-butanone

[1214] Under a static nitrogen atmosphere, 30.0 g (150 mmol) 5-butyl-3-dimethoxy-1H-1,2,4-triazole (from Step 1 of Example 23 was added in small portions to 165 mmol of sodium hydride in 300 ml anhydrous THF; stirring was continued for 1 h. The anion solution was cooled to −10° C. (methanol/ice) and treated with Sem-Cl dropwise. The reaction was allowed to warm to ambient temperature and stir overnight. The solvent was removed in vacuo. The residue was dissolved in methylene chloride, washed with water, dried (MgSO4), and the solvent removed again in vacuo. Silica gel chromatography using 20% ethyl acetate/hexane followed by ethyl acetate provided 13.6 g of the faster movfing isomer as an oil: NMR (CDCl3) δ−0.07 (s, 9H), 0.82-0.92 (m, 5H), 1.26-1.40 (m, 2H), 1.62-1.74 (m, 2H), 2.67 (t, J=8 Hz, 2H), 3.38 (s, 6H), 3.53-3.62 (m, 2H), 5.47 (s, 2H), 5.55 (s, 1H). Under a static nitrogen atmosphere, 12.6 g (38.2 mmol) of the faster moving Sem-protected triazole isomer from above was dissolved in 630 ml of anhydrous THF, cooled to −78° C., and 45.8 mmol of sec-butyl lithium was added dropwise. The solution was stirred for 1 h and then the anion was quenched with 4.5 ml (45.8 mmol) of n-propyl iodide. The solution was stirred at −78° C. for 5 h and then allowed to warm to ambient temperature overnight. The solvent was removed in vacuo. The residue was dissolved in methylene chloride, washed with water, dried (MgSO4) and the solvent removed providing 12.4 g of crude Sem-protected 5-butyl-3-(1,1-dimethoxybutane)-1H-1,2,4-triazole: NMR (CDCl3) δ−0.04 (s, 9H), 0.75-0.93 (m, 8H), 0.98-1.11 (m, 2H), 1.25-1.41 (m, 2H), 1.62-1.74 (m, 2H), 1.99-2.08 (m, 2H), 2.68 (t, J=8 Hz, 2H), 3.20 (s, 6H), 3.62 (t, J=8 Hz, 2H), 5.56 (s, 2H). A 1.0 g (2.7 mmol) sample of the crude dimethoxybutyl compound was dissolved in 5 ml of ethanol and 5 ml of 3M HCl and stirred at reflux for 2.5 h. The solvent was removed in vacuo providing 560 mg of the crude HCl salt of 5-butyl-3-(1-butanone)-1H-1,2,4-triazole: NMR (DMSO-d6) δ0.83-0.94 (m, 6H), 1.21-1.36 (m, 2H), 1.55-1.75 (m, 4H), 2.83 (t, J=8 Hz, 2H), 2.97 (t, J=8 Hz, 2H). The crude HCl salt of the triazole was dissolved in 20 ml of fresh methanol, 3 Å molecular sieves were added, and the mixture stirred at reflux under nitrogen overnight. The solution was filtered through celite and the solvent removed in vacuo. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The solvent was dried (MgSO4) and removed in vacuo providing 390 mg of crude 5-butyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazole: NMR (CDCl3) δ0.90 (t, J=8 Hz, 3H), 0.99 (t, J=8 Hz, 3H), 1.29-1.46 (m, 2H), 1.66-1.84 (m, 4H), 2.80 (t, J=8 Hz, 2H), 3.06 (t, J=8 Hz, 2H), 3.18 (s, 6H). Under a static nitrogen atmosphere, 380 mg (1.6 mmol) of this material in 5 ml of anhydrous dimethylformamide (DMF) was added to 1.9 mmol sodium hydride in 5 ml of DMF; stirring was continued for 1 h. The anion solution was cooled to 0° C. and 890 mg (1.6 mmol) of the alkylating reagent prepared in from step 1 of Example 3 was added as a solid. The reaction was allowed to warm to ambient temperature and stir overnight. Methanol (1 ml) was added to destroy any unreacted sodium hydride and the DMF was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, and dried (MgSO4). The solvent was removed in vacuo providing 1.2 g of crude material which was dissolved in 10 ml ethanol and 10 ml 3N HCl and stirred at reflux for 2 h. The solvent was removed in vacuo. Purification by reverse phase chromatography (Water Delta Prep 3000) using isocratic 37% acetonitrile/water (0.05% TFA) for 40 minutes followed by 50% acetonitrile/water (0.05% TFA) provided the TFA salt. The salt was dissolved in basic water (pH 9-10), the water was acidified to pH 4 with 3N HCl, and the product extracted with ethyl acetate. The ethyl acetate was dried (MgSO4) and removed in vacuo yielding a solid which was recrystallized from acetonitrile providing 146 mg (21%) of 1-[[5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-3-yl]methyl]-1-butanone mp 150.5-152.5° C.; NMR (CDCl3) δ0.85 (t, J=8 Hz, 3H), 0.96 (t, J=8 Hz, 3H), 1.23-1.39 (m, 2H), 1.54-1.77 (m, 4H), 2.67 (t, J=8 Hz, 2H), 2.97 (t, J=8 Hz, 2H), 5.28 (s, 2H), 7.02 (d, J=8 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 7.37 (d, J=8 Hz, 1H), 7.43-7.62 (m, 2H), 7.86 (d, J=8 Hz, 1H); MS (FAB) m/e (rel intensity) 430 (6), 207 (12); HRMS. Calc'd for M+H: 430.2355. Found: 430.2404.

EXAMPLE 31

[1215] 89

N-[[5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-3-yl]methyl]acetamide

[1216] A 92.9 mg (0.22 mmol) sample of 5-[4′-[(5-butyl-3-methylamine-1H-1,2,4-triazol-1-yl)methyl]-(1,1′-biphenyl-2-yl]-1H-tetrazole hydrochloride from Example 27 was dissolved in 5 ml of water and the pH was adjusted to 9 with 1M potassium carbonate (K2CO3). The solution was cooled to 0° C. and 0.22 ml of 1M K2CO3 was added followed by 0.22 mmol of acetic anhydride. Additional K2CO3 was added as needed to maintain a pH of 9. At 30 min intervals, this addition was repeated until analytical reverse phase chromatography showed that all starting material has been consumed. The pH was adjusted to three with 1N HCl and extracted with ethyl acetate. The ethyl acetate was removed in vacuo and the product lyophilized from acetonitrile/water providing 36 mg (39%) of N-[[5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-3-yl]methyl]acetamide as a colorless solid: NMR (CDCl3) δ0.80 (t, J=8 Hz, 3H), 1.18-1.37 (m, 2H), 1.47-1.64 (m, 2H), 1.94 (s, 3H), 2.63 (t, J=8 Hz, 2H), 4.22 (d, J=8 Hz, 2H), 5.18 (s, 2H), 6.95 (d, J=8 Hz, 2H), 7.04-7.21 (m, 2H), 7.44 (d, J=8 Hz, 1H), 7.50-7.66 (m, 2H), 7.90 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 431 (42), 207 (100); HRMS. Calc'd for M+H: 431.2308. Found: 431.2271.

EXAMPLE 32

[1217] 90

5-[4′-[(5-butyl-3-methyl-1H-1,2,4-triazol-1-yl)methyl1-[1,1′-biphenyl]-2-yl-1H-tetrazole

[1218] Following General Procedure A, 700 mg (5.0 mmol) of 5-butyl-3-methyl-1H-1,2,4-triazole was coupled with 2.8 g (5.0 mmol) of the aklylating reagent prepared in step 1 of Example 3. Silica gel chromatography using ethyl acetate/toluene (35:65) produced 2.75 g (90%) of a mixture of the two isomers which was dissolved in 30 ml 10% water/acetic acid and sitrred at ambient temperature for 3 days. The solvent was removed in vacuo and the residue dissolved in dilute base, washed with toleune, acidified to pH 4 with 1N HCl and the product extracted with ethyl acetate. Purification of the isomeric product mixture by reverse phase chromatography (Water Delta Prep-3000) using isocratic acetonitrile/water (23:77) (0.05% TFA) provided two isomers. The faster moving isomer compound was dissolved in dilute base, acidified to pH 3-4 and extracted with ethyl acetate. The solvent was removed in vacuo; recrystallization from acetonitrile gave 199 mg (12%) of 5-[4′-[(5-butyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl]-[1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: mp 170.0-170.5° C.; NMR (CDCl3) δ0.79 (t, J=8 Hz, 3H), 1.18-1.32 (m, 2H), 1.44-1.56 (m, 2H), 1.99 (s, 3H), 2.49 (t, J=8 Hz, 2H), 5.15 (s, 2H), 6.87 (d, J=8 Hz, 2H), 7.08 (d, J=8 Hz, 2H),7.44 (dd, J=8 and 2 Hz, 1H), 7.51-7.65 (m, 2H), 7.90 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 374 (100), 235 (13), 207 (100), 140 (29); HRMS. Calc'd for M+H: 374.2093. Found: 374.2062.

EXAMPLE 33

[1219] 91

5-[4′-[(3-butyl-5-methyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1220] The slower moving isomer from Example 32 was dissolved in dilute base, acidified to pH 3-4, and extraced with ethyl acetate. The solvent was removed in vacuo and the product lyophilized from acetonitrile/water which gave 536 mg (33%) of 5-[4′-[(3-butyl-5-methyl-1H-1,2,4-triazol-1-yl)methyl]-[1,1′-biphenyl]-1-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ0.82 (t, J=8 Hz, 3H), 1.21-1.35 (m, 2H), 1.53-1.66 (m, 2H), 2.35 (s, 3H), 2.56 (t, J=8 Hz, 2H), 5.23 (s, 2H), 7.03 (d, J=8 Hz, 2H), 7.11 (d, J=8 Hz, 2H), 7.42 (dd, J=8 and 2 Hz, 1H), 7.47-7.63 (m, 2H), 7.88 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 374 (65), 331 (12), 235 (13), 207 (100), 192 (38), 140 (56); HRMS. Calc'd for M+H: 374.2093. Found: 374.2071.

EXAMPLE 34

[1221] 92

1,1-dimethylethyl[3-butyl-[1-2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-5-yl]methylcarbamate

[1222] Following General Procedure A, 6.0 g (25 mmol) of [(5-butyl-1H-1,2,4-triazol-3-yl)methyl]carbamate was coupled with 16.4 g (25 mmol) of the alkylating reagent prepared in step 1 of Example 3. Silica gel chromatography (Waters Prep 500A) using ethyl acetate/hexane (2:3) gave 4.29 g (24%) of a faster moving isomer: NMR (CDCl3) δ0.94 (t, J=8 Hz, 3H), 1.33-1.46 (m, 2H), 1.43 (s, 9H), 1.66-1.78 (m, 2H), 2.69 (t, J=8 Hz, 2H), 4.26 (d, J=8 Hz, 2H), 5.24 (s, 2H), 6.87-6.93 (m, 7H), 7.01 (d, J=8 Hz, 2H), 7.11 (d, J=8 Hz, 2H), 7.21-7.28 (m, 5H), 7.30-7.37 (m, 4H), 7.42-7.52 (m, 2H), 7.94 (dd, J=8 and 2 Hz, 1H) and 9.74 g (54%) of a slower moving isomer: NMR (CDCl3) δ0.87 (t, J=8 Hz, 3H), 1.24-1.36 (m, 2H), 1.44 (s, 9H), 1.57-1.69 (m, 2H), 2.58 (t, J=8 Hz, 2H), 4.38 (d, J=8 Hz, 2H), 5.12 (s, 2H), 6.91 (d, J=8 Hz, 8H), 7.11 (d, J=8 Hz, 2H), 7.21-7.28 (m, 6H), 7.30-7.37 (m, 4H), 7.42-7.52 (m, 2H), 7.91-7.96 (m, 1H). The faster moving isomer was dissolved in 30 ml of water/acetic acid (1:4) and stirred at ambient temperature overnight. The solvent was removed in vacuo; the residue dissolved in dilute base and washed with toluene. The water layer was acidified to pH 3-4 and extracted with ethyl acetate. Recrystallization from acetonitrile gave 2.53 g (88%) of 1,1-dimethylethyl[3-butyl-[1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-5-yl]methylcarbamate as a colorless solid: mp 144-147° C.; NMR (CDCl3) δ0.88 (t, J=8 Hz, 3H), 1.22-1.45 (m, 2H), 1.36 (s, 9H), 1.54-1.66 (m, 2H), 2.56 (t, J=8 Hz, 2H), 4.05 (d, J=8 Hz, 2H), 5.38 (s, 2H), 5.50 (s, 1H), 7.06 (d, J=8 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 7.45 (dd, J=8 and 2 Hz, 1H), 7.50-7.63 (m, 2H), 7.99 (d, J=8 Hz, 1H); MS (FAB) m/e (rel intensity) 495 (12), 395 (38), 367 (15), 207 (100), 178 (42); HRMS. Calc'd for M+Li: 495.2808. Found: 495.2771.

EXAMPLE 35

[1223] 93

1,1-dimethylethyl[5-butyl-[1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-3-yl]methylcarbamate

[1224] The slower moving isomer from Example 34 was dissolved in 70 ml of water/acetic acid (1:4) and stirred at ambient temperature overnight. The solvent was removed in vacuo; the residue dissolved in dilute base and washed with toluene. The water layer was acidified to pH 4 with 1N HCl and extracted with ethyl acetate. The ethyl acetate was dried (MgSO4) and removed in vacuo. Lyophilization from acetonitrile/water gave 5.0 g (76%) of 1,1-dimethylethyl[5-butyl-[1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-3-yl]methylcarbamate as a colorless solid: NMR (CDCl3) δ0.77 (t, J=8 Hz, 3H), 1.16-1.30 (m, 2H), 1.40 (s, 9H), 1.42-1.56 (m, 2H), 2.57 (t, J=8 Hz, 2H), 4.12 (d, J=8 Hz, 2H), 5.19 (s, 2H), 5.59 (s, 1H), 6.94 (d, J=8 Hz, 2H), 7.08 (d, J=8 Hz, 2H), 7.43 (dd, J=8 and 2 Hz, 1H), 7.50-7.63 (m, 2H), 7.92 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 495 (29), 367 (38), 338 (21), 207 (100), 178 (48); HRMS. Calc'd for M+Li: 495.2808. Found: 495.2800.

EXAMPLE 36

[1225] 94

3-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-5-methanamine

[1226] Under nitrogen, 219 mg (0.45 mmol) of 1,1-dimethylethyl [3-butyl-[1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-5-yl]methylcarbamate from Example 34 was suspended in 10 ml of 4N HCl in dioxane. After 30 minutes, 10 ml of methylene chloride was added. The mixture was stirred at ambient temperature overnight. The solvent was removed in vacuo. Lyophilization from acetonitrile/water gave 201 mg (100%) of 3-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-5-methanamine as the colorless hydrochloride salt: NMR (CDCl3) δ0.82 (t, J=8 Hz, 3H), 1.21-1.35 (m, 2H), 1.59-1.72 (m, 2H), 2.72 (t, J=8 Hz, 2H), 4.97 (s, 2H), 5.69 (s, 2H), 6.93 (d, J=8 Hz, 2H), 7.23 (d, J=8 Hz, 2H), 7.32 ((d, J=8 Hz, 1H), 7.39 (dt, J=8 and 2 Hz, 1H), 7.51 (dt, J=8 and 2 Hz, 1H), 7.74 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 389 (55), 207 (100), 192 (39), 178 (26); HRMS. Calc'd for M+H: 389.2202. Found: 389.2170.

EXAMPLE 37

[1227] 95

5-[4′-[[3-butyl-5-(2,2-diethyoxyethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1228] Following General Procedure A, 4.7 g (19.5 mmol) of 5-butyl-3-(2,2-diethoxyethyl)-1H-1,2,4-triazole was coupled with 19.5 mmol of the alkylating reagent prepared in step 1 of Example 3. Silica gel chromatography (Waters Prep 500A) using ethyl acetate/hexane (2:3) gave 5.98 g (43%) of a faster moving isomer: NMR (CDCl3) δ0.94 (t, J=8 Hz, 3H), 1.13 (t, J=8 Hz, 6H), 1.33-1.48 (m, 2H), 1.67-1.79 (m, 2H), 2.70 (t, J=8 Hz, 2H), 2.94 (d, J=8 Hz, 2H), 3.39-3.51 (m, 2H), 3.63-3.75 (m, 2H), 4.81 (t, J=7 Hz, 1H), 5.22 (s, 2H), 6.87-6.98 (m, 8H), 7.09 (d, J=8 Hz, 2H), 7.21-7.29 (m, 6H), 7.30-7.37 (m, 4H), 7.41-7.52 (m, 2H), 7.91-7.96 (m, 1H) and 6.3 g (45%) of a slower moving isomer: NMR (CDCl3) δ0.88 (t, J=8 Hz, 3H), 1.15 (t, J=7 Hz, 6H), 1.24-1.37 (m, 2H), 1.56-1.68 (m, 2H), 2.57 (t, J=8 Hz, 2H), 3.06 (d, J=7 Hz, 2H), 3.46-3.60 (m, 2H), 3.66-3.78 (m, 2H), 5.05 (t, J=7 Hz, 1H), 5.14 (s, 2H), 6.87-6.95 (m, 8H), 7.10 (d, J=8 Hz, 2H), 7.21-7.29 (m, 6H), 7.31-7.37 (m, 4H), 7.42-7.53 (m, 2H), 7.90-7.96 (m, 1H). The faster moving isomer was dissolved in 50 ml of acetic acid/water (4:1) and stirred at ambient temperature for 3 days. The solvent was removed in vacuo; the residue dissolve it dilute base and washed with toluene. The water layer was cooled to 0° C., acidified to pH 4-5 and extracted with ethyl acetate. Lyophilization from acetonitrile/water gave 3.8 g (98%) of 5-[4′-[[3-butyl-5-(2,2-diethyoxyethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ0.80 (t, J=8 Hz, 3H), 1.10 (t, J=8 Hz, 6H), 1.10-1.24 (m, 2H), 1.37-1.49 (m, 2H), 2.31 (t, J=8 Hz, 2H), 2.66 (d, J=7 Hz, 2H), 3.34-3.47 (m, 2H), 3.59-3.71 (m, 2H), 4.75 (t, J=7 Hz, 1H), 5.28 (s, 2H), 6.88 (d, J=8 Hz, 2H), 7.06 (d, J=8 Hz, 2H), 7.46 (dd, J=8 and 2 Hz, 1H), 7.55 (dt, J=8 and 2 Hz, 1H), 7.62 (dt, J=8 and 2 Hz, 1H), 7.91 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 476 (20), 430 (28), 356 (13), 235 (15), 207 (100), 192 (67); HRMS. Calc'd for M+H: 476.2773. Found: 476.2723.

EXAMPLE 38

[1229] 96

5-[4′-[[5-butyl-3-(2,2-diethyoxyethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1230] The 6.2 g (8.6 mmol) of the slower moving isomer from Example 37 was dissolved in 50 ml of acetic acid/water (4:1) and stirred at ambient temperature for 3 days. The solvent was removed in vacuo; the residue dissolved in dilute base, and washed with toluene. The water layer was cooled to 0° C., acidified with 1N HCl to pH 4-5, and extracted with ethyl acetate. Lyophilization from acetonitrile/water gave 3.7 g (92%) of 5-[4′-[[5-butyl-3-(2,2-diethyoxyethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as colorless solid: NMR (CDCl3) δ0.85 (t, J=8 Hz, 3H), 1.09 (t, J=8 Hz, 6H), 1.24-1.38 (m, 2H), 1.51-1.63 (m, 2H), 2.55 (t, J=8 Hz, 2H), 2.75 (d, J=7 Hz, 2H), 3.38-3.50 (m, 2H), 3.54-3.66 (m, 2H), 4.87 (t, J=7 Hz, 1H), 5.19 (s, 2H), 6.99 (d, J=8 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 7.42 (dd, J=8 and 2 Hz, 1H), 7.50-7.65 (m, 2H), 7.97 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 476 (3), 430 (28), 235 (10), 207 (100), 192 (61); HRMS. Calc'd for M+H: 476.2773. Found: 476.2760.

EXAMPLE 39

[1231] 97

5-[4′-[(5-butyl-3-ethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1232] Following General Procedure A, 770 mg (5 mmol) of 5-butyl-3-ethyl-1H-1,2,4-triazole was coupled with 2.8 g (5 mmol) of the alkylating reagent prepared in step 1 of Example 3. Silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (2:3) gave 2.24 g (72%) of a mixture of the two isomers which was dissolved in 30 ml of acetic acid/water (9:1) and stirred at ambient temperature for 4 days. The solvent was removed in vacuo; the residue dissolved in dilute base, and washed with toluene. The water layer was acidified to pH 4 and extracted with ethyl acetate. The extracts were combined, dried (MgSO4) and concentrated in vacuo. Purification of a 600 mg sample of the isomeric product mixture by reverse phase chromatography (Waters Delta Prep-3000) using isocratic acetonitrile/water (25:75) (0.05% TFA) provided two isomers. The faster moving isomer was dissolved in dilute base, acidified, extracted with ethyl acetate, dried (MgSO4) and the ethyl acetate removed in vacuo. Lyophilization from acetonitrile/water gave 209 mg of 5-[4′-[(5-butyl-3-ethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ0.88 (t, J=8 Hz, 3H), 1.33-1.40 (m, 2H), 1.38 (t, J=8 Hz, 3H), 1.58-1.70 (m, 2H), 2.67-2.85 (m, 4H), 5.26 (s, 2H), 7.10 (s, 4H), 7.41 (dd, J=8 and 2 Hz, 1H), 7.74-7.62 (m, 2H), 7.86 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 388 (58), 207 (100), 192 (35); HRMS. Calc'd for M+H: 388.2249. Found: 388.2218.

EXAMPLE 40

[1233] 98

5-[4′-[(3-butyl-5-ethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1234] The slower moving isomer from Example 39 was dissolved in dilute base, acidified to pH 3-4, extracted with ethyl acetate, dried (MgSO4), and the ethyl acetate removed in vacuo. Lyophilization from acetonitrile/water gave 188 mg of 5-[4′-[(3-butyl-5-ethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ0.87 (t, J=8 Hz, 3H), 1.16 (t, J=8 Hz, 3H), 1.21-1.35 (m, 2H), 1.52-1.65 (m, 2H), 2.50 (t, J=8 Hz, 2H), 2.67 (q, J=8 Hz, 2H), 5.23 (s, 2H), 7.02 (d, J=8 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 7.43 (dd, J=8 and 2 Hz, 1H), 7.50-7.65 (m, 2H), 7.89 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 388 (35), 207 (100), 192 (47); HRMS. Calc'd for M+H: 388.2249. Found: 388.2222.

EXAMPLE 41

[1235] 99

N2-acetyl-N-[[5-butyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-1,2,4-triazol-3-yl]methyl]-L-glutamine, 1,1-dimethylethyl ester

[1236] Under nitrogen, 30 ml of TFA was added dropwise to a solution of 4.9 g (10 mmol) of 1,1dimethylethyl [5-butyl-[1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-3-yl]methyl]carbamate from Example 35 in 30 ml of methylene chloride at −10° C. (methanol/ice). The mixture was allowed to warm to ambient temperature and stir overnight. The solvent was removed in vacuo giving the TFA salt of the free amine. The TFA salt was dissolved in 35 ml of anhydrous DMF along with 8.7 ml (50 mmol) of anhydrous diisopropyl ethyl amine and treated with 20 mmol of the symmetrical anhydride of N-Boc-γ-glutamic acid t-butyl ester in 55 ml of anhydrous DMF. The reaction was stirred at ambient temperature overnight. The DMF was removed in vacuo; the residue dissolved in ethyl acetate, washed with cold 1M K2CO3 and water. The ethyl acetate was dried (MgSO4) and the solvent removed in vacuo. Under nitrogen, 30 ml of TFA was added dropwise to a solution of this material in 30 ml of methylene chloride at −10° C. (methanol/ice). The reaction was allowed to warm to ambient temperature and stir overnight. The solvent was removed in vacuo giving the TFA salt of the free amine. The TFA salt was dissolved in 30 ml of water and cooled to 0° C. The pH was adjusted to nine with 1M K2CO3. The solution was cooled to 0° C., 0.94 ml (10 mmol) of acetic anhydride was added followed by 5 ml of 1M K2CO3, and the pH was adjusted to 9 with additional 1M K2CO3. At 30 minute intervals, this addition was repeated until 5 additions had been made. The pH was adjusted to 4 with 6N HCl and the solution extracted with ethyl acetate. The ethyl acetate was dried (MgSO4) and removed in vacuo. Purification by silica gel chromatography (Waters Prep 500A) using isopropanol/acetic acid/chloroform (20:5:75) followed by lyophilization from acetonitrile/water gave 2.5 g (41%) of N2-acetyl-N-[[5-butyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-1,2,4-triazol-3-yl]methyl]-L-glutamine, 1,1-dimethylethyl ester as a colorless solid: NMR (CDCl3) δ0.89 (t, J=8 Hz, 3H), 1.27-1.41 (m, 2H), 1.52-1.71 (m, 2H), 1.56 (s, 9H), 2.00 (s, 3H), 2.05-2.29 (m, 2H), 2.31-2.55 (m, 2H), 2.73 (t, J=8 Hz, 2H), 4.48-4.58 (m, 3H), 5.24 (s, 2H), 7.09 (d, J=8 Hz, 2H), 7.17 (d, J=8 Hz, 2H), 7.36-7.42 (m, 1H), 7.44-7.55 (m, 2H), 7.90 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 616 (20), 263 (23), 235 (26), 207 (100); HRMS. Calc'd for M+H: 616.3360. Found: 616.3353.

EXAMPLE 42

[1237] 100

5-[4′-[[3-butyl-5-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1238] Following General Procedure A, 1.2 g (5 mmol) of 5-butyl-3-(2-cyclohexylethyl)-1H-1,2,4-triazole was coupled with 5 mmol of the alkylating reagent prepared in step 1 of Example 3. Silica gel chromatography (Waters Prep 500A) using ethyl acetate/hexane (1:3) gave 3.6 g (100%) of a mixture of the two isomers which was dissolved in 50 ml of acetic acid/water (9:1) and stirred at ambient temperature overnight. The solvent was removed in vacuo; the residue dissolved in dilute base, acidified and washed with ethyl acetate. The ethyl acetate was removed in vacuo. Purification of a small sample of the isomer product mixture by reverse phase chromatography (Water Delta Prep-3000) using isocratic acetonitrile/water (41:59) (0.05% TFA) provided two isomers. The faster moving isomer was dissolved in dilute base, acidified to pH 3-4, extracted with ethyl acetate, dried (MgSO4) and the ethyl acetate removed in vacuo. Lyophilization from acetonitrile/water gave 58 mg of 5-[4′-[[3-butyl-5-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ0.78-0.95 (m, 5H), 1.07-1.40 (m, 6H), 1.48-1.74 (m, 9H), 2.66 (t, J=8 Hz, 2H), 2.78 (t, J=8 Hz, 2H), 5.24 (s, 2H), 7.10 (q, J=8 Hz, 4H), 7.41 (dd, J=8 and 2 Hz, 1H), 7.48-7.63 (m, 2H), 7.89 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 470 (45), 236 (35), 207 (100), 192 (33); HRMS. Calc'd for M+H: 470.3032. Found: 470.2990.

EXAMPLE 43

[1239] 101

5-[4′-[[5-butyl-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1240] The slower moving isomer from Example 42 was dissolved in dilute base, acidified to pH 3-4, extracted with ethyl acetate, dried (MgSO4), and the ethyl acetate removed in vacuo. Lyophilization from acetonitrile/water gave 29 mg of 5-[4′-[[5-butyl-3-(2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ0.95-1.00 (m, 5H), 1.10-1.43 (m, 6H), 1.59-1.77 (m, 9H), 2.83 (t, J=8 Hz, 2H), 2.92 (t, J=8 Hz, 2H), 5.31 (s, 2H), 7.10-7.18 (m, 4H), 7.40 (dd, J=8 and 2 Hz, 1H), 7.47-7.61 (m, 2H), 7.89 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 470 (35), 236 (33), 207 (100), 192 (33); HRMS. Calc'd for M+H: 470.3032. Found: 470.2994.

EXAMPLE 44

[1241] 102

5-[4′-[[5-butyl-3-(phenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1242] Under nitrogen, 0.74 g (2.2 mmol) of N2-[4-[(2-cyanophenyl)phenyl]methyl]phenyl acetic acid hydrazide was dissolved in 5 ml of absolute ethanol and treated with 0.28 g (2.2 mmol) of ethyl iminovalerate. The reaction was stirred at relux for 3 days. The solvent was removed in vacuo, 5 ml of xylene was added and the reaction stirred at reflux under nitrogen for an additional 3 days. The solvent was removed in vacuo. Purification by silica gel chromatography (Chromatatron, 4 mm plate) using a step gradient of ethyl acetate/chloroform gave 410 g (31%) of 5-[4′-[[5-butyl-3-(phenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl-2-yl]nitrile: NMR (CDCl3) δ0.88 (t, J=8 Hz, 3H), 1.27-1.41 (m, 2H), 1.59-1.72 (m, 2H), 2.67 (t, J=8 Hz, 2H), 4.06 (s, 2H), 5.30 (s, 2H), 7.14-7.37 (m, 8H), 7.39-7.50 (m, 3H), 7.53 (dt, J=8 and 2 Hz, 1H), 7.75 (dd, J=8 and 2 Hz, 1H). Under nitrogen, 230 mg (1.13 mmol) of trimethyl tin azide was added to a solution of the nitrile in 5 ml of xylene. The reaction was stirred at reflux for 3 days. The solvent was removed in vacuo and the residue dissolved in 10 ml of acetic acid/water (9:1) and stirred at ambient temperature overnight. The solvent was removed in vacuo. Reverse phase chromatography (Delta Prep 3000) using acetonitrile/water (35-45:65-55) gave the TFA salt. The salt was dissolved in dilute base, acidified to pH 3-4, extracted with ethyl acetate, dried (MgSO4) and the ethyl acetate removed in vacuo. Lyophilization from acetonitrile/water gave 182 mg (45%) of 5-[4′-[[5-butyl-3-(phenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ0.84 (t, J=8 Hz, 3H), 1.22-1.36 (m, 2H), 1.51-1.64 (m, 2H), 2.59 (t, J=8 Hz, 2H), 3.85 (s, 2H), 5.20 (s, 2H), 7.02 (d, J=8 Hz, 2H), 7.14 (d, J=8 Hz, 2H), 7.17-7.28 (m, 5H), 7.43 (dd, J=8 and 2 Hz, 1H), 7.51-7.65 (m, 2H), 7.96 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 450 (56), 207 (100), 192 (30), 178 (22); HRMS. Calc'd for M+H: 450.2406. Found: 450.2434.

EXAMPLE 45

[1243] 103

5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-propanol

[1244] Following General Procedure A, 920 mg (5.0 mmol) of 5-butyl-1H-1,2,4-triazole-3-propanol was coupled with 5.0 mmol of the alkylating reagent prepared in step 1 of Example 3. Silica gel chromatography (Waters Prep 500A) using isopropanol/chloroform (5:95) gave a mixture of the two pure isomers which was dissolved in 40 ml acetic acid/water (9:1) and stirred at ambient temperature for 3 days. The solvent was removed in vacuo. Purification of an aliquot by reverse phase chromatography (Waters Delta Prep 3000) using acetonitrile/water (26:74) (0.05% TFA) provided two isomers. Lyophilization of the faster moving isomer from acetonitrile/water gave 124 mg of 5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-propanol as the colorless FTA salt: NMR (CDCl3) δ0.71 (t, J=8 Hz, 3H), 1.10-1.24 (m, 2H), 1.42-1.54 (m, 2H), 1.70-1.81 (m, 2H), 2.49 (t, J=8 Hz, 2H), 2.60 (t, J=8 Hz, 2H), 3.46 (t, J=6 Hz, 2H), 5.02 (s, 2H), 6.92 (q, J=8 Hz, 4H), 7.24-7.34 (m, 2H), 7.40 (dt, J=8 and 2 Hz, 1H), 7.52 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 418 (100), 207 (48), 184 (10); HRMS. Calc'd for M+H: 418.2355. Found: 418.2370.

EXAMPLE 46

[1245] 104

3-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-1ylmethyl]-1H-1,2,4-triazole-5-propanol

[1246] Lyophilization of the slower moving isomer from Example 45 gave 114 mg of 3-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-1-ylmethyl]-1H-1,2,4-triazole-5-propanol as the colorless TFA salt: NMR (CDCl3) δ0.75 (t, J=8 Hz, 3H), 1.13-1.27 (m, 2H), 1.48-1.60 (m, 2H), 1.64-1.75 (m, 2H), 2.52 (t, J=8 Hz, 2H), 2.66 (t, J=8 Hz, 2H), 3.39 (t, J=6 Hz, 2H), 5.12 (s, 2H), 6.94 (s, 4H), 7.25-7.35 (m, 2H), 7.40 (dt, J=8 and 2 Hz, 1H), 7.52 (d, J=8 Hz, 1H); MS (FAB) m/e (rel intensity) 418 (100), 207 (30); HRMS. Calc'd for M+H: 418.2355. Found: 418.2344.

EXAMPLE 47

[1247] 105

5-[4′-[[5-butyl-3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1248] Following General Procedure A, 470 mg (2.7 mmol) of 5-butyl-3-(difluoromethyl)-1H-1,2,4-triazole was coupled with 2.7 mmol of the alkylating reagent prepared in step 1 of Example 3. Purification by reverse phase chromatography (Waters Delta Prep 3000) using acetonitrile/water (36:64) (0.05% TFA) gave two isomers. The faster moving isomer was dissolved in dilute base, acidified to pH 3-4, extracted with ethyl acetate, dried (MgSO4), and the ethyl acetate removed in vacuo. Lyophilization from acetonitrile/water gave 471 mg (27%) of 5-[4′-[[5-butyl-3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl][1.1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ0.88 (t, J=8 Hz, 3H), 1.28-1.43 (m, 2H), 1.60-1.73 (m, 2H), 2.72 (t, J=8 Hz, 2H), 5.32 (s, 2H), 6.61 (t, J=54 Hz, 1H), 7.12 (d, J=8 Hz, 2H), 7.18 (d, J=8 Hz, 2H), 7.42 (dd, J=8 and 2 Hz, 1H), 7.51-7.65 (m, 2H), 8.00 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 410 (45), 235 (55), 207 (100), 192 (57); HRMS. Calc'd for M+H: 410.1905. Found: 410.1903.

EXAMPLE 48

[1249] 106

5-[4′-[[3-butyl-5-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1250] The slower moving isomer from Example 47 was dissolved in dilute base, acidified, extracted with ethyl acetate, dried (MgSO4), and the ethyl acetate removed in vacuo. Lyophilization from acetonitrile/water gave 104 mg (6%) of 5-[4′-[[3-butyl-5-(difluoromethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ0.91 (t, J=8 Hz, 3H), 1.25-1.41 (m, 2H), 1.60-1.73 (m, 2H), 2.64 (t, J=8 Hz, 2H), 5.43 (s, 2H), 6.81 (t, J=52 Hz, 1H), 7.20 (d, J=8 Hz, 2H), 7.28 (d, J=8 Hz, 2H), 7.43 (dd, J=8 and 2 Hz, 1H), 7.52-7.65 (m, 2H), 8.10 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 410 (87), 235 (100), 207 (83); HRMS. Calc'd for M+H: 410.1905. Found: 410.1903.

EXAMPLE 49

[1251] 107

5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-carboxaldehyde

[1252] A 92 mg sample of 5-[4′-[[5-butyl-3-(dimethoxymethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole from Example 24 was dissolved in 20 ml of ethanol and 2 ml of 3N HCl. The reaction was stirred at ambient temperature for 3 days. The solvent was removed in vacuo. Lyophilization from acetonitrile/water gave 70 mg (81%) of 5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-carboxaldehyde as the colorless hydrochloride salt: NMR (CDCl3) δ0.89 (t, J=8 Hz, 3H), 1.30-1.44 (m, 2H), 1.66-1.78 (m, 2H), 2.78 (t, J=8 Hz, 2H), 5.38 (s, 2H), 7.17 (q, J=8 Hz, 4H), 7.40 (d, J=8 Hz, 1H), 7.50-7.64 (m, 2H), 8.02 (d, J=8 Hz, 1H); MS (FAB) m/e (rel intensity) 388 (36), 235 (42), 207 (100), 192 (50); HRMS. Calc'd for M+Li: 395.2046. Found: 395.2049.

EXAMPLE 50

[1253] 108

5-[4′-[[5-butyl-3-(phenylacetyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1254] Under nitrogen, 7.3 mmol of sec-butyl lithium was added dropwise to 2.0 g (6.1 mmol) of the Sem-protected 5-butyl-3-(dimethoxymethyl)-1H-1,2,4-triazole from Example 30 in 100 ml of anhydrous THF at −78° C. The reaction was stirred for 1 h and then quenched with 0.87 ml (7.3 mmol) of benzyl bromide. The reaction was allowed to warm to ambient temperature and stir overnight. The THF was removed in vacuo; the residue dissolved in methylene chloride, washed with water and dried (MgSO4). The methylene chloride was removed in vacuo. The residue was dissolved in 10 ml of ethanol and 10 ml of 3M HCl and stirred at reflux for 2.5 h. The solvents were removed in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, and dried (MgSO4). Silica gel chromatography (Waters Prep 500A) using ethyl acetate/hexane (35:65) gave 460 mg (31%) of 5-butyl-3-(phenylacetyl)-1H-1,2,4-triazole: NMR (CDCl3) δ0.92 (t, J=8 Hz, 3H), 1.31-1.55 (m, 2H), 1.70-1.83 (m, 2H), 2.88 (t, J=8 Hz, 2H), 4.39 (s, 2H), 7.21-7.38 (m, 5H). Following General Procedure A, 440 mg (1.8 mmol) of this material was reacted with 1.8 mmol of the alkylating reagent prepared in step 1 of Example 3. The crude product was dissolved in 10 ml of acetic acid/water (9:1) and stirred at ambient temperature for 4 days. The solvent was removed in vacuo; the residue dissolved in dilute base and washed with toluene. The water was acidified and extracted with ethyl acetate. Purification by reverse phase chromatography (Waters Delta Prep 3000) using acetonitrile/water (45:55) gave 50 mg (5%) of 5-[4′-[[5-butyl-3-(phenylacetyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as the colorless TFA salt: NMR (DMSO-d6) δ0.86 (t, J=8 Hz, 3H), 1.23-1.38 (m, 2H), 1.52-1.65 (m, 2H), 2.80 (t, J=8 Hz, 2H), 4.32 (s, 2H), 5.52 (s, 2H), 7.11 (d, J=8 Hz, 2H), 7.19 (d, J=8 Hz, 2H), 7.23-7.35 (m, 5H), 7.52-7.63 (m, 2H), 7.65-7.74 (m, 2H); MS (FAB) m/e (rel intensity) 478 (100), 244 (8), 235 (8), 207 (34), 192 (12); HRMS. Calc'd for M+H: 478.2355. Found: 478.2414.

EXAMPLE 51

[1255] 109

5-[4′-[[5-butyl-3-(1,1-difluoro-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-1-yl]-1H-tetrazole

[1256] Under nitrogen, 8.5 g (48 mmol) of 5-butyl-3-(difluoromethyl)-1H-1,2,4-triazole from Example 47 was added in portions to 53 mmol of sodium hydride in 85 ml of anhydrous THF; stirring was continued for 1 h. The anion solution was cooled to 0° C. and treated dropwise with 8.9 ml (50 mmol) of Sem-Cl. The reaction was allowed to warm to ambient temperature and stir overnight. The THF was removed in vacuo; the residue dissolved in methylene chloride, washed with water, and dried (MgSO4). Purification by silica gel chromatography (Waters Prep 500A) using ethyl acetate/hexane (1:9) gave 4.9 g 34% of the Sem-protected triazole as an oil: NMR (CDCl3) δ−0.04 (s, 9H), 0.86-0.95 (m, 5H), 1.39-1.43 (m, 2H), 1.65-1.76 (m, 2H), 2.71 (t, J=8 Hz, 2H), 3.62 (t, J=8 Hz, 2H), 5.53 (s, 2H), 6.82 (t, J=52 Hz, 1H). Under nitrogen, 14.2 mmol of sec-butyllithium was added dropwise to 3.6 g (11.8 mmol) of the Sem-protected triazole in 200 ml of anhydrous THF at −78° C. The reaction was allowed to stir for 1 h prior to the addition of 1.7 ml (14.2 mmol) of benzyl bromide. After stirring at −78° C. for 2 h, the reaction was allowed to warm to ambient temperature and stir overnight. The solvent was removed in vacuo; the residue dissolved in methylene chloride, washed with water, and dried (MgSO4). Silica gel chromatography (Waters Prep 500A) using ethyl acetate/hexane (5:95) gave 600 mg (10%) of the Sem protected 5-butyl-3-(1,1-difluoro-2-phenylethyl)-1H-1,2,4-triazole: NMR (CDCl3) δ−0.04 (s, 9H), 0.85 (t, J=8 Hz, 2H), 0.94 (t, J=8 Hz, 3H), 1.30-1.44 (m, 2H), 1.67-1.79 (m, 2H), 2.73 (t, J=8 Hz, 2H), 3.54 (t, J=8 Hz, 2H), 3.70 (t, J=16 Hz, 2H), 5.34 (s, 2H), 7.21-7.31 (m, 5H). The Sem protected triazole was dissolved in 5 ml of ethanol and 5 ml of 3M HCl and allowed to stir at reflux for 3 h. The ethanol was removed in vacuo and the pH adjusted to nine with dilute sodium hydroxide. The resulting solution was extracted with methylene chloride; the extracts were combined, dried (MgSO4), and concentrated in vacuo to provide 5-butyl-3-(1,1-difluoro-2-phenethyl-1H-1,2,4-triazole. Following General Procedure A, 1.4 mmol of this material was coupled with 1.4 mmol of the alkylating reagent prepared in step 1 of Example 3. The crude product was dissolved in 10 mL of acetic acid/water (9:1) and stirred at ambient temperature for 3 days. The solvent was removed in vacuo; the residue dissolved in dilute base and washed with toluene. The water was acidified to pH 3-4, extracted with ethyl acetate, and dried (MgSO4). Purification by reverse phase chromatography (Waters Delta Prep 3000) using acetonitrile/water (47:53) (0.05% TFA) gave the TFA salt. The salt was dissolved in dilute base, acidified to pH 3-4, extracted with ethyl acetate, and dried (MgSO4). Lyophilization from acetonitrile/water gave 290 mg (42%) of 5-[4′-[[5-butyl-3-(1,1-difluoro-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-1-yl]-1H-tetrazole: NMR (CDCl3) δ0.86 (t, J=8 Hz, 3H), 1.21-1.36 (m, 2H), 1.54-1.68 (m, 2H), 2.64 (t, J=8 Hz, 2H), 3.57 (t, J=16 Hz, 2H), 5.23 (s, 2H), 6.92 (d, J=8 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 7.16-7.25 (m, 5H), 7.39 (dd, J=8 and 2 Hz, 1H), 7.50-7.65 (m, 2H), 7.99 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 500(100), 266 (6), 235 (8), 207 (25), 192 (8); HRMS. Calc'd for M+H: 500.2374. Found: 500.2358.

EXAMPLE 52

[1257] 110

5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-carboxylic acid

[1258] A 3.36 g (7.1 mmol) sample of 5-[4′-[[5-butyl-3-(2,2-diethyoxyethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole from Example 38 was dissolved in 15 ml of ethanol and 15 ml of 3M HCl. The reaction was stirred at ambient temperature overnight and then at reflux for 2 h. The solvent was removed in vacuo, the residue dissolved in 15 ml of THF and 15 ml of 3M HCl and stirred for 3 days at ambient temperature. The solvent was removed in vacuo; the residue dissolved in dilute base, acidified and extracted with ethyl acetate and methylene chloride. The solvents were combined and dried (MgSO4). The solvents were removed in vacuo. The residue was dissolved in 70 ml of acetone and 35 ml of water. Potassium permanganate was added in 4 equal portions of 190 mg after each preceeding portion had reacted. The mixture was filtered through celite and the solvent removed in vacuo. Purification by reverse phase chromatography (Waters Delta Prep 3000) gave 88 mg (7%) of 5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-carboxylic acid as the colorless TFA salt after lyophilization from acetonitrile/water: NMR (DMSO-d6) δ0.85 (t, J=8 Hz, 3H), 1.23-1.38 (m, 2H), 1.52-1.62 (m, 2H), 2.78 (t, J=8 Hz, 2H), 5.46 (s, 2H), 7.13 (q, J=8 Hz, 4H), 7.51-7.62 (m, 2H), 7.64-7.73 (m, 2H); MS (FAB) m/e (rel intensity) 404 (100), 235 (20), 207 (91), 192 (24); HRMS. Calc'd for M+H: 404.1835. Found: 404.1882.

EXAMPLE 53

[1259] 111

5-[4′-[(5-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1260] Following general procedure A , 630 mg (5 mmol) of 3-butyl-1H-1,2,4-triazole was reacted with 5 mmol of the alkylating reagent prepared in step 1 of Example 3 to give 2.3 g (76%) of a mixture of the two isomers. Deprotection of the faster isomer provided 5-[4′-[(5-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]1H-tetrazole: NMR (CDCl3) δ0.87 (t, J=8 Hz, 3H), 1.35-1.41 (m, 2H), 1.59-1.72 (m, 2H), 2.72 (t, J=8 Hz, 2H), 5.30 (s, 2H), 7.09 (d, J=8 Hz, 2H), 7.17 (d, J=8 Hz, 2H), 7.44 (dd, J=8 and 2 Hz, 1H), 7.52-7.66 (m, 2H), 7.72 (s, 1H), 8.01 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 360 (88), 235 (20), 207 (100),192 (31), 178 (22); HRMS. Calc'd for M+H: 360.1936. Found: 360.1938.

EXAMPLE 54

[1261] 112

5-[4′-[(3-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1262] The slower moving isomer from Example 53 was deprotected to provide 5-[4′-[(3-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole: NMR (CDCl3) δ0.74 (t, J=8 Hz, 3H), 1.19-1.33 (m, 2H), 1.51-1.63 (m, 2H), 2.55 (t, J=8 Hz, 2H), 5.23 (s, 2H), 7.10 (q, J=8 Hz, 4H), 7.44 (dd, J=8 and 2 Hz, 1H), 7.50-7.64 (m, 2H), 7.92 (dd, J=8 and 2 Hz, 1H), 8.02 (s, 1H); MS (FAB) m/e (rel intensity) 360 (84), 135 (18), 207 (100), 192 (26), 178 (16), 126 (22); HRMS. Calc'd for M+H: 360.1936. Found: 360.1971.

EXAMPLE 55

[1263] 113

5-[4′-[[3-butyl-5-(tricyclo[3.3.13.7]dec-1-yl]-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1264] Following general procedure A, 1.3 g (5.0 mmol) of 5-butyl-3-adamantyl-1H-1,2,4-triazole was reacted with 5.0 mmol of the alkylating reagent prepared in step 1 of Example 3 to give 2.94 g (72%) of a mixture of the two isomers. Deprotection of the faster moving isomer provided 5-[4′-[[3-butyl-5-(tricyclo[3.3.13.7]dec-1-yl]-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole: NMR (CDCl3) δ0.90 (t, J=8 Hz, 3H), 1.27-1.41 (m, 2H), 1.42-1.55 (m, 3H), 1.58-1.73 (m, 5H), 1.76-1.91 (m, 9H), 2.28-2.43 (m, 2H), 5.42 (s, 2H), 6.72-6.83 (m, 2H), 7.07 (d, J=8 Hz, 2H), 7.45-7.66 (m, 3H), 7.88 (t, J=8 Hz, 1H); MS (FAB) m/e (rel intensity) 494 (100), 260 (37), 207 (74), 178 (22); HRMS. Calc'd for M+H: 494.3032. Found: 494.3014.

EXAMPLE 56

[1265] 114

5-[4′-[[-5-butyl-3-(tricyclo]3.3.1.13.7]dec-1-yl]-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1266] The slower moving isomer from Example 55 was deprotected to provide 5-[4′-[[5-butyl-3-(tricyclo[3.3.1.13.7]dec-1-yl]-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl1-1H-tetrazole: NMR (CDCl3) δ0.87 (t, J=8 Hz, 3H), 1.31-1.47 (m, 2H), 1.52-1.71 (m, 9H), 1.78 (s, 7H), 1.88 (s, 3H), 2.20-2.35 (m, 2H), 5.22 (s, 2H), 6.87 (d, J=8 Hz, 2H), 7.13 (d, J=8 Hz, 2H), 7.42 (dd, J=8 and 2 Hz, 1H), 7.49-7.63 (m, 2H), 7.93 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 494 (73), 451 (10), 260 (24), 207 (66), 178 (21); HRMS. Calc'd for M+H: 494.3032. Found: 494.3026.

EXAMPLE 57

[1267] 115

5-[4′-[[3-butyl-5-(3-cyclohexylpropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1268] Following general procedure A, 1.25 g (5 mmol) of 5-butyl-3-(3-cyclohexylpropyl)-1H-1,2,4-triazole was reacted with 5 mmol of the alkylating reagent prepared in step 1 of Example 3 to give 3.1 g (85%) of a mixture of the two isomers. Deprotection of the faster moving isomer provided 5-[4′-[[3-butyl-5-(3-cyclohexylpropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole: NMR (CDCl3) δ0.73-0.92 (m, 2H), 0.87 (t, J=8 Hz, 3H), 1.06-1.21 (m, 6H), 1.22-1.36 (m, 2H), 1.53-1.71 (m, 9H), 2.51 (t, J=8 Hz, 2H), 2.61 (t, J=8 Hz, 2H), 5.22 (s, 2H), 7.01 (d, J=8 Hz, 2H), 7.12 (d, J=8 Hz, 2H), 7.42 (dd, J=8 and 2 Hz, 1H), 7.51-7.64 (m, 2H), 7.94 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 484 (83), 250 (38), 207 (100), 178 (25); HRMS. Calc'd for M+H: 484.3189. Found: 484.3223.

EXAMPLE 58

[1269] 116

5-[4′-[[5-butyl-3-(3-cyclohexylpropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1270] The slower moving isomer from Example 57 was deprotected to provide 5-[4′-[[5-butyl-3-(3-cyclohexylpropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole: NMR (CDCl3) δ0.74-0.90 (m, 2H), 0.83 (t, J=8 Hz, 3H), 1.05-1.22 (m, 6H), 1.23-1.35 (m, 2H), 1.50-1.70 (m, 9H), 2.40 (t, J=8 Hz, 2H), 2.57 (t, J=8 Hz, 2H), 5.20 (s, 2H), 6.96 (d, J=8 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 7.43 (dd, J=8 and 2 Hz, 2H), 7.50-7.64 (m, 2H), 7.92 (dd, J=8 and 2 Hz, 2H); MS (FAB) m/e (rel intensity) 484 (65), 250 (26), 207 (100), 178 (18); HRMS. Calc'd for M+H: 484.3189. Found: 484.3181.

EXAMPLE 59

[1271] 117

5-[4′-[[5-butyl-3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1272] Following general procedure A, 790 mg (5.0 mmol) of 5-butyl-3-(fluoromethyl)-1H-1,2,4-triazole was reacted with 5 mmol of the alkylating reagent prepared in step 1 of Example 3 to give 1.3 g (42%) of a mixture of the two isomers. Deprotection of the faster moving isomer provided 5-[4′-[[5-butyl-3-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole: NMR (CDCl3) δ0.86 (t, J=8 Hz, 3H), 1.26-1.40 (m, 2H), 1.56-1.69 (m, 2H), 2.67 (t, J=8 Hz, 2H), 5.16 (s, 1H), 5.27 (s, 2H), 5.32 (s, 1H), 7.06 (d, J=8 Hz, 2H), 7.16 (d, J=8 Hz, 2H), 7.43 (dd, J=8 and 2 Hz, 1H), 7.52-7.65 (m, 2H), 7.99 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 392 (100), 235 (22), 207 (66), 192 (18), 178 (14); HRMS. Calc'd for M+H: 392.1999. Found: 392.1932.

EXAMPLE 60

[1273] 118

5-[4′-[[3-butyl-5-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl -1H-tetrazole

[1274] The slower moving isomer from Example 59 was deprotected to provide 5-[4′-[[3-butyl-5-(fluoromethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole: NMR (CDCl3) δ0.89 (t, J=8 Hz, 3H), 1.24-1.40 (m, 2H), 1.59 (m, 2H), 2.65 (t, J=8 Hz, 2H), 5.38 (s, 3H), 5.55 (s, 1H), 7.21 (s, 4H), 7.43 (d, J=8 Hz, 1H), 7.51-7.65 (m, 2H), 8.05 (d, J=8 Hz, 1H); MS (FAB) m/e (rel intensity) 392 (90), 235 (56), 207 (100), 192 (51), 178 (24); HRMS. Calc'd for M+H: 392.1999. Found: 392.1944.

EXAMPLE 61

[1275] 119

5-[4′-[[3-butyl-5-(tricyclo[3.3.1.13.7]dec-1-ylmethyl]-1H-1,2,4-triazole-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1276] Following general procedure A, 1.4 g (5.0 mmol) of 5-butyl-3-adamantyl-1H-1,2,4-triazole was reacted with 5.0 mmol of the alkylating reagent prepared in step 1 of Example 3 to give a mixture of the two isomers. Deprotection of the faster moving isomer provided 5-[4′-[[3-butyl-5-(tricyclo[3.3.1.13.7]dec-1-ylmethyl]-1H-1,2,4-triazole-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole: NMR (CDCl3) δ0.84 (t, J=8 Hz, 3H), 1.16-1.30 (m, 2H), 1.41 (s, 6H), 1.44-1.56 (m, 5H), 1.65 (d, J=12 Hz, 3H), 1.92 (s, 3H), 2.18 (s, 2H), 2.30 (t, J=8 Hz, 2H), 5.18 (s, 2H), 6.79 (d, J=8 Hz, 2H), 7.01 (d, J=8 Hz, 2H), 7.46 (d, J=8 Hz, 1H), 7.52 (m, 2H), 7.85 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 508 (45), 274 (25), 207 (100), 192 (31); HRMS. Calc'd for M+H: 508.3189. Found: 508.3162.

EXAMPLE 62

[1277] 120

5-[4′-[[5-butyl-3-(tricyclo[3.3.1.13.7]dec-1-ylmethyl]-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1278] The slower moving isomer from Example 61 was deprotected to provide 5-[4′-[[5-butyl-3-(tricyclo[3.3.1.13.7]dec-1-ylmethyl]-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole: NMR (CDCl3) δ0.85 (t, J=8 Hz, 3H), 1.21-1.37 (m, 8H), 1.44-1.58 (m, 5H), 1.62 (d, J=10 Hz, 3H), 1.86 (s, 3H), 2.07 (s, 2H), 2.49 (t, J=8 Hz, 2H), 5.21 (s, 2H),6.89 (d, J=8 Hz, 2H), 7.07 (d, J=8 Hz, 2H), 7.53 (dd, J=8 and 2 Hz, 1H), 7.52-7.65 (m, 2H), 7.91 (dd, J=8 and 2 Hz, 1H), MS (FAB) m/e (rel intensity) 508 (42), 274 (22), 207 (100), 192 (34); HRMS. Calc'd for M+H: 508.3189. Found: 508.3142.

EXAMPLE 63

[1279] 121

5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-propanoic acid

[1280] A 2.18 g sample of the mixture of the two isomers from Example 45 was oxidized to the corresponding aldehydes with oxalyl chloride/dimethyl sulfoxide and subsequently oxidized to the acids with potassium permanganate to give 1.8 g of a mixture of the two propanoic isomers. Deprotection of the faster moving isomer provided 5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-propanoic acid: NMR (CDCl3) δ0.99 (t, J=8 Hz, 3H), 1.28-1.43 (m, 2H), 1.61-1.74 (m, 2H), 2.67-2.80 (m, 4H), 2.94 (t, J=6 Hz, 2H), 5.18 (s, 2H), 7.04-7.14 (m, 4H), 7.42 (dd, J=8 and 2 Hz, 1H), 7.50 (dt, J=8 and 2 Hz, 1H), 7.59 (dt, J=8 and 2 Hz, 1H), 7.90 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 432 (89), 389 (15), 237 (36), 198 (100); HRMS. Calc'd for M+H: 432.2148. Found: 432.2216.

EXAMPLE 64

[1281] 122

3-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-5-propanoic acid

[1282] The slower moving isomer from Example 63 was deprotected to give 3-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-5-propanoic acid: NMR (CDCl3) δ0.92 (t, J=8 Hz, 3H), 1.30-1.40 (m, 2H), 1.65-1.78 (m, 2H), 2.70 (t, J=8 Hz, 2H), 2.84-2.91 (m, 2H), 2.93-3.00 (m, 2H), 5.40 (s, 2H), 7.20 (d, J=8 Hz, 2H), 7.34 (d, J=8 Hz, 2H), 7.37-7.42 (m, 1H), 7.51-7.62 (m, 2H), 8.30-8.36 (m, 1H); MS (FAB) m/e (rel intensity) 432 (100) 198 (45); HRMS. Calc'd for M+H: 432.2148. Found: 432.2214.

EXAMPLE 65

[1283] 123

5-[4′-[(3-butyl-5-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1284] Following General Procedure A, 2.07 g (10 mmol) of 3-butyl-5-cyclohexyl-1H-1,2,4-triazole was reacted with 6.5 g (11.8 mmol) of the alkylating reagent prepared in step 1 of Example 3 to give 6.3 g (9.2 mmol) of a mixture of the two isomers. Deprotection of the faster moving isomer provided 33 mg of 5-[4′-[(3-butyl-5-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-1,2,4-triazole as a colorless solid: mp 157.5-159.5° C.; NMR (CDCl3) δ0.87 (t, J=7 Hz, 3H), 1.11-1.36 (m, 6H), 1.45-1.70 (m, 6H), 1.70-1.80 (m, 2H), 2.50 (t, J=7 Hz, 2H), 2.64-2.78 (m, 1H), 5.23 (s, 2H), 6.98 (d, J=8 Hz, 2H), 7.08 (d, J=8 Hz, 2H), 7.41 (dd, J=5 and 1 Hz, 1H), 7.49 (dt, J=5 and 1 Hz, 1H), 7.57 (dt, J=5 and 1 Hz, 1H), 7.80 (dd, J=5 and 1 Hz, 1H): MS (FAB) m/e (rel intensity), 442 (100), 414 (10), 399 (20), 235 (8), 207 (65), 192 (18).

EXAMPLE 66

[1285] 124

5-[4′-[(5-butyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1286] The slower moving isomer from Example 65 was deprotected to provide 135 mg of 5-[4′-[(5-butyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: mp 125-127° C.; NMR (CDCl3) δ0.85 (t, J=7 Hz, 3H), 1.12-1.40 (m, J=8 Hz, 8H), 1.52-1.75 (m, J=8 Hz, 4H), 1.81 (d, J=8 Hz, 2H), 2.50 (t, J=8 Hz, 3H), 5.20 (s, 2H), 6.94 (d, J=8 Hz, 2H), 7.09 (d, J=8 Hz, 2H), 7.42 (dd, J=8 and 2 Hz, 1H), 7.50-7.64 (m, J=8 Hz, 2H), 7.88 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 442 (100), 414 (10), 399 (20), 235 (10), 207 (75), 192 (17).

EXAMPLE 67

[1287] 125

1,1-dimethylethyl 3-butyl-[1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-5-yl]propylcarbamate

[1288] Following General Procedure A, 6.0 g (20 mmol) of 3-butyl-5-(N-Boc-3-aminopropyl)-1H-1,2,4-triazole was reacted with 13.1 g (24 mmol) of the alkylating reagent prepared in step 1 of Example 3. Deprotection of the faster moving isomer gave 3.52 g (33%) of 1,1-dimethylethyl 3-butyl-[1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-5-yl]propylcarbamate as a colorless solid: NMR (DMSO-d6) δ0.88 (t, J=8 Hz, 3H), 1.22-1.34 (m, J=8 Hz, 2H), 1.36 (s, 9H), 1.54-1.66 (m, J=7 Hz, 2H), 1.66-1.78 (m, J=7 Hz, 2H), 2.5 (t, J=8 Hz, 2H), 2.67 (t, J=8 Hz, 2H), 2.96 (q, J=8 Hz, 2H), 5.26 (s, 2H), 7.08 (s, 4H), 7.55 (q, J=8 Hz, 2H), 7.65 (d, J=8 Hz, 2H); MS (FAB) m/e (rel intensity) 517 (60), 489 (10), 461 (10), 439 (10), 417 (23), 389 (18), 357 (8), 323 (8), 305 (15), 283 (80), 227 (70), 207 (100), 183 (65); HRMS. Calc'd for M+H: 517.3039. Found 517.3001.

EXAMPLE 68

[1289] 126

1,1-dimethylethyl 5-butyl-[1-[2′-(1H-tetrazol-5yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-3-yl]propylcarbamate

[1290] The slower moving isomer from Example 67 was deprotected to give 3.43 g (33%) of 1,1-dimethylethyl 5-butyl-[1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-3-yl]propylcarbamate as a colorless solid: NMR (DMSO-d6) δ0.84 (t, J=7 Hz, 3H), 1.29 (q, J=8 Hz, 2H), 1.38 (s, 9H), 1.48-1.59 (m, J=8 Hz, 2H), 1.72 (t, J=8 Hz, 2H), 2.53 (t, J=7 Hz, 2H), 2.67 (t, J=8 Hz, 2H), 2.97 (q, J=8 Hz, 2H), 5.28 (s, 2H), 7.08 (s, 4H), 7.50 (d, J=8 Hz, 1H) 7.55 (d, J=8 Hz, 1H), 7.61-7.68 (m, J=7 Hz, 2H); MS (FAB) m/e (rel intensity) 517 (40), 439 (10) 417 (40), 390 (20), 357 (10), 207 (100), 192 (40); HRMS. Calc'd for M+H: 517.3039. Found: 517.3014.

EXAMPLE 69

[1291] 127

5-[4′-[[3-(1,1,2,2,2,-pentafluoroethyl)-5-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazol

[1292] Following General Procedure A, 1.21 g (5.0 mmol) of 3-perfluoroethyl-5-butyl-1H-1,2,4-triazole was reacted with 3.2 g (5.7 mmol) of the alkylating reagent prepared in step 1 of Example 3. Deprotection provided 409 mg of 5-[4′-[[3-(1,1,2,2,2-pentafluoroethyl)-5-butyl-1H-1,2,4-triazol-1-yl]methyl[1,1-biphenyl]-2-yl]-1H-tetrazole as a colorless oil: NMR (CDCl3) δ0.90 (t, J=7 Hz, 3H), 1.36 (q, J=7 Hz, 2H), 1.67 (t, J=7 Hz, 2H), 2.78 (t, J=7 Hz, 2H), 5.38 (s, 2H), 7.18 (s, 4H), 7.42 (d, J=8 Hz, 1H), 7.51-7.67 (m, J=8 Hz, 2H), 7.98 (d, J=8 Hz, 1H); MS (FAB) m/e (rel intensity) 478 (40), 452 (15), 235 (90), 207 (100), 178 (40), 152 (35); HRMS. Calc'd. for M+H: 478.1778. Found: 478.1807.

EXAMPLE 70

[1293] 128

5-[4′-[[3-(1,2,2,3,3,3-heptafluoropropyl)-5-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1294] Following General Procedure A, 1.46 g (5.0 mmol) of 5-butyl-3-perfluoropropyl-1H-1,2,4-triazole was reacted with 3.20 g (5.7 mmol) of the alkylating reagent prepared in step 1 of Example 3. Deprotection provided 210 mg of 5-[4′-[[3-(1,1,2,2,3,3,3-heptafluoropropyl)-5-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless oil: NMR (CDCl3) δ0.90 (t, J=7 Hz, 3H), 1.36 (q, J=8 Hz, 2H), 1.63-1.75 (m, J=8 Hz, 2H), 2.78 (t, J=8 Hz, 2H), 5.40 (s, 2H), 7.20 (q, J=7 Hz, 4H), 7.42 (dd, J=8 and 2 Hz, 1H), 7.52-7.65 (m, J=8 Hz, 2H), 8.04 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 528 (35), 502 (15), 294 (12), 235 (90), 207 (100), 136 (15); HRMS. Calc'd for M+H: 528.1747. Found: 528.1701.

EXAMPLE 71

[1295] 129

5-[4′-[[3-butyl-5-(3-aminopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1296] Under a static nitrogen atmosphere 2.40 g (4.7 mmol) of 5-[4′-[[3-butyl-5-(N-Boc-3-aminopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole from Example 67 was dissolved in 30 mL of 4N HCl in dioxane at ambient temperature and allowed to stir overnight. The solvents were removed in vacuo; the residue was triturated with diethyl ether and filtered providing 2.08 g (98%) of 5-[4′-[[3-butyl-5-(3-aminopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as the hydrochloride salt: NMR (DMSO-d6) δ0.88 (t, J=7 Hz, 3H), 1.25-1.39 (m, 2H), 1.57-1.69 (m, 2H), 1.92-2.40 (m, 2H), 2.62 (t, J=7 Hz, 2H), 2.89 (q, J=8 Hz, 2H), 2.98 (t, J=8 Hz, 2H), 5.38 (s, 2H), 7.10 (d, J=8 Hz, 2H), 7.19 (d, J=8 Hz, 2H), 7.54 (d, J=8 Hz, 1H), 7.59 (dd, J=8 and 2 Hz, 1H), 7.66 (s, 1H), 7.70 (dd, J=8 and 2 Hz, 1H), 8.10 (br s, 2H); MS (FAB) m/e (rel intensity) 417 (38), 389 (10), 357 (10), 207 (100), 166 (50), 139 (10) 115 (10); HRMS. Calc'd for M+H: 417.2515. Found: 417.2563.

EXAMPLE 72

[1297] 130

5-[4′-[[3-(3-aminopropyl)-5-butyl-1H-1,2,4-triazol-1-yl)methyl](1,1′-biphenyl)-2-yl]-1H-tetrazole

[1298] Under a-static nitrogen atmosphere 2.30 g (4.5 mmol) of 5-[4′-[[3-(N-Boc-3-aminopropyl)-5-butyl-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole from Example 68 was dissolved in 30 mL of 4N HCl in dioxane at ambient temperature and allowed to stir overnight. The solvents were removed in vacuo; the residue was triturated with diethyl ether and filtered providing 1.99 g (98%) of 5-[4′-[[3-(3-aminopropyl)-5-butyl-1H-1,2,4-triazol-1-yl]methyl](1,1′-biphenyl)-2-yl]-1H-tetrazole as the hydrochloride salt: NMR (DMSO-d6) δ0.85 (t, J=7 Hz, 3H), 1.22-1.38 (m, 2H), 1.59 (t, J=8 Hz, 2H), 1.96 (t, J=8 Hz, 2H), 2.71-2.79 (m, 2H) 2.80-2.92 (m, 4H), 5.40 (s, 2H) 7.10 (d, J=8 Hz, 2H), 7.18 (d, J=8 Hz, 2H) 7.52 (d, J=8 Hz, 1H), 7.59 (d, J=8 Hz, 1H), 7.68 (d, J=8 Hz, 2H); MS (FAB) m/e (rel intensity) 417 (60), 389 (10), 357 (10), 263 (5), 235 (10), 207 (100), 166 (40), 136 (15); HRMS. Calc'd for M+H: 417.2515. Found: 417.2510.

EXAMPLE 73

[1299] 131

5-[4′-[(3-butyl-5-cyclohexylmethyl-1H-1,2,4-triazol-1-yl-)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1300] Following General Procedure A, 2.21 g (10.0 mmol) of 3-butyl-5-cyclohexylmethyl-1H-1,2,4-triazole was reacted with 6.55 g (11.8 mmol) of the alkylating reagent prepared in step 1 of Example 3 to give 5.90 g (85%) of a mixture of the two isomers. The faster moving isomer was deprotected to provide 64 mg of 5-[4′-[(3-butyl-5-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ0.92 (t, J=7 Hz, 3H) 0.94-1.05 (m, 2H) 1.08-1.25 (m, 3H), 1.25-1.41 (m, 2H), 1.55-1.80 (m, 8H), 2.65 (d, J=7 Hz, 2H), 2.68 (t, J=7 Hz, 2H), 5.27 (s, 2H), 7.11 (q, J=8 Hz, 4H), 7.42 (dd, J=8 and 2 Hz, 1H), 7.49-7.63 (m, 2H), 7.94 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 456 (100), 428 (10), 413 (20), 280 (10), 235 (10), 222 (25), 207 (80), 192 (30); HRMS. Calc'd for M+H: 456.2876. Found: 456.2839.

EXAMPLE 74

[1301] 132

5-[4′-[(3-cyclohexylmethyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1302] The slower moving isomer from Example 73 was deprotected to provide 51 mg of 5-[4′-[(3-cyclohexylmethyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ0.84 (t, J=8 Hz, 3H), 0.92 (q, J=8 Hz, 2H), 1.05-1.22 (m, 3H), 1.22-1.36 (m, 2H), 1.52-1.69 (m, 8H), 2.50 (d, J=7 Hz, 2H), 2.63 (t, J=8 Hz, 2H), 5.18 (s, 2H), 7.05 (q, J=8 Hz, 4H), 7.35-7.55 (m, 3H), 7.68 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 456 (90), 413 (10), 281 (10), 243 (10), 222 (35), 207 (100), 192 (35); HRMS. Calc'd for M+H: 456.2876. Found: 456.2849.

EXAMPLE 75

[1303] 133

4′-[(3-ethyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid

[1304] Following General Procedure A, 1.0 g (6.0 mmol) of 3-ethyl-5-butyl-1H-1,2,4-triazole was reacted with 2.41 g (7.9 mmol) of the alkylating reagent prepared in step 1 of Example 1. Hydrolysis of the faster moving isomer provided 220 mg of 4′-[(3-ethyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid as a colorless solid: NMR (DMSO-d6) δ0.85 (t, J=7 Hz, 3H), 1.19 (t, J=7 Hz, 3H), 1.27-1.38 (m, 2H), 1.52-1.63 (m, 2H), 2.59 (q, J=7 Hz, 2H), 2.74 (t, J=7 Hz, 2H), 5.35 (s, 2H), 7.21 (d, J=8 Hz, 2H), 7.31 (d, J=8 Hz, 2H), 7.35 (dd, J=8 and 2 Hz, 1H), 7.48 (dt, J=8 and 2 Hz, 1H), 7.57 (dt, J=8 and 2 Hz, 1H), 7.72 (dd, J=8 and 2 Hz, 1H).

EXAMPLE 76

[1305] 134

4′-[(3-butyl-5-ethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid

[1306] The slower moving isomer from Example 75 was hydrolyzed to provide 174 mg of 4′-[(3-butyl-5-ethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid as a colorless solid: NMR (DMSO-d6) δ0.89 (t, J=7 Hz, 3H), 1.17 (t, J=7 Hz, 3H), 1.27-1.40 (m, 2H), 1.56-1.68 (m, 2H), 2.58 (t, J=8 Hz, 2H), 2.77 (q, J=8 Hz, 2H), 5.35 s, 2H), 7.21 (d, J=8 Hz, 2H), 7.32 (d, J=8 Hz, 2H), 7.36 (dd, J=8 and 2 Hz, 1H), 7.46 (dt, J=8 and 2 Hz, 1H), 7.57 (dt, J=8 and 2 Hz, 1H), 7.73 (dd, J=8 and 2 Hz, 1H).

EXAMPLE 77

[1307] 135

4′-[(3-butyl-5-methyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid

[1308] Following General Procedure A, 1.0 g (7.2 mmol) of 3-butyl-5-methyl-1H-1,2,4-triazole was reacted with 2.89 g (9.5 mmol) of the alkylating reagent prepared in step 1 of Example 1. Hydrolysis of the slower moving isomer provided 220 mg of 4′-[(3-butyl-5-methyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid as a colorless solid: NMR (DMSO-d6) δ0.88 (t, J=7 Hz, 3H), 1.25-1.38 (m, 2H), 1.54-1.67 (m, 2H), 2.39 (s, 3H), 2.54 (t, J=8 Hz, 2H), 5.32 (s, 2H), 7.21 (d, J=8 Hz, 2H), 7.32 (d, J=8 Hz, 2H), 7.36 (dd, J=8 and 2 Hz, 1H), 7.46 (dt, J=8 and 2 Hz, 1H), 7.56 (dt, J=8 and 2 Hz, 1H), 7.72 (dd, J=8 and 2 Hz, 1H).

EXAMPLE 78

[1309] 136

4′-[(3-methyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid

[1310] The faster moving isomer from Example 77 was hydrolyzed to provide 19 mg of 4′-[(3-methyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid as a colorless solid: NMR (DMSO-d6) δ0.86 (t, J=7 Hz, 3H), 1.25-1.38 (m, 2H), 1.52-1.64 (m, 2H), 2.21 (s, 3H), 2.72 (t, J=7 Hz, 2H), 5.32 (s, 2H), 7.21 (d, J=8 Hz, 2H), 7.32 (d, J=8 Hz, 2H), 7.35 (dd, J=8 and 2 Hz, 1H), 7.45 (dt, J=8 and 2 Hz, 1H), 7.57 (dt, J=8 and 2 Hz, 1H), 7.72 (dd, J=8 and 2 Hz, 1H).

[1311] A class of highly preferred specific conjugates of the invention is provided by conjugates formed from a biphenylmethyl 1H-substituted-1,2,4-triazole AII antagonist compound linked to a cleavable glutamyl residue. Each conjugate of this class contains a diamino linker moiety which connects a terminal carboxylic acid moiety on the biphenylmethyl portion of the AII antagonist compound with a terminal carboxylic acid moiety on the gamma carbon of the cleavable glutamyl residue. Example #79 is a detailed description of a conjugate of this class. Other specific conjugates of Examples #80-#144, as shown in Table IV, may be prepared generally in accordance with the procedures of Example #79.

EXAMPLE 79

[1312] 137

N-acetylglutamic acid, 5-[[4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]]carbonylhydrazide

[1313] To a solution of 10.45 g (34.5 mmol) of N-Boc-L-glutamic acid-α-tertbutyl ester (BACHEM) in 100 mL of methylene chloride under nitrogen was added 3.5 g (17.0 mmol) of solid dicyclohexylcarbodiimide (DCC). The reaction was allowed to stir for 2 h and filtered under nitrogen. The anhydride solution was then added to a solution of 6.03 g (14.9 mmol) of the compound of Example 4 in 75 mL of methylene chloride under nitrogen. The reaction was stirred overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate gave 7.90 g (77%) of pure material by thin-layer chromatography (TLC). This material was redissolved in 100 mL of methylene chloride under nitrogen and cooled to 0° C. prior to the addition of 135 mL of TFA. The stirred reaction was allowed to warm to ambient temperature overnight and concentrated in vacuo.

[1314] The crude product was dissolved in 80 mL of acetonitrile/water (1:1) and the pH adjusted to 9 with 1 M K2CO3. The solution was cooled to 0° C. and 1.1 mL (11 mmol) of acetic anhydride and 11 mL (11 mmol) of 1 M K2CO3 was added every 30 min for 5 h; during the course of this reaction the pH was maintained at 9 and the reaction temperature kept below 5° C. After the last addition, the reaction was allowed to warm to ambient temperature overnight. The pH was adjusted to 4 with 3 M HCl and the reaction concentrated to 300 mL. Purification by reverse phase chromatography (Waters Delta prep-3000) using isocratic 32% acetonitrile/water (0.05% TFA) gave 6.11 g (55%-overall yield from the compound of Example 4) of colorless product: NMR (DMSO-d6) δ0.85 (t, J=8 Hz, 3H), 0.88 (t, J=8 Hz, 3H), 1.23-1.39 (m, 4H), 1.53-1.68 (m, 6H), 1.84 (s, 3H), 2.15-2.24 (m, 2H), 2.55 (t, J=8 Hz, 2H), 2.70 (t, J=8 Hz, 2H), 4.10-4.20 (m, 1H), 5.31 (s, 2H), 7.11-7.19 (m, 2H), 7.37-7.57 (m, 6H); MS (FAB) m/e (rel intensity) 577 (42), 389 (10), 195 (82), 182 (100), 167 (63), 152 (28); HRMS. Calcd. for M+H: 577.3138. Found: 577.3160. Anal. Calcd. for C31H40N6O5.1.5 CF3CO2H: C, 54.65; H, 5.56; N, 11.25; F, 11.50. Found: C, 54.42; H, 5.75, N, 11.35, F, 11.85.

TABLE IV
138
Ex. #	R1	R2	L	B	E	P
80	C4H9(n)	C4H9(n)	—NH—	H	H	H
81	C4H9(n)	C4H9(n)	—NH—	H	CH3	H
82	C4H9(n)	C4H9(n)	—NH—	H	CH3	COCH3
83	C4H9(n)	C4H9(n)	—NH—	H	C2H5	COCH3
84	C4H9(n)	C4H9(n)	—NH—	H	C2H5	H
85	C4H9(n)	C4H9(n)	—NH—	H	H	COCH2Cl
86	C4H9(n)	C4H9(n)	—NH—	H	H	COC4H9(n)
87	Cl	C4H9(n)	—NH—	H	H	COCH3
88	Cl	C4H9(n)	—NH—	H	H	H
89	C4H9(n)	C4H9(n)	—NHCH2CH2—	H	H	COCH3
90	C4H9(n)	C4H9(n)	—NHCH2CH2—	H	H	H
91	C4H9(n)	C4H9(n)	—NHCH2CH2—	H	CH3	H
92	C4H9(n)	C4H9(n)	—NHCH2CH2—	H	CH3	COCH3
93	C4H9(n)	C4H9(n)	—NHCH2CH2—	H	C2H5	COCH3
94	C4H9(n)	C4H9(n)	—NHCH2CH2—	H	C2H5	H
95	C4H9(n)	C4H9(n)	—NHCH2CH2—	H	H	COCH2Cl
96	C4H9(n)	C4H9(n)	—NHCH2CH2—	H	H	COC4H9(n)
97	Cl	C4H9(n)	—NHCH2CH2—	H	H	COCH3
98	Cl	C4H9(n)	—NHCH2CH2—	H	H	H
99	C4H9(n)	C4H9(n)	139	*	H	COCH3
100	C4H9(n)	C4H9(n)	140	*	H	H
101	C4H9(n)	C4H9(n)	141	*	CH3	H
102	C4H9(n)	C4H9(n)	142	*	CH3	COCH3
103	C4H9(n)	C4H9(n)	143	*	C2H5	COCH3
104	C4H9(n)	C4H9(n)	144	*	C2H5	H
105	C4H9(n)	C4H9(n)	145	*	H	COC4H9(n))
106	C4H9(n)	C4H9(n)	146	*	H	COC4H9(n))
107	Cl	C4H9(n)	147	*	H	COCH3
108	Cl	C4H9(n)	148	*	H	H
109	C2H5	C4H9(n)	—NH—	H	H	COCH3
110	C2H5	C4H9(n)	—NH—	H	H	H
111	C3H7(n)	C4H9(n)	—NH—	H	H	COCH3
112	C3H7(n)	C4H9(n)	—NH—	H	H	H
113	C5H11(n)	C4H9(n)	—NH—	H	H	COCH3
114	C5H11(n)	C4H9(n)	—NH—	H	H	H
115	C6H13(n)	C4H9(n)	—NH—	H	H	COCH3
116	C6H13(n)	C6H13(n)	—NH—	H	H	H
117	CF2CH2CH2CH3	C4H9(n)	—NH—	H	H	COCH3
118	CF2CH2CH2CH3	C4H9(n)	—NH—	H	H	H
119	CH2CH2CH(CH3)2	C4H9(n)	—NH—	H	H	COCH3
120	CH2CH2CH(CR3)2	C4H9(n)	—NH—	H	H	H
121	C2H5	C2H5	—NH—	H	H	COCH3
122	C2H5	C2H5	—NH—	H	H	H
123	C3H7(n)	C3H7(n)	—NH—	H	H	COCH3
124	C3H7(n)	C3H7(n)	—NH—	H	H	COCH3
125	C5H11(n)	C5H11(n)	—NH—	H	H	COCH3
126	C5H11(n)	C5H11(n)	—NH—	H	H	H
127	C6H13(n)	C6H13(n)	—NH—	H	H	COCH3
128	C6H13(n)	C6H13(n)	—NH—	H	H	H
129	C2H5	C2H5	—NHCH2CH2—	H	H	COCH3
130	C2H5	C2H5	—NHCH2CH2—	H	H	H
131	C3H7(n)	C3H7(n)	—NHCH2CH2—	H	H	COCH3
132	C3H7(n)	C3H7(n)	—NHCH2CH2—	H	H	H
133	C5H11(n)	C5H11(n)	—NHCH2CH2—	H	H	COCH3
134	C5H11(n)	C5H11(n)	—NHCH2CH2—	H	H	H
135	C6H13(n)	C6H13(n)	—NHCH2CH2—	H	H	COCH3
136	C6H13(n)	C6H13(n)	—NHCH2CH2—	H	H	H
137	C2H5	C2H5	149	*	H	COCH3
138	C2H5	C2H5	150	*	H	H
139	C3H7(n)	C3H7(n)	151	*	H	COCH3
140	C3H7(n)	C3H7(n)	152	*	H	H
141	C5H11(n)	C5H11(n)	153	*	H	COCH381
142	C5H11(n)	C5H11(n)	154	*	H	H
143	C6H13(n)	C6H13(n)	155	*	H	COCH3
144	C6H13(n)	C6H13(n)	156	*	H	H
*B IS INCORPORATED IN A

[1315] Another preferred class of specific conjugates of the invention is provided by conjugates formed from a biphenylmethyl 1H-substituted-1,2,4-triazole AII antagonist compound linked to a cleavable glutamyl residue. Each conjugate of this class contains a terminal amino moiety on the triazole portion of the AII antagonist compound which is connected to a terminal carboxylic acid moiety on the gamma carbon of the cleavable glutamyl residue. Example #145 is a detailed description of a conjugate of this class. Other specific conjugates of Examples #146-#426, as shown in Table V, may be prepared generally in accordance with the procedures of Example #145.

EXAMPLE 145

[1316] 157

N2-acetyl-N-[[5-butyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-1,2,4-triazol-3-yl]methyl]-L-glutamine

[1317] To a solution of 10.45 g (34.5 mmol) of N-Boc-L-glutamic acid-α-tertbutyl ester (BACHEM) in 100 mL of methylene chloride under nitrogen is added 3.5 g (17.0 mmol) of solid dicyclohexylcarbodiimide (DCC). The reaction is allowed to stir for 2 h and filtered under nitrogen. The anhydride solution is then added to a solution of 5.78 g (14.9 mmol) of the compound of Example 3 in 75 mL of methylene chloride under nitrogen. The reaction is stirred overnight and concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives pure material by thin-layer chromatography (TLC). This material is redissolved in 100 mL of methylene chloride under nitrogen and is cooled to 0° C. prior to the addition of 135 mL of TFA. The stirred reaction is allowed to warm to ambient temperature overnight and is concentrated in vacuo. The crude product is dissolved in 80 mL of acetonitrile/water (1:1) and the pH is adjusted to 9 with 1 M K2CO3. The solution is cooled to 0° C. and 1.1 mL (11 mmol) of acetic anhydride and 11 mL (11 mmol) of 1 M K2CO3 is added every 30 min for 5 h; during the course of this reaction the pH is maintained at 9 and the reaction temperature is kept below 5° C. After the last addition, the reaction is allowed to warm to ambient temperature overnight. The pH is adjusted to 4 with 3 M HCl and the reaction is concentrated to 300 mL. Purification by reverse phase chromatography (Waters Delta prep-3000) gives N2-acetyl-N-[[5-butyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-1,2,4-triazol-3-yl]methyl]-L-glutamine.

TABLE V
158
Ex. #	R5	A	B	E	P
146	CO2H	single bond	H	H	COCH3
147	CO2H	single bond	H	H	COCH2Cl
148	CO2H	single bond	H	H	COC4H9
149	CO2H	single bond	H	CH3	COCH3
150	CO2H	single bond	H	C2H5	COCH3
151	CN4H	single bond	H	H	COCH3
152	CN4H	single bond	H	H	COCH2Cl
153	CN4H	single bond	H	H	COC4H9
154	CN4H	single bond	H	CH3	COCH3
155	CN4H	single bond	H	C2H5	COCH3
156	CO2H	single bond	H	H	H
157	CO2H	single bond	H	CH3	H
158	CO2H	single bond	H	C2H5	H
159	CN4H	single bond	H	H	H
160	CN4H	single bond	H	CH3	H
161	CN4H	single bond	H	C2H5	H
162	CO2H	—CH2—	H	H	COCH3
163	CO2H	single bond	H	H	COCH2Cl
164	CO2H	single bond	H	H	COC4H9
165	CO2H	single bond	H	CH3	COCH3
166	CO2H	single bond	H	C2H5	COCH3
167	CN4H	single bond	H	H	COCH2Cl
168	CN4H	single bond	H	H	COC4H9
169	CN4H	single bond	H	CH3	COCH3
170	CN4H	single bond	H	C2H5	COCH3
171	CO2H	—CH2—	H	H	H
172	CO2H	single bond	H	CH3	H
173	CO2H	single bond	H	C2H5	H
174	CN4H	—CH2—	H	H	H
175	CN4H	single bond	H	CH3	H
176	CN4H	single bond	H	C2H5	H
177	CN4H	—CH2—	CH3	H	H
178	CN4H	—CH2—	CH3	H	COCH3
179	CO2H	—CH2CH2—	H	H	COCH3
180	CO2H	single bond	H	H	COCH2Cl
181	CO2H	single bond	H	H	COC4H9
182	CO2H	single bond	H	CH3	COCH3
183	CO2H	single bond	H	C2H5	COCH3
184	CN4H	—CH2CH2—	H	H	COCH3
185	CN4H	single bond	H	H	COCH2Cl
186	CN4H	single bond	H	H	COC4H9
187	CN4H	single bond	H	CH3	COCH3
188	CN4H	single bond	H	C2H5	COCH3
189	CO2H	—CH2CH2—	H	H	H
190	CO2H	single bond	H	CH3	H
191	CO2H	single bond	H	C2H5	H
192	CN4H	—CH2CH2—	H	H	H
193	CN4H	single bond	H	CH3	H
194	CN4H	single bond	H	C2H5	H
195	CO2H	C3H6(n)	H	H	COCH3
196	CO2H	single bond	H	H	COCH2Cl
197	CO2H	single bond	H	H	COCH4H9
198	CO2H	single bond	H	CH3	COCH3
199	CO2H	single bond	H	C2H5	COCH3
200	CN4H	C3H6(n)	H	H	COCH3
201	CN4H	single bond	H	H	COCH2Cl
202	CN4H	single bond	H	H	COC4H9
203	CN4H	single bond	H	CH3	COCH3
204	CN4H	single bond	H	C2H5	COCH3
205	CO2H	C3H6(n)	H	H	H
206	CO2H	single bond	H	CH3	H
207	CO2H	single bond	H	C2H5	H
208	CN4H	C3H6(n)	H	H	H
209	CN4H	single bond	H	CH3	H
210	CN4H	single bond	H	C2H5	H
211	CO2H	C4H8(n)	H	H	COCH3
212	CO2H	single bond	H	H	COCH2Cl
213	CO2H	single bond	H	H	COC4H9
214	CO2H	single bond	H	CH3	COCH3
215	CO2H	single bond	H	C2H5	COCH3
216	CN4H	C4H8(n)	H	H	COCH3
217	CN4H	single bond	H	H	COCH2Cl
218	CN4H	single bond	H	H	COC4H9
219	CN4H	single bond	H	CH3	COCH3
220	CN4H	single bond	H	C2H5	COCH3
221	CO2H	C4H8(n)	H	H	H
222	CO2H	single bond	H	CH3	H
223	CO2H	single bond	H	C2H5	H
224	CN4H	C4H8(n)	H	H	H
225	CN4H	single bond	H	CH3	H
226	CN4H	single bond	H	C2H5	H
227	CO2H	159	H	H	COCH3
228	CO2H	single bond	H	H	COCH2Cl
229	CO2H	single bond	H	H	COC4H9
230	CO2H	single bond	H	CH3	COCH3
231	CO2H	single bond	H	C2H5	COCH3
232	CN4H	160	H	H	COCH3
233	CN4H	single bond	H	H	COCH2Cl
234	CN4H	single bond	H	H	CO4H9
235	CN4H	single bond	H	CH3	COCH3
236	CN4H	single bond	H	C2H5	COCH3
237	CO2H	161	H	H	H
238	CO2H	single bond	H	CH3	H
239	CO2H	single bond	H	C2H5	H
240	CN4H	162	H	H	H
241	CN4H	single bond	H	CH3	H
242	CN4H	single bond	H	C2H5	H
243	CO2H	163	H	H	COCH3
244	CO2H	single bond	H	H	COCH2Cl
245	CO2H	single bond	H	H	COC4H9
246	CO2H	single bond	H	CH3	COCH3
247	CO2H	single bond	H	C2H5	COCH3
248	CN4H	164	H	H	COCH3
249	CN4H	single bond	H	H	COCH2Cl
250	CN4H	single bond	H	H	COC4H9
251	CN4H	single bond	H	CH3	COCH3
252	CN4H	single bond	H	C2H5	COCH3
253	CO2H	165	H	H	H
254	CO2H	single bond	H	CH3	H
255	CO2H	single bond	H	C2H5	H
256	CN4H	166	H	H	H
257	CN4H	single bond	H	CH3	H
258	CN4H	single bond	H	C2H5	H
259	CO2H	167	H	H	COCH3
260	CO2H	single bond	H	H	COCH2Cl
261	CO2H	single bond	H	H	COC4H9
262	CO2H	single bond	H	CH3	COCH3
263	CO2H	single bond	H	C2H5	COCH3
264	CN4H	168	H	H	COCH3
265	CN4H	single bond	H	H	COCH2Cl
266	CN4H	single bond	H	H	COC4H9
267	CN4H	single bond	H	CH3	COCH3
268	CN4H	single bond	H	C2H5	COCH3
269	CO2H	169	H	H	H
270	CO2H	single bond	H	CH3	H
271	CO2H	single bond	H	C2H5	H
272	CN4H	170	H	H	H
273	CN4H	single bond	H	CH3	H
274	CN4H	single bond	H	C2H5	H
275	CO2H	171	H	H	COCH3
276	CO2H	single bond	H	H	COCH2Cl
277	CO2H	single bond	H	H	COC4H9
278	CO2H	single bond	H	CH3	COCH3
279	CO2H	single bond	H	C2H5	COCH3
280	CN4H	172	H	H	COCH3
281	CN4H	single bond	H	H	COCH2Cl
282	CN4H	single bond	H	H	COCH2Cl
283	CN4H	single bond	H	CH3	COCH3
284	CN4H	single bond	H	C2H5	COCH3
285	CO2H	173	H	H	H
286	CO2H	single bond	H	CH3	H
287	CO2H	single bond	H	C2H5	H
288	CN4H	174	H	H	H
289	CN4H	single bond	H	CH3	H
290	CN4H	single bond	H	C2H5	H
291	CN4H	175	H	H	COCH3
292	CO2H	single bond	H	H	COCH2Cl
293	CO2H	single bond	H	H	COC4H9
294	CO2H	single bond	H	CH3	COCH3
295	CO2H	single bond	H	C2H5	COCH3
296	CN4H	176	H	H	H
297	CN4H	single bond	H	H	COCH2Cl
298	CN4H	single bond	H	H	COCH3
299	CN4H	single bond	H	CH3	COCH3
300	CN4H	single bond	H	C2H5	COCH3
301	CN4H	177	H	H	COCH3
302	CO2H	single bond	H	CH3	H
303	CO2H	single bond	H	C2H5	H
304	CN4H	178	H	CH3	H
305	CN4H	single bond	H	CH3	H
306	CN4H	single bond	H	C2H5	H
307	CO2H	179	H	H	COCH3
308	CO2H	single bond	H	H	COCH2Cl
309	CO2H	single bond	H	H	COC4H9
310	CO2H	single bond	H	CH3	COCH3
311	CO2H	single bond	H	C2H5	COCH3
312	CN4H	180	H	H	COCH3
313	CN4H	single bond	H	H	COCH2Cl
314	CN4H	single bond	H	H	COC4H9
315	CN4H	single bond	H	CH3	COCH3
316	CN4H	single bond	H	C2H5	COCH3
317	CO2H	181	H	H	H
318	CO2H	single bond	H	CH3	H
319	CO2H	single bond	H	C2H5	H
320	CN4H	182	H	H	H
321	CN4H	single bond	H	CH3	H
322	CN4H	single bond	H	C2H5	H
323	CO2H	183	H	H	COCH3
324	CO2H	single bond	H	H	COCH2Cl
325	CO2H	single bond	H	H	COC4H9
326	CO2H	single bond	H	CH3	COCH3
327	CO2H	single bond	H	C2H5	COCH3
328	CN4H	184	H	H	COCH3
329	CN4H	single bond	H	H	COCH2Cl
330	CN4H	single bond	H	H	COCH4
331	CN4H	single bond	H	CH3	COCH3
332	CN4H	single bond	H	C2H5	COCH3
333	CO2H	185	H	H	H
334	CO2H	single bond	H	CH3	H
335	CO2H	single bond	H	C2H5	H
336	CN4H	186	H	H	H
337	CN4H	single bond	H	CH3	H
338	CN4H	single bond	H	C2H5	H
339	CO2H	187	H	H	COCH3
340	CO2H	single bond	H	H	COCH2Cl
341	CO2H	single bond	H	H	COCH4H9
342	CO2H	single bond	H	CH3	COCH3
343	CO2H	single bond	H	C2H5	COCH3
344	CN4H	188	H	H	COCH3
345	CN4H	single bond	H	H	COCH2Cl
346	CN4H	single bond	H	H	COC4H9
347	CN4H	single bond	H	CH3	COCH3
348	CN4H	single bond	H	C2H5	COCH3
349	CO2H	189	H	H
350	CO2H	single bond	H	CH3	H
351	CO2H	single bond	H	C2H5	H
352	CN4H	190	H	C2H5	H
353	CN4H	single bond	H	CH3	H
354	CN4H	single bond	H	C2H5	H
355	CO2H	191	H	H	COCH3
356	CO2H	single bond	H	H	COCH2Cl
357	CO2H	single bond	H	H	COC4H9
358	CO2H	single bond	H	CH3	COCH3
359	CO2H	single bond	H	C2H5	COCH3
360	CN4H	192	H	H	COCH3
361	CN4H	single bond	H	H	COCH2Cl
362	CN4H	single bond	H	H	COC4H9
363	CN4H	single bond	H	CH3	COCH3
364	CN4H	single bond	H	C2H5	COOH3
365	CO2H	193	H	H	H
366	CO2H	single bond	H	CH3	H
367	CO2H	single bond	H	C2H5	H
368	CN4H	194	H	H	H
369	CN4H	single bond	H	CH3	H
370	CN4H	single bond	H	C2H5	H
371	CN4H	195	H	H	COCH3
372	CO2H	single bond	H	H	COCH2Cl
373	CO2H	single bond	H	H	COC4H9
374	CO2H	single bond	H	CH3	COCH3
375	CO2H	single bond	H	C2H5	COCH3
376	CN4H	196	H	H	H
377	CN4H	single bond	H	H	COCH2Cl
378	CN4H	single bond	H	H	COC4H9
379	CN4H	single bond	H	CH3	COCH3
380	CN4H	single bond	H	C2H5	COCH3
381	CN4H	197	H	H	COCH3
382	CO2H	single bond	H	CH3	H
383	CO2H	single bond	H	C2H5	H
384	CN4H	198	H	H	H
385	CN4H	single bond	H	CH3	H
386	CN4H	single bond	H	C2H5	H
387	CN4H	199	*	H	COCH3
388	CO2H	single bond	H	H	COCH2Cl
389	CO2H	single bond	H	H	COC4H9
390	CO2H	single bond	H	CH3	COCH3
391	CO2H	single bond	H	C2H5	COCH3
392	CN4H	200	*	H	H
393	CN4H	single bond	H	H	COCH2Cl
394	CN4H	single bond	H	H	COC4H9
395	CN4H	single bond	H	CH3	COCH3
396	CN4H	single bond	H	C2H5	COCH3
397	CN4H	201	*	H	COCH3
398	CO2H	single bond	H	CH3	H
399	CO2H	single bond	H	C2H5	H
400	CN4H	202	*	H	H
401	CN4H	single bond	H	CH3	H
402	CN4H	single bond	H	C2H5	H
403	CN4H	203	*	H	COC3
404	CO2H	single bond	H	H	COCH2Cl
405	CO2H	single bond	H	H	COCH4H9
406	CO2H	single bond	H	CH3	COCH3
407	CO2H	single bond	H	C2H5	COCH3
408	CN4H	204	* H	H
409	CN4H	single bond	H	H	COCH2Cl
410	CN4H	single bond	H	H	COC4H9
411	CN4H	single bond	H	CH3	COCH3
412	CN4H	single bond	H	C2H5	COCH3
413	CN4H	205	*	H	COCH3
414	CO2H	single bond	H	CH3	H
415	CO2H	single bond	H	C2H5	H
416	CN4H	206	*	H	H
417	CN4H	single bond	H	CH3	H
418	CN4H	single bond	H	C2H5	H
419	CN4H	207	*	H	COCH3
420	CN4H	single bond	H	H	COCH2Cl
421	CN4H	single bond	H	H	COC4H9
422	CN4H	single bond	H	CH3	COCH3
423	CN4H	single bond	H	C2H5	COCH3
424	CN4H	208	*	H	H
425	CN4H	single bond	H	CH3	H
426	CN4H	single bond	H	C2H5	H
*B is incorporated in A

[1318] Another preferred class of specific conjugates of the invention is provided by conjugates formed from a biphenylmethyl 1H-substituted-1,2,4-triazole AII antagonist compound linked to a cleavable glutamyl residue. Each conjugate of this class contains a diamino linker moiety which connects a terminal carboxylic acid moiety on the triazole portion of the AII antagonist compound with a terminal carboxylic acid moiety on the gamma carbon of the cleavable glutamyl residue. Example #427 is a detailed description of a conjugate of this class. Other specific conjugates of Examples #428-#834, as shown in Table VI, may be prepared generally in accordance with the procedures of Example #427.

EXAMPLE 427

[1319] 209

N-acetyl-L-glutamic acid, 5-[5-butyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl-1H-1,2,4-triazol-3-yl]acetylhydrazide

[1320] Step 1: Preparation of 5-[4′-[(5-butyl-3-hydrazinylcarbonylmethyl-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole

[1321] Under nitrogen, 8.34 g (20 mmol) of the compound of Example 7 is dissolved in 200 mL of absolute methanol at −10° C. (ice/methanol) and is treated dripwise with 3.0 g (25 mmol) of thionyl chloride. After the addition is complete, the reaction is allowed to warm to ambient temperature for 2 h prior to stirring at reflux overnight. All volitiles are removed in vacuo and the residue redissolved in 100 mL of methanol. Under nitrogen, 20 g (625 mmol) of anhydrous hydrazine is added and the reaction is stirred at reflux overnight. Concentration in vacuo gives the crude product; purification by silica gel chromatography provides 5-[4′-[(5-butyl-3-hydrazinocarbonylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole.

[1322] Step 2: Preparation of N-acetyl-L-glutamic acid, 5-[5-butyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl-1H-1,2,4-triazol-3-yl]acetylhydrazide

[1323] To a solution of 10.45 g (34.5 mmol) of N-Boc-L-glutamic acid-α-tertbutyl ester (BACHEM) in 100 mL of methylene chloride under nitrogen is added 3.5 g (17.0 mmol) of solid dicyclohexylcarbodiimide (DCC). The reaction is allowed to stir for 2 h and filtered under nitrogen. The anhydride solution is then added to a solution of 6.42 g (14.9 mmol) of the compound of Example 20 in 75 mL of methylene chloride under nitrogen. The reaction is stirred overnight and is concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) gives pure material by thin-layer chromatography (TLC). This material is redissolved in 100 mL of methylene chloride under nitrogen and cooled to 0° C. prior to the addition of 135 mL of TFA. The stirred reaction is allowed to warm to ambient temperature overnight and is concentrated in vacuo. The crude product is dissolved in 80 mL of acetonitrile/water (1:1) and the pH is adjusted to 9 with 1 M K2CO3. The solution is cooled to 0° C. and 1.1 mL (11 mmol) of acetic anhydride and 11 mL (11 mmol) of 1 M K2CO3 is added every 30 min for 5 h; during the course of this reaction the pH is maintained at 9 and the reaction temperature is kept below 5° C. After the last addition, the reaction is allowed to warm to ambient temperature overnight. The pH was adjusted to 4 with 3 M HCl and the reaction concentrated to 300 mL. Purification by reverse phase chromatography (Waters Delta prep-3000) gives N-acetyl-L-glutamic acid, 5-(5-butyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl-1H-1,2,4-traizol-3-yl]acetylhydrazide.

TABLE VI
210
Ex. #	A	L	B	E	P
428	single bond	—NH—	H	H	COCH3
429	single bond	—NH—	H	H	COCH2Cl
430	single bond	—NH—	H	H	COC4H9
431	single bond	—NH—	H	CH3	COCH3
432	single bond	—NH—	H	C2H5	COCH3
433	single bond	—NH—	H	H	H
434	single bond	—NH—	H	CH3	H
435	single bond	—NH—	H	C2H5	H
436	single bond	—NHCH2CH2—	H	H	COCH3
437	single bond	—NHCH2CH2—	H	H	COCH2Cl
438	single bond	—NHCH2CH2—	H	H	COC4H9
439	single bond	—NHCH2CH2—	H	CH3	COCH3
440	single bond	—NHCH2CH2—	H	C2H5	COCH3
441	single bond	—NHCH2CH2—	H	H	H
442	single bond	—NHCH2CH2—	H	CH3	H
443	single bond	—NHCH2CH2—	H	C2H5	H
444	single bond	211	*	H	COCH3
445	single bond	212	H	H	COCH2Cl
446	single bond	213	H	H	COC4H9
447	single bond	214	H	CH3	COCH3
448	single bond	215	H	C2H5	COCH3
449	single bond	216	*	H	H
450	single bond	217	H	CH3	H
451	single bond	218	H	C2H5	H
452	CH2	—NH—	H	H	COCH2Cl
453	CH2	—NH—	H	H	COC4H9
454	CH2	—NH—	H	CH3	COCH3
455	CH2	—NH—	H	C2H5	COCH3
456	CH2	—NH—	H	H	H
457	CH2	—NH—	H	CH3	H
458	CH2	—NH—	H	C2H5	H
459	CH2	—NHCH2CH2—	H	H	COCH3
460	CH2	—NHCH2CH2—	H	H	COCH2Cl
461	CH2	—NHCH2CH2—	H	H	COC4H9
462	CH2	—NHCH2CH2—	H	CH3	COCH3
463	CH2	—NHCH2CH2—	H	C2H5	COCH3
464	CH2	—NHCH2CH2—	H	H	H
465	CH2	—NHCH2CH2—	H	CH3	H
466	CH2	—NHCH2CH2—	H	C2H5	H
467	CH2	219	*	H	COCH3
468	CH2	220	H	H	COCH2Cl
469	CH2	221	H	H	COC4H9
470	CH2	222	H	CH3	COCH3
471	CH2	223	H	C2H5	COCH3
472	CH2	224	*	H	H
473	CH2	225	H	CH3	H
474	CH2	226	H	C2H5	H
475	CH2CH2	—NH—	H	H	COCH3
476	CH2CH2	—NH—	H	H	COCH2Cl
477	CH2CH2	—NH—	H	H	COC4H9
478	CH2CH2	—NH—	H	CH3	COCH3
479	CH2CH2	—NH—	H	C2H5	COCH3
480	CH2CH2	—NH—	H	H	H
481	CH2CH2	—NH—	H	CH3	H
482	CH2CH2	—NH—	H	C2H5	H
483	CH2CH2	—NHCH2CH2—	H	H	COCH3
484	CH2CH2	—NHCH2CH2—	H	H	COCH2Cl
485	CH2CH2	—NHCH2CH2—	H	H	COC 4H9
486	CH2CH2	—NHCH2CH2—	H	CH3	COCH3
487	CH2CH2	—NHCH2CH2—	H	C2H5	COCH3
488	CH2CH2	—NHCH2CH2—	H	H	H
489	CH2CH2	—NHCH2CH2—	H	CH3	H
490	CH2CH2	—NHCH2CH2—	H	C2H5	H
491	CH2CH2	227	*	H	COCH3
492	CH2CH2	228	H	H	COCH2Cl
493	CH2CH2	229	H	H	COC4H9
494	CH2CH2	230	H	CH3	COCH3
495	CH2CH2	231	H	C2H5	COCH3
496	CH2CH2	232	*	H	H
497	CH2CH2	233	H	CH3	H
498	CH2CH2	234	H	C2H5	H
499	C3H6(n)	—NH—	H	H	COCH3
500	C3H6(n)	—NH—	H	H	COCH2Cl
501	C3H6(n)	—NH—	H	H	COC4H9
502	C3H6(n)	—NH—	H	CH3	COCH3
503	C3H6(n)	—NH—	H	C2H5	COCH3
504	C3H6(n)	—NH—	H	H	H
505	C3H6(n)	—NH—	H	CH3	H
506	C3H6(n)	—NH—	H	C2H5	H
507	C3H6(n)	—NHCH2CH2—	H	H	COCH3
508	C3H6(n)	—NHCH2CH2—	H	H	COCH2Cl
509	C3H6(n)	—NHCH2CH2—	H	H	COC4H9
510	C3H6(n)	—NHCH2CH2—	H	CH3	COCH3
511	C3H6(n)	—NHCH2CH2—	H	C2H5	COCH3
512	C3H6(n)	—NHCH2CH2—	H	H	H
513	C3H6(n)	—NHCH2CH2—	H	CH3	H
514	C3H6(n)	—NHCH2CH2—	H	C2H5	H
515	C3H6(n)	235	*	H	COCH3
516	C3H6(n)	236	H	H	COCH2Cl
517	C3H6(n)	237	H	H	COC4H9
518	C3H6(n)	238	H	CH3	COCH3
519	C3H6(n)	239	H	C2H5	COCH3
520	C3H6(n)	240	*	H	H
521	C3H6(n)	241	H	CH3	H
522	C3H6(n)	242	H	C2H5	H
523	C4H8(n)	—NH—	H	H	COCH3
524	C4H8(n)	—NH—	H	H	COCH2Cl
525	C4H8(n)	—NH—	H	H	COC4H9
526	C4H8(n)	—NH—	H	CH3	COCH3
527	C4H8(n)	—NH—	H	C2H5	COCH3
528	C4H8(n)	—NH—	H	H	H
529	C4H8(n)	—NH—	H	CH3	H
530	C4H8(n)	—NH—	H	C2H5	H
531	C4H8(n)	—NHCH2CH2—	H	H	COCH3
532	C4H8(n)	—NHCH2CH2—	H	H	COCH2Cl
533	C4H8(n)	—NHCH2CH2—	H	H	COC4H9
534	C4H8(n)	—NHCH2CH2—	H	CH3	COCH3
535	C4H8(n)	—NHCH2CH2—	H	C2H5	COCH3
536	C4H8(n)	—NHCH2CH2—	H	H	H
537	C4H8(n)	—NHCH2CH2—	H	CH3	H
538	C4H8(n)	—NHCH2CH2—	H	C2H5	H
539	C4H8(n)	243	*	H	COCH3
540	C4H8(n)	244	H	H	COCH2Cl
541	C4H8(n)	245	H	H	COC4H9
542	C4H8(n)	246	H	CH3	COCH3
543	C4H8(n)	247	H	C2H5	COCH3
544	C4H8(n)	248	*	H	H
545	C4H8(n)	249	H	CH3	H
546	C4H8(n)	250	H	C2H5	H
547	251	—NH—	H	H	COCH3
548	252	—NH—	H	H	COCH2Cl
549	253	—NH—	H	H	COC4H9
550	254	—NH—	H	CH3	COCH3
551	255	—NH—	H	C2H5	COCH3
552	256	—NH—	H	H	H
553	257	—NH—	H	CH3	H
554	258	—NH—	H	C2H5	H
555	259	—NHCH2CH2—	H	H	COCH3
556	260	—NHCH2CH2—	H	H	COCH2Cl
557	261	—NHCH2CH2—	H	H	COC4H9
558	262	—NHCH2CH2—	H	CH3	COCH3
559	263	—NHCH2CH2—	H	C2H5	COCH3
560	264	—NHCH2CH2—	H	H	H
561	265	—NHCH2CH2—	H	CH3	H
562	266	—NHCH2CH2—	H	C2H5	H
563	267	268	*	H	COCH3
564	269	270	H	H	COCH2Cl
565	271	272	H	H	COC4H9
566	273	274	H	CH3	COCH3
567	275	276	H	C2H5	COCH3
568	277	278	*	H	H
569	279	280	H	CH3 H
570	281	282	H	C2H5	H
571	283	—NH—	H	H	COCH3
572	284	—NH—	H	H	COCH2Cl
573	285	—NH—	H	H	COC4H9
574	286	—NH—	H	CH3	COCH3
575	287	—NH—	H	C2H5	COCH3
576	288	—NH—	H	H	H
577	289	—NH—	H	CH3	H
578	290	—NH—	H	C2H5	H
579	291	—NHCH2CH2—	H	H	COCH3
580	292	—NHCH2CH2—	H	H	COCH2Cl
581	293	—NHCH2CH2—	H	H	COC4H9
582	294	—NHCH2CH2—	H	CH3	COCH3
583	295	—NHCH2CH2—	H	C2H5	COCH3
584	296	—NHCH2CH2—	H	H	H
585	297	—NHCH2CH2—	H	CH3	H
586	298	—NHCH2CH2—	H	C2H5	H
587	299	300	*	H	COCH3
588	301	302	H	H	COCH2Cl
589	303	304	H	H	COC4H9
590	305	306	H	CH3	COCH3
591	307	308	H	C2H5	COCH3
592	309	310	*	H	H
593	311	312	H	CH3	H
594	313	314	H	C2H5	H
595	315	—NH—	H	H	COCH3
596	316	—NH—	H	H	COCH2Cl
597	317	—NH—	H	H	COC4H9
598	318	—NH—	H	CH3	COCH3
599	319	—NH—	H	C2H5	COCH3
600	320	—NH—	H	H	H
601	321	—NH—	H	CH3	H
602	322	—NH—	H	C2H5	H
603	323	—NHCH2CH2—	H	H	COCH3
604	324	—NHCH2CH2—	H	H	COCH2Cl
605	325	—NHCH2CH2—	H	H	COC4H9
606	326	—NHCH2CH2—	H	CH3	COCH3
607	327	—NHCH2CH2—	H	C2H5	COCH3
608	328	—NHCH2CH2—	H	H	H
609	329	—NHCH2CH2—	H	CH3	H
610	330	—NHCH2CH2—	H	C2H5	H
611	331	332	*	H	COCH3
612	333	334	H	H	COCH2Cl
613	335	336	H	H	COC4H9
614	337	338	H	CH3	COCH3
615	339	340	H	C2H5	COCH3
616	341	342	*	H	H
617	343	344	H	CH3	H
618	345	346	H	C2H5	H
619	347	—NH—	H	H	COCH3
620	348	—NH—	H	H	COCH2Cl
621	349	—NH—	H	H	COC4H9
622	350	—NH—	H	CH3	COCH3
623	351	—NH—	H	C2H5	COCH3
624	352	—NH—	H	H	H
625	353	—NH—	H	CH3	H
626	354	—NH—	H	C2H5	H
627	355	—NHCH2CH2—	H	H	COCH3
628	356	—NHCH2CH2—	H	H	COCH2Cl
629	357	—NHCH2CH2—	H	H	COC4H9
630	358	—NHCH2CH2—	H	CH3	COCH3
631	359	—NHCH2CH2—	H	C2H5	COCH3
632	360	—NHCH2CH2—	H	H	H
633	361	—NHCH2CH2—	H	CH3	H
634	362	—NHCH2CH2—	H	C2H5	H
635	363	364	*	H	COCH3
636	365	366	H	H	COCH2Cl
637	367	368	H	H	COC4H9
638	369	370	H	CH3	COCH3
639	371	372	H	C2H5	COCH3
640	373	374	*	H	H
641	375	376	H	CH3	H
642	377	378	H	C2H5	H
643	379	—NH—	H	H	COCH3
644	380	—NH—	H	H COCH2Cl
645	381	—NH—	H	H COC4H9
646	382	—NH—	H	CH3	COCH3
647	383	—NH—	H	C2H5	COCH3
648	384	—NH—	H	H	H
649	385	—NH—	H	CH3	H
650	386	—NH—	H	C2H5	H
651	387	—NHCH2CH2—	H	H	COCH3
652	388	—NHCH2CH2—	H	H	COCH2Cl
653	389	—NHCH2CH2—	H	H	COC4H9
654	390	—NHCH2CH2—	H	CH3	COCH3
655	391	—NHCH2CH2—	H	C2H5	COCH3
656	392	—NHCH2CH2—	H	H	H
657	393	—NHCH2CH2—	H	CH3	H
658	394	—NHCH2CH2—	H	C2H5	H
659	395	396	*	H	COCH3
660	397	398	H	H	COCH2Cl
661	399	400	H	H	COC4H9
662	401	402	H	CH3	COCH3
663	403	404	H	C2H5	COCH3
664	405	406	*	H	H
665	407	408	H	CH3	H
666	409	410	H	C2H5	H
667	411	—NH—	H	H	COCH3
668	412	—NH—	H	H	COCH2Cl
669	413	—NH—	H	H	COC4H9
670	414	—NH—	H	CH3	COCH3
671	415	—NH—	H	C2H5	COCH3
672	416	—NH—	H	H	H
673	417	—NH—	H	CH3	H
674	418	—NH—	H	C2H5	H
675	419	—NHCH2CH2—	H	H	COCH3
676	420	—NHCH2CH2—	H	H	COCH2Cl
677	421	—NHCH2CH2—	H	H	COC4H9
678	422	—NHCH2CH2—	H	CH3	COCH3
679	423	—NHCH2CH2—	H	C2H5	COCH3
680	424	—NHCH2CH2—	H	H	H
681	425	—NHCH2CH2—	H	CH3	H
682	426	—NHCH2CH2—	H	C2H5	H
683	427	428	*	H	COCH3
684	429	430	H	H	COCH2Cl
685	431	432	H	H	COC4H9
686	433	434	H	CH3	COCH3
687	435	436	H	C2H5	COCH3
688	437	438	*	H	H
689	439	440	H	CH3	H
690	441	442	H	C2H5	H
691	443	—NH—	H	H	COCH3
692	444	—NH—	H	H	COCH2Cl
693	445	—NH—	H	H	COC4H9
694	446	—NH—	H	CH3	COCH3
695	447	—NH—	H	C2H5	COCH3
696	448	—NH—	H	H	H
697	449	—NH—	H	CH3	H
698	450	—NH—	H	C2H5	H
699	451	—NHCH2CH2—	H	H	COCH3
700	452	—NHCH2CH2—	H	H	COCH2Cl
701	453	—NHCH2CH2—	H	H	COC4H9
702	454	—NHCH2CH2—	H	CH3	COCH3
703	455	—NHCH2CH2—	H	C2H5	COCH3
704	456	—NHCH2CH2—	H	H	H
705	457	—NHCH2CH2—	H	CH3	H
706	458	—NHCH2CH2—	H	C2H5	H
707	459	460	*	H	COCH3
708	461	462	H	H	COCH2Cl
709	463	464	H	H	COC4H9
710	465	466	H	CH3	COCH3
711	467	468	H	C2H5	COCH3
712	469	470	*	H	H
713	471	472	H	CH3	H
714	473	474	H	C2H5	H
715	475	—NH—	H	H	COCH3
716	476	—NH—	H	H	COCH2Cl
717	477	—NH—	H	H	COC4H9
718	478	—NH—	H	CH3	COCH3
719	479	—NH—	H	C2H5	COCH3
720	480	—NH—	H	H	H
721	481	—NH—	H	CH3	H
722	482	—NH—	H	C2H5	H
723	483	—NHCH2CH2—	H	H	COCH3
724	484	—NHCH2CH2—	H	H	COCH2Cl
725	485	—NHCH2CH2—	H	H	COC4H9
726	486	—NHCH2CH2—	H	CH3	COCH3
727	487	—NHCH2CH2—	H	C2H5	COCH3
728	488	—NHCH2CH2—	H	H	H
729	489	—NHCH2CH2—	H	CH3	H
730	490	—NHCH2CH2—	H	C2H5	H
731	491	492	*	H	COCH3
732	493	494	H	H	COCH2Cl
733	495	496	H	H	COC4H9
734	497	498	H	CH3	COCH3
735	499	500	H	C2H5	COCH3
736	501	502	*	H	H
737	503	504	H	CH3	H
738	505	506	H	C2H5	H
739	507	—NH—	H	H	COCH3
740	508	—NH—	H	H	COCH2Cl
741	509	—NH—	H	H	COC4H9
742	510	—NH—	H	CH3	COCH3
743	511	—NH—	H	C2H5	COCH3
744	512	—NH—	H	H	H
745	513	—NH—	H	CH3	H
746	514	—NH—	H	C2H5	H
747	515	—NHCH2CH2—	H	H	COCH3
748	516	—NHCH2CH2—	H	H	COCH2Cl
749	517	—NHCH2CH2—	H	H	COC4H9
750	518	—NHCH2CH2—	H	CH3	COCH3
751	519	—NHCH2CH2—	H	C2H5	COCH3
752	520	—NHCH2CH2—	H	H	H
753	521	—NHCH2CH2—	H	CH3	H
754	522	—NHCH2CH2—	H	C2H5	H
755	523	524	*	H	COCH3
756	525	526	H	H	COCH2Cl
757	527	528	H	H	COC4H9
758	529	530	H	CH3	COCH3
759	531	532	H	C2H5	COCH3
760	533	534	*	H	H
761	535	536	H	CH3	H
762	537	538	H	C2H5	H
763	539	—NH—	H	H	COCH3
764	540	—NH—	H	H	COCH2Cl
765	541	—NH—	H	H	COC4H9
766	542	—NH—	H	CH3	COCH3
767	543	—NH—	H	C2H5	COCH3
768	544	—NH—	H	H	H
769	545	—NH—	H	CH3	H
770	546	—NH—	H	C2H5	H
771	547	—NHCH2CH2—	H	H	COCH3
772	548	—NH—	H	H	COCH2Cl
773	549	—NH—	H	H	COC4H9
774	550	—NH—	H	CH3	COCH3
775	551	—NH—	H	C2H5	COCH3
776	552	—NHCH2CH2—	H	H	H
777	553	—NHCH2CH2—	H	CH3	H
778	554	—NHCH2CH2—	H	C2H5	H
779	555	556	*	H	COCH3
780	557	558	H	H	COCH2Cl
781	559	560	H	H	COC4H9
782	561	562	H	CH3	COCH3
783	563	564	C2H5		COCH3
784	565	566	*	H	H
785	567	568	H	CH3	H
786	569	570	H	C2H5	H
787	571	—NH—	H	H	COCH3
788	572	—NH—	H	H	COCH2Cl
789	573	—NH—	H	H	COC4H9
790	574	—NH—	H	CH3	COCH3
791	575	—NH—	H	C2H5	COCH3
792	576	—NH—	H	H	H
793	577	—NH—	H	CH3	H
794	578	—NH—	H	C2H5	H
795	579	—NHCH2CH2—	H	H	COCH3
796	580	—NHCH2CH2—	H	H	COCH2Cl
797	581	—NHCH2CH2—	H	H	COC4H9
798	582	—NHCH2CH2—	H	CH3	COCH3
799	583	—NHCH2CH2—	H	C2H5	COCH3
800	584	—NHCH2CH2—	H	H	H
801	585	—NHCH2CH2—	H	CH3	H
802	586	—NHCH2CH2—	H	C2H5	H
803	587	588	*	H	COCH3
804	589	590	H	H	COCH2Cl
805	591	592	H	H	COC4H9
806	593	594	H	CH3	COCH3
807	595	596	H	C2H5	COCH3
808	597	598	*	H	H
809	599	600	H	CH3	H
810	601	602	H	C2H5	H
811	603	H	H	COCH3
812	604	—NH—	H	H	COCH2Cl
813	605	—NH—	H	H	COC4H9
814	606	—NH—	H	CH3	COCH3
815	607	—NH—	H	C2H5	COCH3
816	608	—NH—	H	H	H
817	609	—NH—	H	CH3	H
818	610	—NH—	H	C2H5	H
819	611	—NHCH2CH2—	H	H	COCH3
820	612	—NHCH2CH2—	H	H	COCH2Cl
821	613	—NHCH2CH2—	H	H	COC4H9
822	614	—NHCH2CH2—	H	CH3	COCH3
823	615	—NHCH2CH2—	H	C2H5	COCH3
824	616	—NHCH2CH2—	H	H	H
825	617	—NHCH2CH2—	H	CH3	H
826	618	—NHCH2CH2—	H	C2H5	H
827	619	620	*	H	COCH3
828	621	622	H	H	COCH2Cl
829	623	624	H	H	COC4H9
830	625	626	H	CH3	COCH3
831	627	628	H	C2H5	COCH3
832	629	630	*	H	H
833	631	632	H	CH3	H
834	633	634	H	C2H5	H

BIOLOGICAL EVALUATION

[1324] In order to identify suitable angiotension II antagonists for use as the first component of the conjugate of the invention, certain compounds of Examples 1-17 were evaluated variously in three biological assays (Assays “A”, “B” and “C”). In a fourth assay, blood-pressue lowering effects of conjugate of the invention of Example 18 were evaluated (Assay “D”).

[1325] Assay A: Angiotensin II Binding Activity

[1326] Compounds of Formula I were tested for ability to bind to the smooth muscle angiotensin II receptor using a rat uterine membrane preparation. Angiotensin II (AII) was purchased from Peninsula Labs. 125I-angiotensin II (specific activity of 2200 Ci/mmol) was purchased from Du Pont-New England Nuclear. Other chemicals were obtained from Sigma Chemical Co. This assay was carried out according to the method of Douglas et al [Endocrinology, 106, 120-124 (1980)]. Rat uterine membranes were prepared from fresh tissue. All procedures were carried out at 4° C. Uteri were stripped of fat and homogenized in phosphate-buffered saline at pH 7.4 containing 5 mM EDTA. The homogenate was centrifuged at 1500×g for 20 min., and the supernatant was recentrifuged at 100,000×g for 60 min. The pellet was resuspended in buffer consisting of 2 mM EDTA and 50 mM Tris-HCl (pH 7.5) to a final protein concentration of 4 mg/ml. Assay tubes were charged with 0.25 ml of a solution containing 5 mM MgCl2, 2 mM EDTA, 0.5% bovine serum albumin, 50 mM Tris-HCl, pH 7.5 and 125I-AII (approximately 105 cpm) in the absence or in the presence of unlabelled ligand. The reaction was initiated by the addition of membrane protein and the mixture was incubated at 25° C. for 60 min. The incubation was terminated with ice-cold 50 mM Tris-HCl (pH 7.5) and the mixture was filtered to separate membrane-bound labelled peptide from the free ligand. The incubation tube and filter were washed with ice-cold buffer. Filters were assayed for radioactivity in a Micromedic gamma counter. Nonspecific binding was defined as binding in the presence of 10 μM of unlabelled AII. Specific binding was calculated as total binding minus nonspecific binding. The receptor binding affinity of an AII antagonist compound was indicated by the concentration (IC50) of the tested AII antagonist which gives 50% displacement of the total specifically bound 125I-AII from the high affinity AII receptor. Binding data were analyzed by a nonlinear least-squares curve fitting program. Results are reported in Table VI.

[1327] Assay B: In Vitro Vascular Smooth Muscle-Response for AII

[1328] Compounds of Formula I were tested for antagonist activity in rabbit aortic rings. Male New Zealand white rabbits (2-2.5 kg) were sacrificed using an overdose of pentobarbital and exsanquinated via the carotid arteries. The thoracic aorta was removed, cleaned of adherent fat and connective tissue and then cut into 3-mm ring segments. The endothelium was removed from the rings by gently sliding a rolled-up piece of filter paper into the vessel lumen. The rings were then mounted in a water-jacketed tissue bath, maintained at 37° C., between moveable and fixed ends of a stainless steel wire with the moveable end attached to an FT03 Grass transducer coupled to a Model 7D Grass Polygraph for recording isometric force responses. The bath was filled with 20 ml of oxygenated (95% oxygen/5% carbon dioxide) Krebs solution of the following composition (nM): 130 NaCl, 15 NaHC03, 15 KCl, 1.2 NaH2P04, 1.2 MgS04, 2.5 CaCl2, and 11.4 glucose. The preparations were equilibrated for one hour before approximately one gram of passive tension was placed on the rings. Angiotensin II concentration-response curves were then recorded (3×10−10 to 1×10−5 M). Each concentration of AII was allowed to elicit its maximal contraction, and then AII was washed out repeatedly for 30 minutes before rechallenging with a higher concentration of AII. Aorta rings were exposed to the test antagonist at 10−5 M for 5 minutes before challenging with AII. Adjacent segments of the same aorta ring were used for all concentration-response curves in the presence or absence of the test antagonist. The effectiveness of the test compound was expressed in terms of pA2 values and were calculated according to H. O. Schild [Br. J. Pharmacol. Chemother., 2,189-206 (1947)]. The pA2 value is the concentration of the antagonist which increases the EC50 value for AII by a factor of 2. Each test antagonist was evaluated in aorta rings from two rabbits. Results are reported in Table VI.

[1329] Assay C: In Vivo Intraduodenal Pressor Assay Response for AII Antagonists

[1330] Male Sprague-Dawley rats weighing 225-300 grams were anesthetized with Inactin (100 mg/kg, i.p.) and catheters were implanted into the trachea, femoral artery, femoral vein and duodenum. Arterial pressure was recorded from the femoral artery catheter on a Gould chart recorder (Gould, Cleveland, Ohio). The femoral vein catheter was used for injections of angiotensin II, mecamylamine and atropine. The tracheal catheter allow for airway patency, and the duodenal catheter was used for intraduodenal (i.d.) administration of test compounds. After surgery, the rats were allowed to equilibrate for 30 minutes. Mecamylamine (3 mg/kg, 0.3 ml/kg) and atropine (400 ug/kg, 0.3 ml/kg) were then given i.v. to produce ganglion blockade. These compounds were administered every 90 minutes throughout the test procedure. Angiotensin II was given in bolus does i.v. (30 ng/kg in saline with 0.5% bovine serum albumin, 0.1 ml/kg) every 10 minutes three times or until the increase in arterial pressure produced was within 3 mmHg for two consecutive AII injections. The last two AII injections were averaged and were taken as the control AII pressor response. Ten minutes after the final control AII injection, the test compound of Formula I (dissolved in sodium bicarbonate) was administered i.d. at a dose of 30 or 100 mg/kg in a volume of 0.2 ml. Angiotensin II injections were then given 5, 10, 20, 30, 45, 60, 75, 90, and 120 minutes after administration of the test compound and response of arterial pressure was monitored. The response to AII was calculated as percent of the control response and then the percent inhibition is calculated as 100 minus the percent control response. Duration of action of a test compound was defined as the time from peak percent inhibition to 50% of peak. One compound at one dose was tested in each rat. Each test compound was tested in two rats and the values for the two rats were averaged. Results are reported in Table IV.

TABLE IV
In Vivo and In Vitro Angiotensin II
Activity of Compounds of the Invention
Test
Compound
Duration	1Assay A			3Assay C
Example #	IC50	2Assay B	Dose	Inhibition
(min.)	(nM)	pA2	(mg/kg)	(%)
1	NT	NT	NT	NT	NT
2	95	7.37/7.59	10	95	60
			30	98	90-120
3	5.4	8.70 ± 0.2	10	50	>180
			30	100	200+
4	NT	NT	NT	NT	NT
5	200	7.48/6.91	30	38	20-30
6	1300	6.55/6.82	100	90	120
7	84	8.01/8.05	30	90	130
8	17,000	NT	NT	NT	NT
9	700	6.67/6.12	30	80	75
			100	100	130
10	4.9	8.19/7.59	3	86	100
			30	100	240
11	160	6.45/6.77	NT	NT	NT
12	6.0	8.66/8.59	NT	NT	NT
13	17	8.70/8.85	NT	NT	NT
14	7.2	8.84/8.71	NT	NT	NT
15	16	8.31/8.30	NT	NT	NT
16	6.4	8.95/9.24	NT	NT	NT
11	4.0	8.64/8.40	NT	NT	NT
18	970	6.14/6.09	NT	NT	NT
19	12,000	5.18/5.35	NT	NT	NT
20	78,000	5.89/5.99	100	10	45
21	87	7.71.7.21	NT	NT	NT
22	460	6.60/6.46	NT	NT	NT
23	430	6.48/7.15	NT	NT	NT
24	10	7.56/7.73	NT	NT	NT
25	480	6.80/6.73	NT	NT	NT
26	3.2	9.83/9.66	10	50	>180
27	180	NT	NT	NT	NT
28	570	5.57/6.00	NT	NT	NT
29	160	NT	NT	NT	NT
30	22	7.73/7.88	30	50	>180
31	14	NT	NT	NT	NT
32	16	7.68/7.29	NT	NT	NT
33	630	6.73/6.36	NT	NT	NT
34	640	5.34/5.69	NT	NT	NT
35	41	7.25/7.47	NT	NT	NT
36	1400	5.92/5.68	NT	NT	NT
37	340	6.90/6.85	NT	NT	NT
38	10	7.82/8.36	NT	NT	NT
39	10	7.88/7.84	NT	NT	NT
40	83	7.94/7.61	NT	NT	NT
41	3700	5.68/5.96	NT	NT	NT
42	370	6.56/6.26	NT	NT	NT
43	19	8.97/8.61	NT	NT	NT
44	16	8.23/7.70	NT	NT	NT
45	4.4	8.41/8.24	NT	NT	NT
46	110	6.80/6.64	NT	NT	NT
47	21	7.85/7.58	NT	NT	NT
48	680	6.27/6.75	NT	NT	NT
49	120	7.06/7.07	NT	NT	NT
50	54	7.71/7.89	NT	NT	NT
51	8.7	8.39/8.51	NT	NT	NT
52	100	8.14/8.12	NT	NT	NT
53	65	7.56/7.83	NT	NT	NT
54	3100	6.02	NT	NT	NT
55	80	6.56/7.13	NT	NT	NT
56	5.0	9.04/8.35	NT	NT	NT
57	2300	6.00	NT	NT	NT
58	140	6.45/6.57	NT	NT	NT
59	120	7.23/7.59	NT	NT	NT
60	2200	6.40/6.03	NT	NT	NT
61	110	7.29/7.70	NT	NT	NT
62	26	8.69/8.61	NT	NT	NT
63	61	7.77/7.67	NT	NT	NT
64	54	7.00/6.77	NT	NT	NT
65	23	7.85/7.75	NT	NT	NT
66	12	9.34/8.58	NT	NT	NT
67	3100	5.88/5.78	NT	NT	NT
68	8.6	8.19/8.65	NT	NT	NT
69	15	7.80/8.28	NT	NT	NT
70	44	7.71/8.05	NT	NT	NT
71	12,000	*	NT	NT	NT
72	83	6.11/6.10	NT	NT	NT
73	790	7.65/7.46	NT	NT	NT
74	6.5	8.56/8.39	NT	NT	NT
75	570	6.00/5.45	NT	NT	NT
76	5400	5.52/5.78	NT	NT	NT
77	15,000	5.77	NT	NT	NT
78	480	6.41/6.35	NT	NT	NT
NT = NOT TESTED
* Antagonist activity not observed up to 10 μM of test compound.
1Assay A: Angiotensin II Binding Activity
2Assay B: In Vitro Vascular Smooth Muscle Response
3Assays C/D: In Vivo Pressor Response (test compounds administered intraduodenally, except for compounds of Examples #3, #26 and #30 which were given intragastrically).

[1331] Assay D: In Vivo Effects of Chronic Infusion of Conjugate of the Invention

[1332] A conjugate of the invention as synthesized in Example 79 was evaluated biologically by in vivo assays to determine the ability of the conjugate to selectively inhibit renal action and thereby control blood pressure. This in vivo experiment was conducted to characterize the effects of the Example 79 conjugate on spontaneously hypertensive rats (SHR) by acute administration i.v. and by chronic administration i.v. The Example 18 compound or saline vehicle was infused continuously for four days in SHR. Mean arterial pressure was measured (Gould Chart Recorder, model 3800; Statham P23Db pressure transducer) via an indwelling femoral artery catheter between 10:00a.m. and 2:00 P. M. each day. The Example 79 conjugate (10 mg/hr) or saline was infused via a jugular vein catheter with a Harvard infusion pump. After administration of the Example 79 conjugate, there was observed a lowered mean arterial pressure as compared to the saline vehicle control as reported in Table V and also in FIG. 1. A test was conducted to determine whether the Example 79 conjugate would antagonize non-renal, vascular angiotensin II receptors. In this test AII was administered by bolus injection (100 ng/kg) to the SHR rats (described above) on the control day and on days 1, 3 and 4 during conjugate infusion. No evidence for systemic angiotensin II receptor antagonism was observed, given the similar pressor responses to injections of angiotensin II on the control day and days 1, 3 and 4 of infusion of the Example 79 conjugate (see FIG. 2). Tachycardia was observed on day 1 of the conjugate infusion, but heart rate was returned to control level during the next three days (see FIG. 3).

TABLE V
Effect of Ex. #79 Conjugate on Mean
Arterial Pressure: Chronic Administration
	Time (days):
	1	2	3	4
	Control	Ex. #18 Conjugate (10 mg/hr)
	MAP (mm Hg):	183	159	155	154	166
	(SD)	±5	±7	±4	±6	±9

[1333]

TABLE VI
Effect of Ex. #18 Conjugate on
All Pressor Response
	Time (days):
	1	3	4
	Control	Ex. #18 Conjugate (10 mg/hr)
	31	30	29	25
(SD)	±4	±6	±5	±3

[1334]

TABLE VII
Effect of Ex. #79 Conjugate on Heart Rate
	Time (days):
	1	2	3	4
	Control	Ex. #18 Conjugate (10 mg/hr)
	Beats/min.:	352	395	352	344	374
	(SD)	±9	±21	±12	±22	±20

[1335] Also embraced within this invention is a class of pharmaceutical compositions comprising one or more conjugates which comprises a first component selected from angiotensin II antagonist compounds of Formula I linked to a second component provided by an enzyme-cleavable moiety. Such pharmaceutical compositions further comprise one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as “carrier” materials) and, if desired, other active ingredients. The conjugates of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of a conjugate of the present invention required to prevent or arrest the progress of the medical condition are readily ascertained by one of ordinary skill in the art. The conjugates and composition may, for example, be administered intra-vascularly, intraperitoneally, subcutaneously, intra-muscularly or topically.

[1336] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the conjugate. Examples of such dosage units are tablets or capsules. These may with advantage contain an amount of conjugate from about 1 to 250 mg, preferably from about 25 to 150 mg. A suitable daily dose for a mammal may vary widely depending on the condition of the patient and other factors. However, a dose of from about 0.1 to 3000 mg/kg body weight, particularly from about 1 to 100 mg/kg body weight, may be appropriate.

[1337] The conjugate may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier. A suitable daily dose is from about 0.1 to 100 mg/kg body weight injected per day in multiple doses depending on the disease being treated. A preferred daily dose would be from about 1 to 30 mg/kg body weight. Conjugates indicated for prophylactic therapy will preferably be administered in a daily dose generally in a range from about 0.1 mg to about 100 mg per kilogram of body weight per day. A more preferred dosage will be a range from about 1 mg to about 100 mg per kilogram of body weight. Most preferred is a dosage in a range from about 1 to about 50 mg per kilogram of body weight per day. A suitable dose can be administered, in multiple sub-doses per day. These sub-doses may be administered in unit dosage forms. Typically, a dose or sub-dose may contain from about 1 mg to about 100 mg of active compound per unit dosage form. A more preferred dosage will contain from about 2 mg to about 50 mg of active compound per unit dosage form. Most preferred is a dosage form containing from about 3 mg to about 25 mg of active compound per unit dose.

[1338] The dosage regimen for treating a disease condition with the conjugates and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex and medical condition of the patient, the severity of the disease, the route of administration, and the particular conjugate employed, and thus may vary widely.

[1339] For therapeutic purposes, the conjugates of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the conjugate may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of conjugate in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The conjugates may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

[1340] Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations. Various equivalents, changes and modifications may be made without departing from the spirit and scope of this invention, and it is understood that such equivalent embodiments are part of this invention.

Claims

1. A conjugate comprising a residue of a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound, said conjugate being renal selective.

2. Conjugate of claim 1 comprising a first residue and a second residue, said first and second residues connected together by a cleavable bond, wherein said first residue is provided by said biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound, and wherein said second residue is capable of being cleaved from said first residue selectivity in the kidney.

3. Conjugate of claim 2 wherein said first and second residues are provided by precursor compounds wherein the precursor compound of one of said first and second residues has a reactable carboxylic acid moiety and the precursor of the other of said first and second residues has a reactable amino moiety or a moiety convertible to a reactable amino moiety, whereby a cleavable bond may be formed between said carboxylic acid moiety and said amino moiety.

4. Conjugate of claim 3 wherein said angiotensin II antagonist compound is selected from a class of compounds defined by Formula I:

5. Conjugate of claim 4 wherein m is one; wherein each of R1 through R11 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula

6. Conjugate of claim 5 wherein m is one; wherein each of R1 through R11 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, alkylthio, cycloalkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalklylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula

7. Conjugate of claim 6 wherein m is one; wherein each of R1 and R2 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula

8. Conjugate of claim 7 wherein m is one; wherein each of R1 and R2 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, benzoyl, phenoxy, phenoxyalkyl, phenalkyloxy, phenylthio, phenalkylthio, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula

9. Conjugate of claim 8 wherein m is one; wherein each of R1 and R2 is independently selected from alkyl, aminoalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, benzoyl, phenoxy, phenoxyalkyl, phenalkyloxy, phenylthio, phenalkylthio, aralkoxy, alkoxyalkyl, acetyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, mercaptoalkyl, mercaptocarbonyl, alkoxycarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, phthalimido, phthalimidoalkyl, imidazoalkyl, tetrazole, tetrazolealkyl, alkylthio, cycloalkylthio, and amino and amido radicals of the formula

10. Conjugate of claim 9 wherein m is one; wherein each of R1 and R2 is independently selected from amino, aminomethyl, aminoethyl, aminopropyl, CH2OH, CH2OCOCH3, CH2Cl, Cl, CH2OCH3, CH2OCH(CH3)2, I, CHO, CH2CO2H, CH(CH3)CO2H, NO2, Cl,

11. Conjugate of claim 10 wherein m is one; wherein R1 is selected from amino, aminomethyl, aminoethyl, aminopropyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, halo, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein R2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl and neopentyl; wherein each of R3, R4, R6, R7, R8, R10, and R11 is hydrido; wherein one of R5 and R9 is hydrido and the other of R5 and R9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH,

12. Conjugate of claim 3 wherein said second residue forms a kidney-enzyme-cleavable amide bond with the residue of said angiotensin II antagonist compound.

13. Conjugate of claim 3 wherein said second residue is preferably selected from a class of compounds of Formula II:

14. Conjugate of claim 13 wherein each G substituent is hydroxy.

15. Conjugate of claim 14 wherein each G substituent is hydroxy; wherein R50 is hydrido; and wherein R51 is selected from

16. Conjugate of claim 15 wherein said second residue is

17. Conjugate of claim 3 wherein said first residue is a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound containing a terminal primary or secondary amino moiety selected from amino and linear or branched aminoalkyl moieties containing linear or branched alkyl groups selected from aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminosecbutyl, aminoisobutyl, aminotertbutyl, aminopentyl, aminoisopentyl and aminoneopentyl.

18. Conjugate of claim 3 wherein said first residue is provided by a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound containing a moiety convertible to a primary or secondary amino terminal moiety.

19. Conjugate of claim 18 wherein said moiety convertible to an amino terminal moiety is a carboxylic acid group reactable with an amino moiety of a diamino-terminated linker group to provide a terminal amino moiety which may then be further reacted with a carboxylic acid moiety of a compound providing said second residue so as to form a hydrolyzable amide bond.

20. Conjugate of claim 19 wherein said diamino-terminated linker group is a divalent radical of Formula III:

21. Conjugate of claim 20 wherein each of R200 and R201 is hydrido.

22. Conjugate of claim 19 wherein said diamino-terminated linker group is a divalent radical of Formula IV:

23. Conjugate of claim 22 wherein said diamino-terminated linker group is a divalent radical of Formula V:

24. Conjugate of claim 23 wherein each of R202 and R203 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number independently selected from two through four, inclusive.

25. Conjugate of claim 24 wherein each of R202 and R203 is independently selected from hydrido, amino, monoalkylamino and carboxyl; and wherein each of p and q is independently selected from the numbers two and three.

26. Conjugate of claim 25 wherein each of R202 and R203 is hydrido; and wherein each of p and q is two.

27. Conjugate of claim 19 wherein said diamino-terminated linker group is a divalent radical of Formula VI:

28. Conjugate of claim 27 wherein each of R214 and R215 is hydrido; wherein each of R216 and R217 is independently selected from hydrido, alkyl, phenalkyl, phenyl, alkoxyalkyl, hydroxyalkyl, haloalkyl and carboxyalkyl; and wherein p is two or three.

29. Conjugate of claim 28 wherein each of R214 and R215 is hydrido; wherein each of R216 and R217 is independently selected from hydrido and alkyl; and wherein p is two.

30. Conjugate of claim 29 wherein each of R214, R215, R216 and R217 is hydrido; and wherein p is two.

31. Conjugate of claim 11 wherein said angiotensin II antagonist compound is selected from the group consisting of methyl 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylate; 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid, hydrazide; 4′-[(5-butyl-3-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3-butyl-5-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(2-cyclohexylethyl))-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-cyclohexanoyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-phenyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-phenylmethyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-benzoyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[3-butyl-5-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-dipropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-disecbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-diisobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-ditertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-dipentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-diisopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 5-[4′-[(5-butyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; and 5-[4′-[[3-butyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole.

32. Conjugate of claim 21 which is N-acetylglutamic acid, 5-[[4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]]carbonylhydrazide.

33. Conjugate of claim 17 which is N2-acetyl-N-[[5-butyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-1,2,4-triazol-3-yl]methyl]-L-glutamine.

34. Conjugate of claim 21 which is N-acetyl-L-glutamic acid, 5-[5-butyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl-1H-1,2,4-traizol-3-yl]acetylhydrazide.

35. A pharmaceutical composition comprising one or more pharmaceutically-acceptable carriers or diluents and a therapeutically-effective amount of a renal-selective conjugate, said renal selective conjugate comprising a residue of a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound.

36. The composition of claim 35 comprising a first residue and a second residue, said first and second residues connected together by a cleavable bond, wherein said first residue is provided by said biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound, and wherein said second residue is capable of being cleaved from said first residue selectivity in the kidney.

37. The composition of claim 36 wherein said first and second residues are provided by precursor compounds wherein the precursor compound of one of said first and second residues has a reactable carboxylic acid moiety and the precursor of the other of said first and second residues has a reactable amino moiety or a moiety convertible to a reactable amino moiety, whereby a cleavable bond may be formed between said carboxylic acid moiety and said amino moiety.

38. The composition of claim 37 wherein said angiotensin II antagonist compound is selected from a class of compounds defined by Formula I:

39. The composition of claim 38 wherein m is one; wherein each of R1 through R11 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, hetetoaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula

40. The composition of claim 39 wherein m is one; wherein each of R1 through R11 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, alkylthio, cycloalkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalklylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula

41. The composition of claim 40 wherein m is one; wherein each of R1 and R2 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula

42. The composition of claim 41 wherein m is one; wherein each of R1 and R2 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, benzoyl, phenoxy, phenoxyalkyl, phenalkyloxy, phenylthio, phenalkylthio, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula

43. The composition of claim 42 wherein m is one; wherein each of R1 and R2 is independently selected from alkyl, aminoalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, benzoyl, phenoxy, phenoxyalkyl, phenalkyloxy, phenylthio, phenalkylthio, aralkoxy, alkoxyalkyl, acetyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, mercaptoalkyl, mercaptocarbonyl, alkoxycarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, phthalimido, phthalimidoalkyl, imidazoalkyl, tetrazole, tetrazolealkyl, alkylthio, cycloalkylthio, and amino and amido radicals of the formula

44. The composition of claim 43 wherein m is one; wherein each of R1 and R2 is independently selected from amino, aminomethyl, aminoethyl, aminopropyl, CH2OH, CH2OCOCH3, CH2Cl, Cl, CH2OCH3, CH2OCH(CH3)2, I, CHO, CH2CO2H, CH(CH3)CO2H, NO2, Cl,

45. The composition of claim 44 wherein m is one; wherein R1 is selected from amino, aminomethyl, aminoethyl, aminopropyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, halo, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein R2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl and neopentyl; wherein each of R3, R4, R6, R7, R8, R10, and R11 is hydrido; wherein one of R5 and R9 is hydrido and the other of R5 and R9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH,

46. The composition of claim 37 wherein said second residue forms a kidney-enzyme-cleavable amide bond with the residue of said angiotensin II antagonist compound.

47. The composition of claim 37 wherein said second residue is preferably selected from a class of compounds of Formula II:

48. The composition of claim 47 wherein each G substituent is hydroxy.

49. The composition of claim 48 wherein each G substituent is hydroxy; wherein R50 is hydrido; and wherein R51 is selected from

50. The composition of claim 49 wherein said second residue is

51. Conjugate of claim 37 wherein said first residue is provided by a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound containing a terminal primary or secondary amino moiety selected from amino and linear or branched aminoalkyl moieties containing linear or branched alkyl groups selected from aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminosecbutyl, aminoisobutyl, aminotertbutyl, aminopentyl, aminoisopentyl and aminoneopentyl.

52. The composition of claim 37 wherein said first residue is provided by a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound containing a moiety convertible to a primary or secondary amino terminal moiety.

53. The composition of claim 52 wherein said moiety convertible to an amino terminal moiety is a carboxylic acid group reactable with an amino moiety of a diamino-terminated linker group to provide a terminal amino moiety which may then be further reacted with a carboxylic acid moiety of a compound providing said second residue so as to form a hydrolyzable amide bond.

54. The composition of claim 53 wherein said diamino-terminated linker group is a divalent radical of Formula III:

55. The composition of claim 54 wherein each of R200 and R201 is hydrido.

56. The composition of claim 53 wherein said diamino-terminated linker group is a divalent radical of Formula IV:

57. The composition of claim 56 wherein said diamino-terminated linker group is a divalent radical of Formula V:

58. The composition of claim 57 wherein each of R202 and R203 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number independently selected from two through four, inclusive.

59. The composition of claim 58 wherein each of R202 and R203 is independently selected from hydrido, amino, monoalkylamino and carboxyl; and wherein each of p and q is independently selected from the numbers two and three.

60. The composition of claim 59 wherein each of R202 and R203 is hydrido; and wherein each of p and q is two.

61. The composition of claim 53 wherein said diamino-terminated linker group is a divalent radical of Formula VI:

62. The composition of claim 61 wherein each of R214 and R215 is hydrido; wherein each of R216 and R217 is independently selected from hydrido, alkyl, phenalkyl, phenyl, alkoxyalkyl, hydroxyalkyl, haloalkyl and carboxyalkyl; and wherein p is two or three.

63. The composition of claim 62 wherein each of R214 and R215 is hydrido; wherein each of R216 and R217 is independently selected from hydrido and alkyl; and wherein p is two.

64. The composition of claim 63 wherein each of R214, R215, R216 and R217 is hydrido; and wherein p is two.

65. The composition of claim 45 wherein said angiotensin II antagonist compound is selected from the group consisting of methyl 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylate; 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid, hydrazide; 4′-[(5-butyl-3-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3-butyl-5-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(2-cyclohexylethyl))-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-cyclohexanoyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-phenyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-phenylmethyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-benzoyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[3-butyl-5-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-dipropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-disecbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-diisobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-ditertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-dipentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-diisopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 5-[4′-[(5-butyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; and 5-[4′-[[3-butyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole.

66. The composition of claim 55 wherein said angiotensin II antagonist compound is N-acetylglutamic acid, 5-[[4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]]carbonylhydrazide.

67. The composition of claim 51 wherein said angiotensin II antagonist compound is N2-acetyl-N-[[5-butyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-1,2,4-triazol-3-yl]methyl]-L-glutamine.

68. The composition of claim 55 wherein said angiotensin II antagonist compound is N-acetyl-L-glutamic acid, 5-[5-butyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl-1H-1,2,4-traizol-3-yl]acetylhydrazide.

69. A method for treating a circulatory disorder, said method comprising administering to a patient afflicted with or susceptible to said disorder a therapeutically-effective amount of a renal-selective conjugate, said renal-selective conjugate comprising a residue of a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound.

70. The method of claim 69 comprising a first residue and a second residue, said first and second residues connected together by a cleavable bond, wherein said first residue is provided by said biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound, and wherein said second residue is capable of being cleaved from said first residue selectivity in the kidney.

71. The method of claim 70 wherein said first and second residues are provided by precursor compounds wherein the precursor compound of one of said first and second residues has a reactable carboxylic acid moiety and the precursor of the other of said first and second residues has a reactable amino moiety or a moiety convertible to a reactable amino moiety, whereby a cleavable bond may be formed between said carboxylic acid moiety and said amino moiety.

72. The method of claim 71 wherein said angiotensin II antagonist compound is selected from a class of compounds defined by Formula I:

73. The method of claim 72 wherein m is one; wherein each of R1 through R11 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula

74. The method of claim 73 wherein m is one; wherein each of R1 through R11 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, alkylthio, cycloalkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalklylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula

75. The method of claim 74 wherein m is one; wherein each of R1 and R2 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula

76. The method of claim 75 wherein m is one; wherein each of R1 and R2 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, benzoyl, phenoxy, phenoxyalkyl, phenalkyloxy, phenylthio, phenalkylthio, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl wherein each of said heteroaryl- and cycloheteroalkyl-containing groups has one or more hetero ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 through R11 may be further independently selected from amino and amido radicals of the formula

77. The method of claim 76 wherein m is one; wherein each of R1 and R2 is independently selected from alkyl, aminoalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, benzoyl, phenoxy, phenoxyalkyl, phenalkyloxy, phenylthio, phenalkylthio, aralkoxy, alkoxyalkyl, acetyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, mercaptoalkyl, mercaptocarbonyl, alkoxycarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, phthalimido, phthalimidoalkyl, imidazoalkyl, tetrazole, tetrazolealkyl, alkylthio, cycloalkylthio, and amino and amido radicals of the formula

78. The method of claim 77 wherein m is one; wherein each of R1 and R2 is independently selected from amino, aminomethyl, aminoethyl, aminopropyl, CH2OH, CH2OCOCH3, CH2Cl, Cl, CH2OCH3, CH2OCH(CH3)2, I, CHO, CH2CO2H, CH(CH3)CO2H, NO2, Cl,

79. The method of claim 78 wherein m is one; wherein R1 is selected from amino, aminomethyl, aminoethyl, aminopropyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, halo, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein R2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl and neopentyl; wherein each of R3, R4, R6, R7, R8, R10, and R11 is hydrido; wherein one of R5 and R9 is hydrido and the other of R5 and R9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH,

80. The method of claim 71 wherein said second residue forms a kidney-enzyme-cleavable amide bond with the residue of said angiotensin II antagonist compound.

81. The method of claim 71 wherein said second residue is preferably selected from a class of compounds of Formula II:

82. The method of claim 81 wherein each G substituent is hydroxy.

83. The method of claim 82 wherein each G substituent is hydroxy; wherein R50 is hydrido; and wherein R51 is selected from

84. The method of claim 83 wherein said second residue is

85. The method of claim 71 wherein said first residue is a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound containing a terminal primary or secondary amino moiety selected from amino and linear or branched aminoalkyl moieties containing linear or branched alkyl groups selected from aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl, aminosecbutyl, aminoisobutyl, aminotertbutyl, aminopentyl, aminoisopentyl and aminoneopentyl.

86. The method of claim 71 wherein said first residue is provided by a biphenylalkyl 1H-substituted-1,2,4-triazole angiotensin II antagonist compound containing a moiety convertible to a primary or secondary amino terminal moiety.

87. The method of claim 86 wherein said moiety convertible to an amino terminal moiety is a carboxylic acid group reactable with an amino moiety of a diamino-terminated linker group to provide a terminal amino moiety which may then be further reacted with a carboxylic acid moiety of a compound providing said second residue so as to form a hydrolyzable amide bond.

88. The method of claim 87 wherein said diamino-terminated linker group is a divalent radical of Formula III:

89. The method of claim 88 wherein each of R200 and R201 is hydrido.

90. The method of claim 87 wherein said diamino-terminated linker group is a divalent radical of Formula IV:

91. The method of claim 90 wherein said diamino-terminated linker group is a divalent radical of Formula V:

92. The method of claim 91 wherein each of R202 and R203 is independently selected from hydrido, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q is a number independently selected from two through four, inclusive.

93. The method of claim 92 wherein each of R202 and R203 is independently selected from hydrido, amino, monoalkylamino and carboxyl; and wherein each of p and q is independently selected from the numbers two and three.

94. The method of claim 93 wherein each of R202 and R203 is hydrido; and wherein each of p and q is two.

95. The method of claim 87 wherein said diamino-terminated linker group is a divalent radical of Formula VI:

96. The method of claim 95 wherein each of R214 and R215 is hydrido; wherein each of R216 and R217 is independently selected from hydrido, alkyl, phenalkyl, phenyl, alkoxyalkyl, hydroxyalkyl, haloalkyl and carboxyalkyl; and wherein p is two or three.

97. The method of claim 96 wherein each of R214 and R215 is hydrido; wherein each of R216 and R217 is independently selected from hydrido and alkyl; and wherein p is two.

98. The method of claim 97 wherein each of R214, R215, R216 and R217 is hydrido; and wherein p is two.

99. The method of claim 79 wherein said angiotensin II antagonist compound is selected from the group consisting of methyl 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][l,1′-biphenyl]-2-carboxylate; 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid, hydrazide; 4′-[(5-butyl-3-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3-butyl-5-chloro-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-propyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-secbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-isobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-tertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-pentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-isopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(2-cyclohexylethyl))-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-cyclohexanoyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxo-2-cyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-phenyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-phenylmethyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(5-butyl-3-benzoyl-1,2,4,-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxo-2-phenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-dimethoxypropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-dimethoxybutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxopropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1-oxopentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-difluoroethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl)-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-difluoropropyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[3-butyl-5-(1,1-difluorobutyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[[5-butyl-3-(1,1-difluoropentyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-dipropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-isopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-disecbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-diisobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-ditertbutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-dipentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 4′-[(3,5-diisopentyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-carboxylic acid; 5-[4′-[(5-butyl-3-amino-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-aminomethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-aminoethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-aminopropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-aminobutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminophenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminophenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminophenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminomethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminomethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminoethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminocyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminocyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminocyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminomethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminomethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-aminoethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxy-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[(5-butyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxyphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxyphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxyphenylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4-[[3-butyl-5-(4-carboxymethylphenylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxymethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxyethylphenyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxycyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxycyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxycyclohexylethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxymethylcyclohexylmethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; 5-[4′-[[3-butyl-5-(4-carboxymethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole; and 5-[4′-[[3-butyl-5-(4-carboxyethylcyclohexyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole.

100. The method of claim 89 wherein said renal-selective conjugate is N-acetylglutamic acid, 5-[[4′-[(3,5-dibutyl-1H-1,2,4-triazol-1-yl)methyl][1,1′-biphenyl]-2-yl]]carbonylhydrazide.

101. The method of claim 85 wherein said renal-selective conjugate is N2-acetyl-N-[[5-butyl-1-[[2′-(1H-tetrazol-5-yl)[1,1-biphenyl]-4-yl]methyl]-1H-1,2,4-triazol-3-yl]methyl]-L-glutamine.

102. The method of claim 89 wherein said renal-selective conjugate is N-acetyl-L-glutamic acid, 5-[5-butyl-1-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl-1H-1,2,4-traizol-3-yl]acetylhydrazide.

103. The method of claim 69 wherein said circulatory disorder is a hypertensive-related disorder.

104. The method of claim 103 wherein said hypertensive-related disorder is chronic hypertension.

105. The method of claim 69 wherein said circulatory disorder is a sodium-retaining disorder.

106. The method of claim 105 wherein said sodium-retaining disorder is congestive heart failure.

107. The method of claim 105 wherein said sodium-retaining disorder is cirrhosis.

108. The method of claim 105 wherein said sodium-retaining disorder is nephrosis.