PT98807A - Process for the preparation of selective renal conjugates antagonistic to angiotensin II, containing a residue from a biphenylmethyl-1H-substituted 1,2,4-triazole, which are useful for the treatment of hypertension - Google Patents

Abstract

The present invention relates to a process for the preparation of selective renal compounds, which, in one of the embodiments, are pro-drugs that are converted, preferentially in the kidney, into compounds able to block the angiotensin II (AII) receptors. These pro- drugs are conjugates formed from two components, namely, a first component supplied by an AII antagonist compound and a second component which can be cleaved from the first component when both components are chemically bound inside the conjugate. The two components are chemically bound by means of a bond which is selectively cleaved in the kidney, by an enzyme for example. The AII antagonist compound released is then available for blocking the AII receptors in the kidney. Conjugates of particular interest are the glutamyl derivatives of biphenylmethyl- 1H-substituted triazole compounds, including the 5-[[4'- [(3,5-dibutyl-1H-1,2,4-triazol-1-ylmethyl][1,1'-biphenyl]- 2-yl]carbonyl]hydrazide of N-acetylglutamic acid, of which an example is presented below <IMAGE> Said process involves performing a reaction between the precursors of the first and second residues, in which one of the precursors must contain a reactive acid moiety, and the other precursor must contain a reactive amino moiety, so as to obtain a conjugate which has a cleavable bond, in which any of the precursors of the first and second residues can contain such reactive acid or amino moieties.

Description

Amateur Patent Application

This patent application is a continuation in part of U.S. Patent Application Serial No. 07 / 744,314 filed August 28, 1990.

Field of the Invention

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

BACKGROUND OF THE INVENTION The renin-angiotensin system is one of the hormonal mechanisms involved in the regulation of pressure / volume homeostasis and in the 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 angotensin II, the primary active species of this system. Angiotensin II is a potent vaso-constrictor agent and also produces other physiological effects such as promotion of aldosterone secretion, promotion of sodium and fluid retention, inhibition of renin secretion, increased activity of the nervous system increase the secretion of vasopressin, cause positive cardiac inotropic effect and modulation of other hormonal systems.

Previous studies have shown that antagonizing angio-tensin II in its receptors is a viable method to inhibit the renin-angiotensin system, given the essential role played by this octapeptide, which causes actions of the renin-angiotensin system through interaction with several tissue receptors. There are several known antagonists of angotensin II, most of which are peptidic in nature. Such peptidic compounds are of limited use because of their lack of oral bioavailability or their short duration of action. In addition, commercially available angiotensin II peptidic antagonists (for example Saralasin) have significant residual agonist activity which also limits their therapeutic application.

Non-peptidic compounds with angiotensin II antagonist properties are known. For example, the sodium salt of n-butyl-4-chloro-1- (2-chlorobenzyl) imidazole-5-acetic acid has competitive angiotensin II-specific antagonist activity as shown in a series of binding experiments, functional and in vivo tests [P. C. Wong et al, J. Pharmol. Exp. Ther., 247 (1). 1-7 (1988)]. Also, the sodium salt of 2-butyl-4-chloro-1- (2-nitrobenzyl) imidazole-5-acetic acid has competitive angiotensin-specific antagonist activity as shown in a series of binding experiments, functional assays and tests in vivo [A. T. Chiu et al, Eurooean J. Pharmacol., 157, 3121 (1988)]. A family of 1-benzoimidazole-5-acetate derivatives has shown to have competitive antagonistic properties specific for angiotensin II [A. T. Chiu et al., J. Pharmacol. Exp. Ther., 250 (3), 867-874 (1989)]. U.S. Patent No. 4,816,463 to Blankey et al discloses a family of 4,5,6,7-tetrahydro-1H-imidazo (4,5-c) tetrahydropyridine derivatives useful as anti- hypertensive drugs, some of which are reported to antagonize labeled angiotensin II binding to the rat adrenal receptor preparation and thereby cause a significant decrease in mean arterial blood pressure in conscious hypertensive rats. EP No. 253 310, published January 20, 1988, discloses 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 issued July 12, 1989 describes four classes of angiotensin II antagonists, namely, biphenylmethylpyrrolols, biphenylmethylpyrazoles, biphenylmethyl-1,2,3-triazoles and 4H-1,2,4-triazoles 4 substituted biphenylmethyl compounds, including the 3,5-dibutyl-4 - [(2'-carboxyphenyl-4-yl) methyl] -4H-1,2,4-triazole compound. U.S. Patent No. 4,880,804 to Carini et al discloses a family of biphenylmethylbenzimidazole compounds as angiotensin II receptor blockers for use in the treatment of hypertension and congestive heart failure.

A disadvantage of these angiotensin II antagonist compounds is that the effect of reducing hypertension can be compensated for by compensatory stimulation induced by hypotension of the renin-angiotensin system or stimulation of the sympathetic nervous system, either of which may result in the promotion of sodium retention and Water. Some angiotensin II antagonists may also have systemic toxicological effects, which prevents their use in doses necessary to be effective in reducing blood pressure.

To avoid such systemic side effects, drugs may be directed to the kidney by the creation of a conjugate compound which is a specific renal prodrug containing the drug modified with a chemical carrier moiety. Cleavage of the drug responsively to the carrier moiety by enzymes predominantly located in the kidney releases the drug into the kidney. Gamma-glutamyl-transpeptidase and acylase are examples of such cleavage enzymes found in the kidney, which can be used to cleave targeted drug from the vehicle of its prodrug into the kidney. -v Pro-directed drugs for the kidney are known for the administration of a drug selectively to the kidney. For example, the dopamine L-β-glutamyl amide compound, when administered to dogs, has been reported to generate dopamine in vivo by β-glutamyl transpeptidase-specific enzymatic cleavage [J. J. Kyncl et al., Adv. Biosc. . 20, 369-380 (1979)]. In another study, γ-glutamyl and N-acyl-γ-glutamyl derivatives of the antibacterial compound sulfamethoxazole have been shown to release relatively high concentrations of sulfamethoxazole in the kidney, which involved the enzymatic cleavage of the prodrug by the acylamino acid deacylase and γ- glutamyl-transpeptidase [M. Orlowskki et al, J. Pharmacol. Exp. Ther., 212. 167-172 (1980)]. The β-β-glutamyl derivatives of 2-, 3-, or 4-aminophenol and β-fluoro-L-phenylalanine have been shown to be readily solvololized in vitro by γ-glutamyl transpeptidase [S. D. J. Magnan et al., J. Med. Chem., 25, 1018-1021 (1982)]. The hydralazine vasodilator, 2-hydrazino-5-n-butylpyridine (which stimulates guanylate cyclase activity), when substituted with the N-acetyl-β-glutamyl residue, resulted in a prodrug that provided selective vasodilation renal [K. G. Hofbauer et al., J. Pharmacol. Exp. Ther. , 21, 838-844 (1985)]. The dopamine pro-drug, β-L-glutamyl-L-dopa (&quot; glu-dopa &quot;) has been shown to be relatively specific to the kidney and to increase renal blood flow, glomerular filtration and v. ... 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 may be blocked by the carbidopa dopa-decarboxylase inhibitor [R. F. Jeffrey et al, Br. J. Clin. Pharmac .. 7

25, 195-201 (1988)]. A class of 4-ureido derivatives of isoquinolin-3-ol has been investigated for specific renal effects, such as increased renal vasodilation and renal blood flow [R. M. Kanojia et al., J. Med. Chem. . 32, 990-997 (1989)].

BRIEF DESCRIPTION OF THE DRAWING FIGURES Fig. 1 is a graph showing the reduction of mean arterial pressure through intravenous administration of a conjugate of the invention to rats over a period of four days. 2 is a graph showing the pressure response to angiotensin II by administration of a conjugate of the invention to rats over a period of four days. Fig. 3 is a graph showing variation in heart rate following intravenous administration of a conjugate of the invention to rats over a period of four days.

DISCLOSURE OF THE INVENTION Treatment of circulatory disorders, which include cardiovascular disorders, such as chronic hypertension, disorders related to sodium retention such as congestive heart failure, cirrhosis and nephrosis, may be carried out by administration to a susceptible individual or suffering from said disorders, a therapeutically effective amount of a renal selective prodrug capable of causing blood pressure-lowering effects by means of selective action on the kidney. An advantage of this renal selective prodrug therapy is that it reduces or avoids adverse side effects associated with systemically acting drugs.

The advantages of a renal selective antihypertensive compound are several. Firstly, the renal selective compound is directed to the pathophysiological mechanisms that occur primarily in the kidney. In second place, the regulation of other organ systems is not affected; in this way, the normal physiological regulation of other organs is maintained. Third, fewer side effects can be expected, since the compound remains inactive until it is cleaved in the kidneys. Similarly, fewer negative drug-drug interactions can be predicted. Finally, since renal selective activation of the active compound, which is not dependent on levels of the parent compound in plasma, may occur, lower doses of the renal selective compound compared to the parent active compound may be used.

A renal selective prodrug is provided by a conjugate comprising a residue of an angiotensin II antagonist compound, which conjugate is renal selective. The term &quot; renal selective &quot; as used to characterize a conjugate of the invention, encompasses any of the following pharmacological actions: (1) o is selectively absorbed by the kidney and is selectively cleaved into the kidney; (2) the conjugate is not selectively absorbed by the kidney, but is selectively cleaved in the kidney; (3) the conjugate is selectively absorbed by the kidney and then cleaved into the kidney; or (4) when the conjugate itself is active as an angiotensin II antagonist, the conjugate is selectively absorbed by the kidney, without cleavage of the hydrolysable linkage. 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 cleavable, preferably, from the first residue. Cleavage of the first and second residues can be accomplished by a variety of mechanisms. For example, the linkage may be cleaved by means of an enzyme in the kidney. The residue providing the first component may be characterized as the &quot; active AII &quot; antagonist residue. This &quot; active residue &quot; may be provided by means of a compound having an AII antagonistic activity or by means of a metabolite of such a compound having AII antagonistic activity. The residue providing the second component may be characterized as being capable of forming a cleavable bond by bonding the first &quot; active &quot; and the second residue. Such binding is cleavable by means of an enzyme located in the kidney. In a preferred embodiment, such a cleavable bond is typically a hydrolysable amide bond, i.e., a bond between a carbonyl terminated moiety and the reactive moiety terminated in nitrogen, such as an amino terminated moiety, which may be cleaved by of an enzyme found in the kidney but which is not substantially cleaved by enzymes located in other organs or tissues of the body. Enzymes for binding cleavage can be found predominantly in the kidney. The conjugate containing the residue of an AII antagonist compound and containing the cleavable fragment or residue may possess AII antagonistic activity comparable to or greater 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 that of the AII antagonist component that forms the conjugate. In another embodiment of the invention, the conjugate will have AII receptor blocking activity lower than that of the AII antagonist component that forms the conjugate. One advantage of this differential activity between the conjugate and the AII antagonist component is that certain side effects associated with systemic, non-renal, blockage of the AII receptors can be avoided or reduced. For example, at least one conjugate of the invention has been shown to have a 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 it allows therapeutically effective antihypertensive doses of the conjugate to be administered so as to cause selective renal blocking action of the AII receptors resulting from the enzyme-specific hydrolysis of the kidney or metabolism of the conjugate in order to release the receptor blocker of active AII, into the kidney. To the extent that this renal selective conjugate has relatively low AII receptor blocking activity compared to that of the AII receptor antagonist compound forming the conjugate, this conjugate will have fewer adverse side effects associated with an undesired systemic interaction with Non-renal AIIs such as those found in the vascular bed.

DETAILED DESCRIPTION OF THE INVENTION The first residue of the conjugate can be selected from any class of compounds, or their metabolites, having angiotensin II antagonistic activity. An example of such an angiotensin II antagonist compound class is provided by a class of substituted biphenylalkyl-1H-1,2,4-triazole compounds defined by Formula I:

wherein m represents a number selected from one to four, inclusive; Wherein each of R1 to R2 is independently selected from hydrogen, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl alkoxycarbonyloxy, alkylcarbonylalkyl, alkoxycarbonylalkyl, aralkyloxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylcarbonylthio, alkylcarbonylthio, alkylcarbonylthio, alkylcarbonylthio, alkylcarbonylthio, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aryl alkylthio, heteroarylalkyl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, and cycloheteroalkylcarbonylalkyl, wherein each of the substituents selected from the group consisting of hydrogen, alkyl, arylalkylsulfonyl, arylsulfinyl, aralkylthio, aralkylsulfonyl, aralkylthioalkyl, said heteroaryl and cyclohetero containing groups have one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R 1 through R 11 may additionally be independently selected from amino radicals and starch of the formula: R 12 X R 14 X / N XR 13 / &quot; / R 15 1 (-fCH NC-R16 2 n, R18 X R19 X R21 R23 X - * ch2 + t; 1 MN - C / - N, XR20 &quot;; Wherein X represents an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R to R 2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R 2 and R 3 taken together, R 1 and R 1 taken together, R 16 and R 9 taken together, R 9 and R 29 taken together and R 2 and R taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and wherein the heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur and wherein the heterocyclic group may be

saturated or partially unsaturated; in which each of R 13. 14 15 19

and R 2 taken together, R 3 and R 4 taken together, R 13 20 2122 and R 3 taken together and R 2 and R taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and wherein the heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; And wherein each of R to R may also be independently selected from hydrogen and haloalkyl, and from acidic moieties of the formula:

-YA n wherein n represents a number selected from zero to three inclusive, and wherein A represents an acidic group selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic portions; wherein Y represents 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 ; And wherein any of the aforementioned groups R to R, Y and A having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, trifluoromethyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyloxy, arylthio, arylthio, alkylthio, arylthio, alkyl, arylsulfinyl, arylsulfinyl, arylsulfinyl,

aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino or starch radicals of the formula:

X is selected from an oxygen atom and a sulfur atom; wherein each of R 25, R 26, R 27, R 28 and R 25 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR and

R 31 /

-N-

Wherein D is selected from an oxygen atom and a sulfur atom and R 30 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 25, R 26, R 27, R 28, R 29, R 29 and R 32 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxy, alkylsulfinyl, alkylsulphonyl, arylsulfinyl, arylsulphonyl, haloalkylsulfinyl, haloalkylsulphonyl, aralkyl and aryl, and wherein each of R 25, R 26, R 27, R 28, R 29, R 31 and R 32 is also independently selected from amino and amido radicals of the formula: R33 X R35 X / &quot; N, -CN and -NC-R NR34 &gt; R38 wherein X is an oxygen atom or a sulfur atom; wherein each of R33, R34, R35, R36, R37 and R38 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl aralkyl and aryl; wherein each of R 26 and R 23 taken together and each of R 21 and R 21 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido , wherein the heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur atoms and wherein the heterocyclic group may be saturated or 2-6

partially unsaturated; wherein each of R3 and R3 taken together and each of R4 and R4 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and wherein the the heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; with the proviso that at least one of said R1 to R24, Y and A substituents contain a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof.

The conjugates of this invention are therapeutically effective in the treatment of cardiovascular disorders by direct action, or by providing cleavable components selected from compounds of Formula I, such as angiotensin II receptor (IIA) antagonists. Thus, the conjugates of Formula I may be therapeutically effective in the treatment of cardiovascular disorders or may be precursors to, or prodrugs of, therapeutically effective medicaments.

Preferred compounds of Formula I, from which a cleavable component may be selected, are all characterized by having a substituent, other than hydrogen, at each of either the four and five positions of the imidazole ring. Such substituents are selected from the above-mentioned R 1 and R groups. Also especially useful are compounds having one of the substituents R and R selected from alkylcarbonyl, monoalkoxyalkyl, dialkoxyalkyl and difluoroalkyl groups. When the substituent selects. It is particularly useful that both fluoro atoms of the difluoroalkyl group will replace the carbon atom of the difluoroalkyl group attached to the R or R positions of the thaazole ring. Such a difluoro alkyl group may be characterized as a "difluoro-difluoro-substituted alpha carbon" group, or as an "alpha, alpha-difluoro-substituted alkyl group". When the substituent selected for 12. . R or R is monoalkoxyalkyl or dialkoxyalkyl, then it is particularly useful with respect to the single alkoxy group or the two alkoxy groups, respectively, to substitute the carbon atom of the selected substituent, which is attached to the R or R positions of the thaazole ring . Such alkoxyalkyl groups may be characterized as &quot; alkoxyalkyl groups monoalkoxy- or dialkoxy-substituted on alpha carbon &quot;, respectively, or &quot; alpha-monoalkoxy-substituted or alpha, alpha-dialkyl-substituted alkyl groups respectively. When the selected substituent is alkoxycarbonyl, then it is particularly useful for the carbonyl group to be attached at the R1 or 2R positions of the thaazole ring. Such an alkylcarbonyl group may be characterized as &quot; an alpha-oxo-substituted alkyl group &quot; and may be exemplified by the 1-oxoethyl, 1-oxopropyl and 1-oxobutyl substituents. When compounds of Formula I contain any of the aforementioned particularly useful alpha-substituted R or R groups on the three or five position of the triazole ring, it is preferred that such a particularly useful group is attached to the three position, i.e., as an R1 substituent. The phrase &quot; acidic group selected so as to contain at least one acidic hydrogen atom &quot; as used to define the -YA moiety, is intended to encompass chemical groups which, when attached to any of the R-to R-positions of Formula I, impart acidic character to the compound of Formula I. &quot; Acidic character &quot; means proton-donating ability, i.e. the ability 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 so as to have proton-donating ability such that the product compound of Formula I has a pKa in the range of about one to about twelve. More typically, the compound of Formula I should have a pKa in the range of about two to about seven. An example of an acidic group containing at least one acidic hydrogen atom is the carboxyl group (-COOH). When n is zero and A is -COOH, in the -YA moiety, such a carboxyl group should be attached directly to one of the R to R positions. The compound of Formula I may have a -YA moiety attached to one of the R-to R positions, or may have a series of such -YA moieties attached to more than one of the R-positions R a R up to a maximum of nine of such portions -Y AA.

There are many examples of acidic groups other than the carboxyl group, which may be selected so as to contain at least one acidic hydrogen atom. These other acidic groups may be collectively referred to as &quot; carboxylic acid bioisosters &quot; or referred to as &quot; acidic bioisosters &quot;. Specific examples of such acidic bioisosters are described further below in this specification. Compounds of Formula I having the -YnA moiety attached to one of the R 1, R 6, R 8 and R 9 positions should be expected to have preferred properties, although attachment at R or R may be most preferred. and

A preferred class of compounds within the subclass defined by Formula I consists of those compounds wherein m represents one; wherein each of R1 to R11 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkyloxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiocarbonylthio, alkylthiocarbonylthio, alkylthiocarbonylthio, arylthiocarbonylthio, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiothiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonylthio, aralkylthiocarbonylthio, thiothiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl

cycloheteroalkylcarbonylalkyl, wherein each of said heteroaryl and cycloheteroalkyl containing groups has one or more ring heteroatoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R 1 through R 11 may additionally be independently selected from amino and amido radicals of the formula:

R12 X R14 X / &quot;## STR2 ## embedded image V5-NCH2- NC-R 2 n | i17 R18 X R19 X R21 R23 X1 / &quot; / 1 &quot;## STR1 ## wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; wherein each of R 1 to R 2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R to R may also be independently selected from hydrogen and haloalkyl, and from acidic moieties of the formula:

20 y 20 20

.26

X II -C-R 25

-N wherein n represents a number selected from zero to three, inclusive; and wherein A represents 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 so as to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y represents 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 ; 124 and in which any of the aforementioned R, Y, and A groups having a substitutable position may be substituted by one or more groups selected from alkyl, alkenyl, aralkyl, hydroxyalkyl, trifluoromethyl, difluoroalkyl, alkoxy , aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercaptocarbonyl, alkylthio, alkylthiocarbonyl, and amino or amido radicals of the formula:

X

II 28

and -NC-R27 wherein X is selected from an oxygen atom and a sulfur atom; wherein each of R 25, R 26, R 27, R 28 and R 29 is selected from hydrogen, alkyl, cycloalkyl, 3 ciclo cycloalkylalkyl, aralkyl, aryl, and DR and

31 -N

Wherein D is selected from an oxygen atom and a sulfur atom, and R 39 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R25, R26, R27, R28, R29, R31 and R32 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl , aralkyl and aryl, and wherein each of R 25, R 26, R 27, R 28, R 29, R 31 and R 32 is also independently selected from amino and amido radicals of the formula:

-N

X &quot; / -CN .35

And wherein X is selected from an oxygen atom or a sulfur atom; Wherein each of R to R 2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, and aryl; with the proviso that at least one of said 24, R to R, Y and A substituents contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof.

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 to R11 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl alkoxycarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, alkylthio, cycloalkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylthioalkylthio, aralkylthioalkylthio, , aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl groups, wherein each of said heteroaryl and cycloheteroalkyl containing groups has one or more heteroatoms of selected ring s from oxygen, sulfur and nitrogen atoms, and wherein each of R 1 through R 11 may additionally be independently selected from amino and starch radicals of the formula: ????????

-CH 2 R 13 X R 14 &quot; / CNV 5 X II -fCH, - NC-R 2 n | il7 16 23

R18 X

-CH2-N-C

-CH 2 'n 20 X R &quot; / OCN \ 21

Wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R to R 2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; And wherein each of R to R may also be independently selected from hydrogen and haloalkyl, and from acidic moieties of the formula: wherein n is a number selected from zero to three, inclusive; wherein A is selected from a carboxylic acid and carboxylic acid bioisosters selected from:

w W • 1 II P-WH, -P-NH and t -P-WH or -41

Wherein each W is independently selected from an oxygen atom, a sulfur atom and NR, in each of R, R1, R2, R3, R 2, R 3 and R 4 are independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R 1, R 2, R 3 and R 4 may also be independently selected from an amino radical of the formula:

Wherein each of R1 and R2 is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R3 and R4 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, wherein the heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur atoms and wherein the the heterocyclic group may be saturated or partially unsaturated; wherein R and R taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and wherein the aromatic heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from of oxygen, nitrogen and sulfur; wherein each of R¹ and R² may also be independently selected from hydroxy, alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and aralkoxy; and the amide, ester and salt derivatives of said acidic groups; Wherein said carboxylic acid bioisostere may also be selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, wherein the ring contains at least one heteroatom selected from oxygen atoms , sulfur and nitrogen, wherein said heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and wherein the heterocyclic ring may be attached at a single position selected from R to R or may be attached to any two adjacent positions Are selected from R to R so as to form a ring system condensed with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y represents a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; And any of the aforementioned groups R to R, Y and A 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 or amido radicals of the formula:

X II -C-R

X

II 25

-N 28

and -NC-R27 wherein X is selected from an oxygen atom and a sulfur atom; wherein each of R, R, R, R and R is selected from hydrogen, alkyl, cycloalkyl, Cycloalkylalkyl, aralkyl, aryl and DR and

R 31 /

-N-

Wherein D is selected from an oxygen atom and a sulfur atom, wherein R is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R25, R26, R27, R28, R29, R31 and R32 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl aralkyl and aryl; with the proviso that at least one of said R1 to R, Y and A substituents contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof.

An even more preferred class of compounds within the subclass 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, alkylcarbonyloxy-alkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl , aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl groups, wherein each of said heteroaryl and cycloheteroalkyl containing groups has one or more heteroatoms rings selected from atoms oxygen, sulfur and nitrogen, and wherein each of R 1 through R 11 may additionally be independently selected a. amino and starch radicals of the formula:

-CH 2 -NR 13 M + CNV ???????? * 17 16

R18 X N ~ c R / N, \ 19

-CH 2n 20 X R &quot; / OCN \ 21 22

Wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R to R 2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; Wherein each of R to R 2 is independently selected from hydrogen, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl alkenyl, cycloalkenyl, alkynyl, cycloalkyl, cyano, nitro, carboxyl, alkylthio, aralkylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulphonyl, arylsulfinyl, arylsulphonyl and heteroaryl groups having one or more ring atoms selected from of oxygen, sulfur and nitrogen atoms; And wherein each of R to R may also be independently selected from acidic moieties of the formula:

'Y n A wherein n represents a number selected from zero to three, inclusive; wherein A is selected from a carboxylic acid and carboxylic acid bioisosters selected from:

W II -C-WH, -S-WH, W W II II S-WH and -P-WH II W WR

-OH, -SH, -NR 39, wherein each W is independently selected from an oxygen atom, a sulfur atom and NR 39 R 43 in each of R 1, R 2 and R 3 is independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R 39 and R 42 may also be independently selected from an amino radical of the formula:

Wherein each of R1 and R2 is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl. And wherein R and R taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, wherein the heterocyclic group may additionally contain one or more heteroatoms as members of ring selected from oxygen, nitrogen and sulfur atoms and wherein the heterocyclic group may be. Saturated or partially unsaturated; wherein R and R taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and wherein the aromatic heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from of oxygen, nitrogen and sulfur; and the amide, ester and salt derivatives of said acidic groups; wherein said carboxylic acid bioisostere may also be selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, wherein the ring contains at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, wherein said heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and wherein the heterocyclic ring may be attached at a single selected position a. 3 11. from R to R or may be attached to any two adjacent positions selected from R to R so as to form a ring system fused to one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acid groups; wherein Y represents a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; a and wherein each of R to R, Y and A may be independently substituted in 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; with the proviso that at least one of said substituents 1 24. R 2 to R 3, Y and A contain a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof.

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

R12

X .14

/ -FCH N 2 η χ R 13

&quot; / - + CH 2 - CN

R17

R18 X R / N, \ 19

2 H-NMR

X R &quot; / OCN 21

23 R X

Wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R1 to R2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl and phenyl; Wherein each of R through R is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio, mercapto and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; And wherein each of R to R may be an acidic moiety also independently selected from acyclic moieties of the formula: wherein n is a number selected from zero to two, inclusive ; and wherein A is selected from a carboxylic acid and carboxylic acid bioisosters selected from:

W II -C-WH, -S-WH, w W H II S-WH and -P-WH 11 I 1 42 W WR

Wherein each W is independently selected from an oxygen atom, a sulfur atom and NR2, in each of R1, R2 and R3 is independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benzyl; wherein each of R4 and R4 'may also be independently selected from an amino radical of the formula:

R44 /

Wherein each of R1 and R2 is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, benzyl and phenyl; and the amide, ester and salt derivatives of said acidic groups; wherein said carboxylic acid bioisostere may also be selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, wherein the ring contains at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, wherein said heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and wherein the heterocyclic ring may be attached at a single position selected from 3 '. . R 2 to R 3 may be attached to any two adjacent positions selected from R to R so as to form a ring system fused to one of the phenyl rings of the biphenyl moiety of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y represents a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenalkyl and aralkyl; and wherein each of R1 to R1, Y and A may be independently substituted at any substitutable position with one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, oxo, trifluoromethyl, difluoroal alkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy groups; With the proviso that at least one of said R 1 substituents up to R 1, Y and A contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof.

An even more highly preferred class of compounds within Formula I consists of those compounds wherein m is 1; wherein each of R1 and R2 is independently selected from alkyl, aminoalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, benzoyl,. alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, mercaptoalkyl, mercaptocarbonyl, alkoxycarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonylalkyl, aralkoxycarbonylalkyl, alkoxycarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkoxycarbonylalkyl, phthalimidoalkyl, tetrazole, tetrazolealkyl, alkylthio, cycloalkylthio, and amino and amido radicals of the formula: m

R12 X R14 X / &quot;## STR2 ## R 18 X R 19 X R 21 R 23 X 1 · / &quot; / 1 &quot; - + CH2 * 5 N-C-N, XR20 -fCH, -) - OCN, and R22 is -CH2 &gt; n &quot; Wherein X is selected from an oxygen atom or a sulfur atom; Wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R to R 2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl and phenyl; Wherein each of R to R 2 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkoxy, alkoxyalkyl, acetyl alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; And wherein each of R 1 to R 2 may be an acidic moiety also independently selected from acylic moieties consisting of CO 2 H, CO 2 CH 3, SH, CH 2 SH, C 2 H 4 SH, P 3 H 2, NHSO 2 CF 3, NHSO 2 C 6 F 5, SO 3 H, CONHNH 2, COOHNHSO 2 CF 3 , CONHOCH 3, CONHOC 2 H 5, CONHC F 3, OH, CH 2 OH, C 2 H 4 OH, O P 3 H 2, SO 3 H, 36 Λ

selected from H, Cl, CN, NO 2, CF 3, C 2 F 5, C 3 F ', CHF 2, CH 2 F, CO 2 CH 3, CO 2 C 2 H 5, SO 2 CH 3, SO CF 3 and SO 2 C 6 F 5; wherein Z is selected from O, S, NR 4 and CH 2; wherein R49 is selected from hydrogen, CH3 and CH2 CgH5; and wherein said acidic moiety may be a heterocyclic acidic group attached to any two adjacent positions selected from R to R so as to form a fused ring system which includes one of the phenyl rings of the biphenyl moiety of Formula , 4 37 37

I, said biphenyl condensed ring system being selected from

and the amide, ester and salt derivatives of said acidic moieties; with the proviso that at least one of said R 1 to R 2 substituents contains a primary or secondary amino terminus or a moiety convertible to a primary or secondary amino terminus; or a tautomer or a pharmaceutically acceptable salt thereof.

A class of compounds of particular interest within the subclass defined by Formula I consists of those compounds wherein m represents one; wherein each of R 1 and R 2 is independently selected from amino, aminomethyl, aminoethyl, aminopropyl, CH 2 OH, CH 2 OCOCH 3, CH 2 OCH (CH 3) 2, I, CHO, CH 2 Cl,

Cl,

N-N

-CHa-C-N-N

CH 2 CO 2 H, CH (CH 3) CO 2 2H, NO 2, Cl, I CH 2 OCOCH 2 CH 2

-CH 2 NHCO 2 C 3 H 7, -CH 2 NHCO 2 C 3 H 7, -CH 2 NHC 2 CH 2 (CH 3), -CH 2 NHC 2 C 4 Hg, -CH 2 NHC 2 - adamantyl, -CH 2 NHC 2 - (1- naphthyl), -CH2NHCONHCH3, -CH2NHCONHC2H5, -CH2NHCONHC3H7, -CH2NHCONHC4Hg, -CH2NHCONHCH (CH3) 2, -CH2NHCONH (1-naphthyl), -CH2 NHCONH (1-adamantyl), CO2CH2 -CH2 -CH2 -CO- , -CH2CH2CH2CO2H, -CH2CH2F, -CH2OCONHCH3, -CH2OCSNHCH3, -CH2NHCSOC3H7, -CH2CH2CH2F, -CH2 NO2,

-ch2o - &lt; 2 &gt; wherein R 1, R 2, R 3 and R 4 are independently selected from the group consisting of 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, dimethoxypentyl, hydroxyalkyl, halo, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 39

• 3 11 1,1-difluoropentyl; and wherein each of R 1 to R 2 is hydrogen, with the proviso that at least one of R 5, R 6, R 6 and R 8 represents an acidic group selected from CO 2 H, SH, P 3 H 2, SO 3 H, CONHNH 2, HNHSO2 CF3, OH, HIN-N '/' Λ. N '

H I N-N N

r46

H

selected from Cl, CN, NO 47 R and independently 2, CF 3, CO 2 CH 3 and SO 2 CF 3; with the proviso that at least one of said R1 to R11 substituents contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof.

A class of compounds of more particular interest within the subclass defined by Formula I consists of those compounds wherein m represents 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, 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 R is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl and neopentyl; wherein each of R 3, R 4, R 6, R 5, R 5, R 5, and R 11 is hydrogen; in one of 59. 5 9

between R 1 and R 2 is hydrogen and the other of R 1 and R 2 represents an acidic group selected from CO 2 H, SH, po 3 H 2, SO 3 H, CONHNH 2, CONHNHSO 2 CF 3, OH, H 1 NHIN-N 1 N-N and N wherein each of R¹ and R² is independently selected from Cl, CN, NO₂, CF,, CO₂CH e and SO₂CF;; with the proviso that at least one of said R1 to R11 substituents contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. The second component of a conjugate of the invention is provided by a residue which forms an amide cleavable amide bond in the kidney with the residue of the first compound compound AII antagonist. This residue is preferably selected from a class of compounds of Formula II; 41

(I.e.

II

Ο C-G &quot; Wherein each of R 5 and R 51 may be independently selected from hydrogen, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein G is • 52 53

selected from hydroxyl, halo, mercapto, -OR, -SR and / or wherein each of R 1, R 2 and R 3 is independently selected from alkyl; and wherein R may be further selected from hydrogen; with the proviso that said cleavable bond is within an amide group formed between the first and second residues, wherein said first residue has a terminal primary or secondary amino moiety provided by one of said R 1 to R 11 substituents of said Formula I or provided by a linker group attached to one of said R 1 --R 3 substituents of Formula I, and wherein said second residue has a carbon bond attached to the carbon of the gamma position of said compound of Formula II, wherein amide bond is formed from the amine moiety of said first residue and the carbonyl moiety of said second residue. More preferred compounds of Formula II are those in which each G is hydroxy. 42

A class of highly preferred racemic compounds within Formula II consists of those compounds wherein each G is hydroxy; wherein R 5 is hydrogen; and wherein R51 is selected from

O

II «« 55

-CR 55. wherein R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and chloromethyl.

A more highly preferred compound of Formula II is N-acetyl-β-glutamic acid, which provides a residue for the second component of a conjugate of the invention as shown below:

0 COOH

&quot; I

-CCH CH CHNHCCH Γ Ζ β α &quot; The phrase &quot; primary or secondary amino terminal portion or a moiety convertible to a primary or secondary amino terminal portion &quot; discloses a structural requirement regarding the selection of an appropriate angiotensin II antagonist compound as the &quot; first &quot; active &quot; of a conjugate of the invention. Such an amino-terminal moiety must be available to react with a carboxyl terminal portion of the second cleavable residue to form a specific enzymatically hydrolyzable binding in the kidney.

In one embodiment of the invention, the first component used to form a conjugate of the invention provides 43

a first residue derived from an angiotensin II antagonist compound containing a primary or secondary amino terminus. Examples of such an amino terminal moiety are amino and linear or branched aminoalkyl moieties containing linear or branched alkyl groups selected from aminomethyl, aminoethyl, aminopropyl, amino-isopropyl, aminobutyl, amino-sec -butyl, amino-isobutyl, amino-tert-butyl butyl, aminopentyl, amino-isopentyl and amino-neopentyl groups.

In another 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 moiety convertible to a primary or secondary amino terminus. An example of a moiety that can be converted to an amino terminal moiety is a carboxylic acid group which has been reacted with hydrazine in order to convert the acid moiety to carboxylic acid hydrazide. The hydrazide moiety thus contains the amino terminal portion which can then be further reacted with the carboxylic acid-containing second component residue to form a hydrolysable amide linkage. Such a hydrazide moiety thus constitutes a &quot; linker &quot; between the first and second components of a conjugate of the invention.

Suitable linker groups may be provided by a class of diamino terminated linker groups based on hydrazine as defined by Formula III: R200 R201

Wherein each of R200 and R201 may be independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, haloalkyl, amino, monoalkylamino, dialkylamino, cyanoamino, carboxyalkyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; and wherein n is zero or a number selected from three to seven inclusive. In Table I is presented a class of specific examples of diamino terminated linker groups within the scope of Formula III, identified as Linker Nos. 1-73. These linker groups may be suitable for forming a conjugate between the carbonyl moiety of an AII antagonist (designated &quot; I &quot;) and a carbonyl moiety of a second carbonyl terminated residue such as the carbonyl portion of the gamma carbon of a glutamyl residue (designated as &quot; T &quot;).

TABLE I

I - N N T I 2 n | R200 R201 I = inhibitor T = acetyl-γ-glutamyl

LINER NO. n R201 R201 1 0 HH 2 0 CH 3 H 3 0 C 2 H 5 H 4 0 C 3 H 7 H 5 0 CH (CH 3) 2 H 6 0 C 4 H 9 H 7 0 CH (CH 3) CH 2 CH 3 H 8 0 c (ch 3) 3 H 9 0 C 5 H 9 H 10 0 C 6 H 11 (cycl °) H 11 0 C 6 H 5 H 12 0 CH 2 C 6 H 5 H 46 NO. n r200 R201 13 0 H CH3 140 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 C6 H13 22 0 H C6 H5 23 0 H CH2 C6 H5 24 0 H C6 H11 (cyclo) 25 0 C6 H13 H 26 0 CH3 CH3 27 0 C2H5 C2H5 28 0 C3H7 C3H7 47 1 LINER 1 NO. 1 n r200 R201 | 1 1 29 0 CH (CH 3) 2 CH (CH 3) 2 30 0 C 4 H 9 C 4 H 9 31 CH (CH 3) CH 3 CH 3 CH (CH 3) CH 2 CH 3 32 (CH 3) 3 C (CH 3) 333. C5H9 C5H9 34 0 C6H13 C6H13 35 0 C6H11 (cycl) C6H11 (cycl) 36 0 C6H5 C6H5 37 0 CH2C6H5 CH2C6H5 38 3 H H 39 3 CH 3 H 40 3 H CH 3 41 3 C 6 H 5 H 42 3 H C 6 H 5 43 3 ch 3 C 6 H 5 48

1 1 LINER 1 NO. 1 n R200 i 1 1 44 3 C6H5 CH3 45 3 CH2C6H5 H 46 3 H CH2C6H5 47 4 H H 48 4. CH 3 H 49 4 H CH 3 50 4 C 6 H 5 H 51 4 H C 6 H 5 52 4 CH 3 C 6 H 5 53 4 C 6 H 5 CH 3 54 4 CH 2 C 6 H 5 H 4 H CH 2 C 6 H 5 56 5 H H 57 5 ch 3 H 58 5 H CH 3 59 5 C 6 H 5 H

LINER NO. n R201 R201 60 5 H C6 H5 61 5 CH3 C6 H5 62 5 C6 H5 CH3 63 5 CH2 C6 H5 H6 5 H CH2 C6 H5 65 6 HH 66 6 CH 3 H 67 6 H CH 3 68 6 C 6 H 5 H 69 6 H C 6 H 5 70 6 CH 3 C 6 H 5 71 6 C 6 H 5 CH 3 72 6 CH 2 C 6 H 5 H 73 6 H CH 2 C 6 H 5 50

Another class of suitable diamino terminated linker groups is defined by Formula IV:

(IV) wherein each of Q and T represents one or more groups independently selected from

R 202 and R 202 are each independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy , aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl.

A preferred class of linker groups within Formula IV is defined by Formula V: 51

Wherein each of R1 and R2 is independently selected from hydrogen, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxy, carboxy alkyl and alkanoyl; and wherein each of p and q represents a number independently selected from one to six, inclusive; with the proviso that when each of R and R3 is selected from halo, hydroxy, amino, monoal- • 202

and the carbon to which either R or R is attached in Formula V is not adjacent to a nitrogen atom of Formula V.

A preferred class of linking groups of Formula V2 02 consists of divalent radicals each of R320 and. R 2 is independently selected from hydrogen, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q represents a number independently selected from two to four, inclusive, and more preferred are the linker groups wherein each of R1 and R2 is independently selected from hydrogen, amino, monoalkylamino and carboxyl; and wherein each of p and q represents a number independently selected from the two and three numbers. Most preferred is a linker group wherein each of R 203 and R 9 is hydrogen; and wherein each of p and q represents two; this most preferred linker group is derived from a piperazinyl group and has the structure -N N -

A class of specific examples of cyclized diamino terminated linker groups within the scope of Formula V are set forth in Table II. These linker groups, identified as Binder Nos. 74-95 may be suitable for forming a conjugate between the carbonyl moiety of an AII antagonist (designated &quot; I &quot;) and a carbonyl moiety of a second carbonyl terminated residue such as the carbonyl portion of the gamma carbon of a glutamyl residue (designated as &quot; T &quot;).

TABLE II R209 r212

I = inhibitor T = acetyl-γ-glutamyl BINDER R206 NO. r207 R2 08 R209 R210 R211 R212 R213 74 HHHHHHH 75 CH3 HHHHHH 76 HHH CH3 HHH 77 CH3 HHH CH3 HHH 78 CH3 H CH3 HHHHH 79 CH3 HHHHH CH3 H 80 CH3 CH3 HHHHHH 81 HHHH CH3 CH3 HH 82 CH3 O) HH 83 CH 3 CH 3 CH 3 CH 3 H HHH 84 CH 3 CH 3 HHHH CH 3 CH 3 54 ι

LINER NO. r2 ° 6 R207 R2 08 r209 R210 R211 R212 R213 85 H H H CH3 CH3 CH3 CH3 86 C6H5 H H H H H H H H H C6H5 H H 88 C6H5 H H H C6H5 H H 89 C6H5 H H. H H H C6H5 H 90 C6H5 H C6H5 H H H H H H H H H H H H C H H H H H H H H H H H H H H H H H H H H H H H H H H H H 55 H

Another class of diamino terminal linker groups is defined by Formula VI:

Wherein each of R to R 2 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, aryl, halo (C 1 -C 6) alkyl, , amino, monoalkylamino, dialkylamino, cyanoamino, carboxyalkyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; and wherein p represents a number selected from one to six inclusive.

A preferred class of linker groups within Formula VI consists of divalent radicals wherein each of R 1 and R 2 represents hydrogen; wherein each of R1 and R2 is independently selected from hydrogen, alkyl, phenalkyl, phenyl, alkoxyalkyl, hydroxyalkyl, haloalkyl and carboxyalkyl; and wherein p represents two or three. A more preferred class of linker groups within Formula VI consists of divalent radicals wherein each of R 1 and R 2 is hydrogen; wherein each of R1 and R2 is independently selected from hydrogen and alkyl; and wherein p represents two. A specific example of a more preferred linker within Formula VI is the divalent ethylenediamine radical. A class of specific examples of diamino terminated linker groups within the scope of Formula VI is set forth in Table III. These linker groups, identified as Binder Nos. 96-134 may be suitable for forming a conjugate between the carbonyl moiety of an AII antagonist (designated &quot; I &quot;) and a carbonyl moiety of a second carbonyl terminated residue such as the carbonyl portion of the gamma carbon of a residue glutamyl (designated &quot; T &quot;).

TABLE II

R 221 R 223 1 R I = inhibitor τ = acetyl-γ-glutamyl

LINER NO. R218 R219 R220 R221 R222 R223 96 H H H H H 97 H H H H H CH CH 3 H H H CH CH 3 H CH 3 100 CH 3 H H H H 101 H CH 3 H H H H H CH CH 3 CH 3 103 H H CH 3 O X ω H H 57

LINER NO. R218 R219 R220 R221 R222 R223 104 CH3 CH3 HHH 105 HHH C6 H5 106 HHH C6 H5 HH 107 HHH C6 H5 H C6 H5 108 C6 H5 HHHH 109 H C6 H5 HHHH 109 HHHH C6 H5 C6 H5 111 HH C6 H5 C6H5 HH 112 C6 H5 C6 H5 HHHH 113 HHHHH C2 H5 114 HHH C2 H5 115 HH 115 HHH C 2 H 5 H C 2 H 5 116 C 2 H 5 HHHHH 117 H C 2 H 5 HHHH 118 HHHH C 2 H 5 C 2 H 5 119 HH C 2 H 5 C 2 H 5 H 58

LINER NO. R218 R219 r22 ° R221 r222 R223 120 C2H5 C2H5 HHHH 121 CH3 H C6H5 HHH 122 CH3 HHH C6H5 H 123 H CH3 C6H5 HHH 124 H CH3 HH C6H5 H 125 CH3 CH3 H C6H5 HH 126 CH3 CH3 HHH C6H5 127 HHHHH2C6H5 128 HHH CH2C6H5 HH 129 CH2 C6 H5 HHHHH 130 H CH2 C6 H5 HHHH 131 CH3 H CH2C6 H5 HHH 132 CH3 HHH2 6 5 H 133 H CH 3 CH 2 C 6 H 5 HHH 134 H CH 3 HH CH 2 C 6 H 5 H 59

The term &quot; hydrogen &quot; means a single hydrogen atom (H). This atom may be attached, for example, to a carbon atom to form a group /

Or is bonded to an oxygen atom to form a hydroxyl group; or as another example, two hydrogen groups may be attached to a carbon atom to form a -CH 2 - group. When the term &quot; alkyl &quot; is used either alone or within other terms, such as &quot; haloalkyl &quot; and &quot; hydroxyalkyl &quot;, the term &quot; alkyl &quot; comprises straight and branched radicals having from one to about twenty carbon atoms, or preferably from one to about twelve carbon atoms. More preferred alkyl radicals are &quot; lower alkyl &quot; having one to about ten carbon atoms, or preferably one to about twelve carbon atoms. More preferred are &quot; lower alkyl &quot; having from one to about ten carbon atoms. More preferred are lower alkyl radicals having one to about five carbon atoms. The term &quot; cycloalkyl &quot; comprises cyclic radicals having from three to about ten carbon atoms, such as cyclopropyl and cyclobutyl. The term &quot; halo- • 4-alkyl &quot; comprises radicals in which any one or more of the carbon atoms is substituted with one or more halo groups, preferably selected from bromo, chloro and fluoro. Specifically encompassed by the term &quot; haloalkyl &quot; are the monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for example, may have one atom of either bromine, chlorine or fluoro within the group. The 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, 60

may have two fluoro atoms, such as difluoromethyl and difluorobutyl groups, or two chlorine atoms, such as a dichloromethyl group, or a fluoro atom and a chlorine 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 &quot; difluoroalkyl &quot; comprises alkyl groups having two fluoro atoms to substitute any one or two of the carbon atoms of the alkyl group. Preferably, when the difluoroalkyl group is attached at the R and R positions of the thaazole ring of Formula I, the two fluoro atoms will replace the carbon atom which is attached directly to the triazole ring. This preferred difluoroalkyl group may be characterized as a &quot; difluoro-substituted difluoroalkyl group on alpha carbon &quot;. The terms &quot; alkylol &quot; and &quot; hydroxyalkyl &quot; comprise straight or branched alkyl groups having one to about ten carbon atoms, any of which may be substituted with one or more hydroxyl groups. The term &quot; alkenyl &quot; comprises linear or branched radicals having from two to about twenty carbon atoms, preferably from three to about ten carbon atoms, and containing at least one carbon-carbon double bond, which carbon-carbon double bond may have the geometry either cis either trans within the alkenyl moiety. The term &quot; alkynyl &quot; comprises linear or branched radicals having from two to about twenty carbon atoms, preferably from two to about ten carbon atoms, and containing at least one carbon-carbon triple bond. The term &quot; cycloalkenyl &quot; comprises cyclic radicals having from three to about ten ring carbon atoms including one or more double bonds involving adjacent ring carbon atoms. The terms &quot; alkoxy &quot; and &quot; alkoxyalkyl &quot; comprise linear or branched oxy radicals having each alkyl moieties of one to ten carbon atoms, such as the methoxy group. The term &quot; alkoxyalkyl &quot; 61

also comprises radicals having two or more alkoxy groups attached to the alkyl radical, i.e., to form monoalkoxyalkyl or dialkoxyalkyl groups. The radicals &quot; alkoxy &quot; or &quot; alkoxyalkyl &quot; may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or haloalkoxyalkyl groups. The term &quot; alkylthio &quot; comprises radicals containing a linear or branched alkyl group of one to about ten carbon atoms attached to a divalent sulfur atom, such as a methylthio group. The term &quot; aryl &quot; comprises aromatic radicals such as phenyl, naphthyl and biphenyl. The term &quot; aralkyl &quot; comprises aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, phenylbutyl and diphenylethyl. The terms &quot; benzyl &quot; and &quot; phenylmethyl &quot; are interchangeable. The terms &quot; aryloxy &quot; and &quot; arylthio &quot; means, 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 &quot; sulfinyl &quot; and &quot; sulfonyl &quot;, whether used alone or linked to other terms, represent, respectively, divalent radicals SO and SO2. The term &quot; aralkoxy &quot;, alone or within another term, comprises an aryl radical attached to an alkoxy group to form, for example, benzyloxy. The term &quot; acyl &quot; when used alone, or within a term such as acyloxy, means a radical provided by the residue after removal of hydroxy from an organic acid, examples of such acetyl and benzoyl radical being examples. The term &quot; heteroaryl &quot; comprises aromatic ring systems containing one or two heteroatoms 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 a heteroaryl may be attached as substituent via a carbon atom of the heterocyclic ring system or may be attached through a carbon atom of a moiety replacing a member carbon of the heteroaryl ring, through the methylene substituent of the imidazolylmethyl moiety. Likewise, this heteroaryl may be attached through a ring nitrogen atom provided that the aromaticity of the heteroaryl moiety is preserved after the bonding. The term &quot; starch &quot; represents a radical consisting of a nitrogen atom attached to a carbonyl group, which radical may be further substituted in the manner described in this specification. The amido radical may be attached to the core of a compound of the invention via the carbonyl moiety or the nitrogen atom of the amido radical. The term &quot; alkenylalkyl &quot; represents a radical having a double bond unsaturation site between two carbons, and wherein the radical may consist of only two carbons or may additionally be substituted with alkyl groups which may additionally contain additional double bond unsaturation. With respect to any of the radicals defined above, the preferred radicals are those containing from one to about ten carbon atoms.

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 an unsaturated bond, such as an allyl group, or may have a number of unsaturated bonds, such series being either adjacent, such as allene-like structures, either in conjunction or separated by several carbons saturated.

Conjugates of this invention formed from compounds of Formula I have been shown to inhibit the action of angiotensin II in mammals. Accordingly, the compounds of Formula I are therapeutically useful in methods for the treatment of 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 in order to release an active antagonist species of angiotensin II. The phrase &quot; hypertensive patient &quot; means in this context a mammalian subject suffering from the effects of hypertension or is susceptible to a hypertensive condition if not treated in order to prevent or control such hypertension.

Within the scope of the invention are conjugates of compounds of Formula I which are tautomeric forms of the described compounds, isomeric forms, including diastereomers, and pharmaceutically acceptable salts thereof. The term &quot; pharmaceutically acceptable salts &quot; comprises the salts normally 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 as long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of the 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 acids. Suitable organic acids may be selected from the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethane- sulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,

malonic, galactaric and galacturonic. Pharmaceutically acceptable base addition salts of the compounds of Formula I include metal salts obtained from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts obtained from N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All such salts may be prepared by conventional means from the corresponding compound of Formula I by reaction, for example, of the appropriate acid or base with the compound of Formula I. Also, the pharmaceutically acceptable salts may be formed either with a compound of Formula I which is contained in the conjugate, or such salts can be formed with the conjugate itself.

Conjugates of the invention may possess one or more asymmetric carbon atoms and are therefore capable of existing as optical isomers, as well as in the form of their racemic and non-racemic mixtures. Optical isomers may be obtained by resolution of the racemic mixtures according to conventional procedures, for example by the formation of diastereomeric salts by treatment with an optically active acid or base. Examples of suitable acids are tartaric, diacetotartaric, dibenzoyltartaric, ditoluyltartaric and camphor sulfonic acid, followed by separation of the diastereomeric mixture by crystallization followed by liberation of the optically active bases from such salts. A different process for the separation of optical isomers involves the use of an optimally chosen chiral chromatography cabinet in order to maximize the separation of the enantiomers. Yet another available method involves the synthesis of covalent diastereomeric molecules by reacting conjugates with an optically pure acid in an activated form or with an optically pure isocyanate. The synthesized diastereomers may be separated by conventional means, such as by chromatography, distillation, crystallization or sublimation, and then hydrolyzed to liberate the enantiomerically pure compound. Optically active conjugates can likewise be obtained by the use of optically active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt. The first and second residues are provided by the precursor compounds having suitable chemical moieties which react with each other to form a cleavable bond between the first and second residues. For example, the precursor compound of one of the residues should have an amino moiety that can react or a moiety convertible to an amino moiety that can react such that a cleavable amide bond can be formed between the carboxylic acid moiety and the amino moiety.

The conjugates of the invention may be prepared using highly active angiotensin II antagonist precursors of Formula I. Examples of suitable less active precursors are the acid chloride, esters and amides of angiotensin II antagonists of Formula I. For example, the precursor esters of angiotensin II antagonists may be reacted with hydrazine to provide an amino-terminal moiety which may be reacted with a glutamic acid derivative to form a conjugate of the invention. These precursors or intermediates may themselves be relatively strong, relatively weak or inactive AII antagonists. Also, the conjugates of the invention may be prepared using angiotensin II antagonists which lack an amino-terminus moiety. Such angiotensin II antagonists may be modified so as to contain an acid terminal moiety which may be attached to a glutamyl residue 66 through a diamino terminated linker group as shown in Tables I-III.

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 the following biphenylmethyl-1H-substituted-1,2,4-triazole compounds having a terminal carboxylic acid moiety or a carboxylic acid moiety modified to be a hydrazide terminal moiety. All of these compounds are characterized by having such carboxylic acid in one of the R 1 to R positions of Formula I. Such compounds having a terminal carboxyl moiety may be reacted with one of the aforementioned linker groups, such as a hydrazine or piperazine linker, of to provide an amino-terminal moiety which may then be reacted with the carboxylic acid moiety of a second conjugate component, such as a glutamic acid residue, to form an enzyme cleavable bond. Specific examples of these compounds are as follows: 4 '- [3,5-dibutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2- 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-ethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 67

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; 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 '- [(5-butyryl-sec-butyl-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-butyryl-3-tert-butyl-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-mercapto-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-butyl-3-thiomethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid;

4 '- [(5-Butyl-3-thioethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-butyl-3-thiopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-Butyl-3-hydroxy-1 H -1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-Butyl-3-methoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-Butyl-3-ethoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-buty-3-propoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-Butyl-3-butoxy-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-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 69 69

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-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(3-butyl-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-1H-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- -amide; 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- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 70 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 '- [[5-propyl-3-ethyl-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-diisopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-isopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-sec-butyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-isobutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-tert-butyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-pentyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-isopentyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-mercapto-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-thiomethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-thioethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-thiopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-hydroxy-1 H -1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-methoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-ethoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-propoxy-1 H -1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propy-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1-biphenyl] -2-carboxylic acid; 4 '- [(5-propy-3- (2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] 2-carboxylic acid; 4 '- [(5-propy-3-phenyl-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3-phenylmethyl-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 73

4 '- [(5-propyl-3- (2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propi-3-benzoyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-propyl-3- (1-oxo-2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2- carboxylic acid; 4 '- [[5-propyl-3- (1,1-dimethoxypropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-propyl-3- (1,1-dimethoxybutyl) -1H-1,2,4-triazol-1-yl] methyl] [Î ±, Î''-biphenyl] -2-carboxylic acid; 4 '- [[5-propyl-3- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-propyl-3- (1-oxopropyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-propyl-3- (1-oxobutyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-propyl-3- (1-oxopentyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-propyl-3- (1,1-difluoroethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-propyl-3- (1,1-difluoropropyl) -1H-1,2,4-triazol-1-yl] methyl] [Î ±, Î''-biphenyl] -2-carboxylic acid; 4 '- [[5-propyl-3- (1,1-difluorobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-propyl-3- (1,1-difluoropentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(3,5-diethyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-Ethy-3-propyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-ethyl-3-isopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; Methyl 4 '- [(5-ethyl-3-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylate; 4 '- [(5-ethyl-3-sec-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-ethyl-3-isobutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-Ethy-3-tert-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-ethyl-3-pentyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-ethyl-3-isopentyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 75

4 '- [(S-ethyl-S-mercapto-1H-1,2,4-triazol-1-ylmethyl] [1,1'-biphenyl] -2-carboxylic acid 4' - [(5-ethyl- 4 '- [(5-ethyl-3-thioethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] 4 '- [(5-ethyl-3-thiopropyl) -1H-1,2,4-triazol-1-yl] methyl] -1,1- 4 '- [(5-ethyl-3-hydroxy-1H-1,2,4-triazol-1-yl] -piperidin-4-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid, 4 '- [(5-ethyl-3-methoxy-1H-1,2,4-triazol- , 4 '- [(5-ethyl-3-ethoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl- 4 '- [(5-ethyl-3-propoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2- carboxylic acid 4 '- [(5-ethyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; '- [(5-ethyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; ethyl-3- (2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2 -carboxylic acid;

4 '- [(5-ethyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl) methyl) - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-ethyl-3- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) ethyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [(5-ethyl-3-phenyl-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-Ethy-3-phenylmethyl-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-Ethyl-3- (2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-Ethy-3-benzoyl-1H-1,2,4-triazol-1-yl) methyl] [1,17-biphenyl] -2-carboxylic acid; 4 '- [(5-ethyl-3- (1-oxo-2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid ; 4 '- [[5-ethyl-3- (1,1-dimethoxypropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-ethyl-3- (1,1-dimethoxybutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-ethyl-3- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-ethyl-3- (1-oxopropyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 47 - [[5-Ethyl-3- (1-oxobutyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1-biphenyl] -2-carboxylic acid; 4 - [[5-Ethyl-3- (1-oxopentyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 - [[5-ethyl-3- (1,1-difluoroethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,17-biphenyl] -2-carboxylic acid; 4 - [[5-Ethyl-3- (1,1-difluoropropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,17-biphenyl] -2-carboxylic acid; 4 - [[5-Ethyl-3- (1,1-difluorobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,17-biphenyl] -2-carboxylic acid; 4 - [[5-Ethyl-3- (1,1-difluoropentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,17-biphenyl] -2-carboxylic acid; 4 - [(5-sec-butyl-3-ethyl-1H-1,2,4-triazol-1-yl) methyl] [1,17-biphenyl] -2-carboxylic acid; 47 - [(5-sec-butyl-3-propyl-1H-1,2,4-triazol-1-yl) methyl] - [1,17-biphenyl] -2-carboxylic acid; 4 - [(5-sec-butyl-3-isopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,17-biphenyl] -2-carboxylic acid; Methyl 7 - [(5-sec-butyl-3-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,17-biphenyl] -2-carboxylate; 4 - [(3,5-di-sec-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,17-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-isobutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-tert-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-pentyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-isopentyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-mercapto-1H-1,2,4-triazol-1-yl) methyl] -1 - [[1-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-thiomethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-thioethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-thiopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-hydroxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-methoxy-1H-1,2,4-triazol-1-yl) methyl] &lt; t1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-ethoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 79 4 '- [(5-sec-butyl-3-propoxy-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3- (2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2- -amide; 4 '- [(5-sec-butyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3-phenyl-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 - [(5-sec-butyl-3-phenylmethyl-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3- (2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid ; 4 '- [(5-sec-butyl-3-benzoyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-sec-butyl-3- (1-oxo-2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2- -carboxylic acid; 80

4 '- [[5-sec-butyl-3- (1,1-dimethoxypropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5-sec-butyl-3- (1,1-dimethoxybutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5-sec-butyl-3- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid ; 4 '- [[5-sec-butyl-3- (1-oxopropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid ; 4 '- [[5-sec-butyl-3- (1-oxobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid ; 4 '- [[5-sec-butyl-3- (1-oxopentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid ; 4 '- [[5-sec-butyl-3- (1,1-difluoroethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5-sec-butyl-3- (1,1-difluoropropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5-sec-butyl-3- (1,1-difluorobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5-sec-butyl-3- (1,1-difluoropentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [(5-isobutyl-3-ethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 81

4 '- [(5-isobutyl-3-propyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-isopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; Methyl 4 '- [(5-isobutyl-3-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylate; 4 '- [(5-isobutyl-3-sec-butyl-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 '- [(5-isobutyl-3-tert-butyl-1H-1,2,4-triazol-1-yl) methyl] - [Î ±, Î''-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-pentyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-isopentyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-mercapto-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-thiomethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-thioethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-thiopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-hydroxy-1 H -1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-methoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-ethoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-propoxy-1H-1,2,4-triazol-1-yl) methyl] - [1,1-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3- (2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2- -carboxylic acid; 4 '- [(5-isobutyl-3-phenyl-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 83 83

4 '- [(5-isobutyl-3-phenylmethyl-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3- (2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] -1,1-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3-benzoyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isobutyl-3- (1-oxo-2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] [[1', 2'-biphenyl] -2-carboxylic acid ; 4 '- [[5-isobutyl-3- (1,1-dimethoxypropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-isobutyl-3- (1,1-dimethoxybutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-isobutyl-3- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-isobutyl-3- (1-oxopropyl) -1H-1,2,4-triazol-1-yl] methyl] [Î ±, Î''-biphenyl] -2-carboxylic acid; 4 '- [[5-isobutyl-3- (1-oxobutyl) -1H-1,2,4-triazol-1-yl] methyl] [Î ±, Î''-biphenyl] -2-carboxylic acid; 4 '- [[5-isobutyl-3- (1-oxopentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-isobutyl-3- (1,1-difluoroethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 84

47 - [[5-isobutyl-3- (1,1-difluoropropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,17-biphenyl] -2-carboxylic acid; 47 - [[5-isobutyl-3- (1,1-difluorobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,17-biphenyl] -2-carboxylic acid; 4 '- ([5-isobutyl-3- (1,1-difluoropentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 47 - [(5-tert-butyl-3-ethyl-1H-1,2,4-triazol-1-yl) methyl] [1,17-biphenyl] -2-carboxylic acid; 5-tert-butyl-3-propyl-1H-1,2,4-triazol-1-yl) methyl] - [1,17-biphenyl] -2-carboxylic acid; -3-isopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,17-biphenyl] -2-carboxylic acid 4 - [(5-tert-butyl-3-butyl-1H methyl-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylate, 47 - [(5-tert-butyl-3-sec-butyl-1H- 1,2,4-triazol-1-yl) methyl] - [1,17-biphenyl] -2-carboxylic acid, 4 '- [(5- tert -butyl-3-isobutyl-1H- triazol-1-yl) methyl] - [1,17-biphenyl] -2-carboxylic acid, 47 - [(3,5-di-tert-butyl-1H-1,2,4-triazol- methyl] [1,1'-biphenyl] -2-carboxylic acid, 47 - [(5-tert-butyl-3-pentyl-1H-1,2,4-triazol-1-yl) methyl] - [1 , 17-biphenyl] -2-carboxylic acid;

4 '- [(5-tert-butyl-3-isopentyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3-mercapto-1H-1,2,4-triazol-1-yl) methyl] and 1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3-thiomethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3-thioethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid;

4 '- [(5-tert-butyl-3-thiopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid ; 4 '- [(5-tert-butyl-3-hydroxy-1 H -1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3-methoxy-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3-ethoxy-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3-propoxy-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 86

4 '- [(5-tert-butyl-3- (2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2- -amide; 4 '- [(5-tert-butyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3-phenyl-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3-phenylmethyl-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3- (2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3-benzoyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-tert-butyl-3- (1-oxo-2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2- -carboxylic acid; 4 '- [[5-tert-butyl-3- (1,1-dimethoxypropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5-tert-butyl-3- (1,1-dimethoxybutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5-tert-butyl-3- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 87

4 '- [[5-tert-butyl-3- (1-oxopropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-tert-butyl-3- (1-oxobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid ; 4 '- [[5-tert-butyl-3- (1-oxopentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid ; 4 '- [[5-tert-butyl-3- (1,1-difluoroethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5-tert-butyl-3- (1,1-difluoropropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5-tert-butyl-3- (1,1-difluorobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 - [[5-tert-butyl-3- (1,1-difluoropentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5-pentyl-3-ethyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-propyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-isopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-sec-butyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-isobutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-tert-butyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(3,5-di-pentyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-isopentyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-penty-3-mercapto-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-thiomethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-thioethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-thiopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-hydroxy-1 H -1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-penty-3-methoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 89

4 '- [(5-pentyl-3-ethoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-propoxy-1 H -1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3- (2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] 2-carboxylic acid; 4 '- [(5-pentyl-3-phenyl-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-phenylmethyl-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3- (2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-pentyl-3-benzoyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 90

4 '- [(5-pentyl-3- (1-oxo-2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5-pentyl-3- (1,1-dimethoxypropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-pentyl-3- (1,1-dimethoxybutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-pentyl-3- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-pentyl-3- (1-oxopropyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-pentyl-3- (1-oxobutyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-pentyl-3- (1-oxopentyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-pentyl-3- (1,1-difluoroethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-pentyl-3- (1,1-difluoropropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-pentyl-3- (1,1-difluorobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid;

4 '- [[5-pentyl-3- (1,1-difluoropentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 91

4 '- [(5-isopentyl-3-ethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-propyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-isopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; Methyl 4 '- [(5-isopentyl-3-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylate; 4 '- [(5-isopentyl-3-sec-butyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-isobutyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-tert-butyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-pentyl-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; 4 '- [(5-isopentyl-3-mercapto-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-thiomethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-thioethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-thiopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-hydroxy-1 H -1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-methoxy-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-ethoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-propoxy-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-cyclohexyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3- (2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2- -carboxylic acid; 93

4 '- [(5-isopentyl-3-phenyl-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-phenylmethyl-1,2,4-triazol-1-yl) methyl] - [1,17-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3- (2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3-benzoyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-isopentyl-3- (1-oxo-2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid ; 4 '- [[5-isopentyl-3- (1,1-dimethoxypropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-isopentyl-3- (1,1-dimethoxybutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-isopentyl-3- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-isopentyl-3- (1-oxopropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-isopentyl-3- (1-oxobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-isopentyl-3- (1-oxopentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid;

4 '- [[5-isopentyl-3- (1,1-difluoroethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-isopentyl-3- (1,1-difluoropropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-isopentyl-3- (1,1-difluorobutyl) -1H-1,2,4-triazol-1-yl] methyl] (1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5-isopentyl-3- (1,1-difluoropentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (1-butenyl) -3-ethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; '- [[5- (1-butenyl) -3-propyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 - [[5- (1-butenyl) -3-isopropyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] (1-butenyl) -3-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylate; - (1-butenyl) -3-sec-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; (1-butenyl) -3-isobutyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid, 4 '- [[5- (1 -butenyl) -3-tert-butyl-1H-1,2,4-triazol-1-yl] methyl] [Î ±, Î''-biphenyl] -2-carboxylic acid;

4 '- [[5- (1-butenyl) -3-pentyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5- (1-butenyl) -3-isopentyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [] 5- (1-butenyl) -3-mercapto-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid, 4' - [[5- (1-butenyl) -3-thiomethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid, 4 '- [ [5- (1-butenyl) -3-thioethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; - (1-butenyl) -3-thiopropyl-1H-1,2,4-triazol-1-yl) ethyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (1-butenyl) -3-hydroxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (1-butenyl) -3-methoxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 - [[5- (1-butenyl) -3-ethoxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (1-butenyl) -3-propoxy-1 H -1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (1-butenyl) -3-cyclohexyl-1H-1,2,4-triazol-1-yl]) methyl] [1,1'-biphenyl] -2- -amide; 96

4 '- [[(5- (i-butenyl) -3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl]) methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[(5- (1-butenyl) -3- (2-cyclohexylethyl) -1H-1,2,4-triazol-2-ylmethyl] [1,1'-biphenyl] -2- carboxylic acid 4 '- [[5- (1-butenyl) -3-cyclohexanoyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- 4-carboxylic acid, 4 '- [[5- (1-butenyl) -3- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] 1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (1-butenyl) -3-phenyl-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (1-butenyl) -3-phenylmethyl-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (1-butenyl) -3- (2-phenylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- ([5- (1-butenyl) -3-benzoyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; '- [[5- (1-butenyl) -3- (1-oxo-2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (1-butenyl) -3- (1,1-dimethoxypropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (1-butenyl) -3- (1,1-dimethoxybutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 97

4 '- [[5- (1-butenyl) -3- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (1-butenyl) -3- (1-oxopropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5- (1-butenyl) -3- (1-oxobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -carboxylic acid; 4 '- [[5- (1-butenyl) -3- (1-oxopentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5- (1-butenyl) -3- (1,1-difluoroethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (1-butenyl) -3- (1,1-difluoropropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [(5- (1-butenyl) -3- (1,1-difluorobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid 4 '- [[5- (1-butenyl) -3- (1,1-difluoropentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1' biphenyl] -2-carboxylic acid 4 '- [[5- (2-butenyl) -3-ethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl ] -2-carboxylic acid, 4 '- ((5- (2-butenyl) -3-propyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] - 2-carboxylic acid, 4 '- [5- (2-butenyl) -3-isopropyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid ;

Methyl [5- (2-butenyl) -3-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylate; 4 '- [[5- (2-butenyl) -3-sec-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butenyl) -3-isobutyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butenyl) -3-tert-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butenyl) -3-pentyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5- (2-butenyl) -3-isopentyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid, 4' - [] 5- (2-butenyl) -3-mercapto-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid, 4 '- [ [5- (2-butenyl) -3-thiomethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; (2-butenyl) -3-thioethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid, 4 '- [ 4 '- [[5- (2-butenyl) -3-thiopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] butenyl) -3-hydroxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid;

4 '- [[5- (2-butenyl) -3-methoxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butenyl) -3-ethoxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butenyl) -3-propoxy-1 H -1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5- (2-butenyl) -3-cyclohexyl-1H-1,2,4-triazol-1-yl]) methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[(5- (2-butenyl) -3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- carboxylic acid; 4 '- [[(5- (2-butenyl) -3- (2-cyclohexylethyl) -1H-1,2,4-triazol-yl] methyl] [1,1'-biphenyl] - 4 '- [[5- (2-butenyl) -3-cyclohexanoyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] 2-carboxylic acid 4 '- [[5- (2-butenyl) -3- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] 1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butenyl) -3-phenyl-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butenyl) -3-phenylmethyl-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butenyl) -3- (2-phenylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5- (2-butenyl) -3- (1,1-dimethoxypropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (2-butenyl) -3- (1,1-dimethoxybutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (2-butenyl) -3- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (2-butenyl) -3- (1-oxopropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5- (2-butenyl) -3- (1-oxobutyl) -1H-1,2,4-triazol-1-yl] methyl] [Î ±, Î''-biphenyl] -2- -carboxylic acid; 4 '- [[5- (2-butenyl) -3- (1-oxopentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5- (2-butenyl) -3- (1,1-difluoroethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (2-butenyl) -3- (1,1-difluoropropyl) -1H-1,2,4-triazol-1-yl] methyl) [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (2-butenyl) -3- (1,1-difluorobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (2-butenyl) -3- (1,1-difluoropentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (3-butenyl) -3-ethyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butenyl) -3-propyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [5- (3-butenyl) -3-isopropyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; Methyl 4 '- [[5- (3-butenyl) -3-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylate; 4 '- [[5- (3-butenyl) -3-sec-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid ; 4 '- [[5- (3-butenyl) -3-isobutyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butenyl) -3-tert-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid ; 4 '- [[5- (3-butenyl) -3-pentyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5- (3-butenyl) -3-isopentyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [] 5- (3-butenyl) -3-mercapto-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2- - [[5- (3-butenyl) -3-thiomethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid, 4 '- [ [5- (3-butenyl) -3-thioethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid;

4 '- [[5- (3-butenyl) -3-thiopropyl-1H-1,2,4-triazol-1-yl) methyl] [Î ±, Î''-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butenyl) -3-hydroxy-1 H -1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butenyl) -3-methoxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butenyl) -3-ethoxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butenyl) -3-propoxy-1 H -1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butenyl) -3-cyclohexyl-1H-1,2,4-triazol-1-yl]) methyl] [Î ±, Î''-biphenyl] -2- -amide; 4 '- [[(5- (3-butenyl) -3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl]) methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[(5- (3-butenyl) -3- (2-cyclohexylethyl) -1H-1,2,4-triazol-yl] methyl] [1,1'-biphenyl] -2- 4 '- ([5- (3-butenyl) -3-cyclohexanoyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -carboxylic acid;

4 '- [[5- (3-butenyl) -3- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1' -biphenyl] -2-carboxylic acid; 4 '- [(5- (3-butenyl) -3-phenyl-1,2,4-triazol-1-yl] methyl] (1,1'-biphenyl] -2-carboxylic acid, 4'- 4 '- [[5- (3-butenyl) -3-phenylmethyl-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] (3-butenyl) -3- (2-phenylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid, 4 '- [[ 4 '- [[5- (3-butenyl) -3-benzoyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] (3-butenyl) -3- (1-oxo-2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; '- [[5- (3-butenyl) -3- (1,1-dimethoxypropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] 4 '- [[5- (3-butenyl) -3- (1,1-dimethoxybutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'- biphenyl] -2-carboxylic acid 4 '- [[5- (3-butenyl) -3- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] , 4 '- [[5- (3-butenyl) -3- (1-oxopropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butenyl) -3- (1-oxobutyl) -1H-1,2,4-triazol-1-yl] yl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butenyl) -3- (1-oxopentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5- (3-butenyl) -3- (1,1-difluoroethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 47 - ([5- (3-butenyl) -3- (1,1-difluoropropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,17-biphenyl] -2- 4-yl] methyl] [1,1'-biphenyl] -4- (3-butenyl) -3- (1,1-difluorobutyl) -1H-1,2,4- -2-carboxylic acid, 47 - [[5- (3-butenyl) -3- (1,1-difluoropentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,17- 4,7 - [[5- (1-butynyl) -3-ethyl-1H-1,2,4-triazol-1-yl] methyl] - (1,17-biphenyl) -biphenyl] -2-carboxylic acid; 2-carboxylic acid, 47 - [[5- (1-butynyl) -3-propyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid ; 4,7- [5- (1-butynyl) -3-isopropyl-1H-1,2,4-triazol-1-yl] methyl] - [1,17-biphenyl] -2-carboxylic acid, - [[5- (1-butynyl) -3-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,17-biphenyl] -2-carboxylate; 5- (1-butynyl) -3-sec-butyl-1H-1,2,4-triazol-1-yl) perethyl] [1,1'-biphenyl] -2-carboxylic acid, 4,7 - [[ 4 - [[5- (1-butynyl) -3-isobutyl-1H-1,2,4-triazol-1-yl] methyl] - (1,17-biphenyl) -2-carboxylic acid; -butynyl) -3-tert-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,17- -biphenyl] -2-carboxylic acid; 4 - [[5- (1-butynyl) -3-pentyl-1H-1,2,4-triazol-1-yl] methyl] - [1,17-biphenyl] -2-carboxylic acid; 4 '- [(5- (1-butynyl) -3-isopentyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- (1-butynyl) -3-mercapto-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid, 4' - [[5- (1-butynyl) -3-thiomethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid, 4 '- [ [5- (1-butynyl) -3-thioethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (1-butynyl) -3-thiopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] (1-butynyl) -3-hydroxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid, 4 '- [[5- 4 '- [[5- (1-butynyl) -3-methoxy-1H-1,2,4-triazol-1-yl] methyl] (1,1'-biphenyl] ) -3-ethoxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid, 4 '- [[5- (1-butynyl) 4 '- [[5- (1-butynyl) -3-propoxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] cyclohexyl-1H-1,2,4-triazol-1-yl] -ethyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[(5- (1-butynyl) -3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl]) methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[(5- (1-butynyl) -3- (2-cyclohexylethyl) -1H-1,2,4-triazol-yl] methyl] [1,1'-biphenyl] -2- 4 '- [[5- (1-butynyl) -3-cyclohexanoyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] -1- , 4 '- [[5- (1-butynyl) -3-phenyl-1,2,4-triazol-1-yl] methyl] [1,1'- biphenyl] -2-carboxylic acid, 4 '- [[5- (1-butynyl) -3-phenylmethyl-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2- 4 - [[5- (1-butynyl) -3- (2-phenylethyl) -1H-1,2,4-triazol-1-yl] methyl] [[1 ', 2'-biphenyl] -2-carboxylic acid 4 '- ([5- (1-butynyl) -3-benzoyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2- 4 - [[5- (1-butynyl) -3- (1-oxo-2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] -1,1- 4 '- [[5- (1-butynyl) -3- (1,1-dimethoxypropyl) -1H-1,2,4-triazol-1-yl] methyl] 4 '- [[5- (1-butynyl) -3- (1,1-dimethoxybutyl) -1H-1,2,4-triazol-1-yl] yl] m ethyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (1-butynyl) -3- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (1-butynyl) -3- (1-oxopropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5- (1-butynyl) -3- (1-oxobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -carboxylic acid; 4 '- [[5- (1-butynyl) -3- (1-oxopentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5- (1-butynyl) -3- (1,1-difluoroethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (1-butynyl) -3- (1,1-difluoropropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- [[5- (1-butynyl) -3- (1,1-difluorobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 41 - [[5- (1-butynyl) -3- (1,1-difluoropentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -carboxylic acid; 4 '- [[5- (2-butynyl) -3-ethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butynyl) -3-propyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; Methyl 4 '- [(5- (2-butynyl) -3-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylate; 4 '- [[5- (2-butynyl) -3-sec-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butynyl) -3-isobutyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid, 4' - [[5- (2-butynyl) -3-tert-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; '- [[5- (2-butynyl) -3-pentyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; [(5- (2-butynyl) -3-isopentyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid, 4 '- [ ] 5- (2-butynyl) -3-mercapto-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid, 4 '- [[5 - (2-butynyl) -3-thiomethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid, 4 '- [[5- 2-butynyl) -3-thioethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid 4 '- [[5- (2- butynyl) -3-thiopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid 4 '- [[5- (2- nyl) -3-hydroxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butynyl) -3-methoxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butynyl) -3-ethoxy-1 H -1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 109

4 '- [[5- (2-butynyl) -3-propoxy-1 H -1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butynyl) -3-cyclohexyl-1H-1,2,4-triazol-1-yl]) methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[(5- (2-butynyl) -3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl]) methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[(5- (2-butynyl) -3- (2-cyclohexylethyl) -1H-1,2,4-triazol-yl] methyl] [1,1'-biphenyl] -2- 4 '- [[5- (2-butynyl) -3-cyclohexanoyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- 4 - [[5- (2-butynyl) -3- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] -1- , 1'-biphenyl] -2-carboxylic acid; 4 '- [(5- (2-butynyl) -3-phenyl-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid, 4'- 4 '- [[5- (2-butynyl) -3-phenylmethyl-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] (2-butynyl) -3- (2-phenylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid, 4 '- ([ 4 '- [[5- (2-butynyl) -3-benzoyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] (2-butynyl) -3- (1-oxo-2-phenylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; '- [[5- (2-butynyl) -3- (1,1-dimethoxypropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- 4 - [[5- (2-butynyl) -3- (1,1-dimethoxybutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] ] -2-carboxylic acid 4 '- [[5- (2-butynyl) -3- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] 4 - [[5- (2-butynyl) -3- (1-oxopropyl) -1H-1,2,4-triazol-1-yl] methyl] 4 '- [[5- (2-butynyl) -3- (1-oxobutyl) -1H-1,2,4-triazol-1-yl] til] [1 , 1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (2-butynyl) -3- (1-oxopentyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5- (2-butynyl) -3- (1,1-difluoroethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid; 4 '- ([5- (2-butynyl) -3- (1,1-difluoropropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid 4 '- [[5- (2-butynyl) -3- (1,1-difluorobutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1' 4 '- [[5- (2-butynyl) -3- (1,1-difluoropentyl) -1H-1,2,4-triazol-1-yl] methyl] - [ 4 '- [[5- (3-butynyl) -3-ethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] 1'-biphenyl] -2-carboxylic acid;

4 - [[5- (3-butynyl) -3-propyl-1H-1,2,4-triazol-1-yl] methyl] - [1,17-biphenyl] -2-carboxylic acid; 47- [5- (3-butynyl) -3-isopropyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; Methyl 4 '- [[5- (3-butynyl) -3-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylate; 47 - [[5- (3-butynyl) -3-sec-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butynyl) -3-isobutyl-1H-1,2,4-triazol-1-yl] methyl] - [1,17-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butynyl) -3-tert-butyl-1H-1,2,4-triazol-1-yl] methyl] [1,17-biphenyl] -2-carboxylic acid; 4 - [(5- (3-butynyl) -3-isopentyl-1H-1,2,4-triazol-1-yl] methyl] [1,17-biphenyl] -2-carboxylic acid; - [(5- (3-butynyl) -3-pentyl-1H-1,2,4-triazol-1-yl] methyl] - [1,17-biphenyl] -2-carboxylic acid, 4 '- [ 5- (3-butynyl) -3-mercapto-1H-1,2,4-triazol-1-yl] methyl] - [1,17-biphenyl] -2-carboxylic acid; 1,2,4-triazol-1-yl] methyl] - [1,17-biphenyl] -2-carboxylic acid, 4 - [[5- (3-butynyl) 3-thioethyl-1H-1,2,4-triazol-1-yl] methyl] - [1,17-biphenyl] -2-carboxylic acid;

47 - [[5- (3-butynyl) -3-thiopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 - [[5- (3-butynyl) -3-hydroxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 47 - [[5- (3-butynyl) -3-methoxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 47 - [[5- (3-butynyl) -3-ethoxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 - [[5- (3-butynyl) -3-propoxy-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butynyl) -3-cyclohexyl-1H-1,2,4-triazol-1-yl]) methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[(5- (3-butynyl) -3-cyclohexylmethyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[(5- (3-butynyl) -3- (2-cyclohexylethyl) -1H-1,2,4-triazol-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid ; 4 '- [[5- (3-butynyl) -3-cyclohexanoyl-1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid ; 4 - [[5- (3-butynyl) -3- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] '-biphenyl] -2-carboxylic acid; 4,7 - [[5- (3-butynyl) -3-phenyl-1,2,4-triazol-1-yl] methyl] (1,17-biphenyl] -2-carboxylic acid;

4- [5- (3-butynyl) -3-phenylmethyl-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butynyl) -3- (2-phenylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- -amide; 4 '- [[5- (3-butynyl) -3-benzoyl-1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [[5- (3-butynyl) -3- (1-oxo-2-phenylethyl) -1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl ] -2-carboxylic acid; 4 '- [(5- (3-butynyl) -3- (1,1-dimethoxypropyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-carboxylic acid 4 '- [[5- (3-butynyl) -3- (1,1-dimethoxybutyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1' 4 '- [[5- (3-butynyl) -3- (1,1-dimethoxypentyl) -1H-1,2,4-triazol-1-yl] methyl] - [ 4 '- [[5- (3-butynyl) -3- (1-oxopropyl) -1H-1,2,4-triazol-1-yl] methyl] ] [1,1'-biphenyl] -2-carboxylic acid 4 '- [[5- (3-butynyl) -3- (1-oxobutyl) -1H-1,2,4-triazol-1-yl] methyl-4 '- [[5- (3-butynyl) -3- (1-oxopentyl) -1H-1,2,4-triazol-1 -yl] -methyl] [1,1'-biphenyl] -2-carboxylic acid, 4 '- [[5- (3-butynyl) -3- (1,1-difluoroethyl) -1H-1,2,4- 4 '- [(5- (3-butynyl) -3- (1,1-difluoropropyl) -1H-1-benzothiazol-4-yl] 1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid, 4 '- [[5- (3-butynyl) -3- (1,1-difluorobutyl) 4 '- [[5- (3-butynyl) -3- (1,1'-biphenyl-2-carboxylic acid, 1-difluoropent 1 H -1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(3'5-diethoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphen-2-yl] -2-carboxylic acid; 4 '- ((3,5-dipropoxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; (5-d i-isopropoxy-1H-1,2,4-triazol-1-yl) methyl] [Î ±, 7-biphenyl] -2-carboxylic acid, 4 '- [(3,5-dibutoxy- 4 '- [(3,5-dithiomethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid, 4 '- [(3,5-dithioethyl-1H-1,2,4-triazol- 4 '- [(3,5-dithiopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid, 4-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid, 4 '- [(3', 5-dithioisopropyl-1 H -1,2,4-triazol- -amide;

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

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 the following biphenylmethyl-1H-substituted-1,2,4-triazole compounds having a terminus to the R 1, R 2 or R positions of Formula I. Such an amino-terminal moiety may be reacted with the carboxylic acid moiety of a second conjugate component, such as a glutamic acid residue, to form an enzyme cleavable bond . Specific examples of these compounds are as follows: 5- [4 '- [(5-ethyl-3-amino-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] - 2-yl] -1H-tetrazole; 5- [4 '- (5-ethyl-3-aminomethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-ethyl-3-aminoethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 5- [4 '- [(5-ethyl-3-aminopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 5- [4 '- [(5-ethyl-3-aminobutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 5- [4 '- [[(3-ethyl-5- (4-aminophenyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-yl ] -lH-tetrazole; 5- [4 '- [[(3-ethyl-5- (4-aminophenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl ] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Ethyl-5- (4-aminophenylethyl) -1H-1,2,4-triazol-1-yl] methyl] biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-ethyl-5- (4-aminomethylphenylmethyl) -1 H -1,2,4-triazol-1- yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole 5- [4 '- [[(3-ethyl-5- (4-aminomethylphenyl) -1H-1,2,4- 5 - [4 '- [[(3-ethyl-5- (4-aminoethylphenyl) -1H-benzimidazol-1-yl] -1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-ethyl-5- (4- -amide] -1 H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole;

5- [4 '- [[(3-ethyl-5- (4-aminocyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 5- [4 '- [[(3-ethyl-5- (4-aminocyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1 biphenyl] -2-yl] -1H-tetrazole; 5- [4 - [[(3-ethyl-5- (4-aminomethylcyclohexylmethyl) -1H-1,2,4-triazol-1 -yl] methyl] [1,1'-biphenyl] -2-yl] -α-tetrazole; 5 "[4 '- [[(3-ethyl-5- (4-aminomethylcyclohexyl) -1H- Trihydroxy-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; hexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 3-amino-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole 5- [4 '- [ 1-yl) methyl] [1,1'-biphenyl] -2-yl] -α-tetrazole; 5- [4 '- [( 5-propyl-3-aminoethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [ (5-propyi-3-aminopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [ 5-propyl-3-aminobutyl-1H-1,2,4-triazole yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-propyl-5- (4-aminophenyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] triethyl-1-yl] methyl] [1,1'-biphenyl] -1H-1,2,4-triazol-1-yl] methyl] -1H-tetrazole: 5- [4 '- [[(3-propyl-5- (4-aminophenylmethyl) ] -2-yl] -1H-tetrazole; [4 '- [[(3-propyl) -5- (4-aminophenylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1 , 4 '- [[(3-propyl) -5- (4-aminomethylphenylmethyl) -1H-1,2,4-triazol-1-yl] yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-propyl-5- (4-aminomethylphenyl) -1H-1,2,4- 5- [4 '- [[(3-propyl) -5- (4-aminoethylphenyl) -1H-indol-1-yl] -1H-benzo [ -1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-propyl- (4-aminocyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [ [(3-propyl] -5- (4-aminocyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-propi-5- (4-aminocyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 -yl] -1H-tetrazole: 5- [4 '- [[(3-propyl-5- (4-aminomethylcyclohe exilmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-propi-5- (4-aminomethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- yl] -1H-tetrazole: 5- [4 '- [[(3-propyl) -5- (4-aminoethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-isopropyl-3-amino-1H-1,2,4-triazol-1-yl) methyl] 2-yl] -1H-tetrazole; 5 "C4 '- [(5-Isopropyl-3-aminomethyl-1H-1,2,4-triazol-1-yl) methyl] 5- [4 '- [(5-Isopropyl-3-aminoethyl-1H-1,2,4-triazol-1-yl) methyl] - [1 5 '[4' - [(5-isopropyl-3-aminopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] 5- [4 '- [(5-Isopropyl-3-aminobutyl-1H-1,2,4-triazol-1-yl) methyl] - 5- [4 '- [[(3-Isopropyl-5- (4-aminophenyl) -1H-1,2,4-triazol-1-yl) -1H-tetrazole; 5- [4 '- [[(3-isopropyl-5- (4-aminophenylmethyl) -1H-1,2,3-thiadiazol- 4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -NH-tetrazole; 5- [4 '- [[(3-Isopropyl-5- (4-aminophenylethyl) -1,2,4-triazol-1 1] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isopropyl-5- (4-aminomethylphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] 5- [4 '- ([(3-isopropyl-5- (4-aminomethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] [Î ±, Î''-biphenyl ] -2-yl] -1H-tetrazole; 5- [4 '- [((3-Isopropyl-5- (4-aminoethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] biphenyl] -2-yl] -1H-tetrazole;

5 '[4' - [[(3-isopropyl-5- (4-aminocyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 -yl] -1H-tetrazole: 5- [4 '- [[(3-Isopropyl-5- (4-aminocyclohexylmethyl) -1 H -1,2,4-triazol-1-yl] methyl] 5- [4 '- [[(3-Isopropyl-5- (4-aminocyclohexylethyl) -1H-1,2,4-triazol-1-yl] 1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Isopropyl-5- (4-aminomethylcyclohexylmethyl) -1H-1 1,2,4-triazol-1-ylmethyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 - [[(3-Isopropyl-5- (4-aminomethylcyclo) 1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[( 3-isopropyl-5- (4-aminoethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-butyl-3-amino-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; [4 '- [(5-butyryl-3-aminomethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; - [4 '- [(5-butyryl-3-aminoethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5 - [[4 - [(5-butyl-3-aminopro 1 H -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 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 - [[1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Butyl-5- (4-aminomethylphenylmethyl) -1H-1,2,4-triazole yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Butyl-5- (4-aminomethylphenyl) -1H-1 1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole: 5- [4 '- [[(3-Butyl-5- (4- 1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Aminoethylphenyl) -1H-1,2,4- 5- (4-aminocyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; - [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- biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Butyl-5- (4-aminomethyl) cyclohexylmethyl) -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-sec-butyl-3-amino-1H-1,2,4-triazol-1-yl) methyl] [1,1'- phenyl] -2H-tetrazole; 5- [4 '- (5-sec-butyl-3-aminomethyl-1H-1,2,4-triazol-1-yl) methyl] 5 '[4' - [(5-sec-butyl-3-aminoethyl-1H-1,2,4-triazol-1-yl) methyl] -1H-benzoimidazole; [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-sec-butyl-3-aminopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole; [4 '- [(5-sec-butyl-3-aminobutyl-1H-1,2,4-triazol-1-yl ) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5 '[4' - [[(3-sec-butyl-5- (4-aminophenyl) -1H-1,2 5- [4 '- [[(3-sec-butyl-5- (4-aminophenyl) methyl] -1H-tetrazole, 4-triazol-1-yl] methyl] [1,1'-biphenyl] ) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 - [[(3- 5- (4-aminophenylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; - [[(3-sec-butyl] -5- (4-aminomethylphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] , 1-biphenyl] -2-yl] -1H-tetrazole; 5 '[4' - [[(3-sec-butyl-5- (4-aminomethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 -yl] -1H-tetrazole: 5- [4 '- [[(3-sec-butyl-5- (4-aminoethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] B] phenyl] -2H-tetrazole; 5- [4 '- [[(3-sec-butyl] -5- (4-aminocyclohexyl) -1H-1,2,4- triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5 '[4' - [[(3-sec-butyl] -5- (4-aminocyclohexylmethyl ) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-sec-butyl -5- (4-aminocyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; '- [[(3-sec-butyl-5- (4-aminomethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl ] -1H-tetrazole; 5- [4 - [[(3-sec-butyl-5- (4-aminomethylcyclohexyl) -1 H -1,2,4-triazol-1-yl] methyl] , 5 '- [4' - [[(3-sec-butyl-5- (4-aminoethylcyclohexyl) -1H-1,2,4-triazole, 1'-biphenyl] -2-yl] -1H-tetrazole; Yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 - [(5-Isobutyl-3-amino-1H-1,2,4-triazole 1-yl) methyl] [1,1'-biphenyl] -2-yl] -NH-tetrazole; '- [(5-isobutyl-3-aminomethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-isobutyl-3-aminoethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 5- [4 '- [(5-isobutyl-3-aminopropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 5- [4 '- [(5-isobutyl-3-aminobutyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H -tetrazole; 5- [4 '- [[(3-isobutyl-5- (4-aminophenyl) -1H-1,2,4-triazol-1-yl] methyl] -1,1- biphenyl] -2-yl ] -1H-tetrazole: 5- [4 '- [[(3-isobutyl-5- (4-aminophenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'- biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isobutyl-5- (4-aminophenylethyl) -1H-1,2,4-triazol-1-yl] 5- [4 '- [[(3-isobutyl-5- (4-aminomethylphenylmethyl) -1H-1,2,4-triazol-2-yl] -1H-tetrazole; yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isobutyl-5- (4-aminomethylphenyl) -1H-1,2 5- [4 '- [[(3-isobutyl-5- (4-aminoethylphenyl) -1H-benzofuran- -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isobutyl-5- - (4-aminocyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; [[(3-isobutyl-5- (4-aminocyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole (4-aminocyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -1H- 2-yl] -1H-tetrazole; 5- [4 '- [[(3-isobut yl-5- (4-aminomethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] (1,17-biphenyl] -2-yl] -1H-tetrazole; 125

5- [4 '- [[(3-isobutyl-5- (4-aminomethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-yl] -1H-tetrazole; 5- [4 '- [[(3-isobutyl-5- (4-aminoethylcyclohexyl) -1H-1,2,4-triazol-1-yl] biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-tert-butyl-3-amino-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-tert-Butyl-3-aminomethyl-1H-1,2,4-triazol-1-yl ) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole 5- [4 '- [(5-tert-butyl-3-aminoethyl-1H-1,2,4- yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-tert-Butyl-3-aminopropyl-1H-1,2,4- 1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5 '[4' - [(5-tert-butyl-3-aminobutyl- 1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3- tert -Butyl-5- (4- -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3- tert- 5- (4-aminophenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; '- [[(3-tert-butyl] -5- (4-aminophenylethyl) -1H-1,2,4-triazol-1-yl] methyl 1] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-tert-butyl-5- (4-aminomethylphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl ] -1H-tetrazole; 5- [4 '- [[(3-tert-butyl-5- (4-aminomethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-tert-butyl-5- (4-aminoethylphenyl) -1H-1,2,4-triazol- 5- [4 '- [[(3-tert-butyl-5- (4-aminocyclohexyl) -1H-benzimidazol-1-yl] methyl] [1,1'-biphenyl] 1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3- tert -butyl- (4-aminocyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [ [(3-tert-butyl-5- (4-aminocyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] - tert-Butyl-5- (4-aminomethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'- biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-tert-butyl-5- (4-aminomethylcyclohexyl) -1H-1,2,4-triazol-1 5- [4 '- [[(3-tert-butyl-5- (4-aminoethylcyclohexyl) -1H-pyrazol- 1,2,4-triazol-1-yl] methyl] [1,2- 1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-pentyl-3-amino-1 H -1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-pentyl-3-aminomethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 5- [4 '- [(5-penty-3-aminoethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 5- [4 '- [(5-pentyl-3-aminopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -β-tetrazole; 5- [4 '- [(5-pentyl-3-aminobutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 5- [4 '- [[(3-pentyl-5- (4-aminophenyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-yl ] -Α-tetrazole; 5- [4 '- [[(3-penty] -5- (4-aminophenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'- biphenyl] -2-yl] -α-tetrazole; 5- [4 '- [[(3-penti] -5- (4-aminophenylethyl) -1H-1,2,4-triazol-1-yl] methyl] 1 - [((3-pentyl-5- (4-aminomethylphenylmethyl) -1H-1,2,4-triazol-1-yl) -1H-tetrazole; 5- [4 '- [[(3-penty] -5- (4-aminomethylphenyl) -1H-1,2,3,4-tetrahydro- 4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-penti] -5- (4-aminoethylphenyl) 1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-pentyl-5- 4-aminocyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [ (3-penty] -5- (4-aminocyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; - [4 '- [[(3-penti] -5- (4-aminocyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- yl] -α-tetrazole; 5- [4 '- [[(3-pentyl-5- (4-aminomethylci 1-yl] methyl] [1,1'-biphenyl] -2-yl] -α-tetrazole [5- (4 '' - [( 3-pentyl-5- (4-aminomethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -β-tetrazole; 5- [4 '- [[(3-pentyl-5- (4-aminoethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 1-yl) methyl] (1,1'-biphenyl) -1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid [ -2-yl] -β-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl- ] -2-yl] -1H-tetrazole; 5- [4 '- [(5-Isopentyl-3-aminoethyl-1H-1,2,4-triazol-1-yl) methyl] - [ biphenyl] -2-yl] -β-Tetrazole; 5- [4 '- [(5-Isopentyl-3-aminopropyl-1H-1,2,4-triazol-1-yl) methyl] - [ biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-Isopentyl-3-aminobutyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1 2-yl] -1H-tetrazole 5- [4 '- ([(3-isopentyl-5- (4-aminophenyl) -1H-1,2,4-triazol-1-yl] methyl ] [Î ±] - [[(3-isopentyl-5- (4-aminophenylmethyl) -1H-1,2,4-triazol-1-yl] yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isopentyl-5- (4-aminophenylethyl) -1H- 2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole;

5- [4 '- [[(3-isopentyl-5- (4-aminomethylphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] 5- [4 '- [[(3-isopentyl-5- (4-aminomethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] ] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isopentyl-5- (4-aminoethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] , 4 '- [[(3-isopentyl-5- (4-aminocyclohexyl) -1H-1,2,4-triazol-1-yl) -1H-tetrazole; 5- [4 '- [[(3-isopentyl-5- (4-aminocyclohexylmethyl) -1H-1-benzyl- 2-yl] -1H-tetrazole; 5- [4 '- [[(3-isopentyl-5- (4-methyl- 5 '[4' - [[(3-Amino-3-methyl-1 H -pyrazolyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -isopentyl-5- (4-aminomethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isopentyl-5- (4-aminomethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- yl] -1H-tetrazole; 5- [4 '- ([(3-isopentyl-5- (4-aminoethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] '-biphenyl] -2-yl] -1H-indole trazole; 5- [4 '- [(5-Hexyl-3-amino-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] tetrazole; 5- [4 - [(5-hexyl-3-aminomethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5 '[4' - [(5-hexyl-3-aminoethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] tetrazole; 5- [4 '- [(5-Hexyl-3-aminopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2- [1] -1H-tetrazole ; 5- [4 '- [(5-hexyl-3-aminobutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 5- [4 '- [[(3-Hexyl-5- (4-aminophenyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-yl ] -lH-tetrazole; 5- [4 '- [[(3-Hexyl-5- (4-aminophenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl ] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Hexyl-5- (4-aminophenylethyl) -1H-1,2,4-triazol-1-yl] methyl] 1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Hexyl-5- (4-aminomethylphenylmethyl) -1H-1,2,4-triazol-1-yl ] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Hexyl-5- (4-aminomethylphenyl) -1H-1,2,4- triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Hexyl-5- (4-aminoethylphenyl) -1H-1 1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Hexyl-5- (4-aminocyclo -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3- 5- (4-aminocyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [ 4 '- [[(3-hexyl-5- (4-aminocyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] 5- [4 '- [[(3-hexyl-5- (4-aminomethylcyclohexylmethyl) -1H-1 , 2-thiazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5 '[4' - [[(3-Hexyl-5- (4-aminomethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 5- [4-aminoethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1 , 1'-biphenyl] -2-yl] -1H-tetrazole.

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 the following biphenylmethyl-1H-substituted-1,2,4-triazole compounds having a terminal carboxylic acid terminated at one of the R or R positions of Formula I. Such compounds having a terminal carboxyl moiety may be reacted with one of the aforementioned linker groups such as a hydrazine or piperazine linker so as to provide a moiety amino terminus which can then be reacted with the carboxylic acid moiety of a second conjugate component, such as a glutamic acid residue, to form an enzyme cleavable bond. Specific examples of these compounds are as follows: 5- [4 '- [(5-ethyl-3-carboxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] - 2-yl] -1H-tetrazole; 5- [4 '- [(5-ethyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole ; (5-ethyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H- tetrazole; 5- [4 '- [(5-ethyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H -tetrazole; 5- [4 '- [(5-ethyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] - (4-carboxyphenyl) -1H-1,2,4-triazol-1-yl] methyl] - N - [1,1'-biphenyl- biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-ethyl-5- (4-carboxyphenylmethyl) -1 H -1,2,4-triazol-1-yl] methyl] 5- [4 '- [[(3-ethyl-5- (4-carboxyphenylethyl) -1H-1,2,4-triazol-1-yl] yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-ethyl-5- (4-carboxymethylphenylmethyl) -1H-1,2,4- 1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 - [(3-Ethyl- (4-carboxymethylphenyl) -1H- (4-methoxyphenyl) -1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole 5- [4 '- [[(3-ethyl-5- (4-carboxyethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-ethyl- (4-carboxycyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-b ifenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-ethyl-5- (4-carboxycyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 -yl] -1H-tetrazole; 5- [4 '- [[(3-ethyl-5- (4-carboxycyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-ethyl-5- (4-carboxymethylcyclohexylmethyl) -1H-1,2,4- 1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 - [[(3-ethyl-5- (4-carboxymethylcyclohexyl) -1H-1 1,2-triazol-1-yl] methyl] [1,1-biphenyl] -2-yl] -1H-tetrazole: 5- [4 '- [[(3-ethyl-5- (4-carboxyethyl) cyclo -hexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-propyl -3-carboxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [ 3-carboxymethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- ( 5-propyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; propyl-S-carboxypropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [ 5-propyl-3-carboxybutyl-1H-1,2,4-triazol-1 -yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-propyl-5- (4-carboxyphenyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- yl] -1H-tetrazole; 5- [4 '- [[(3-propyl-5- (4-carboxyphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'- biphenyl] -2-yl] -1H-tetrazole;

5- [4 '- [[(3-propyl-5- (4-carboxyphenylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl ] -1H-tetrazole; 5 "[4 '- [[(3-propyl-5- (4-carboxymethylphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-propyl-5- (4-carboxymethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] 5- [4 '- [[(3-propyl-5- (4-carboxyethylphenyl) -1H-1,2,4-triazol-1-yl] yl] -methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-propyl-5- (4-carboxycyclohexyl) -1H- 2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-propyl-5- (4-carboxycyclo 1,2-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-propyl- -5- (4-carboxycyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; '- [[(3-propyl-5- (4-carboxymethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] - [4 '- [[(3-propyl-5- (4-carboxymethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] ] -2-yl] -1H-tetrazole 5- [4 '- [[(3-propi-5- (4-carboxyethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-yl] -1H-tetrazole; 5- [4 '- [(5-isopropyl-3-carboxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 5 '[4' - [(5-isopropyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -β-tetrazole ; 5 '[4' - [(5-isopropyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -tetrazole; 5- [4 '- [(5-isopropyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -tetrazole; 5 '[4' - [(5-isopropyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -β-tetrazole ; 5- [4 '- [[(3-isopropyl-5- (4-carboxyphenyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl ] -Α-tetrazole; 5- [4 '- [[(3-Isopropyl-5- (4-carboxyphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isopropyl-5- (4-carboxyphenylethyl) -1H-1,2,4-triazol-1-yl] methyl] 5- [4 '- [[(3-isopropyl) -5- (4-carboxymethylphenylmethyl) -1H-1,2,4-triazol-1-yl] -yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Isopropyl-5- (4-carboxymethylphenyl) -1H- 4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Isopropyl- (4-carboxyethylphenyl) 1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isopropyl- (4-carboxycyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] (1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [ [(3-isopropyl-5- (4-carboxycyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] tetrazole: 5- [4 - [(3-Isopropyl-5- (4-carboxycyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -α-tetr azole; 5- [4 '- [[(3-isopropyl-5- (4-carboxymethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -β-tetrazole; 5- [4 '- [[(3-isopropyl-5- (4-carboxymethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-yl] -1H-tetrazole; 5- [4 '- [[(3-Isopropyl-5- (4-carboxyethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1 '' - [(5-butyryl-3-carboxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-butyryl-3-carboxymethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -α-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- yl) methyl] - [1,1'-biphenyl] -2-yl] -α-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] -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 [4 '- [[(3-butyl-5- (4-carboxymethylphenyl) -1H-1,2,4-triazol-1-yl] 1-yl] -methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Butyl-5- (4-carboxyethylphenyl) -1H- 1,2-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Butyl-5- (4-carboxycyclo- hexyl) -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; '- [[(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; 5- [4 - [[(3-Butyl-5- (4-carboxyethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 -yl] -1H-tetrazole;

5- [4 '- [(5-sec-butyl-3-carboxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H -tetrazole; 5- [4 '- [(5-sec-butyryl-3-carboxymethyl-1H-1,2,4-triazol-1-yl) methyl] -1H, biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-sec-butyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -tetrazole; 5- [4 '- [(5-sec-butyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] tetrazole; 5- [4 - [(5-sec-butyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] tetrazole; 5- [4 '- [[(3-sec-butyl-5- (4-carboxyphenyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 (4-carboxyphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1 , 5 '[4' - [[(3-sec-butyl] -5- (4-carboxyphenylethyl) -1H-1,2,4-triazol-1-yl) -1H-tetrazole; -yl] methyl] [1,1'-biphenyl] -2-yl] -α-tetrazole; 5- [4 '- [[(3-sec-butyl] -5- (4-carboxymethylphenylmethyl) -1H-1 1-yl] methyl] [1,1'-biphenyl] -2-yl] -α-tetrazole; [4 '- [[(3-sec-butyl] carboxymethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole: 5 C 4 '- [[(3-sec -butyl] -5- (4-carboxyethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole;

5- [4 '- [[(3-sec-butyl-5- (4-carboxycyclohexyl) -1H-1,2,4-triazol-1-ylmethyl] [1,1'-biphenyl] -2- yl] -1H-tetrazole; 5- [4 '- [[(3-sec-butyl-5- (4-carboxycyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [4 '- [[(3-sec-butyl-5- (4-carboxycyclohexylethyl) -1H-1,2,4-thiadiazol-2-yl] 5- [4 '- [[(3-sec-butyl-5- (4-carboxyethyl) cyclohexyl] -1 H -pyrazol-5-yl] methyl] [1,1'-biphenyl] hexylmethyl) -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; 5- [ 4 - [[(3-sec-butyl-5- (4-carboxyethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 -yl] -1H-tetrazole; 5- [4 '- {(5-isobutyl-3-carboxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] 2-yl] -1H-tetrazole; 5- [4 '- [(5-isobutyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-isobutyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl ] -2-yl] -1H-tetrazole; 5- (4 '- [(5-isobut yl-3-carboxypropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-isobutyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 140 5- [4 '- [[(3-isobutyl-5- (4-carboxyphenyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 -yl] -1H-tetrazole; 5- [4 '- [[(3-isobutyl-5- (4-carboxyphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isobutyl-5- (4-carboxyphenylethyl) -1H-1,2,4-triazol-1-yl] methyl] (1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isobutyl-5- (4-carboxymethylphenylmethyl) -1H-1,2,4- 5- [4 '- [[(3-isobutyryl-5- (4-carboxymethylphenyl) -1H-benzimidazol-1-yl] methyl] [1,1'-biphenyl] 1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isobutyl- 1-yl] methyl] [1,1'-biphenyl] -2-yl] -α-tetrazole; 5- [4 '- [[(3- isobutyl] -5- (4-carboxycyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [ 4 '- [[(3-isobutyl-5- (4-carboxycyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl ] -1H-tetrazole; 5- [4 '- [(3-Isobutyl-5- (4-carboxycyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] -1,1- '-biphenyl] -2-yl] -1H-tetrazole; 5- [4' - [[(3- 4- (4-carboxymethylexyhexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isobutyl-5- (4-carboxymethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-yl] -1H-tetrazole; 5- [4 '- [[(3-isobutyl-5- (4-carboxyethylcyclohexyl) -1,2,4-triazol-1-yl] methyl] , 5 '- [(5-tert-butyl-3-carboxy-1H-1,2,4-triazol-1-yl) methyl] -1,2,3,4- 5- [4 '- [(5-tert-butyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole 5- [4 '- [(5-tert-butyl-3-carboxyethyl-1H-1,2,4-triazol- yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole 5- [4 '- [(5-tert-butyl-3-carboxypropyl-1H-1,2,4-triazole yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-tert-butyl-3-carboxybutyl-1H- 5- [4 '- [[(3-tert-butyl] -5- (4-carboxyphenyl) -piperazin-1-yl] methyl] -1,1'-biphenyl] -2-yl] -1H-tetrazole; 1H-1,2,4-triazol-1-yl] -methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3- tert- 5- (4-carboxyphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; (3-tert-butyl-5- (4-carboxyphenylethyl) -1H-1,2,4-tri azol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5 &quot; [4 '- [[(3-tert-butyl-5- (4-carboxymethylphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 (4-carboxymethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] (1,1'-biphenyl- biphenyl] -2-yl] -1H-tetrazole; 5- [4 - [(3-tert-butyl-5- (4-carboxyethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] 5- [4 '- [[(3-tert-butyl] -5- (4-carboxycyclohexyl) -1H-1,2,4-b] thiophene- 1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3- tert -butyl-5- (4-carboxycyclohexyl- hexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3- tert-butyl] -5- (4-carboxycyclohexylethyl) -1H-1,2,4-triazol-1-yl] ethyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; [4 '- [[(3-tert-butyl-5- (4-carboxymethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 5- [4 '- [[(3-tert-butyl-5- (4-carboxymethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] - [ 5- [4 '- [[(3-tert-butyl] -5- (4-carboxyethylcyclohexyl) -1H-1,2,4-thiadiazol-1-yl] tr thiazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-pentyl-3-carboxy-1H-1,2,4-triazol-1-yl) methyl] (1,1'-biphenyl) -2-yl] tetrazole; 5- [4 '- [(5-pentyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H -tetrazole; 5- [4 '- [(5-pentyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl) -2-yl] - 1H-tetrazole; 5- [4 '- [(5-pentyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 143 5 - [4 '- [(5-pentyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] tetrazole; 5- [4 - [[(3-pentyl-5- (4-carboxyphenyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- yl] -1H-tetrazole; 5- [4 '- [[(3-pentyl-5- (4-carboxyphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1' biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-pentyl-5- (4-carboxyphenylethyl) -1H-1,2,4-triazol-1-yl] methyl ] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-pentyl-5- (4-carboxymethylphenylmethyl) -1 H -1,2,4-triazol- -1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-pentyl-5- (4-carboxymethylphenyl) 2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-pentyl-5- (4-carboxyethylphenyl) ) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; [4 - [[(3-pentyl- 5- (4-Carboxycyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; - [[(3-pentyl-5- (4-carboxycyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H 5- [4 '- [[(3-pentyl-5- (4-carboxycyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-pentyl -5- (4-carboxymethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; [4 - [[(3-pentyl-5- (4-carboxymethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-yl] -1H-tetrazole; 5- [4 '- [[(3-pentyl-5- (4-carboxyethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] 1 - [(5-isopentyl-3-carboxy-1H-1,2,4-triazol-1-yl) methyl] [1,2,4] 1,1'-biphenyl] -2-yl] -β-Tetrazole; 5- [4 - [(5-Isopentyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl) methyl] [1 '' - [(5-isopentyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -tetrazole; 5- [4 - [(5-Isopentyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl) methyl] - [4 '- [(5-isopentyl-3-carboxybutyl) -1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -1H-tetrazole; ] - [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5 '[4' - [[(3-isopentyl-5- (4-carboxyphenyl) -1H-1,2,4-triazole yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isopentyl-5- (4-carboxyphenylmethyl) -1H- 2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -β-Tetrazole; 5- [4 '- [[(3-Isopentyl-5- (4-carboxyphenylethyl) ) -1H-1, 2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -β-tetrazole; 5- [4 '- [[(3-isopentyl-5- (4-carboxymethylphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2- yl] -1H-tetrazole; 5- [4 '- [[(3-isopentyl-5- (4-carboxymethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isopentyl-5- (4-carboxyethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isopentyl-5- (4-carboxycyclohexyl) -1H-1,2,4- 1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; [4 '- [[(3-isopentyl-5- (4-carboxycyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-isopentyl- 5- (4-carboxycyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; '- [[(3-isopentyl-5- (4-carboxymethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] - (4-carboxymethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl- biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Isopentyl) -5- (4-carboxyethylcyclohexyl) -1H-1,2,4-triazol- yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-hexyl-3-carboxy-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] tetrazole; 5- [4 '- [(5-hexyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 5- [4 - [(5-hexyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole ; [4 '- [(5-hexyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-yl] -tetrazole; 5- [4 '- [(5-hexyl-3-carboxybutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-hexyl-5- (4-carboxyphenyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-yl ] -1H-tetrazole; 5 "[4 '- [[(3-Hexyl-5- (4-carboxyphenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'- biphenyl] -2-yl] -α-tetrazole; 5- [4 '- [[(3-Hexyl-5- (4-carboxyphenylethyl) -1H-1,2,4-triazol-1-yl] methyl] 1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Hexyl-5- (4-carboxymethylphenylmethyl) -1 H -1,2,4-triazol- 5- [4 '- [[(3-Hexyl-5- (4-carboxymethylphenyl) -1H-1,2,3,4-tetrahydro- 4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -α-tetrazole; 5- [4 '- [[(3-Hexyl-5- (4-carboxyethylphenyl) 1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Hexyl- 4-carboxycyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -α-tetrazole; 5- [4 '- [ (3-Hexyl-5- (4-carboxycyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Hexyl-5- (4-carboxycyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 -yl] -β-tetrazole;

5- [4 '- [[(3-hexyl-5- (4-carboxymethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-yl] -α-tetrazole; 5- [4 '- [[(3-Hexyl-5- (4-carboxymethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] 5- [4 '- [[(3-hexyl-5- (4-carboxyethylcyclohexyl) -1H-1,2,4-triazol-1-yl] yl] methyl] [1,1'-biphenyl] -2-yl] -α-tetrazole.

Another family of specific angiotensin II antagonist compounds of the highest interest within the scope of Formula I, from which a suitable first component of the conjugate can be selected, consists of biphenylmethyl-1H-substituted-1,2,4- triazole compounds as set forth below. Such compounds are suitable for forming a carboxylic acid moiety conjugate of a second conjugate component, such as a glutamic acid residue, so as to form an enzyme cleavable amide bond, either by direct reaction or by reaction through a diamine containing linker of the aforementioned type. These angiotensin II antagonist compounds of the highest interest are as follows: 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-sec-butyl-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-butyryl-3-tert-butyl-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; 149 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-1H-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-1H-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- -amide; 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] -V 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; 150 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-diisopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(3,5-di-sec-butyl-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; 151

4 '- [(3,5-di-tert-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(3,5-di-pentyl-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-butyryl-1 H -1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] tetrazole; 5- [4 '- [(5-butyryl-3-aminomethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 5- [4 '- [(5-butyryl-3-aminoethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole ; 5- [4 '- [(5-Butyryl-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 ] -lH-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-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] 5 '[4' - [[(3-butyl-5- (4-aminocyclohexyl) -1 H -1,2,4-tetrazole; 5- [4 - [[(3-butyl-5- (4-aminocyclohexylmethyl) -1 H -pyrazol-2-yl] ) -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; - [[(3-butyl-5- (4-aminomethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] 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- -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 ; 153

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 - [[(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] 5- [4 '- [[(3-butyl-5- (4-carboxymethylphenylmethyl) -1H-1,2,4-triazol-1-yl] -yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-butyl-5- (4-carboxymethylphenyl) -1H- 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- 4-carboxycyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; (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- arboxymethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -β-tetrazole; 5- [4 '- [[(3-Butyl-5- (4-carboxymethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2 -yl] -α-tetrazole and 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

The conjugates of the invention are synthesized by reaction between precursors of the first and second residues. One such precursor must contain a reactive acid moiety, and the other precursor must contain a reactive amino moiety, so as to form a conjugate having a cleavable bond. Any of the precursors of the first and second residues may contain such acidic or reactive 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 an amino-reactive moiety may be chemically modified to provide such an amino-reactive moiety. The chemical modification of these inhibitor compounds lacking a reactive amino group may be accomplished by reacting an acid or ester group in an AII antagonist compound with an amino compound having at least one reactive amino moiety and another reactive heteroatom selected from O, S and N. A suitable amino compound may be a diamino compound such as hydrazine or urea. The hydrazine, for example, may be reacted with an acidic or carboxylic ester portion of an AII antagonist compound to form a hydrazide derivative of such AII antagonist compound. The angiotensin II antagonist compound 4 '- [(3,5-dibutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid can be used as the template compound to illustrate the chemical modification of a carboxylic acid-containing compound to become an amino-containing reactive precursor for the synthesis of a conjugate of the invention. In the following General General Synthetic Procedures, methods for obtaining suitable angiotensin II antagonists of Formula I are first described in Scheme I-VI to be selected as the first component of the conjugate. Then, in Schemes VII-XII, the general methods for obtaining a conjugate by reacting a first AII antagonist component of Formula I with a second cleavable component represented by N-acetyl-β- glutamic acid.

The conjugates of the invention may be prepared using highly active angiotensin II antagonist precursors of Formula I. Examples of suitable, less active precursors are the acid chloride, esters and amides of angiotensin II antagonists of Formula I. For example, the ester precursors of more active angiotensin II antagonists, such as ester-like AII antagonists of Examples Nos. 1, 34, 35, 67 and 68, as well as AII antagonists containing carboxylic acid terminal moieties, from Examples Nos. 2, 6, 8, 13-20, 36, 52, 63, 64, 71-72 and 75-78 may be reacted to provide an intermediate having an amino-terminal moiety which may be reacted with derivative of glutamic acid to form a conjugate of the invention. Such precursors or intermediates, in themselves, may be relatively strong, relatively weak, or inactive AII antagonists. Also, the conjugates of the invention can be prepared using angiotensin II antagonists lacking a reactive amino or acidic moiety. Such angiotensin II antagonists, as shown in Example Nos. 3, 5, 7, 9-16, 21-33, 37-40, 42-51, 53-62, 65, 69-70, 73 and 74, an amino-terminal portion is lacking. These AII antagonists may be modified so as to contain an amino-terminal portion which may then be attached to a glutamyl residue via a diamino terminated linker group, as shown in Tables I-III. i 157

R 1 -c n 5 1 0 R c -c- or 6 1 h 2 h 3 h, h c h h h h 2 h

ΝΗ3 &gt; -15

6a

N-H

1 R-H, CH 3, or C 2 H 5 159

SCHEME III

8, (R5 = co2ch3) 9 (CH3) 3SnN3

8, [R 5 = CN 4 C (C 6 H 5) 3] 10

Synthetic Scheme III shows the preparation of the precursor of the alkylating agent 8 in which R is equal to CNC (C H) from the corresponding methyl ester 8 (R = CC &gt; 2 CH 3). In step 1, the methyl ester is converted to the corresponding acid 5 (R = CO2) by the action of sodium hydroxide / hydrochloric acid. In step 2, the acid is converted to the corresponding acid chloride (R = COCl) by the action of oxalyl chloride. In step 3, the acid chloride is converted to the corresponding primary amide (R = CONH 2) by the action of ammonia. In step 4, the amide is converted into the corresponding nitrile 9 by the action of the refluxing thionyl chloride. The nitrile 9 is reacted with trimethyltin azide in toluene at reflux to give the corresponding trimethyltin protected tetrazole (1c); deprotection with acetic acid / water and reprotection with triphenylmethyl chloride / triethylamine gave N-trityltetrazole 8 (R5 = CN (C, H3)). - '4 6 5 3

W 161

SCHEME IV

Synthetic Scheme IV shows the coupling reaction of 1H-1,2,3-triazole 1 with the appropriate alkylating reagent 7. In the first step, 1 is treated with a base, such as sodium hydride, in order to generate the corresponding anion JL1. The anion 11 is reacted with the alkylating agent 1 in order to obtain a mixture of regioisomers 12a and 12b. The isomer mixture may be converted into mixtures of the corresponding acids 13a and 13b or tetrazoles 14a or 14b by treatment with the appropriate reagent. Or, isomers 12a and 12b may be separated by chromatographic methods, and each isomer may be reacted with the appropriate reagent to provide the final product substituted with acid or tetrazole.

scheme V λ

163

Ν-Η π, | οο2Η5 2 'f

13a or 14a Synthetic Scheme V shows the regioselective synthesis of isomer 13a or 14a from Scheme IV. In the first reaction step, an alkylating agent is reacted with an appropriate hydrazide 3 to provide the substituted hydrazide 15. An imidate 2 is reacted with the hydrazide 15 to afford intermediate 16, which cyclized upon heating to provide the corresponding product compound 13a or 14a.

SCHEME VI

N -H r 1 -c-o-c 2 5 + 2 NH 2 NH 2 R 3 C-N-NHaH 17 R2 C (OC2 H5) 319 ch2

Δ

13b or 14b 18 165 Synthetic Scheme VI shows the regioselective synthesis of isomer 13b or 14b from Scheme IV. In the first step of the reaction, an imidate 2 is reacted with hydrazine to give the imidazone 17. This intermediate is reacted with the alkylating agent 1 to give intermediate 18, which is then cyclized to the the presence of heating and an appropriate orthoester 19 so as to produce the corresponding product compound 13b or 14b.

166 SCHEME VII

(CH2) 3 -CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH

2. TF A

Synthetic Scheme VII shows the preparation of the renal selective angiotensin II antagonists by coupling γ-glutamic acid with an angiotensin II antagonist; 5 the acid portion of the biphenyl of the AII antagonist is coupled to the Γ-acid portion of glutamic acid via a hydrazine linker. In step 1, the methyl ester of the AII antagonist 12b is converted to the hydrazide 2.0 by the action of the hydrazine. In step 2, hydrazide .20 is first reacted with the symmetrical anhydride of protected α-glutamic acid 21 and subsequently reacted with trifluoroacetic acid (TFA) to provide the deprotected coupled material 22. In step 3, the free amino group of 22. is acetylated with acetic anhydride in the presence of base so as to obtain the renal selective angiotensin II antagonists 9a.

(CH 3) 3 C-O-C-N- (CH 2) n-C-OHH

O o 1. DCC || II 1 NH 2 NH 2 &quot; (CH3) 3i> 0-C-N- (CH2, n-C-N, H3NH,

H 2, Δ

O

1. NaH 2. 7. 3. Chromatography R2

The (cH 2) n-N-C-O-C (CH 3) 3 1

H m,

Which can have the amino acid incorporated in R1. The synthetic preparation of the compound of Formula (I) is prepared by the following steps: In step 1, the protected amino acid 6 is first reacted with dicyclohexylcarbodiimide (DCC) and subsequently reacted with hydrazine to provide 2-hydrazide. In step 2, the hydrazide 2 is reacted with imino ester 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 1 in order to obtain a mixture of regioisomers 12a and separated by means of chromatography. In desired 12b is deprotected with free mode TFA 24. AII antagonist.

SCHEME IX

OR

H-C- (CH 2) n-C-OR I OR 6 NH 2 NH 2

-CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH N (CH.VC-H, N &quot; N) 1. NaH CH 2, 2,

(CH 2) n 'C' 0 * CH 3 ρΖ-'Λ) n R N 1 ch 2 ch 2: -K? cy * KJ 26 ^ 25 R = CH3 &gt; C2H3 171

Synthetic Scheme IX shows the preparation of angiotensin II antagonists 25 and 26 which have a carbo-methoxy moiety and an amino moiety, respectively, incorporated into R1. In step 1, the alkyl ester of dialkyl acetal 6 is reacted with hydrazine to give the hydrazide 3. In step 2, the hydrazide 2 is reacted with the imino ester 2 and subsequently cyclized to yield 1H- 1,2,4-triazole 1. In step 3, the anion of 1 is reacted with the appropriate alkylating agent 1 to provide a mixture of regioisomers which can be separated by means of 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 KMnO 4, and subsequently converted to the methyl ester 25 via SOCl3 / CH3 OH at -10 ° or reduced to the corresponding aminomethyl analog 26 (homologue of 24. ) by means of NH 4 OAc / NaBH 3 CN. 172

(CH2) n6a or (CH2) n6a or

CH 2 - (CH 2) n-C-N-NH-H 2 2 .Δ

1. KMn04 2. SOCl2, CH3 OH OII (CH2) n-C-OCH3

I

Synthetic Scheme X shows an alternative preparation of angiotensin II antagonists which have a carbomethoxy moiety incorporated in R1. In step 1, the lactone 6 is reacted with hydrazine to give the hydrazide 3. In step 2, the hydrazide 3 is reacted with the imino ester 2 and subsequently cyclized to yield 1H-1, 2,4-triazole. In step 3, the anion of 1 L is reacted with the appropriate alkylating agent 7 in order to obtain a mixture of regioisomers which can be separated by means of chromatography to obtain 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 means of SOC4 / CH3 OH at -10 °. 173 4Mfc \

174 SCHEME XI

(CH2) n-NH2

OII C02 C (CH3) 3

(CH 2) n-N-C-CH 2 -CH 2 -CH

N JL .N

H N-H I = OC (CH 3) 3 24

oII co2h

(CH2) n-N-C-CH2-CH2-CH, N-H

AC2O base

TFA

(CH2) n-N-C-CH2-CH2-CH

"4-J

c = o ch3 # Λη · Η

I?

H NH2

29 28 175

Synthetic Scheme XI shows the preparation of renal selective angiotensin II antagonists by coupling of angiotensin II-24 antagonists containing amino with α-glutamic acid. In step 1, the AII antagonist is reacted with the symmetrical anhydride of the protected β-glutamic acid 21 to give 217. In step 2, the protected material 27 is reacted with TFA to afford the deprotected coupled material 28. In step 3, the free amino compound 28 is acetylated with acetic anhydride in the presence of base to afford 2- selective renal angiotensin II antagonists 29.

176 SCHEME XII

or

(I.e.

1. 21 2. TFA

Synthetic Scheme XII shows the preparation of renal selective angiotensin II antagonists by coupling r-glutamic acid with an angiotensin II antagonist; 5 the acid portion R of the triazole of the AII antagonist is coupled to the Γ-acid portion of the glutamic acid through a hydrazine linker. In step 1, the methyl ester of the 2β-AII antagonist is converted to the hydrazide 3.0 by the action of the hydrazine. In step 2, the hydrazide 20 is first reacted with the symmetrical anhydride of the protected α-glutamic acid 21 and subsequently reacted with TFA to give the unprotected coupled material 3JL. In step 3, the free amino group of 31 is acetylated with acetic anhydride in the presence of base so as to obtain the renal selective angiotensin II antagonists 32.

The following Examples 1-78 are detailed descriptions of the methods of preparing specific angiotensin II antagonist compounds within the scope of Formula I. These detailed preparations fall within the scope of, and serve to exemplify, the above General Synthetic Procedures described, which form part of the invention. These Examples # 1 - # 78, as well as the methods described in the other preparation examples that follow, are presented for purposes of illustration only and are not intended to restrict the scope of the invention. All parts are by weight and temperatures are expressed in degrees Centigrade, unless otherwise indicated. 178

Example 1

Methyl 4'-β (3,5-dibuty1-1H-1,2,4-triazol-1-yl) methyl] -1,1-biphenyl] -2-carboxylate

Step 1: Preparation of 4-bromomethyl-2'-methoxycarbonylbiphenyl

A sample of 47.46 g (210 mmol) 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 azobis-isobutyronitrile (AIBN) at reflux under nitrogen for 24 hours. The reaction mixture was again treated with 1.0 g (6.1 mmol) of AIBN and stirred at reflux for a further period of 24 hours. The reaction was filtered and the solvent removed in vacuo. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate / hexane (5:95) as eluant afforded 50.0 g (78%) of a colorless solid:

mp 48-51 ° C; NMR (CDCl 3) δ 3.64 (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 dibromo compound (S 6.70); however, no further attempts were made for purification and this mixture was used in all subsequent alkylation reactions.

Step 2: Preparation of 3,5-dibutyl-1H-1,2,4-triazole

A solution of 64.5 g of (0.50 mol) of ethyl iminovalerate [P. Reynaud and R. C. Moreau, Bull. Soc. Chim. Frange, 2997 (1964)] in 100 ml of methanol was slowly added to 58.0 g (0.50 mol) of valeric acid hydrazide (Lencaster Synthesis) in 400 ml of methanol at 0øC under a nitrogen atmosphere. After the addition was complete, the reaction was allowed to warm to room temperature and then stirred 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) as the eluent gave 78.9 g (93%) of a colorless solid: mp 50.5-51.5 ° C; NMR (CDCl 3) 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: Calc'd for M + H: 182.1657.

Found: 182.1661. 180

Step 3: Preparation of methyl 4'- (3,5-dibuty-lH-1,2,4-triazol-1-yl] methyl] -1,1-biphenyl] -2-carboxylate

Under a static atmosphere of nitrogen, 2.01 g (11.0 mmol) of 3,5-dibutyl-1H-1,2,4-triazole were added in small portions to 12 mmol of sodium hydride in 50 ml of dimethylformamide -amide (DMF); stirring was continued until hydrogen evolution ceased. The anion solution was cooled to -10 ° 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 room temperature and stirred 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 (MgSO & &gt; 4). Chromatography on silica gel (Waters Prep-500A) using 40% ethyl acetate / hexane gave 2.0 g (41%) of the compound as an oil. NMR (CDCl3) <0.90 (t, J = 7Hz, 3H), 0.94 (t, J = 7Hz, 3H), 1.28-1.47 (m, 4H) 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, 1 H). 181

Example 2

4 '- [(3,5-Di-butyl-1H-1,2,4-triazol-1-yl] methyl] -1,2,6-trimethyl-2-carboxylic acid

A 2.0 g (4.9 mmol) sample of the methyl ester product compound of Example 1 was dissolved in 80 ml of ethanol and treated with 80 ml of 10% NaOH at room temperature for 3 days. The ethanol was removed in vacuo and the aqueous phase was acidified to pH 1 with hydrochloric acid, which caused precipitation of the product; the filtration and drying in vacuo gave 1.65 g (86%) of colorless compound: mp 134-135 ° C; NMR (DMSO-d6) δ 0.85 (t, J = 7 Hz, 3H), 0.90 (t, J = 7 Hz, 3H), 1.23-1.39 (m, 4H) 1.68 (m, 4H), 2.59 (t, J = 7Hz, 2H), 2.78 (t, J = 7Hz, 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, m, 1H), 7.70-7.75 (m, 1H).

Example 3

5-14 '- (3,5-dibutyl-1H-1,2,4-triazol-1-ylmethyl) -1,1'-biphenyl-2-yl] -1H-tetrazole

Step 1: Preparation of N-Triphenylmethyl-5- [2- (4-bromomethylbiphen-2-yl]

A sample of 542.5 g (2.4 mmol) of methyl 2- (p-tolyl) benzoate (Chemo Dynamics Inc.) was dissolved in 5.5 l of ethanol and treated with 31 (7.5 mol) of 2.5 N sodium hydroxide. The reaction was stirred overnight at ambient temperature and treated with an additional amount of 480 ml (6.0 mol) of sodium hydroxide; the stirring was continued for an additional 24 hours and the ethanol was removed in vacuo. The remaining solution was cooled on ice and acidified to pH 1 with hydrochloric acid, which caused precipitation of the product; filtration and drying in vacuo gave crude 510 g (100%) of crude 2- (p-tolyl) benzoic acid: 183 m.p. 145.0-147.5 ° C; NMR (CDCl 3) δ 2.40 (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 11 of toluene and treated slowly with 400 g (3.15 mol) of oxalyl chloride under nitrogen. The reaction was allowed to stir at room 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 mmol) of anhydrous ammonia. The reaction was filtered and the filtrate concentrated in vacuo, yielding 424 g (84%) of 2- (p-tolyl) benzamide: mp 128-130 ° C; NMR (CDCl 3) δ 2.40 (s, 3H), 5.28 (bs, 1H), 5.77 (bs, 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. After 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) δ 2.42 (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). rJZj

A sample of 286 g (1.48 mol) of the crude nitrile was dissolved in 1630 ml of toluene and treated with 377 g (1.8 mol) of trimethyltin azide at reflux for 24 h. The reaction was 184

cooled; the filtration gave 600 g of N-trimethylstannyl-5- [2- (4-biphen-2-yl) tetrazole: mp 271-272 ° C (dec.); NMR (DMSO-d6) δ , 36 (1H, J = 34Hz, 9H), 2.24 (s, 3H), 6.89-7.06

(M, 4H), 7.35-7.55 (m, 4H). The crude N-trimethylstannyltetrazole was suspended in 4270 ml of toluene and 287 ml of anhydrous tetrahydrofuran (THF) and treated with 63.4 ml (1.73 mol) of anhydrous hydrogen chloride at room 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) δ 2.28 (s, 3H), 6.94-7.02 (m, 2H), 7.08-7.15 (m, 2H), 7.50-7, (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 mmol) 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 (MgSO 4), 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 (CDCl 3) δ 2.27 (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). 185

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'-bromomethyl-biphen-2-yl) tetrazole as a colorless solid: mp 140-142 ° C. ° C; NMR (CDCl 3) δ 4.39 (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 the corresponding dibromo compound (5,6,50); however, no further attempts were made for purification and this mixture was used in all subsequent alkylation reactions.

Step 2: Preparation of 5-butyl-3-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole

Under nitrogen, a solution 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 room 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 sample of 18.9 g (100 mmol) of the hydrazide is dissolved in 100 mL of methanol and is treated with 12.9 g (100 mmol) of ethyl iminova- lerate under nitrogen. The reaction is stirred at reflux overnight and concentrated in vacuo. Purification by means of

Chromatography on silica gel (Waters Prep-500A) gives 5-butyl-3-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole.

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

Under a static atmosphere of nitrogen, 3.81 g (15.0 mmol) of 3-butyl-5- tert -butoxycarbonylamino-1H-1,2,4-triazole are added slowly to 15 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution ceased. The anion solution is cooled to -10 ° C (ice / methanol) and treated with a solution of N-triphenylmethyl-5- [2- (4'-bromomethylbiphen-2- yl)] -tetrazole in 20 ml of dry DMF. The reaction is allowed to warm to room temperature and stirred 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 room temperature overnight. The reaction is cooled to 0 ° C, 100 ml of water is added, and it is allowed to stir at room 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) affords 5- [4 '- [(3-aminomethyl-5-butyl-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -γ-tetrazole as the TFA salt.

X 187

Example 4

4 '- (3,5-dibutyl-1H-1,2,4-triazol-1-ylmethyl] -1' -biphenyl-2-carboxylic acid, hydrazide

A sample of 7.10 g (17.5 mmol) of the methyl ester product compound of Example 1 was dissolved in 150 mL of ethanol and treated with 22 mL (22.2 g, 695 mmol) of anhydrous hydrazine under an atmosphere nitrogen. The reaction was stirred at reflux for 2 days and concentrated in vacuo to give 7.03 g (99%) of the compound, which was a colorless glass: NMR (CDCl3) δ 0.88 (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 (brs, 2H), 5.26 (s, 2H), 6.53 (s, 1H), 7.13-7.63 (m, 8H).

Example 5

3- (3-Aminopropyl) -5-butyl-1H-1,2,4-triazol-1-ylmethyl] -1 H -biphenyl-2-yn-1H-tetrazole

Step 1; Preparation of 5-butyl-3- (3-tert-butoxycarbonylaminopro-Pd-1H-1,2,4-triazole

Under nitrogen, 60.0 g (0.30 mol) of N-BOC-β-aminobutyric acid (BACHEM) are dissolved in 1200 ml of methylene chloride and treated with a solution of 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 room temperature and stirred overnight. Concentration in vacuo gives crude hydrazide, which is purified either by recrystallization or by silica gel chromatography (Waters Prep-500A). A sample of 21.7 g (100 mmol) of the 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 chromatography on silica gel (Waters Prep-500A) gives 5-butyl-3- (tert-butoxycarbonylaminopropyl) -1H-1,2,4-triazole.

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

Under a static atmosphere of nitrogen, 14.4 g (46.0 mmol) of 3- (3-N-BOC-aminopropyl) -5-butyl-1H-1,2,4-triazole are added in small portions to 50 mmol sodium hydride in 250 ml dimethylformamide (DMF); stirring was continued until hydrogen evolution ceased. The anion solution is cooled to -10 ° C (ice / methanol) and treated with a solution of 25.5 g (46.0 mmol) of N-triphenylmethyl 5- [2- (4'-bromomethylbiphen-2- yl)] -tetrazole in 100 ml of dry DMF. The reaction is allowed to warm to room temperature and stirred 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 stirred at room temperature overnight. The reaction is cooled to 0 ° C, 100 ml of water is added, and is allowed to stir at room 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) affords 5- [4 '- [(3-aminomethyl-5-butyl-1H-1,2,4-triazol-1-yl) methyl] -ethyl] [1,1-biphenyl] -2-yl] -β-tetrazole in the form of TFA salt.

Example 6

N

C02H

Cl 4'- (5-But-1-3-chloro-1H-1,2,4-triazol-1-yl) methyl] -1,1'-bi-phenyl] -2-carboxylic acid

Step 1: Preparation of 3-butyl-5-chloro-1H-1,2,4-triazole

A sample of 10.0 g (80 mmol) 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 0øC and chlorine was introduced over 3 h. The reaction was purged with nitrogen overnight and the solution was extracted with chloroform. The extracts were combined, dried (MgSO4), and concentrated in vacuo to give 16.8 g of a colorless oil which was taken up 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 means of gel chromatography 191 191

silica (Waters Prep-500A) using chloroform / methanol (95: 5) gave 9.53 g (75%) of a colorless solid: mp 104-105 ° C; NMR (CDCl 3): δ 0.94 (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: Calc'd for M + H: 160.0642.

Found: 160.0651.

Step 2: Preparation of 4apos; -β- (5-butyl-3-chloro-1H-1,2,4-triazol-1-yl) methyl] -Î ± -biphenyl] -2-carboxylic acid

Under a static atmosphere of nitrogen, 5.0 g (31.3 mmol) of 5-butyl-3-chloro-1H-1,2,4-triazole were added in small portions to 32 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution 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'-methoxycarbonyl-biphenyl in 20 mL of dry DMF. The reaction was allowed to warm to room temperature and stirred 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, which was a clear gold oil. A 4.81 g sample of this material was dissolved in 250 ml of methanol and treated with 250 ml of NaOH at room temperature for 2 days. A portion of the mixture of isomeric acids was separated by reverse phase chromatography (Waters Delta Prep-3000) using 45% isocratic acetonitrile / water 192 (0.05% TFA). The fastest moving isomer (250 mg) identified as the 3-chloro isomer: 192 was NMR (DMSO-d6) <0.86 (t, J = 7 Hz, 3H), 1.23-1.36 2H), 1.54-1.65 (m, J = 7 Hz, 1H), 200 (t, J = 7 Hz, 2H), 7.23-7.58 (m, 7H), 7.72- 7.77 (m, 1H). (m, J = 2 H), 5.40 (s,

Example 7

5 '- [4' - [(5-butyryl-3-carboxymethyl-1H-1,2,4-triazol-1-yl) methyl] -1'-biphenin-2-yl] -1H-tetrazole

Step 1: Preparation of 5-butyl-3- (2,2-diethoxyethyl) -1H-1,2,4-triazole

Under nitrogen, a solution of 38.4 g (1.2 mol) of anhydrous hydrazine in 500 ml of methanol is cooled to 0øC and treated with a solution of 190.0 g (1.0 mmol) of 3.3 -ethoxypropionate (Aldrich) in 50 ml of methanol. The reaction is allowed to warm to room temperature and stirred overnight at reflux. Vacuum concentration gives crude hydrazide, which is purified either by recrystallization or by silica gel chromatography (Waters Prep-500A). A sample of 17.6 g (100 mmol) of the 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-diethoxyethyl) -1H-1,2,4-triazole.

Step 2: Preparation of 5- [4 '- [3-Aminomethyl-5-butyl-1H-1,2,4-triazol-1-yl] methyl] -1-biphenyl] -2-yl} -1H-tetrazole

Under a static atmosphere of nitrogen, 11.1 g (46.0 mmol) of 5-butyl-3- (2,2-diethoxyethyl) -1H-1,2,4-triazole are added in small portions to 50 mmol of sodium hydride in 250 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution ceased. The anion solution is cooled to -10 ° C (ice / methanol) and treated with a solution of 25.5 g (9.2 mmol) of N-triphenylmethyl-5- [2- (4'-bromomethylbiphen-2- yl)] -tetrazole in 100 ml of dry DMF. The reaction is allowed to warm to room temperature and stirred 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. Methanol. The solvent is removed in vacuo and the pH is adjusted to 9 with NaOH. The solution is extracted twice with ethyl acetate to remove triphenylmethanol. The pH is readjusted to 3 with 6N HCl and the solution is extracted 3 times with water, and dried (MgSO4). Concentration in vacuo gives 5- [4 '- [(5-butyl-3-formylmethyl-1H-1,2,4-triazol-1-yl) methyl] (1,1-biphenyl) -2 A free sample of 4.01 g (10.0 mmol) of the free aldehyde is dissolved in 500 ml of acetone / water (1: 1) and treated with 1.65 g (10.4 g) The reaction is allowed to stir overnight and the excess KMnO4 is destroyed by the addition of 100 ml of methanol. The reaction is filtered and acetone is evaporated to dryness. removed in vacuo, the pH is adjusted to 3 195

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 chromatography (Waters Delta Prep-3000) affords 5- [4 '- [(5-butyl-3-carboxymethyl) -1H-1,2,4-triazol-1-yl) -methyl] [1,1-biphenyl] -2-yl] -1H-tetrazole. 196

Example 8

The slower moving isomer (120 mg) gave the title compound as a white solid, mp 218 DEG- isolated in Example 6 was identified as the 5-chloro isomer: NMR (DMSO-d6) δ 0.88 (t, J = 7 Hz, 3H), 1.25-1.35 (m, J = 7 Hz, 2H) , 1.56-1.67 (m, J = 7Hz, 2H), 2.49 (t, J = 7Hz, 2H), 5.37 (s, 2H), 7.23-7.58 (m, 7H), 7.72-7.77 (m, 1H).

Example 9

5-butyl-3- (2-carboxyethyl) -1H-1,2,4-triazol-1-ylmethyl-1 H -1biphenyl-2-yn-1 H -tetrazole

Step 1: Preparation of 5-butyl-3- (3-hydroxypropyl) -1H-1,2,4-triazole

Under nitrogen, a solution of 38.4 g (1.2 mol) of anhydrous hydrazine in 500 ml of methanol is cooled to 0øC and treated with a solution of 86.0 g (1.0 mmol) of γ-butyrolactone (Aldrich) in 100 ml of methanol. The reaction is allowed to warm to room temperature and stirred overnight at reflux. Concentration in vacuo gives crude hydrazide, which is purified either by recrystallization or by silica gel chromatography (Waters Prep-500A). A sample of 11.8 g (100 mmol) of the 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 means of chromatography

on silica gel (Waters Prep-500A) gives 5-butyl-3- (3-hydroxypropyl) -1H-1,2,4-triazole.

Step 2: Preparation of 5 - [[4- (5-butyryl-3- (2-carboxyethyl) -1H-1,2,4-triazol-1-yl) methyl] -1,1-biphenyl] -1H-tetrazole

Under a static atmosphere of nitrogen, 8.4 g (46 mmol) of 5-butyl-3- (3-hydroxypropyl) -1H-1,2,4-triazole are added in small portions to 50 mmol of sodium hydride in 250 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution ceased. The anion solution is cooled to -10 ° C (ice / methanol) and 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 room temperature and stirred 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. Methanol. The solvent is removed in vacuo and the pH is adjusted to 9 with NaOH. The solution is extracted twice with ethyl acetate 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, and dried (MgSO4). Concentration in vacuo gives the 5- [4 '- [(5-butyl-3- (3-hydroxypropyl) and 5- [4- (3-butyl-5- (3-hydroxypropyl) -1H-1 1-yl) methyl] [1,1-biphenyl] -2-yl] -1H-tetrazole A sample of 4.17 g (10.0 mmol) of the isomeric mixture of alcohols is dissolved in 500 ml of acetone / water (1: 1) and treated with 3.30 g (20.8 mmol) of solid KMnO4 for 6 hours at room temperature. The reaction is allowed to stir overnight. 199

and the excess KMn04 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) affords 5- [4 '- [5-butyl-3- (2-carboxyethyl) -1H-1,2,4-triazole -1-yl] methyl] - [1,1-biphenyl] -2-yl] -β-tetrazole. ·· **!

Example 10

5 - [[4 '- [[5-Butyl-3-fluoro-1H-1,2,4-triazol-1-yl] methyl] -3' -biphenyl] -2-carboxylic acid

Step 1: Preparation of 3-butyl-5- (1,1-difluorobutyl-1H-1,2,4-triazole

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 chloride of methylene was cooled to 0 ° C and treated with pure difluoroacetic anhydride [E. Sawicki, J. Oro. Chem., 21, 376 (1956)] at a rate such as to maintain the reaction temperature below 10 ° C. The reaction was allowed to warm to room temperature and stirred overnight. All volatiles were removed in vacuo (bath temperature &lt; 35øC) and the residue was redissolved in methylene chloride; the solution was washed with saturated sodium bicarbonate, dried (MgSO 4), and concentrated to afford 94 g (89%) of a

yellow liquid. Distillation under vacuum gave 86 g (81%) of colorless N-tert-butyl-N-methyldifluoroacetamide: b.p. 87-88 ° C (22 mm);

1 H NMR (CDCl 3) δ 1.37 (s, 9H), 2.39 (t, J = 3 Hz, 3H), 5.97 (t, J = 57 Hz, 1H); 19 F NMR (CDCl 3) δ -122.20 (d, J = 57 Hz, 2 F).

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 diisopropylamide (LDA) in 450 ml of dry THF at -78 ° C . The reaction was allowed to stir for 1 h at -78 ° C before the addition of 17 ml (175 mmol) of 1-iodopropane by syringe. Stirring at -78 ° C was continued for 1 h, then the reaction was allowed to warm to room 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 (MgSO 4) and reconcentrated to give 17.6 g (83%) of crude product. Purification by vacuum distillation gave 13.3 g (62%) of N-tert-butyl-N-methyl-2,2-difluoro-valide: bp 125-130 ° C (84 mm) ; 1 H NMR (CDCl 3) δ 0.94 (t, J = 7 Hz, 3H), 1.37 (s, 9H), 1.40-1.52 (m, 2H), 1.95-2.15 (m, 2H); 19 F NMR (CDCl 3) δ -100.29 (t, J = 20Hz, 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 was dissolved in methylene chloride; the solution was washed with water 202 202

dried (MgSO4) and concentrated to give 9.7 g (100%) of crude N-methyl-2,2-difluorovaheamide: 1 H NMR (CDCl3) δ 0.92 (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 (m, , 1H); 19 F NMR (CDCl 3) δ -106.98 (t, J = 19 Hz, 2 F). The crude N-methyl amide was dissolved in 40 ml of 6N hydrochloric acid and stirred at reflux for 24 h. The reaction was cooled to room 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: 1 H NMR (CDCl 3) δ 1.00 (t, J = = 7 Hz, 3H), 1.46-1.63 (m, 2H), 1.97-2.17 (m, 2H); 19 F NMR (CDCl3) δ -107.16 (t, J = 18 Hz, 2 F).

A 4.83 g (35 mmol) crude acid sample 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 an oil bath at 110 ° C ° C for 6 h. The condenser was replaced with a distillation head and 3.22 g (60%) of 2,2-difluorovaleryl chloride: mp. and. 9.6 ° C; 1 H NMR (CDCl 3) δ 1.03 (t, J = 7 Hz, 3H), 1.48-1.65 (m, 2H), 2.03-2.23 (m, 2H); 19 F NMR (CDCl 3) δ-102.41 (t, J = 18 Hz, 2 F). The 2,2-difluorovaleryl chloride (20.6 mmol) was dissolved in 10 mL of methylene chloride and was added dropwise to a solution of 135 g (42 mmol) of anhydrous hydrazine in 203

20 ml of methylene chloride at 0 ° C. After the addition was complete, the reaction was stirred at room temperature for 1 h, washed with water, dried (MgSO 4), and concentrated to give 3.12 g (91%) of 2,2- difluorovaleric acid: NMR (CDCl3) δ 0.96 (t, J = 7 Hz, 3H), 1.40-1.56 (m, 2H), 1.96-2.17 (m, 2H) 93 (brs, 2H), 7.67 (bs, 1H).

A sample of 2.84 g (18.7 mmol) 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, this 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-1,24-triazole as a colorless solid: mp 92-93 ° C; 1 H NMR (CDCl 3) δ 0.97 (t, J = Hz, 3H), 0.92 (t, J = 7Hz, 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 = 7Hz, 2H). 19 F NMR (CDCl3) δ 97.27 (t, J = 18Hz, 2F); MS (FAB) m / e (rel intensity) 218 (100), 198 (8), 188 (5), 178 (8), 170 (5); HRMS: Calc'd for M + H: 218.1469.

Found: 218.1461.

- V 204

Step 2: Preparation of 5- (4-Butyl-3- (1,1-difluorobutyl) -1H-1,2,4-triazol-1-ylmethyl] [1,1'-biphenyl] -2-carboxylic acid

Under a static atmosphere of nitrogen, 2.0 g (9.2 mmol) of 3-butyl-5- (1,1-difluoro) butyl-1H-1,2,4-triazole were added in small portions to 10 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution ceased. The anion solution was cooled to -10 ° C (ice / methanol) and 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 was allowed to warm to room temperature and stirred 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). Chromatography on silica gel separates the two isomers; the most abundant isomer is dissolved in 80 ml of ethanol and treated with 80 ml of 10% NaOH at room temperature for 3 days. The ethanol is removed in vacuo and the aqueous phase is acidified to pH 1 with hydrochloric acid, which causes precipitation of the product; filtration and drying in vacuo gave 4 '- [(5-butyl-3- (1,1-difluoro-butyl) -1H-1,2,4-triazol-1-yl] methyl] 1'-biphenyl] -2-carboxylic acid.

Example 11

4-Amino-3-butyl-5- (1,1-difluorobutyl) -1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenyl-2-carboxylic acid The less abundant isomer isolated in Example 10 is dissolved in 40 ml of ethanol and treated with 40 ml of 10% NaOH at room temperature for 3 days. The ethanol is removed in vacuo and the aqueous phase is acidified to pH 1 with hydrochloric acid, which causes precipitation of the product; the filtration and drying in vacuo gave 4 '- [[3-butyl-5- (1,1-difluoro-butyl) -1H-1,2,4-triazol-1-yl] methyl] 1'-biphenyl] -2-carboxylic acid.

Example 12

5-propyl-1H-1,2,4-triazol-1-yl] methyl] -1 '-biphenin-2-yl} -tetrazole

Step 1: Preparation of 5-propyl-3-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole

Under nitrogen, a solution of 18.9 (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 mol) of ethyl iminobutyrate . The reaction is stirred at reflux overnight and concentrated in vacuo. Purification by means of silica gel chromatography (silica gel chromatography on silica gel chromatography on silica gel chromatography on silica gel Waters Prep-500A) gave 5-propyl-3-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole.

Step 2: Preparation of 5- [4 '- [(3-Aminomethyl-5-propyl) -1H-1,2,4-triazol-1-yl) methyl) -1,1'-biphenyl] -1H-tetrazole

Under a static atmosphere of nitrogen, 3.81 g (15.0 mmol) of 3-propyl-5- tert -butoxycarbonylaminomethyl-1H-1,2,4-triazole are added to 15 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution ceased. The anion solution was cooled to -10 ° C (ice / methanol) and treated with a solution of N-triphenylmethyl-5- (2- (4'-bromomethylbiphen-2-yl) ] tetrazole in 20 ml of dry DMF was added dropwise the reaction was allowed to warm to room temperature and stirred overnight. Methanol (10 ml) was added to destroy any unreacted sodium hydride and DMF The residue was dissolved in ethyl acetate, washed with water, and dried (MgSO4). Purification by silica gel chromatography gave the desired isomer which was dissolved in 100 ml of TFA and stirred at r.t. The reaction is cooled to 0 ° C, 50 ml of water is added, and it is allowed to stir at room temperature overnight. The solvent is removed in vacuo and the residue is evaporated to dryness. washed with acetonitrile / water. Purification by reverse phase chromatography (Waters Delta Prep-3000 ) affords 5- [4 '- [(3-amino-methyl-5-propyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl ] - ΙΗ-tetrazole in the form of TFA salt. And

Example 13

5 - [(3-Aminomethyl-5-pentyl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenin-2-yl] -1H-tetrazole

Step 1: Preparation of 5-pentyl-3-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole

Under nitrogen, a solution of 18.9 (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 mol) 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) gave 5-pentyl-3-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole 209-209

Step 2: Preparation of 5- [4- (3-Aminomethyl-5-pentyl) -1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenyl] -1H-tetrazole

Under a static atmosphere of nitrogen, 4.02 g (15.0 mmol) of 3-pentyl-5-tert-butoxycarbonylaminomethyl-1H-1,2,4-triazole are added to 15 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution ceased. The anion solution was cooled to -10 ° C (ice / methanol) and treated with a solution of N-triphenylmethyl-5- [2- (4-bromomethylbiphen-2-yl) Jtetrazole in 20 ml of dry DMF. The reaction was allowed to warm to room temperature and stirred 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). Purification by silica gel chromatography gives the desired isomer which is dissolved in 100 ml of TFA and stirred at room temperature overnight. The reaction is cooled to 0 ° C, 50 ml of water is added, and it is allowed to stir at room 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) affords 5- [4 - [(3-amino-methyl-5-pentyl-1H-1,2,4-triazol-1-yl ) methyl] [1,1'-biphenyl] -2-yl] - ΙΗ-tetrazole in the form of TFA salt. \ j

Example 14

5- [4- (5-Butyl-3-propyl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenyl] -2-carboxylic acid

Step 1: Preparation of 5-butyl-3-propyl-1H-1,2,4-triazole

A sample of 3.95 g (38.7 mmol) butyric acid hydrazide (from step 1 of Example 12) was dissolved in 30 ml of methanol and extracted with 5.0 g (38.8 mmol) of ethyl acetate 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) afforded 5.51 g (85%) of 5-butyl-3-pro-pyl-1H -1,2,4-triazole as a colorless solid: mp 48.5-50.0 ° C; NMR (CDCl 3) δ 0.92 (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: Calculated for M + H: 168.1501.

Found: 168.1534. 211 211

Step 2; Preparation of 4 '- (5-Butyl-3-propyl-1H-1,2,4-triazol-1-yl) methyl] biphenyl] -2-yl} -1H-tetrazole

Under a static atmosphere of nitrogen, 2.0 g (12 mmol) of solid 5-butyl-3-propyl-1H-1,2,4-triazole are added in small portions to 12 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution 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 was allowed to warm to room temperature and stirred 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). Chromatography on silica gel 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 room 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 the product isomers to precipitate out. Purification by reverse phase chromatography (Waters Delta Prep-3000) gives the 5-butyl-3-propyl isomer.

V

Example 15

The other isomer of Example 14 is isolated from a compound of the formula (II): wherein R1, R2, R3, R4, identical manner and provides the 3-butyl-5-propyl isomer.

Example 16

4'-β-3-Butyl-5-isopentyl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenyl-2-carboxylic acid

Step 1: Preparation of 3-butyl-5-isopentyl-1H-1,2,4-triazole

Under nitrogen, a solution of 53.8 g (11.8 mol) of anhydrous hydrazine in 300 ml of methanol was cooled to 0øC and treated with 186 g (1.4 mol) of methyl 4-methylvalerate. The reaction was allowed to warm to room temperature and stirred overnight before stirring at reflux for 4 h. The reaction was concentrated in vacuo to give 166 g (93%) of 4-methylvaleric acid hydrazide as a colorless solid: 49-51øC; NMR (CDCl3) Î'0.89 (d, J = 7 Hz, 6H), 1.48-1.64 (m, 3H), 2.15 (t, J = 7 Hz, 2H), 3.91 2H), 6.94 (bs, 1H).

A sample of 7.86 g (60 mmol) of the hydrazide was dissolved in 50 mL of methanol and treated with 7.8 g (60 mmol) of 214

iminovalerate under nitrogen. The reaction was stirred at reflux overnight and concentrated in 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 at about room temperature: NMR (CDCl3) δ 0.81-0.90 (m, 9H), 1.25-1.40 (m, 2H), 1.47-1.74 (m, 5H), 2.70 (t, J = 7Hz, 4H); MS (FAB) m / e (rel intensity) 196 (100); HRMS: Calc'd for M + H: 196.1814.

Found: 196.1832.

Step 2: Preparation of 4apos; -β-butyl-5-isopentyl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenyl] -2-carboxylic acid

Under a static atmosphere of nitrogen, 2.0 g (10.3 mmol) of 3-butyl-5-isopentyl-1H-1,2,4-triazole were added in small portions to 11 mmol of sodium hydride in 50 ml of dimethylformamide (DMF); stirring was continued until hydrogen evolution ceased. The anion solution was cooled to -10 ° C (ice / methanol) and 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 was allowed to warm to room temperature and stirred 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 (MgSO & &gt; 4). The crude material is dissolved in 80 ml of ethanol and treated with 80 ml of 10% NaOH at room temperature for 3 days. The ethanol is removed in vacuo and the aqueous phase is acidified to pH 1 with hydrochloric acid, which causes precipitation of the mixture of the product isomers. Purification by reverse phase chromatography (Waters Delta Prep-3000) gives the 3-butyl-5-isopentyl isomer. 216 216

Example 17

The other isomer of Example 16 is isolated in a similar manner to the title compound as a white solid. and provides the 5-butyl-3-isopentyl isomer. . &gt; 4 217 217

Example 18

4 '- [(5-Butyl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenyl] -2-carboxylic acid

Following General Procedure A, 5.0 g (39.9 mmol) of 5-butyl-1H-1,2,4-triazole were 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 the 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 = 8Hz, 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: 218 218

NMR (CDCl 3): 0.92 (t, J = 8Hz, 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 (τη5H), 7.39 (dt, J = 8 and 2 Hz, 1H), 7.50 (dt, J = 8 and 2 Hz, 1H), 7.83 (dd, J = S and 2 Hz, 1H), 7.94 (s, 1H). The faster moving isomer was hydrolyzed to obtain 2.72 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): δ 0.85 (t, J = 8 Hz, 3H), 1.23-1.38 , 2.76 (t, J = 7Hz, 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), 7.65 (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 1 (7), 224 (8) , 211 (100), 193 (9) • 219

Example 19

4'- (3-Butyl-1H-1,2,4-triazol-1-yl) methine-1,1'-biphenyl-carboxylic acid The slower moving isomer of Example 18 hydrolyzed to give 2 , 3 g (67%) 4 '- [3-yl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid as a colorless solid NMR (DMSO-d6) δ 0.87 (t, J = 8 Hz, 3H), 1.23-1.38 (m, 2H), 1 -1.67 (m, 2H), 2.58 (t , J = 8Hz, 2H), 5.36 (s, 2H), 7.23-7.38 (5H), 7.44 (dt, J = 8 and 2Hz, 1H), 7.56 (dt, J = 8 and 2 Hz, 1H), (dd, J = 8 and 2 Hz, 1H), 8.51 (s, 1H). MS (FAB) m / e (rel intensity) 336 (85), 211 (100), 165 (24), (52). -2- was 54- (m,

Example 20

4'-β- (3,5-Dihydrofluoropropyl-1H-1,2,4-triazol-1-yl) methyl-β-β-biphenyl-2-carboxylic acid

Following General Procedure A, 11.0 g (27.2 mmol) of 3,5-bis (trifluoropropyl) -1H-1,2,4-triazole were coupled with 8.30 g (27.2 mmol) of the reagent (s, 3H), 5.63 (s, 2H), 3.65 (s, 3H), 3.65 (s, 3H) (Dt, J 8 and 2 Hz, 1H), 7.87 (dd, J = 8 and 2 Hz, 1H), 7.25-7.37 (m, 5H), 7.44 = 8 and 2 Hz, 1H).

A sample of 8.5 g (13.5 mmol) 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-carboxylic acid as colorless solid: NMR (CDCl3) δ 5.62 (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, 1H). MS (TSP) M + NH 4 (rel intensity) 633 (100), 211 (12); HRMS: Calc'd for M + Li: 622.0788.

Found: 622.0759.

Example 21

5-butyl] -1,2,4-triazol-1-yl) methyl] (1,1'-biphenyl) -2-yn-tetrazole

Following General Procedure A, 2.0 g (9.9 mmol) of 5-butyl-3-phenyl-1H-1,2,4-triazole were coupled with 5.5 g (9.9 mmol) of the alkylation prepared in Step 1 of Example 3 to give 5.2 g (77%) of a faster moving isomer: NMR (CDCl3) Î'0.90 (t, J = 8 Hz), 1.30 - 1.44 (m, 2H), 1.63-1.77 (m, 2H), 2.67 (t, J = 8Hz, 2H), 5.24 (s, 2H), 6.88-7, 1 (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: 222

NMR (CDCl3) δ 0.96 (t, J = 8Hz, 3H), 1.38-1.52 (m, 2H), 1.75-1.89 (m, 2H), 2.84 (t, J = 8Hz, 2H), 5.27 (s, 2H), 6.88-6.97 (m, 8H), 7.13 (d, J = 8Hz, 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 deprotected 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: 1.24 g (M, 2H), 7.97 (m, 2H), 7.97 (m, 2H), 7.50 , 878 and 2 Hz, 1H); 192 100), 393 (8), 207 (60) /

Example 22

5-phenyl-1H-1,2,4-triazol-1-yl) methyl] (1'-biphenyl) -2-yl] -tetrazole The isomer of The slower movement of 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] -N-tetrazole as a colorless solid: mp 205øC (dec); NMR (CDCl3) δ 0.88 (t, J = 8Hz, 3H), 1.23-1.38 (m, 2H), 1.55-1.68 (m, 2H), 2.52 (t, J = 8Hz, 2H), 5.32 (m, 2H), 7.08 (d, J = 8 Hz, 2H), 7.31-7.61 (m, 8H), 7.90 (dd, J = 8 and 2, 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. 224

Example 23

5 - [[4 '- (3-butyl-5-dimethoxymethyl) -1H-1,2,4-triazol-1-ylmethyl] - (1,1'-biphenyl) -2-yl] -1H-tetrazole. General Procedure A, 2.0 g (10 mmol) of 5-butyl-3- (dimethoxymethyl) -1H-1,2,4-triazole were coupled with 5.6 g (10 mmol) of the alkylating reagent prepared in Step 1 of Example 3 to give 1.65 g (24%) of a faster moving isomer: NMR (CDCl3) δ 0.92 (t, J = 8 Hz, 3H), 1.31-1, 2H), 3.33 (s, 6H), 5.30 (s, 2H), 2.69 (m, 2H), 1.66-1.78 (m, 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) δ 0.85 (t, J = 8 Hz, 3H), 1.22-1.36 (m, 2H), (S, 2H), 5.55 (s, 2H), 3.45 (s, 6H) 1H), 6.89-6.97 (m, 5H), 7.08-7.19 (m, 4H), 7.21-7.37 (m, 11H), 7.41-7.52 (m, m, 2H), 7.90-7.95 (m, 1H). • v 225

The faster isomer of movement was deprotected to give 737 mg (70%) of 5- [4 '- [(3-butyl-5- (dimethoxyimethyl) -1H-1,2,4-triazole yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole as a colorless solid: mp 152.5-153.5 ° C; 2H), 1.53-1.65 (s, 2H), 5.40 (1H), 7.51-7.65 (11), 342 (70); NMR (CDCl3) δ 0.87 (t, J = 8Hz, 3H), 1.20-1.30 (m, (m, 2H), 2.46 (t, J = 8Hz, 2H), 3.30 (s, 6H), 5.37 (s, 1H), 7.05-8.05 (m, 4H), 7.45 (dd, J = 8 and 2 Hz, (m, 2H), 8.02 d, J = 8Hz, 1H), MS (FAB) m / e (rel intensity) 434 (65), 402 (40), (46), 249 (35), 235 (18), 207 (100), 192 (89), 168 HRMS: Calculated for M + H: 434.2304.

Found: 434.2332.

Example 24

5 - [(5-butylyl-3-dimethoxymethyl-1H-1,2,4-triazol-1-ylmethyl) -1,1'-biphenyl-2-yl] -1H-tetrazole

A sample of 3.65 g (5.4 mmol) of the slower moving isomer of Example 23 was deprotected to give 108 mg of 5- [4 '- [[5-butyl-3- (dimethoxymethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] tetrazole after lyophilization: NMR (CDCl3) (T, J = 8 Hz, 2H), 2.66 (t, J = 8 Hz, 3H), 1.24-1.39 (m, 2H) (D, J = 8 Hz, 2H), 7.10 (d, J = 8 Hz, 1H), 3.30 (s, 6H), 5.23 (s, (Dt, J = 8 and 2 Hz, 1H), 7.59 (dt, J = 8 and 2 Hz, 1H), 7.40 (dd, J = 8 and 2 Hz, 7.98 (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: 434.2221. 227

Example 25

5 ', 4' '- (3-butyl-5-phenylethyl-1H-1,2,4-triazol-1-yl) methyl] -1. benzothien-2-yn-1H-tetrazole

Following General Procedure A, 2.3 g (10 mmol) of 3-butyl-5-phenethyl-1H-1,2,4-triazole were coupled with 6.6 g (10 mmol) of the alkylating reagent prepared in Step 1 of the

Example 3 to give 2.67 g (38%) of a faster moving isomer: NMR (CDCl3) δ 0.97 (t, J = 8 Hz, 3H), 1.36-1.50 ( m, 2H), 1.71-1.84 (m, 2H), 2.73 (t, J = 8Hz, 2H), 2.78-2.88 (m, 2H), 2.92-3, (M, 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); NMR (CDCl3) δ 0.88 (t, J = 8Hz, 3H), 1.23-1.38 (m, 2H), 1.33 (m, 2H) 2H), 2.97-3.13 (m, 4H), 5.11 (s, 2H), 6.86 (m, 2H) d, J = 8Hz, 2H), 6.89-6.96 (m, 6H), 7.10 (d, J = 8Hz, 2H), 7.14-7.39 (m, 42-7.54 (m, 2H), 7.93 (dd, J = 8 and 2 Hz, 1H). The faster isomer of movement afforded 1.6 g (88%) of 5- [4 '- [(3 -1,2,4-triazol-1-yl) methyl] [1,1'- biphenyl] -2-yl ester of a colorless solid: NMR (CDCl3) δ 0.86 (t, J = 8Hz, 3H), 1.17-1.3 (m, 2H), 2.42 (t, J = J = 8Hz, 2H), 4.80 (s, 2H), 6.83 (d, J = 8Hz, 2H), 7.08 (d, J = 8Hz, 2H), 7.17-7.32 (m, 3H) 2Hz, 1H), 7.51-7.65 (m, 2H), 7.96 (dd, J = 8, and (rel intensity) 464 (37), 230 (17) HRMS: Calculated for M + H: 464.2563.

Found: 464.2532. was deprotected from -butyl-5-phenethyl-1H-] -tetrazole under 1 (m, 2H), 1.48-1.51 8Hz, 2H), 2.92 (t, 2H) (Dd, J = 8 and e 2 Hz, 1H), (25), 207 (100), 178

Example 26

5- (4-Butyryl-3-phenylethyl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenyl-2-yl] -1H-tetrazole The isomer of The slower movement of Example 25 was deprotected to give 1.5 g (77%) of 5- [4 '- [[5-butyl-3- (2-phenylethyl) -1H- 4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -tetrazole as a colorless solid: mp 156.0-157.2 ° C; NMR (CDCl 3) δ0.84 (t, J = 8Hz, 3H), 1.19-1.34 (m, 2H), 1.47-1.61 (m, 2H), 2.52 (t, J = 8Hz, 2H), 2.66-2.77 (m, 2H), 2.85-2.95 (m, 2H), 5.15 (s, 2H), 6.88 (d, J = 8Hz, 2H), 7.05-7.11 (m, 4H), 7.12-7.28 (m, 5H), 7.41 (dd, J = 8 and 2 Hz, 1H), 7.50 (m, 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. 230

Example 27

5-butyl] -1- [2 '- (1H-tetrazol-1-yl)] - biphenyl] -4-ylmethyl] -1H-1,2,4-triazole-3-methanamine

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 room temperature overnight and then at reflux for 50 min, the course of the reaction being followed by reverse phase analytical HPLC. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate and extracted with saturated sodium bicarbonate solution until the aqueous layer became basic. The aqueous layer was acidified and extracted with a mixture of ethyl acetate / methylene chloride. The organic layer was dried (MgSO4) and removed in vacuo yielding 0.96 g of crude aldehyde: NMR (CDCl3) δ 0.66 (t, J = 8 Hz, 3H), 1.06-1.20 (m, 2H), 1.42-1.54 (m, 2H), 2.53 (t, J = 8Hz, 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). 231

Under a static atmosphere of nitrogen, 0.91 g (2.3 mmol) of this material was dissolved in 10 ml of methanol and 1.77 g (23 mmol) of ammonium acetate was added, followed by 0.10 g ( 1.61 mmol) of sodium cyanoborate. After stirring at room temperature for 3 days, reverse phase analytical HPLC indicated that the reaction was complete. Purification was carried out by reverse phase chromatography (Walters Delta Prep 3000) using 25% acetonitrile / water (0.05% TFA). The solvent from the pure fractions was removed in vacuo and the residue was dissolved in methanol and 3N HCl. After stirring for 30 min the solvent was removed in vacuo and the residue lyophilized from acetonitrile / water to provide 100 mg (10%) of 5-butyl-1- [2 '- (1H-tetrazol-5-yl ) [1,1'-biphenyl] -4-ylmethyl] -1 H -1,2,4-triazole-3-methanamine as the colorless hydrochloride salt: NMR (DMSO-d6) <5 0.85 ( t, J = 8 Hz, 3H), 1.22-1.38 (m, 2H), 1.51-

(M, 2H), 5.40 (s, 2H), 7.01 (m, 2H) 7.25 (m, 4H), 7.39 (s, 1H), 7.48-7.73 (m, 3H); MS (FAB) m / e (rel intensity) 398 (100), 207 (65), 192 (17); HRMS: Calc'd for M + H: 389.2202.

Found: 389.2170. -4

Example 28

5-f 4 '- (3-butyl-5-octyl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenyl-2-yl} -1H-tetrazole

Following General Procedure A, 2.0 g (8.4 mmol) of 3-butyl-5-octyl-1H-1,2,4-triazole were coupled with 5.5 g (8.4 mmol) of the (Waters Prep 500-A) using 25% ethyl acetate / hexane afforded 4.5 g (75.4%) of a mixture of two isomers which was dissolved in 40 ml of 10% water / acetic acid and stirred at room temperature overnight. The solvent was removed in vacuo. Purification of a sample of the mixture of isomeric products 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, 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 233

a solid which was recrystallized from acetonitrile to give 92 mg of 5- (4 '- [(3-butyl-5-octyl-1H-1,2,4-triazol-1-yl ) methyl] [1,1'-biphenyl] -2-yl] -tetrazole as colorless solid: mp 136.5-138.0 ° C; NMR (CDCl3): 0.82 (t 3H), 0.86 (t, J = 8Hz, 3H), 1.11-1.33 (m, 12H), 1.40-1.60 (m, 4H) J = 8Hz, 2H), 5.16 (s, 2H), 6.87 (d, J = 8Hz, 2H), 7.07 (t, 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: Calculated for M + H: 472.3189.

Found: 472.3180.

Example 29

5-Butan-3-yl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenyl] -1H-tetrazole The slower moving isomer of Example 28 was isolated in an identical manner and the product was lyophilized from acetonitrile / water to give 53 mg of 5- [4 '- [(5-butyryl-3-yl- 2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -tetrazole as a colorless solid: NMR (CDCl3) δ 0.83 (t, J = 8Hz, 3H), 0.86 (t, J = 8Hz, 3H), 1.12-1.37 (m, 12H), 1.46-1.63 (m, 4H), 2.35 (m, 2H), 6.92 (d, J = 8 Hz, 2H), 7.09 (d, J = 8 Hz, J = 8Hz, 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

1- (5-Butyl-1- (2 H - tetrazol-5-yl) [1.1'-biphenyl-4-ylmethyl] -1H-1,2,4-triazol-3-yl] methyl] -1-butanone

Under a static atmosphere of nitrogen, 30.0 g (150 mmol) of 5-butyl-3-dimethoxy-1H-1,2,4-triazole (from Step 1 of Example 23) were added in small portions to 165 mmol of sodium hydride in 300 ml of anhydrous THF; the stirring was continued for 1 h. The anion solution was cooled to -10 ° C (ice / methanol) and treated dropwise with SemCl. The reaction was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo. The residue was dissolved in methylene chloride, washed with water, dried (MgSO4), and the solvent was again removed in vacuo. Chromatography on silica gel using 20% ethyl acetate / hexane followed by ethyl acetate provided 13.6 g of the faster moving 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 = 8Hz, 2H), 3.38 (s, 6H), 3.53-3.62 (τη, 2H), 5.47 (s, 2H), 5.55 (s, 1H).

Under a static atmosphere of nitrogen, 12.6 g (38.2 mmol) of the above-mentioned fast-moving No-protected triazole isomer was dissolved in 630 ml of anhydrous THF, cooled to -78øC, and dropwise 45.8 mmol of sec-butyllithium 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 room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in methylene chloride, washed with water, dried (MgSO4) and the solvent removed to provide 12.4 g of 5-butyl-3- (1,1-dimethoxybutane) -1H-1,2,4- protected crude 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 affording 560 mg of crude 5-butyl-3- (1-butanone) -1H-1,2,4-triazole HCl salt: NMR (DMSO-d6) δ 0.83- 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 recent methanol, 3A molecular sieves were added, and the mixture was stirred at reflux under nitrogen overnight. The solution was filtered through celite and the solvent was 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 affording 390 mg of 5-butyl-3- (1,1-dimethoxybutyl) -1H-1,2,4-triazole: NMR (CDCl3) δ, (T, J = 8Hz, 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 atmosphere of nitrogen, 380 mg (1.6 mmol) of this material in 5 mL of dimethylformamide (DMF) were added to 1.9 mmol of sodium hydride in 5 mL of DMF; the stirring was continued for 1 h. The anion solution was cooled to 0 ° C and 890 mg (1.6 mmol) of the alkylation reagent prepared in Step 1 of Example 3 was added as a solid. The reaction was allowed to warm to room temperature and stirred 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 affording 1.2 g of crude material which was dissolved in 10 ml of ethanol and 10 ml of 3N HCl and stirred at reflux for 2 h. The solvent was removed in vacuo. Purification by reverse phase chromatography (Waters Delta Prep-3000) using 37% isocratic 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 was extracted with ethyl acetate. The ethyl acetate was dried (MgSO4) and removed in vacuo to give a solid which was recrystallized from acetonitrile 238

yielding 146 mg (21%) of 1 - [[5-butyl-1- [2 '- (1H-tetrazol-5-yl) [1,1'-biphenyl] -4-ylmethyl] -1H- 2,4-triazol-3-yl] methyl] -1-butanone: mp 150.5-152.5 ° C; NMR (CDCl 3) δ 0.85 (t, J = 8Hz, 3H), 0.96 (t, J = 8Hz, 3H), 1.23-1.39 (m, 2H), 1.54-1, (M, 4H), 2.67 (t, J = 8 Hz, 2H), 2.97 (m, (d, J = 8Hz, 2H), 5.28 (s, 2H), 7.02 (d, J = 8Hz, 2H), 7.10 (d, J = 8Hz, 1H), 7.43-7.62 (m, 2H), 7.86 (d, J = 8Hz, 1H) / MS (FAB) m / e (rel intensity) 430 (6), 207 12); HRMS: Calc'd for M + H: 430.2355.

Found: 430.2404. v

Example 31

N-γ 5 -butyl-1 - [(1H-tetrazol-5-yl) -1,1'-biphenyl] -4-ylmethyl] -1 H -1,2,4-triazol-3-yn-4-yl) acetamide

A sample of 92.9 mg (0.22 mmol) of 5- [4 '- [(5-butyl-3-methylamino-1H-1,2,4-triazol-1-yl) 1'-biphenyl) -2-yl] -1H-tetrazole from Example 27 was dissolved in 5 ml of water and the pH adjusted to 9 with 1M potassium carbonate (K2 CO3). The solution was cooled to 0 ° C and 0.22 ml of 1M CO 2M was added, followed by 0.22 ml of acetic anhydride. An additional amount of K2CC> 3 was added as necessary to maintain the pH of 9. At 30 minute intervals, this addition was repeated until reverse phase analytical chromatography showed that all starting material had 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 to afford 36 mg

(1 H-tetrazol-5-yl) (1,1'-biphenyl] -4-ylmethyl] -1H-1,2,4-triazol-3- yl] methyl] acetamide as a colorless solid: NMR (CDCl3) Î'0.80 (t, J = 8 Hz, 3H) and c H -1.37 (m, 2H), 1.47-1.64 ( 2H), 4.22 (d, J = 8 Hz, 2H), 5.18 (s, 2H), 6.94 (s, 2H) (D, J = 8Hz, 1H), 7.50-7.66 (m, 2H), 7.44 (d, J = , 7.90 (dd, J = 8 and 2 Hz, 1H), MS (FAB) m / e (rel intensity), 431 (42), 207 (100), HRMS: Calculated for M + H: 431.2308.

Found: 431.22271.

Example 32

(5-butyryl-3-methyl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenyl-2-yl] -1H-tetrazole

Following General Procedure A, 700 mg (5.0 mmol) of 5-butyl-3-methyl-1H-1,2,4-triazole were coupled with 2.8 g (5.0 mmol) of the prepared alkylation reagent in Step 1 of Example 3. Chromatography on silica gel using ethyl acetate / toluene (35:65) afforded 2.75 g (90%) of a mixture of two isomers which was dissolved in 30 ml of water at 10 ° C. % / acetic acid and stirred at room temperature for 3 days. The solvent was removed in vacuo and the residue was dissolved in diluted base, washed with toluene, acidified to pH 4 with 1N HCl and the product extracted with ethyl acetate. Purification of the isomeric product mixture by reverse phase chromatography (Waters 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- [t-1 H -1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] a colorless solid: mp 170.0-170.5 ° C; NMR (CDCl 3) δ 0.79 (t, J = 8Hz, 3H), 1.18-1.32 (m, 2H), 1.99 (s, 3H), 2.49 (t, J = 8Hz, 2H), 5 (d, J = 8Hz, 2H), 7.08 (d, J = 8Hz, 2H), 7.44 (1H), 7.51-7.65 (m, 2H), 7.90 ( dd, J = 8 and 2Hz, MS (FAB) m / e (rel intensity), 374 (100), 235-140 (29), HRMS: Calc'd for M + H: 374.2093.

Found: 374.2062. 4 '' (5-butyl-3-methyl-1 H -1-tetrazole-2H), 1.44-1.56 '15 (s, 2H), 6.87 (dd, J = 8 and 2 Hz, 1H); (13), 207 (100),

Example 33

5-methyl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenyl] -1H-tetrazole The more preferred isomer of Example 32 was dissolved in dilute base, acidified to pH 3-4 and extracted with ethyl acetate. the solvent was removed in vacuo and the product lyophilized from acetonitrile / water, which afforded 536 mg (33%) of 5- [4 '- [(3-butyl-5-methyl-1H-1,2 4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -tetrazole as a colorless solid: NMR (CDCl3): δ 0.32 (t, J = 8Hz, 3H), 1.21-1.35 (m, 2H), 1.53-1.66 (m, 2H), 2.35 (s, 3H), 2.56 (t, J = J = 8Hz, 2H), 5.23 (s, 2H), 7.03 (d, J = 8Hz, 2H), 7.11 (d, J = 8Hz, 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. (I.e.

Example 34

1-yl) -1H-tetrazol-5-yl) -1,1'-biphenyl] -4-ylmethyl] -1H-1,2,4-triazole-5-yl] methylcarbamate

Following General Procedure A, 6.0 g (25 mmol) of [(5-butyl-1H-1,2,4-triazol-3-yl) methyl] carbamate were coupled with 16.4 g (25 mmol) of (Waters Prep 500A) using ethyl acetate / hexane (2: 3) afforded 4.29 g (24%) of a faster moving isomer NMR (CDCl 3): 0.94 (t, J = 8Hz, 3H), 1.33-1.46 (m, 2H), 1.43 (S, 9H), 1.66-1.78 ( m), 2.69 (t, J = 8Hz, 2H), 4.26 (d, J = 8Hz, 2H), 5.24 (s, 2H), 6.87-6.93 (τη 7H), 7.01 (d, J = 8Hz, 2H), 7.11 (d, J = 8Hz, 2H), 7.21-7.28 (m, 5H), 7.30-7 (M, 4H), 7.42-7.52 (m, 2H), 7.94 (dd, J = 8 and 2 Hz, 1H), and 9.74 g (54%) of an isomer of NMR (CDCl 3) δ 0.87 (t, J = 8Hz, 3H), 1.24-1.36 (m, 2H), 1.44 (s, 9H), 1.57-1, (D, J = 8Hz, 2H), 5.12 (s, 2H), 6.91 (d, J = 8Hz, 2H) 8Hz), 7.11 (d, J = 8Hz, 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 room temperature overnight. The solvent was removed in vacuo: the residue was dissolved in dilute base and washed with toluene. The aqueous layer was acidified to pH 3-4 and extracted with ethyl acetate. Recrystallization from acetonitrile gave 2.53 g (83%) of [3-butyl- [1- (2 '- (1H-tetrazol-5-yl) [1,1'-biphenyl] -4 -ylmethyl] -1H-1,2,4-triazol-5-yl] methylcarbamate as an inert solid: mp. 144-147 ° C; NMR (CDCl3) δ 0.88 (t, J = 8Hz, 3H), 1.22 (s, 2H), 1.36 (s, 9H), 1.54-1.66 (m, 2H), 2.56 (t, J = 8Hz, 2H), 4.05 (d, J = 8Hz, 2H), 5.38 (s, 2H), 5.50 (s, 1H), 7.06 (d, J = 8Hz, 2H), 7.12 (d, J = 8Hz, 2H), 7.45 (dd, J = 8 and 2Hz, 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: Calculated for M + Li: 495.2808.

Found: 495.2771.

Example 35

5-butyl-1 - [[2 '- (1H-tetrazol-4-yl) -1 H -biphenyl-4-yl] ethyl] -1H-1,2,4-triazol-3-ylmethylcarbamate -dimethylethyl ester The slower moving isomer of Example 34 was dissolved in 70 ml of water / acetic acid (1: 4) and stirred at room temperature overnight. The solvent was removed in vacuo, the residue dissolved in The aqueous layer was acidified to pH 3-4 with HCl and extracted with ethyl acetate. The ethyl acetate was dried (MgSO4) and stripped in vacuo. Lyophilization from acetonitrile / water gave to 5 g (76%) of [5-butyl- [1- [2 - (1H-tetrazol-5-yl) [1,1'-biphenyl] -4-ylmethyl] -1H- 2,4-triazol-3-yl] methylcarbamate as a colorless solid:

NMR (CDCl3) Î'0.77 (t, J = 8Hz, 3H), 1.16-1.30 (m, 2H), 1.40 (S, 9H), 1.42-1.56 ( 2H), 5.12 (d, J = 8 Hz, 2H), 5.19 (s, 2H), 5.59 (s, (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: Calculated for M + Li: 495.2808.

Found: 495.2800. '<4

Example 36

3-butyl-1- [2 '- (1H-tetrazol-5-yl] -1'-biphenyl] -4-ylmethyl] -1H-1,2,4-triazole-5-methanamine

Under nitrogen, 219 mg (0.45 mmol) of [3-butyl- [1- (2 '- (1H-tetrazol-5-yl) [1,1'-biphenyl] -4-ylmethyl] -1H- 1,2,4-triazol-5-yl] -methylcarbamate from Example 34 were suspended in 10 ml of 4N HCl in dioxane After 30 minutes, methylene chloride (10 ml) was added. Lyophilization from acetonitrile / water gave 201 mg (100%) of 3-butyl-1- [2 '- (1H-indol-1-yl) tetrazol-5-yl) - [1,1'-biphenyl] -4-ylmethyl] -1H-1,2,4-triazole as a colorless hydrochloride salt: NMR (CDCl3) δ 0.82 (t, J = 8Hz, 3H), 1.21-1.35 (m, 2H), 1.59-1.72 (m, 2H), 2.72 (t, J = 8Hz, 2H), 4.97 ( (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, BAR) m / e (rel intensity): 389 (55), 207 (100), 192 (39), 178 (26): HRMS: Calculated for M + H: 389.2202.

Found: 389.2170. (I.e.

Example 37

5- (4-methoxyethoxy) -1H-1,2,4-triazol-1-ylmethyl] -1- 1'-biphenyl-2-yn-1H-tetrazole

Following General Procedure A, 4.7 g (19.5 mmol) of 5-butyl-3- (2,2-diethoxyethyl) -1H-1,2,4-triazole were coupled with 19.5 g (25 mmol ) of the alkylating reagent prepared in Step 1 of Example 3. Chromatography on silica gel (Waters Prep 500A) using ethyl acetate / hexane (2: 3) afforded 5.98 g (43%) of an isomer of NMR (CDCl 3)? 0.94 (t, J = 8Hz, 3H), 1.13 (t, J = 8Hz, 6H), 1.33-1.48 (m, 2H) (M, 2H), 2.70 (t, J = 8Hz, 2H), 2.94 (d, J = 8Hz, 2H) , 3.83 (m, 2H), 4.81 (t, J = 7 Hz, 1H), 5.22 (s, 2H), 6.87-6.98 (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) δ 0.88 (t, J = 8 Hz, 3H), 1.15 (t, J = 1.24-1.37 (m, 2H), 1.56-1.68 (m, 2H), 2.57 (t, J = 8Hz, (d, J = 7Hz, 2H), 3.46-3.60 (m, 2H J = 7 Hz, 1H), 5.14 (s, 2H), 6.87-6.95 (m, 8H), 7.10 (d, 2H), 7.21-7.29 (m, 6H), 7.31-7.37 (m, 4H), 7.42-7.53-7Hz 2H), 5.05 J = (m, 6H) , 3.06 (t, 8Hz, 2H), 7.90-7.96 (m, 1H). The faster moving isomer was dissolved in 50 ml of water / acetic acid (4: 1) and stirred at room temperature for 3 days. The solvent was removed in vacuo: the residue was dissolved in dilute base and washed with toluene. The aqueous layer was cooled to 0øC, acidified to pH 4-5 and extracted with ethyl acetate. Lyophilization from acetonitrile / water gave 3.8 g (93%) of 5- [4 '- [[3-butyl-5- (2,2-diethoxyethyl) -1H-1,2 , 4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -tetrazole as a colorless solid: NMR (CDCl3) δ 0.80 (t, J = 8Hz, 3H), 1.10 (t, J = 8Hz, 6H), 1.10-1.24 (m, 2H), 1.37-1.49 (m, 2H), 2.31 (t, J = 8Hz, 2H), 2.66 (d, J = 7Hz, 2H), 3.34-3.47 (m, 2H), 3.59-3.71 (m, 2H), 4.75 (m, (d, J = 8 Hz, 2H), 7.06 (d, J = 8 Hz, 2H), 7.46 (dd, J = 8 and 2 Hz, 1H), 7.62 (dt, J = 8 and 2 Hz, 1H), 7.91 (dd, J = 8 and 2 Hz, 1H) , 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. 251

Example 38

5-butyl-3 - (2,2-diethoxyethyl) -1H-1,2,4-triazol-1-ylmethyl ·) - 1,1apos; -biphenyl-1- 2-yl] -1H-tetrazole 6.2 g (8.6 mmol) of the faster moving isomer of Example 37 were dissolved in 50 ml of water / acetic acid (4: 1) and stirred at room temperature for 3 days. the solvent was removed in vacuo; the residue was dissolved in dilute base and washed with toluene. The aqueous layer was cooled to 0øC, acidified 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-diethoxyethyl) -1,2,3,4- 4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-yl] -β-tetrazole as a colorless solid: Î'252 NMR (CDCl3) Î'0.85 (t, J = = 8Hz, 3H), 1.09 (t, J = 8Hz, 1.24-1.38 (τη, 2H), 1.51-1.63 (m, 2H), 2.55 (t, J = (D, J = 7 Hz, 2H), 3.38-3.50 (m, 2H), 3.54-3.66 (m, 2H), 4.87 (d, J = 7 Hz, 1H) (Dd, J = 8 and 2 Hz, 1H), 7.12 (d, 8HZ, 2H), 7.42 (dd, J = 8 and 2 Hz, MS (FAB) m / e (rel intensity) 476 (3), 430 (28), 235 (10), 50-7.65 (m, 2H), (dd, J = 8 and 2 Hz, (100), 192 (61); HRMS: Calc'd for M + H: 476.2773.

Found: 476.2760. 6H), 2.75 (t, J = 7.97

Example 39

5-Butyl-3-ethyl-1H-1,2,4-triazol-1-ylmethyl] -1,1'-biphenyl-2-yn-1H-tetrazole

Following General Procedure A, 770 mg (5 mmol) of 5-butyl-3-ethyl-1H-1,2,4-triazole were coupled with 2.8 g (5.0 mmol) of the alkylating reagent prepared in Step (Waters Prep-500A) using ethyl acetate / hexane (2: 3) gave 2.24 g (72%) of a mixture of two isomers which was dissolved in 30 ml acetic acid / water (9: 1) and stirred at room temperature for 4 days. The solvent was removed in vacuo. the residue was dissolved in dilute base and washed with toluene. The aqueous 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 mixture of isomeric products by reverse phase chromatography (Waters Delta Prep-3000) using isocratic acetonitrile / water (25:75) (0.05% TFA) provided two isomers. The faster moving isomer compound was dissolved in dilute base, acidified, extracted with ethyl acetate, dried (MgSO4) and 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'-biphenyl] -2-yl] -1H-tetrazole as a colorless solid: NMR (CDCl 3) δ 0.88 (t, J = 8Hz, 3H), 1.33-1.40 2H), 1.38 (t, J = 8Hz, 3H), 1.58-1.70 (m, 2H), 2.67-2.85 (m, 4H), 5.26 (s, 2H ), 7.10 (s, 4 H), 7.41 (dd, J = 8 and 2 Hz, 1H), 7.74-7.62 (m, 2H), 7.86 (dd, J = 8 and MS (FAB) m / e (rel.) 388 (58), 207 (100), 192 (35): HRMS: Calculated for M + H: 388.2449.

Found: 388.22218, m

Example 40

5-Ethyl-5-ethyl-1H-1,2,4-triazol-1-yl) methyl] -1,2-biphenyl] -1H-tetrazole The slower moving isomer of Example 39 was dissolved in dilute base, acidified to pH 3-4, extracted with ethyl acetate, dried (MgSO 4), and the ethyl acetate was removed in vacuo. Lyophilization from acetonitrile / water gave 536 mg of 5- [4 '- [(3-butyl-5-ethyl-1H-1,2,4-triazol-1-yl) methyl] 2-yl] -1H-tetrazole as a colorless solid: NMR (CDCl3) δ 0.87 (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 = 8Hz, 2H), 2.67 (q, J = 8Hz, 2H), 5.23 (s, 2H), 7.02 (d, J = 8Hz, 2H), 7.12 (d, J = 8Hz, 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: Calculated for M + H: 388.2449.

Found: 388.22222.

Example 41

5-yl) -1,1'-biphenyl] -4-yl] methyl] -1H-1,2,4-triazol-3-yl] methyl] -N- -L-glutamine, 1,1-dimethylethyl ester

Under nitrogen, 30 ml of TFA was added dropwise to a solution of 4.9 g (10 mmol) of (5-butyl- [1- [2 '- (1H-tetrazol-5-yl) 1,1'-biphenyl] -4-ylmethyl) -1H-1,2,4-triazol-3-yl] methylcarbamate from Example 35 in 30 mL of methylene chloride at -10 ° C (methanol / ice). The mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo to give the free amine TFA salt. The TFA salt was dissolved in 35 ml of anhydrous DMF along with 8.7 ml (50 ml) of anhydrous diisopropylethylamine and treated with 20 mmol of the N-Boc t-butyl ester symmetrical anhydride -r-glutamic acid in 55 ml of anhydrous DMF. The reaction was stirred at room temperature overnight. DMF was removed in vacuo; the residue was dissolved in ethyl acetate, washed with cold K 2 CO 4 & 3M cold 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 room temperature and stirred overnight. The solvent was removed in vacuo to give the free amine TFA salt. The TFA salt was dissolved in 35 mL of water and cooled to 0 ° C. The pH was adjusted to nine with 1M K 2 CO 3. The solution was cooled to 0 ° C, 0.94 mL (10 mmol) of acetic anhydride was added, followed by 5 mL of 1M K 2 CO 3, and the pH adjusted to 9 with additional K 2 CO 3. At 30 minute intervals, this addition was repeated until 5 additions were made. The pH was adjusted to 4 with 6N HCl and the solution was extracted with ethyl acetate. The ethyl acetate was dried (MgSO 4) and removed in vacuo. Purification by chromatography on silica gel (Waters Prep 500A) using isopropanol / acetic acid / chloroform (20: 5: 75) followed by lyophilization from acetonitrile / water gave 2.5 g (41%) of N 2 -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) δ 0.89 (t, J = 8Hz, 3H), 1.27-1.41 (m, 2H), 1.52-1.71 (m, 2H), 1.56 (s, 9H), 2.00 (s, 3H), 2. (M, 2H), 2.43 (t, J = 8Hz, 2H), 4.48-4.58 (m, 3H) , 7.24 (d, J = 8 Hz, 2H), 7.36-7.42 (m, 1H), 7.97 (d, J = 8 Hz, MS (FAB) m / e (rel intensity) 616 (20), 263 (23), 235 (m) 26), 207 (100); HRMS: Calculated for M + H: 616.3360.

Found: 616.3353.

Example 42

5- (2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl] -biphenyl-2-yl] -1H-tetrazole

Following General Procedure A, 1.2 g (5 mmol) of 5-butyl-3- (2-cyclohexylethyl) -1H-1,2,4-triazole were coupled with 5 mmol of the alkylating reagent prepared in Step (Waters Prep 500A) using ethyl acetate / hexane (1: 3) gave 3.6 g (100%) of a mixture of two isomers which was dissolved in 50 ml acetic acid / water (9: 1) and stirred at room temperature overnight. The solvent was removed in vacuo. the residue was dissolved in dilute base and washed with ethyl acetate. The aqueous layer was acidified to pH 4 and extracted with ethyl acetate. The ethyl acetate was removed in vacuo. Purification of a small sample of the mixture of isomeric products by reverse phase chromatography (Waters 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 (MgSO &) and stripped in vacuo. Lyophilization from yields 58 mg of 5- [4 '- [[3-butyl-5- (2-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - NMR (CDCl3) Î'0.78-0.95 (m, 5H), 1.07-1.40 (9H), 2.66 (t, J = 8 Hz, 2H) J = 8Hz, 7.10 (q, J = 8Hz, 4H), 7.41 (dd, J = 8 and 2Hz 2H), 7.89 (dd, J = 8 and 2 Hz, 1H ), MS (FAB) m / e (rel intensity) 470 (45), 236 (33), HRMS: Calc'd for M + H: 470.3032 and ethyl acetate of acetonitrile / water-cyclohexylethyl) - 1H), 1.48-1.74 (m, 2H), 5.24 (s, 2H),, 1H), 7.48-7.63 (m, 1H) , (35), 207 (100), 192

Example 43

5-butyl-3- (2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] -1H-benzimidazol-2-yl] -1H-tetrazole The isomer slow-moving compound of Example 42 was dissolved in dilute base, acidified to pH 3-4, extracted with ethyl acetate, dried (MgSO4), and the ethyl acetate was 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) δ 0.95-1.00 (m, 5H), 1.10 (M, 9H), 2.83 (t, J = 8Hz, 2H), 2.92 (t, J = 8Hz, 2H), 5.33 (m, (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. 261

Example 4 4

5 - [(5-Butyl-3- (phenylmethyl) -1H-1,2,4-triazol-1-ylmethyl] -1 H -biphenyl] -2-yl] -1H-tetrazole

Under nitrogen, 0.74 g (2.2 mmol) of N2- (4 - [(2-cyanophenyl) phenyl] methyl] phenylacetic acid hydrazide were dissolved in 5 ml of absolute ethanol and treated with 20 g ( 2.2 mmol) of ethyl iminovalerate The reaction was stirred at reflux for 3 days The solvent was removed in vacuo, 5 ml of xylene was added and the reaction was stirred at reflux under nitrogen for an additional 3 Purification by silica gel chromatography (Chromatatron, 4 mm plate) using a step gradient of ethyl acetate / chloroform afforded 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) δ 0.88 (t, J = 8Hz, 3H), 1.27-1.41 (m, 2H), 1.59-1.72 (m, 2H), 2.67 (t, J = 8Hz, 2H), 4.06 (s, 2H), 5.30 (s, 2H), 7.14-7.37 (m, SH), 7.39-7.50 (m, 3H), 7 , Î'(dt, J = 8 and 2 Hz, 1H), 7.75 (dd, J = 8 and 2 Hz, 1H).

Under nitrogen, 230 mg (1/13 mmol) of trimethyltin azide were 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 room temperature overnight. The solvent was removed in vacuo. the residue was dissolved in dilute base and washed with ethyl acetate. Reverse phase chromatography (Waters Delta Prep-3000) using acetonitrile / water (35-45: 65-55) gave the TFA salt. The salt was dissolved in diluted base, acidified to pH 3-4, extracted with ethyl acetate, dried (MgSO 4) and the ethyl acetate removed in vacuo. Lyophilization from acetonitrile / water gave 182 mg (45%) of 5- [4 '- [[5-butyl-3- (phenylmethyl) -1 H -1,2,4-triazol-1- yl] methyl] -1,1'-biphenyl] -2-yl] -tetrazole as a colorless solid: NMR (CDCl3) δ 0.84 (t, J = 8 Hz, 3H ), 1.22-1.36 (m, 2H), 1.51-1.64 (m, 2H), 2.59 (t, J = 8Hz, 2H), 3.85 (s, 2H), 2H), 7.14 (d, J = 8Hz, 2H), 7.17-7.28 (m, 5H), 7.15 (s, 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

5-butyl-1- [2 '- (1H-tetrazol-5-yl) -1,1'-biphenyl] -4-ylmethyl] -1H-1,2,4-triazole-3-propanol

Following General Procedure A, 920 mg (5.0 mmol) of 5-butyl-1H-1,2,4-triazole-3-propanol were coupled with 5.0 mmol of the alkylating reagent prepared in Step 1 of Example 3 (Waters Prep 500A) using isopropanol / chloroform (5:95) gave a mixture of two pure isomers which was dissolved in 40 ml of acetic acid / water (9: 1) and stirred at room 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 a colorless TFA salt: NMR (CDCl3) <0.71 (t, J = 8Hz, 3H), 1.10 (M, 2H), 1.70 (m, 2H), 1.70-1.81 (m, 2H), 2.49 (t, J = 8 Hz, 2H), 2.60 2H), 6.92 (q, J = 4H), 7.24-7.34 (m, 2H), 6.92 (q, J = ), 7.40 (dt, J = 8 and 2 Hz, 1H), 7.52 (dd 8 and 2 Hz, 1H), MS (FAB) to / e (rel intensity) 418 (100), 207 (48), 184 (10) HRMS: Calculated for M + H: 418.2355.

Found: 418.2370. 1.54 J = 8 Hz, J =

Example 46

3-butyl-1- [2 '- (1H-tetrazol-5-yl)] - 1'-biphenin-1-ylmethyl] -1H-1,2,4-triazole-5-propanol Lyophilization of the isomer of movement Example 45 yielded 114 mg of 3-butyl-1- [2 '- (1H-tetrazol-5-yl) [1,1'-biphenyl] -4-ylmethyl] -1H-1,2 , 4-triazole-5-propanol as a colorless TFA salt: NMR (CDCl3) δ 0.75 (t, J = 8 Hz, 3H), 1.13-1.27 (m, 2H), 1. J = 8Hz, 2H), 2.66 (t, J = 8Hz, 2H), 2.60 (m, 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

5-Butyl-3- (difluoromethyl) -1H-1,2,4-triazol-1-ylmethyl] -1 H -benzoyl] -2-yl} -1H-tetrazole

Following General Procedure A, 470 mg (2.7 mmol) of 5-butyl-3- (difluoromethyl) -1H-1,2,4-triazole were coupled with 2.7 mmol of the alkylation 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 (MgSO 4), and the ethyl acetate was removed in vacuo. Lyophilization from acetonitrile / water gave 471 mg of 5- [4 - [(5-butyl-3- (difluoromethyl) -1H-1,2,4-triazol-1-yl] methyl] 1,1'-biphenyl] -2-yl] -β-Tetrazole as a colorless solid: NMR (CDCl3) Î'(m, 2H), 2.72 (1H), 7.12 (d, 2Hz, 1H), MS (FAB) m / e 192 (57), 0.83 (t, J = 8Hz, 3H), 1.28-1.43 (t, J = 8Hz, 2H), 5.32 2H), 7.18 (d, J = 8 Hz, 7.51-7.65 (m, 2H), 8.00 (dd, J = (intensity king) 45), 235 HRMS: Calculated for M + H: 410, 1905.

Found: 410.1903. (m, 2H), 1.60-1.73 6.61 (t, J = 54 Hz, 2H), 7.42 (dd, J = 8 and 2 Hz, 1H); (55), 207 (100),

Example 48

5-fluoro-2-methyl-1H-1,2,4-triazol-1-ylmethyl] -biphenyl-2-yl] -1H-tetrazole The slower moving isomer of Example 47 was dissolved in a dilute, acidified base, extracted with ethyl acetate, dried (MgSO 4), and the ethyl acetate was removed in vacuo. Lyophilization from acetonitrile / water gave 104 mg (6%) of 5- [4 '- [(3-butyl-5- (difluoromethyl) -1 H -1,2,4-triazol-1-yl ] -methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole as a colorless solid: NMR (CDCl3) δ 0.91 (t, J = 8 Hz, 3H), 1.25 (M, 2H), 2.64 (t, J = 8 Hz, 2H), 5.43 (s, 2H), 6.81 (t, 2H) , J = 52Hz,

1H), 7.20 (d, J = 8Hz, 2H), 7.28 (d, J = 8Hz, 2H), 7.43 (dd, J8 and 2Hz, 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: Calculated for M + H: 410, 1905.

Found: 410.1903.

Example 49 Ο

6-t-butoxy-4-ylmethyl] -1H-1,2,4-triazole-3-carboxaldehyde

A sample of 92 mg of 5- [4 '- ([5-butyl-3- (dimethoxymethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1 H -tetrazole of Example 47 was dissolved in 20 ml of ethanol and 2 ml of 3N HCl The reaction was stirred at room temperature for 3 days The solvent was removed in vacuo. acetonitrile / water afforded 74 mg (81%) of 5-butyl-1- [2 '- (1H-tetrazol-5-yl) [1,1'-biphenyl] -4-ylmethyl] -1H- 1,2,4-triazole-3-carboxaldehyde as a colorless hydrochloride salt: NMR (CDCl3) δ 0.89 (t, J = 8Hz, 3H), 1.30-1.44 (m, 2H) , 1.66-1.78 (m, 2H), 2.78 (t, J = 8Hz, 2H), 5.38 (S, 2H), 7.17 (q, J = 8Hz, 4H), 7 (D, J = 8 Hz, 1H), 3.50 (d, J = 8 Hz, 1H), 7.50-7.64 (m, 2H), 8.02 (36), 235 (42), 207 (100), 192 (50): HRMS: Calculated for M + Li: 395.2046.

Found: 395.2049.

Example 50

5-Butyryl-3- (phenylacetyl) -1H-1,2,4-triazol-1-yl] methyl] -1-biphenin-2-yl] -1H-tetrazole

Under nitrogen, 7.3 mmol of sec-butyllithium was added dropwise to 2.0 g (86.1 mmol) of 5-butyl-3- (dimethoxymethyl) -1 H -1,2,4- -triazole of 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 room temperature and stirred overnight. THF was removed in vacuo; the residue was 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 methanol 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). Chromatography on silica gel (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) δ 0.92 (t, J = 8Hz, 3H), 1.31-1.55 (m, 2H), 1.70-1.83 (m, 2H), 2.38 (m, 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 room 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] -tetrazole as a colorless TFA salt: NMR (DMSO- (d, J = 8Hz, 3H), 1.23-1.38 (m, 2H), 1.52-1.65 (m, 2H), 2.80 (t, (D, J = 8 Hz, 2H), 4.32 (s, 2H), 5.52 (s, 2H), 7.11 (d, , 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

5-butyl-3- (1,1-difluoro-2-phenylethyl) -1H-1,2,4-triazol-1-ylmethyl] -1,1'-biphenyl] -1-yl -1H-tetrazole

Under nitrogen, 8.5 g (48 mmol) of 5-butyl-3- (difluoromethyl) -1H-1,2,4-triazole of Example 47 were added in portions to 53 mmol of sodium hydride in 85 mL THF anhydrous; the stirring was continued for 1 h. The anion solution was cooled to 0 ° C and treated dropwise with 8.9 mL (50 mmol) of SemCl. The reaction was allowed to warm to room temperature and stirred overnight. The THF was removed in vacuo. the residue was dissolved in methylene chloride, washed with water, and dried (MgSO4). Purification by chromatography on silica gel using ethyl acetate / hexane (1: 9) afforded 4.9 g (34%) of the protected triazole with Noe, as an oil: 273

NMR (CDCl3) δ -0.04 (s, 9H), 0.86-0.95 (m, 5H), 1.39-1.43 (m, 2H), 1.65-1.76 (m J = 8Hz, 2H), 2.71 (t, J = 8Hz, 2H), 3.62 (t, J = 8Hz, 2H), 5.53 (s, 2H), 6.82 (t, J = ).

Under nitrogen, 14.2 nunol of sec-butyllithium was added dropwise to 3.6 g (11.8 mmol) of the protected triazole with Sem in 200 ml of anhydrous THF at -78 ° C. The reaction was allowed to stir for 1 h before 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 room temperature and stirred overnight. The solvent was removed in vacuo; the residue was dissolved in methylene chloride, washed with water and dried (MgSO 4). Chromatography on silica gel (Waters Prep 500A) using ethyl acetate / hexane (5:95) gave 600 mg (10%) of 5-butyl-3- (1,1-difluoro-2-phenylethyl) - 1H-1,2,4-triazole: NMR (CDCl3) Î'-0.04 (s, 9H), 0.85 (t, J = 8Hz, 2H), 0.94 (t, J = 8Hz, 3H) , 1.30-1.44 (m, 2H), 1.67-1.79 (m, 2H), 2.73 (t, J = 8Hz, 2H), 3.54 (t, J = 8Hz, 2H), 3.70 (t, J = 16Hz, 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. General procedure A, 1.4 mmol of this material was coupled with 1.4 mmol of the alkylation 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 The solvent was removed in vacuo.

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 of 5- [4 '- [[5-butyl-3- (1,1-difluoro-2-phenylethyl) -1H-1,2,4-triazole 1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole: NMR (CDCl3): δ 0.86 (t, J = 8Hz, 3H), 1.21-1 2H), 3.57 (t, J = 16 Hz, 2H), 5.64 (t, J = 8 Hz, (D, J = 8Hz, 2H), 7.10 (d, J = 8Hz, 2H), 7.16-7.25 (m, 5H) (Dd, J = 8 and 2 Hz, 1H), 7.50-7.65 (m, 2H), 7.99 (dd, J = 8 and 2 Hz, 1H). ) 500 (100), 266 (6), 235 (8), 207 (25), 192 (8): HRMS: Calculated for M + H: 500.2374.

Found: 500.2358. m - v

Example 52

5-Butyl-1- (5-hydroxy-5-yl) -1,1'-biphenyl-4-ylmethyl] -1H-1,2,4-triazole-3-carboxylic acid

A sample of 3.36 g (7.1 mmol) of 5- (4 '- [[5-butyl-3- (2,2-deethoxyethyl) -1H-1,2,4-triazol-1-yl ] methyl] (1,1'-biphenyl] -2-yl] -α-tetrazole from Example 38 was dissolved in 15 ml of ethanol and 15 ml of 3M HCl The reaction was stirred at room temperature overnight. the residue was dissolved in 15 ml of THF and 15 ml of 3M HCl and stirred for 3 days at room temperature The solvent was removed in vacuo and the residue dissolved The residue was dissolved in 70 ml of acetone and 35 ml of water, and the residue was dissolved in acetonitrile (50 ml) and water (35 ml) was added and the solvent was evaporated to dryness (MgSO4). potassium permanganate in 4 equal portions of 190 ml after each preceding portion was reacted.The mixture was filtered through celite and the solvent removed in vacuo.

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] -1 H -1,2,4-triazole-3-carboxylic acid as colorless TFA salt after lyophilization from acetonitrile / water: NMR (DMSO-d6) δ 0.85 (t, J = 8Hz, 3H), 1.23-1.38 (m, 2H), 1.52-1.62 (m, 2H), 2.78 (t, J = 8Hz (M, 2H), 5.46 (s, 2H), 7.13 (q, J = 8Hz, 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

5- (4-Butyl-1H-1,2,4-triazol-1-yl) methyl] -1H-benzoyl] -2H-tetrazole

Following General Procedure A, 630 mg (5 mmol) of 3-butyl-1H-1,2,4-triazole were 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 afforded 5- [4 '- [(5-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl ] - 1H-tetrazol-1: NMR (CDCl3) δ 0.87 (t, J = 8Hz, 3H), 1.35-1.41 (m, 2H), 1.59-1.72 (m, 2H 7.17 (d, J = 8 Hz, 2H), 7.22 (t, J = 8Hz, 2H), 5.30 (s, 2H), 7.09 (d, J = 8Hz, 2H), 7.17 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

5-β '' - (3-butyl-1H-1,2,4-triazol-1-yl) methyl] -1,1-biphenyl-2-yn-1H-tetrazole The slower moving isomer of Example 53 was deprotected to give 5- [4 '- [(3-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] tetrazole: NMR (CDCl3) Î'0.74 (t, J = 8 Hz, 3H), 1.19-1.33 (m, 2H), 1.51-1.63 (m, 2H), 2. (D, J = 8 Hz, 2H), 7.10 (q, J = 8 Hz, 4H), 7.44 , 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), 235 (18), 207 (100), 192 (26), 178 (16), 126 (22); HRMS: Calc'd for M + H: 360.1936.

Found: 360.1971.

Example 55

(3-butyl-5- (tricyclo3,3.1.1,7,7-dec-1-yl) -1H-1,2,4-triazin-1-yl) methyl] -1,1'- -biphenyl-2-yn-1 H -tetrazole

Following General Procedure A, 1.3 g (5.0 mmol) of 5-butyl-3-adamantyl-1H-1,2,4-triazole were 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 afforded 5- [4 '- [[3-butyl] -5- (tricyclo [3.1.13,7] dec-1-yl] -1H-1,2,4- 1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole: NMR (CDCl3): δ 0.90 (t, J = 8Hz, 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 = 8Hz, 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: Calculated for M + H: 494.3032.

Found: 494.3014.

Example 56

1-yl) -1H-1,2,4-triazol-1-yl) methyl] -1,1,1-a] [1,4] The slower moving isomer of Example 55 was deprotected to afford 5- [4 '- [[5-butyl-3- (tricyclo [3.3.1.1.3,7] ] -1H] -1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole: 2H) NMR (CDCl3): δ 0.87 (t, J = 8 Hz, 1H), 7.30 (d, J = 3H), 1.31-1.47 (m, (m, 9H), 1.78 (s, 7H), 1.88 (s, 3H), 2.20-2.35 (m, 2H), J = 8Hz, 2H), 8 and 2Hz, 1H), 7.49-7.63 (m, 2H), 7.93 (d, J = 8Hz, 2H) dd, J = 8 and MS (FAB) m / e (rel intensity) 494 (73), 451 (10), (66), 178 (21): HRMS: Calculated for M + H: 494.3032.

Found: 494.3026.

Example 57

5-f] [3 - [(3-cyclohexylpropyl) -1H-1,2,4-triazol-1-ylmethyl] -1 H -biphenyl-2-yl] -1H-tetrazole

Following General Procedure A, 1.25 g (5 mmol) of 5-butyl-3- (3-cyclohexylpropyl) -1H-1,2,4-triazole were reacted with 5 mmol of the alkylation 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 afforded 5- [4 '- ([3-butyl] -5- (3-cyclohexylpropyl) -1H-1,2,4-triazol-1-yl] methyl] [ 1,1'-biphenyl] -2-yl] -1H-tetrazole: NMR (CDCl3) δ 0.73-0.92 (m, 2H), 0.87 (t, J = 8Hz, 3H) (M, 6H), 1.22-1.36 (m, 2H), 1.53-1.71 (m, 9H), 2.51 (t, J = 8Hz, 2H), (D, J = 8 Hz, 2H), 7.12 (d, J = 8 Hz, 2H), 7.22 (s, (Dd, J = 8 and 2 Hz, 1H), 7.51-7.64 (m, 2H), 7.94 (dd, J = 8 and 2 Hz, 1H); ): 484 (83), 250 (38), 207 (100), 178 (25): HRMS: Calculated for M + H: 484.3189.

Found: 484.3223.

Example 58

5 - [(5-Butyl-3- (3-cyclohexylpropyl) -1H-1,2,4-triazol-1-ylmethyl) -1'-biphenyl] -2-yl] -1H-tetrazole Slower isomer of Example 57 was deprotected to afford 5- [4 '- [[5-butyl-3- (3-cyclohexylpropyl) -1H-1,2,4-triazol-1- yl] methyl] [1,1'-biphenyl] -2-yl] -β-tetrazole: NMR (CDCl3) Î'0.74-0.90 (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) (D, J = 8 Hz, 2H), 7.10 (d, J = 8 Hz, 2H), 2.57 (t, J = 8 Hz, 2H), 5.20 (s, 2H), 6.96 ), 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

5-Butyl-3- (fluoromethyl) -1H-1,2,4-triazol-1-ylmethyl] -1 H -biphenyl] -2-yl] -1H-tetrazole

Following General Procedure A, 790 mg (5.0 mmol) of 5-butyl-3- (fluoromethyl) -1H-1,2,4-triazole were 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 afforded 5- [4 '- ([5-butyl-3- (fluoromethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,4] 2-yl] -1H-tetrazole: NMR (CDCl3): 0.86 (t, J = 8Hz, 3H), 1.26-1.40 (m, 2H), 1.56 - 1.69 (m, 2H), 2.67 (t, J = 8Hz, 2H), 5.16 (s, 1H), 5.27 (s, 2H), 5.32 (s, 1H), 7 (D, J = 8 Hz, 1H), 7.52-7.65 (m, 2H) 2H), 7.99 (dd, J = 8 and 2, 1H), MS (FAB) m / e (rel intensity), 92 (100), 235 (22), 207 (66), 192 (18) , 178 (14); HRMS: Calculated for M + H: 392.1999.

Found: 392.1932.

Example 60

5-fluoro-1H-1,2,4-triazol-1-ylmethyl] -1 H -benzen-2-yl] -1H-tetrazole The slower moving isomer of Example 59 was deprotected to give 5- [4 '- [[3-butyl-5- (fluoromethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1 H -tetrazole: NMR (CDCl3) δ 0.89 (t, J = 8Hz, 3H), 1.24-1.40 (m, 2H), 1.59 (m, 2H J = 8Hz, 2H), 5.38 (s, 3H), 5.55 (s, 1H), 7.21 (s, 4H), 7.43 (d, J = 8Hz, 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

5-yl) -1H-1,2,4-triazol-1-yl] methyl] -1'-biphenyl] -2-yl] -1H- Following General Procedure A, 1.4 g (5.0 mmol) of 5-butyl-3-adamantyl-1H-1,2,4-triazole were reacted with 5.0 mmol of the prepared alkylation reagent in Step 1 of Example 3, in order to obtain a mixture of the two isomers. Deprotection of the faster moving isomer gave 5- [4 '- [[3-butyl] -5- (tricyclo [3.3.1.13,7] dec-1-yl) methyl] -1H-1,2,4- 1-yl) methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole: NMR (CDCl3) δ0.84 (t, J = 8Hz, 3H), 1.16-1 2H), 1.41 (s, 6H), 1.44-1.56 (m, 5H), 1.65 (d, J = 12Hz, 3H), 1.92 (s, 3H) J = 8Hz, 2H), 5.18 (s, 2H), 6.79 (d, J = 8Hz, 2H), 7.01 (s, 2H) d, J = 8 Hz, 2H), 7.46 (d, J = 8 Hz, 1H), 7.52 (m, 2H), 7.85 (dd, J2 = 8 and 2 Hz, 1H); MS (FAB) m / e (rel intensity) 508 (45), 274 (25), 207 (100), 192 (31); HRMS: Calculated for M + H: 508.3189.

Found: 508.3162.

Example 62

5-butyl-3- (3-tricyclo [3.3.1.13,7] dec-1-ylmethyl-1H-1,2,4-triazol-1-ylmethyl] -1'-biphenyl] -2- yl] -1H-tetrazole The slower moving isomer of Example 61 was deprotected to afford 5- [4 '- [[5-butyl-3- (tricyclo [3.3.1.1 3,7] dec-1- yl) methyl] -1H-1,2,4-triazol-1-yl] methyl] (1,1-biphenyl] -2H-tetrazole: NMR (CDCl3) δ 0.85 (t J = 8Hz, 3H), 1.21-1.37 (m, 8H), 1.44-1.58 (m, 5H), 1.62 (d, J = 10Hz, 3H), 1.86 (s, 3H), 2.07 (s, 2H), 2.49 (t, J = 8Hz, 2H), 5.21 (s, 2H), 6.89 (d, J = 8Hz, 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). MS (FAB) m / e (rel intensity) 508 (42), 274 (22), 207 (100), 192 (34): HRMS: Calculated for M + H: + 508.3189.

Found: 508.3142.

Example 63

5-Butyl-1- [2 '- (1H-tetrazol-5-yl) Î ±' '- biphenin-4-ylmethyl-1 H -1,2,4-triazole-3-propanoic acid

A sample of 2.18 g of the mixture of the two isomers of 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 afforded 5-butyl] -1- [2 '- (1H-tetrazol-5-yl] [1,1'-biphenyl] -4-ylmethyl] -1H-1 (CDCl 3) δ 0.99 (t, J = 8Hz, 3H), 1.28-1.43 (m, 2H), 1.61-1.74 (m, (m, 2H), 2.67-2.80 (m, 4H), 2.94 (t, J = 6Hz, 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, 1 H-NMR (CDCl 3) δ (CDCl 3): δ (CDCl 3, 300 MHz) H: 432.2148.

Found: 432.2216. 288

Example 64

N

3-Butyl-1- [2 - [(1H-tetrazol-5-yl) -1,1'-biphenyl-4-ylmethyl] -1H-1,2,4-triazole-5-propanoic acid The slower moving isomer of Example 63 was deprotected to provide 3-butyl-1- [2 '-tetrazol-5-yl] [1,1'-biphenyl] -4-ylmethyl] -1H-1,2,4-triazole-5-panoic acid : NMR (CDCl3) δ 0.92 (t, J = 8Hz, 3H), 1.30-1.40 (m, 2H), 1.65, (m, 2H), 2.70 (t, J = 8Hz, 2H), 2.84-2.91 (m, 2H), 2.93-3.00 2H), 5.40 (s, 2H) , 7.20 (d, J = 8Hz, 2H), 7.34 (d, J = 8Hz, 7.37-7.42 (m, 1H), 7.51-7.62 (m, 2H), MS (FAB) m / e (rel intensity) 432 (100), 198 (45): HRMS: Calculated for M + H: 432.2148.

Found: 432.2214. (1 H-pro-1,78 (m, 2H), 289

5-Cyclohexyl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenin-2-yn-1H-tetrazole

Following General Procedure A, 2.07 mg (10 mmol) of 3-butyl-5-cyclohexyl-1H-1,2,4-triazole were reacted with 6.5 g (11.8 mmol) of the reagent of alkylation 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 afforded 33 mg of 5- (4 '- [(3-butyl-5-cyclohexyl-1H-1,2,4-triazol-1-yl) methyl] 1'-biphenyl] -2-yl] -1H-tetrazole as a colorless solid: mp 157.5-159.5 ° C; NMR (CDCl3) δ 0.87 (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, (D, J = 8 Hz, 2H), 2.64-2.78 (m, 1H), 5.23 (s, 2H), 6.98 (d, , 7.41 (dt, J = 5 and 1 Hz, 1H), 7.57 (dt, J = 5 and 1 Hz, 1H), 7.80 (dd, MS (FAB) m / e (rel intensity) 442 (100), 414 (10), 399 (20), 235 (8), 207 (65), 192 (18) (i.e.

Example 66

5-β '- (5-butyryl-3-cyclohexyl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenyl-2-yl] -1H-tetrazole The isomer of The slower motion of 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] -? -Tetrazole as a colorless solid: mp 125-127 ° C; NMR (CDCl 3) δ 0.85 (t, J = 7Hz, 3H), 1.12-1.40 (m, J = 8Hz, 8H), 1.52-1.75 (m, J = 8Hz, 4H (D, J = 8 Hz, 2H), 2.81 (d, J = 8 Hz, 2H), 2.50 (t, J = 8 Hz, 3H), 5.20 (s, 2H), 6.94 7.09 (d, J = 8Hz, 2H), 7.42 (dd, J = 8 and 2Hz, 1H), 7.50-7.64 (m, J = 8Hz, 2H), 7.88 (dd, , J = 8 and 2 Hz, 1H); MS (FAB) m / e (rel intensity) 442 (100), 414 (10), 399 (20), (10), 207 (75), 192 (17). 235

Example 67

3-butyl-β1-β '- (1H-tetrazol-5-yl) -1,1'-biphenyl-4-ylmethyl] -1H-1,2,4-triazol-5-yl] propylcarbamate

Following General Procedure A, 6.0 g (20 mmol) of 3-butyl-5- (N-BOC-3-aminopropyl) -1H-1,2,4-triazole were reacted with 13.1 g 24 mmol) of the alkylation reagent prepared in Step 1 of Example 3. Deprotection of the faster moving isomer gave 3.52 g (33%) of 3-butyl- [1- (2 '- (1H-tetrazole -1H-1,2,4-triazol-5-yl] propylcarbamate as a colorless solid: 1 H NMR (D, J = 8 Hz, 3H), 1.22-1.34 (m, J = 7Hz, 2H), 1.66-1.78 (m, J = 7Hz, 2H), 2.5 (t, J = 8Hz, 2H), 2.67 (t, J = 8Hz, 2H), 2.96 (q, J = 8Hz, 2H), 5.26 (s, 2H), 7.08 (s, 4H), 7.55 (q, J = 8Hz, 2H), 7 1 H-NMR (DMSO-d 6) δ (DMSO-d 6) δ (DMSO-d 6) δ (d, J = 8Hz, 2H); 18), 357 (8), 323 (8), 305 (15), 283 (80), 227 (70), 207 (100), 183 (65): HRMS: Calculated for M + H: 517.3039.

Found: 517.3001. 292

Example 68

1,1-dimethylethyl 5-butyl-β-2 '- (1H-tetrazol-5-yl) γ-biphenin-4-ylmethyl-1H-12,4-triazol-3-ylpropylcarbamate The isomeric Example 67 was deprotected to provide 3.43 g (33%) of 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: m NMR (DMSO-d6) <0.84 ( (m, J = 8 Hz, 2H), 1.38 (s, 9H), 1.48-1.59 (m, (T, J = 8Hz, 2H), 2.67 (t, J = 8Hz, 2H), 2.67 (t, J = 8Hz, 2H), 2.53 7.50 (d, J = 8 Hz, 1H), 7.55 (d, J = 8 Hz, 1H), 7.61 (s, 2H) 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: Calculated for M + H: 517.3039.

Found: 517.3014. (I.e.

Example 69

5-butyl-1H-1,2,4-triazol-1-ylmethyl] -1,1'-biphenin-2-yn-1 H -1,2,4- -tetrazole

Following General Procedure A, 1.21 g (5.0 mmol) of 3-perfluoroethyl-5-butyl-1H-1,2,4-triazole were reacted with 3.2 g (5.7 mmol) of the reagent of the alkylation prepared in Step 1 of Example 3. Deprotection afforded 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) δ 0.90 (t, J = (T, J = 7 Hz, 2H), 1.36 (q, J = 7Hz, 2H) (D, J = 8 Hz, 1 H), 7.51-7.67 (m, J = 8 Hz, 2 H) 7.98 (d, J = 8Hz, 1H), MS (FAB) m / e (rel intensity) 478 (40), 452 (15), 235 (90), 207 (100), 178 (40), 152 (35); M + H: 478.1778.

Found: 478.1807.

Example 70

C3F7 (n)

5- [4 - [[3- (1,1,2,2,3,3,3-heotafluoroprooxy) -5-butyl-1H-1,2,4-triazol-1-ynyl] -biphenyl] -2-yl] -1H-tetrazole

Following General Procedure A, 1.46 g (5.0 mmol) of 5-butyl-3-perfluoropropyl-1H-1,2,4-triazole were reacted with 3.20 g (5.7 mmol) of the reactant of alkylation prepared in Step 1 of Example 3. Deprotection afforded 210 mg of 5- [4 '- [[3- (1,1,2,2,3,3,3-heptafluoroethyl) -5-butyl-1H- 1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -tetrazole as a colorless oil: NMR (CDCl3) δ 0.90 (t, J = 7Hz, 3H), 1.36 (q, J = 8Hz, 2H), 1.63-1.75 (m, J = 8Hz, 2H), 2.78 (t, J = 8Hz, 2H), (D, J = 8 Hz, 1H), 7.52 (s, 2H), 7.20 (q, J = 7 Hz, 4H) 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

5-β4'-β-3-butyl] -5- (3-aminopropyl) -1H-1,2,4-triazol-1-yl] methyl] -1,1,1-biphenin-2-yl] -1H-tetrazole

Under a static atmosphere of nitrogen 2.40 g (4.7 mmol) of 5- [4 '- [[3-butyl-5- (N-BOC-3-aminopropyl) -1H-1,2,4-triazole 1-yl] methyl] (1,1'-biphenyl] -2-yl] -1H-tetrazole from Example 67 were dissolved in 30 ml of 4N HCl in dioxane at room temperature and allowed to stir overnight. The residue was triturated with diethyl ether and filtered to afford 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) CDCl3) δ 0.88 (t, J = 7 Hz, 3H), 1.25-1.39 (m, 2H), 1.57-1.69 (m, 2H), 1.92-2.40 (m 2H), 2.98 (t, J = 8 Hz, 2H), 5.38 (s, 2H), 2.82 (t, J = , 7.10 (d, J = 8Hz, 2H), 7.19 (d, J = 8Hz, 2H), 7.54 (d, J = 8Hz, 1H), 7.59 (dd, J = 8). (dd, J = 8 and 2 Hz, 1H), 8.10 (bs, 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

5 - [[4 - [[3- (3-aminopropyl) -5-butyl-1H- 2,4-triazol-1-ylmethyl] -1'-biphenyl] -2-yl] -1H-tetrazole

Under a static atmosphere of nitrogen 2.30 g (4.5 mmol) of 5- [4 '- [(3- (N-BOC-3-aminopropyl) -5-butyl-1H-1,2,4-triazole yl] methyl] [1,1'-biphenyl] -2-yl] -tetrazole from Example 68 were dissolved in 30 ml of 4N HCl in dioxane at room temperature and allowed to stir overnight. The solvents were removed in vacuo, the residue triturated with diethyl ether and filtered to provide 1.99 g (98%) of 5- [4 '- [[3- (3-aminopropyl) -5-butyl- 1 H -1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole as the hydrochloride salt: NMR (DMSO-d6) (T, J = 8Hz, 2H), 1.96 (t, J = 8Hz, 2H), 1.59 (t, J = 7Hz, 3H), 1.22-1.38 (m, 2H), 1.59 2H), 2.80-2.92 (m, 4H), 5.40 (s, 2H), 7.10 (d, J = 8 Hz, 2H) (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) Calc'd for M + H: 417.2515.

Found: 417.2510. (I.e.

Example 73

5-β '' - (3-Butyl-5-cyclohexylmethyl-1H-1,2,4-triazol-1-yl] methyl] -1'-biphenyl] -2-yl] -1H-tetrazole

Following General Procedure A, 2.21 mg (10.0 mmol) of 3-butyl-5-cyclohexylmethyl-1H-1,2,4-triazole were 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. Deprotection of the faster moving isomer afforded 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 = 7Hz, 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 (m, d, J = 7Hz, 2H), 2.68 (t, J = 7Hz, 2H), 5.27 (s, 2H), 7.11 (q, J = 8 and 2HZ, 1H), 7.49-7.63 (m, 2H), 7.94 (dd, J = 8 and 2 Hz, 1H), MS (FAB) m / e (100), 428 (10), 413 (20), 280 (10), 235 (10), 222 (2, 5), 207 (80), 192 (30), HRMS: Calculated for M + H : 456.2876.

Found: 456.2839.

Example 74

5-yl) methyl] -1H-benzimidazol-2-yl] -1H-tetrazole The isomer The title compound was obtained as a white solid from Example 73 and was deprotected to give 51 mg of 5- [4 - [(3-cyclohexylmethyl-5-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -β-Tetrazole as a colorless solid: NMR (CDCl3) Î'0.84 (t, J = 8 Hz, 3H), 0.92 ( q, J = 8Hz, 2H), 1.05-1.22 (m, 3H), 1.22-1.36 (m, 2H), 1.52-1.69 (m, 8H) (D, J = 8 Hz, 2H), 2.63 (t, J = 8 Hz, 2H) 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: Calculated for M + H: 456.2876.

Found: 456.2849. 299

Example 75

4'- (3-Ethyl-5-butyl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-biphenyl-2-carboxylic acid

Following General Procedure A, 1.0 g (6.0 mmol) of 3-ethyl-5-butyl-1H-1,2,4-triazole were reacted with 2.41 g (7.9 mmol) of the reagent of the alkylation prepared in Step 1 of

Example 1. The hydrolysis of the faster moving isomer afforded 220 mg of 4 '- [(3-ethyl-5-butyl-1H-1,2,4-triazol-1-yl) methyl] 1 H-NMR (DMSO-d 6) δ 0.35 (t, J = 7 Hz, 3H), 1.19 (t, J = 7 Hz, 3H) ),

(M, 2H), 2.54 (q, J = 7 Hz, 2H), 2.74 (t, J = 7 Hz, 2H), 5.35 (s, 2H), 7.21 (d, J = 8Hz, 2H), 7.31 (d, J = 8Hz, 2H), 7.35 (dd, J = 8 and 2Hz, 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). 300 300

Example 76

The slower moving isomer of Example 75 was hydrolyzed from (1S, 2S, 3S, 3R, 4R, 4R) -4- to provide 174 mg of 4 '- [(3-butyl-5-ethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2- (DMSO-d 6) δ 0.89 (t, J = 7 Hz, 3H), 1.17 (t, J = 7 Hz, 3H), 1.27-1.40 (m, 2H), 2.77 (q, J = 8Hz, 2H), 5.35 (s, 2H), 1.56-1.68 (m, 2H), 2.58 (t, (Dt, 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). 301

Example 77

4 '- [(3-Butyl-5-methyl-1H-1,2,4-triazol-1-yl) methyl] -1,1'-bi-phenyl] -2-carboxylic acid

Following General Procedure A, 1.0 g (7.2 mmol) of 3-butyl-5-methyl-1H-1,2,4-triazole were reacted with 2.89 g (9.5 mmol) of the reagent of the alkylation prepared in Step 1 of Example 3. The hydrolysis of the slower moving isomer 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): δ 0.88 (t, J = 7 Hz, 3H), 1.25-1.38 2H), 1.54-1.67 (m, 2H), 2.39 (s, 3H), 2.54 (t, J = 8 Hz, 2H), 5.32 (s, 2H (D, J = 8 Hz / 2H), 7.36 (dd, J = 8 and 2 Hz, 1H), 7.46 (dt, J = 8 Hz, , J = 8 and 2 Hz, 1H), 7.65 (dt, J = 8 and 2 Hz, 1H), 7.72 (dd, J = 8 and 2 Hz, 1H).

Example 78

The faster-moving isomer of Example 77 was hydrolyzed to give the title compound as a white solid. The title compound was obtained as a white solid, mp 228-221øC. 1 H-NMR (CDCl 3) yield 19 mg of 4 '- ((3-methyl-5-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid in the form of a colorless solid: NMR (DMSO-d6) δ 0.86 (t, J = 7 Hz, 3H), 1.25-1.38 (m, 2H), 1.52-1.64 (m, 2H 2H), 5.32 (s, 2H), 7.21 (d, J = 8 Hz, 2H), 7.32 (s, 3H) d, J = 8 Hz, 2H), 7.35 (dd, J = 8 and 2 Hz, 1H), 7.45 (dt, J = 8 and 2 Hz, , 1H), 7.72 (dd, J = 8 and 2 Hz, 1H).

One class of highly preferred specific conjugates of the invention is provided by conjugates formed from an AII antagonist biphenylmethyl-1H-substituted 1,2,4-triazole compound attached to a cleavable glutamyl residue. Each conjugate contains a diamino linker moiety which bonds a terminal carboxylic acid moiety to the biphenylmethyl moiety of the angiotensin II antagonist compound with a terminal carboxylic acid moiety on the gamma carbon of the convertible 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 generally be prepared according to the procedures of Example # 79.

Example 79

N-Acetylmutamic acid, 5 - [[4- (3,5-dibutyl-1H-1,2,4-triazol-1-yl) methyl] -1'-biphenyl] -2-carbonylhydrazide. To a solution of N-BOC-L-glutamic acid (BACHEM) α-tert-butyl ester (BACHEM) (10.45 g, 34.5 mmol) in methylene chloride (100 ml) under nitrogen was added 3.5 g 0 mol) of dicyclohexylcarbodiimide (DCC). The reaction was allowed to stir for 2 hours and filtered under nitrogen. The anhydride solution is 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 the pure material by thin layer chromatography (TLC). This material was redissolved in 100 ml of methylene chloride under nitrogen and cooled to 0øC before the addition of 135 ml of TFA. The stirred reaction was allowed to warm to room temperature and concentrated in vacuo. The crude product was dissolved in 80 ml of acetonitrile / water (1: 1) and the pH adjusted to 9 with K 2 CO 3. The solution was cooled to 0 ° C and 1.1 ml (11 mmol) of acetic anhydride and 11 ml (11 mmol) of K2CC> 34 M were added every thirty minutes; during the course of this reaction the pH was maintained at 9 ° C and the reaction temperature maintained below 5 ° C. After the last addition, the reaction was allowed to warm to room temperature overnight. The pH was adjusted to 4 with 3M HCl and the reaction was concentrated to 300 ml. Purification by reverse phase chromatography (Waters Delta Prep-3000) using 32% isocratic acetonitrile / water (0.05% TFA) gave 6.11 g (55% overall yield from compound of Example 4) of colorless product: NMR (DMSO-d6) δ 0.85 (t, J = 8Hz, 3H), 0.88 (t, J = 8Hz, 2H), 1.23-1.39 , 4H), 1.53-1.68 (m, 6H), 1.84 (s, 3H), 2.15-2.24 (m, 2H, (t, J = 8Hz, 2H) (M, 1H), 5.31 (s, 2H), 7.11-7.19 (m, 3H), 7.37 (s, 7.57 (-, 6H); MS (FAB) m / e (rel intensity) 577 (42), 389 (10), 195 (82), 182 (100, 167 (63), 152 (28); : Calculated for M + H: 577.3138.

Found: 577.3160.

Anal. Calculated for C19 H18 N2 O • 1, c 314065 5 CF3 COOH: C, 54.65; H, 5.56; N, 11.25; F, 11.50. Found: C, 54.22; H, 5.75; N, 11.35; F, 11.85.

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B Ξ

P

(N) -NHCH2 CH3 (n) -NHCH2 -NHCH2 -NHCH2 -NHCH2 -NHCH2 -NHCH3 -NHCH2 -NHCH2 -NHCH2 -NHCH2 -NHCH2 -NHCH2 -NHCH2 -NHCH2 -NHCH2 -NHCH2 -NHCH2 -NHCH3 (N) -NHCH2 CH3 -CH3 CH3 CO3 93 C4 H9 (n) C4 H9 (n) &quot; (N) -NHCH 2 CH 2 --H C 2 H 5 H 95 C 4 H 9 (n) C 4 H 9 (n) -NHC (CH 2) (N) 97 Cl C4 H9 (n) -NHC (CH3) 3 H -CH3 98 Cl C4 H9 (n) HHH-3 Ο 7; ## STR11 ## C4 H9 (n) C4 H9 (n) C4 H9 (n) C4 H9 (n) C4 H9 (n) (n) C4 H9 (n) 106 C4 H9 (n) C4 H9 (n)

* H COCH. * Η H * CH, H * CH3 COCH3 C-jH C COCH3 C2H5

H H COC 4 H 9 (n)) Η H COC 4 H 9 (n)} Εχ. # r1 R2 L B Ξ P 107 Cl C4H9 &lt; &quot; (n) -NH-HH coch 3 110 C 2 H 5 C 4 H 9 (n) -NH-HHH 111 C 3 H 7 (n) C 4 H 9 (n) (N) -NH-HH coch 3 114 C 5 H n (n) C 4 H 6 (n) -NH-HH 115 C 6 H 13 (n) C4 H9 (n) -NH-HHCH3 C6 H13 (n) C4 H9 (n) -NH- HHH CFCCH2 CH2 CH3 C4 Hg (n)

Εχ. # Rl r2 L B E P j 118 119 120 121 122 123 124 125 126 127 128

(N) -NH-H C2 H5 -NH-H C2 H5 C2 H5 -NH-H C3 H7 (n) -NH- (CH2) (N) -NH-H (C) H (n) -NH-H (C6 H11) n NH3 (n) ) · C 6 H 13 (n) -NH- H C 6 H 13 (n) C 6 H 13 (n) -NH-H

H

H

H

H

H

H

H

H

H

H

H

H coch3

H coch3

H coch3 coch3 coch3

H COCH3

H 310 Ex. # R1 R2 LB Ξ P 129 c2 H5 C2 H5 -nhch2ch2- h H COCH3 130 C2H5 c2h5 -nhch2ch2-h HH 131 C3H7 (n) C3H7 (n) -nhch2ch2- h H 'coch3 132 C3H7 (n) C3H7 (n) n) -nhch2ch2-h HH 133 C5H11 <n). C6 H13 (n) -nhch2ch2- h H COCH3 134 C5H11 C5H1: L (n) -nhch2ch2- h HH 135 C6H13 (n) C6H13 (n) -nhch2ch2- h H COCH3 136 C6H13 (n) C6Hi3ta) -nhch2ch2 -H H 137 C2 H5 C2 H5 * H COCH3 138 2H5 C2 '5 *

(N) C3 H7 (n) C3 H7 (n) * H C14 H7 (n) C H H 141 C3 H7 (n) (N) co HH 143 CHiH3 n (n) CHiH3 ((n) * H coch 3 144 CHiH3 ((n) CHH ^ -νννΝHΝ

B is embedded in A

Another preferred class of specific conjugates of the invention is provided by conjugates formed from an AII-antagonist biphenylmethyl-1H-substituted 1,2,4-triazole compound attached to a cleavable glutamyl residue. Each conjugate of this class contains a terminal amino moiety in the triazole moiety which is attached 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, can generally be prepared according to the procedures of Example # 145.

Example 145

N-acetyl-N-t-butyl-1-T-2 '- (1H-tetrazol-5-yl) -1,1'-biphenyl] -4Hydimethyl] -1H-1,2,4-triazol-3-ylmethyl] -L-glutamine A a solution of N-BOC-L-glutamic acid α-tert-butyl ester (BACHEM) in 100 ml of methylene chloride under nitrogen is added 3.5 g (17 mmol) The solution of anhydride is then added to a solution of 5.78 g (14.9 mmol) of the titanium dioxide 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 the material pure by thin layer chromatography (TLC) This material is redissolved in 100 ml of methylene chloride under nitrogen and cooled to 0øC before the addition of 135 ml of TFA.The stirred reaction is allowed to warm to room temperature and concentrated The crude product is dissolved in 80 ml of acetonitrile / water (1: 1) and the pH is adjusted to 9 with K 2 CO 3. The solution is cooled to 0 ° C and added every 30 minutes. , 1 ml (11 mmol) of acetic anhydride and 11 ml (11 mmol) of K2CC> 3 1 M; during the course of this reaction the pH is maintained at 9 ° C and the reaction temperature maintained below 5 ° C. After the last addition, the reaction is allowed to warm to room temperature overnight. The pH was adjusted to 4 with 3M HCl and the reaction was concentrated to 300 ml. Purification by reverse phase chromatography (Waters Delta Prep-3000) gave N -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.] 315 315

TABLE V

Ex: # R5 ABEP 146 CO2H single bond HH COCH3 147 CO2H single bond HH COCH2C1 148 CO2H single bond HH COC4H9 149 CO2H single bond H CH3 COCH 3 150 CO2H single bond H C2H5 COCH 3 151 CN4H single bond HH COCH 3 152 CN4H bond simple HH COCH 2 Cl 153 CN4H single bond HH COC4H9 316 Εχ: # R5 ABEP 154 CN4H single bond H CH3 COCH 3 155 CN4H single bond H C2H5 COCH3 156 CO2H single bond HHH 157 CO2H single bond H CH3 H 158 CO2H single bond H C2H5 H 159 CN4H single bond HHH 160 CN4H single bond H CH3 H 161 CN4H single bond H. C2H5 H 162 C H3 C H3 C H3 C H3 C H3 C H3 C H3 C H3 C H3 C H3 C H3 C H3 C H3 C H4 C H4 C6 H3 simple HH COCH2CI 168 CN4H single bond HH COC4H9 169 CN4H single bond H CH3 COCH 3 170 CN4H single bond H C2H5 COCH3 171 CO2H -CH2 -HHH 172 CO2H single bond H CH3 H 173 CO2H single bond H C2H5 H 174 CN4H- HH. H 175 CN 4 H single bond H CH 3 H 176 CN 4 H single bond H C 2 -5 H 177 CN 4 H -CH 2 -CH 3 H H 178 CN 4 H -CH 2 -t CH 3 H COCH 3 179 CO 2 H 2 -CH 2 CH 2 -H H COCH 3

Εχ: ## EQU1 ## Single bond C H H COCH 2 Cl C H 2 C H 2 C H 2 C H 2 C H 2 C H 2 C H 2 C H 2 C H 4 C simple HH COC4H9 187 cn4h single bond H CH3 COCH 3 188 CN4H single bond H C2H5 COCH 3 189 C02H -CH2CH2- HHH 190 C02H single bond H CH3 H 191 C02H single bond H C2H5 H 192 CN4H -CH2CH2- HHH 319

Εχ: # ABEP 193 CN4H single bond H CN C4 H9 simple bond H H COCH2 C3H6 (n) HH COCH 3 196 COOH single bond H C2H5 coch3 200 CN4H C3H6 (n) H. H COCH3 203 CN4H single bond HH COCH2Cl 202 CN4H single bond HH COC4H9 203 CN4H single bond H CH3 COCH 3 204 CN4H single bond H C2H5 COCH 3 205 C02H C3H6 (n) single bond C H H C H H C H H C H H C H H C H H C H H C H H COCH 3 Cl H simple C H 2 C H 4 C H 4 C C3 H4 C4 H8 (n) HH COCH3 CN4 H single bond HH COCH2 Cl CN4H single bond HH COC4H9 219 220 221 222 223 224 225 226 227 228 229 230 231 cn4h single bond H CH3 COCH3 cn4h single bond H C2 H5 COCH3 CO2 H C4 H8 ( n) HHH C4H8 (n) HHH C4H8 (n) HHHCn4h single bond H CH3 C4H8 simple bond H C2H5 H C02HOHH COCH3CO2H single bond HH COCH2Cl CO2 bond m H H C0 C4 H9 co2 h single bond H CH3 COCH3 C02 H single bond H C2 H5 COCH3

Ex: # ABPA 232 cn4h HH COCH3 233 cn4h single bond HH COCH2CI 234 cn4h single bond HH COC 4Hg 235 cn4h single bond H CH3 COCH3 236 cn4h single bond H C2H5 COCH3 237 co2h OHHH 238 C02H single bond H CH3 H 239 COOH single bond H C2 H5 H 240 cn4h -OHHH 241 cn4h single bond H CH3 H 242 cn4h single bond H C2 H5 H 243 C02 H H COCH 3 244 C02 H single bond HH COCH2 Cl

single bond H H COCH 2 Cl CN 4 H single bond H H COC 4 Hg CN 4 H single bond H ch 3 coch 3 CN 4 H single bond H 'C 2 H 5 COCH 3 C02H -chK &gt; H H H C02H single bond H CH3 H C02H single bond H C2H5 H cn4h H H H

Ex: ## STR8 ## Single bond H H COCH2 261 C02H single bond HH COC 4Hg 262 C02H single bond H ch3 coch3 263 co2h bond simple H C2H5 COCH3 264 CN4H 268 CN4H 266 CN4H single bond HH COCH2 Cl 266 CN4H single bond HH COC4H9 267 cn4h single bond H3 COCH3 268 CN4H single bond h C2 H5 COCH 3 269

H

325 'N

Ex: # 270 271 272 273 274 275 276 277 278 279 280 281 282

R5 A B

CO 2 H CN 4 H CN 4 H CN 4 H 2 CO 2 H 2 CO 2 H 2 CO 2 H 2 CO 2 H CN 4 H CN 4 H CN 4 H single bond single bond

single bond simple bond

simple connection simple connection simple connection simple connection

single bond simple bond

H H H H H H H H H H H H H

E CH3 C2 H5 H CH3 C2 H5 H H H CH3 C2 H5 H H H H H H H COCH 3 C 0 C H 2 Cl COC 4 H 9 coch 3 C 3 HCO 3 COCH 2 Cl COC 4 H 9 326Ex: # 283 284 285 286 287 288 289 290 291 292 293 294 295

 € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ5 C4 H4 N4 H4 CO

C02H

C02H

C02H

C02H

A B single bond single bond

single bond single bond cn4h

single bond simple bond

simple connection simple connection simple connection simple connection

H H H H H H H H H H H E CH3 C2H5 H CH3 C2H5 H CH3 C2H5 H H H CH3 C2H5 P coch3 COCH3 .H H H H H H COCH3 COCH2CI COC 4Hg COCH3 coch3

R &gt; 5A BE

CN4H -CH2CH2-4 j- Η H

CN4H single bond HH cn4h single bond HH CN4H single bond H CH3 CN4H single bond H C2H5 CN4H -Q-ch2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 -CH2 CH3 C02H single bond H 'C2H5 CN4H - {> ch2-ch2-HH CN4H bond single bond H H Ί.

Single bond H H COCH2C1 314 cn4h single bond HH COC4H9 315 CN4H single bond H H C2 H5 coch3 312 CN4H single bond H H COCH3 312 CN4H single bond HH CH3 coch3 316 CN4H single bond H C2H5 coch3 317 CO2H HHH 318 CO 2 H single bond H CH 3 H 319 CO 2 H single bond H C 2 H 5 H 320 C 4 H 4 H 4 H 4 N

Εχ: # r5 ABEP t 322 cn4h single bond H C3 H5 323 C02 H H COCH3 324 CO2 H single bond HH COCH2 Cl 325 H single bond HH COC4H9 326 CO2H single bond H ch3 coch3 327 CO2H single bond H C2H5 coch3 328 CN4H HH COCH 3 329 CN4H single bond HH COCH2 Cl 330 CN4H single bond H 'H COC4H9 331 CN4H single bond H CH3 COCH 3 332 CN4H single bond H C2H5 COCH3 333 C02H HHH 334 CO2H single bond H ch3 H 335 CO2H single bond H C2H5 H \ 330 Εχ: R5 ABEP 336 CN4H HHH 337 CN4H single bond H CH3 C3 H3 C3 H3 C3 H3 C3 H3 C3 H3 C3 H3 C3 H3 C3 H3 C3 H3 C3 H4 C3 H4 C3 H4 C3 H4 C3 H4 C3 H4 C3 H4 C3 H4 C3 H4 CH4 C4 H34 C4 H4 C4 H9 C4 H9 C4 H9 C4 H9 C4 H9 C4 H9 C4 H9 C4 H4 C4 H9 C4 H9 C4 H9 C4 H9 C4 H9 C4 H4 C4 H5 COC H3 331 β3 H 352 CN4 H C12 H5 354 CN4 H single bond H CH3 H 354 CN4 H single bond H C2 H5 H 355 C02 H / - TCK2 ~ HH COCH3 356 CO2H single bond HH COCH2CI 357 CO2H single bond HH COC4H9 358 CO2H single bond H ch3 coch3 359 single bond H C2H5 coch3 360 cn4h -CHP - ^ - HH COCH3 361 CN4H single bond HH COCH2C1 362 cn4h single bond HH COC 4H'9 363 cn4h single bond H ch3 coch3 364 CN4H single bond H C2H5 co CH3 366 CO2H single bond H CH3 H 367 co2H single bond H C2H5 H 368 CN4H CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CNH₂CH₂CH₂CH₂CH₂CH₂CH₂CH₂CNH coch3 375 C02H single bond H C2H5 co ch3

378 CN4H single bond HH COC4H9 379 CN4H single bond H CH3 COCH 3 380 CN4H single bond H C2H5 coch3 381 cn4h HH COCH 3 382 C02H single bond H CH3 H 383 C02H single bond H 384 CN4H3R4H2CH2CH2 -HHH 385 CN4H single bond H CH3 H 386 CN4H single bond H C2H5 H 387 CN4H * H COCH3 388 C02H single bond HH COCH2CI - 334 -

Single bond H H COCH3 390 CN4H single bond HH COCH3 392 CN4H single bond HH COCH3 392 CN4H single bond HH COCH3 392 CN4H single bond HH H CH3 COCH3 396 cn4h single bond H C2H5 COCH3 397 CN4H * H COCH3 398 C02H single bond H CH3 H 399 C02H single bond H C2H5 H 400 CN4H: k HH 401 cn4h single bond H ch3 H 402 cn4h single bond H C2H5 H 335

## STR1 ## Single bond C H H COCH 2 Cl C H 4 C H 4 C H 4 C H 4 C H 4 C H 4 C H 4 C H 3 C - * HH 409 CN4H single bond HH COCH2CI 410 CN4H single bond HH COC4H9 411 CN4H single bond H * CH3 COCH 3 412 CN4H single bond H C2H5 COCH 3 413 CN4H and ------ -CH? -N- &quot; '' &Quot; ' IR (KBr)::::::::: CH 414 C H 2 C

Ex: ## STR8 ## Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino Amino A jt- '

Ex: # R5 A BE P

421 cn4h single bond HH CCC 4Hg 422 cn4h single bond H CK3 COCH 3 423 CN4H single bond H C2H5 coca 3 424 CN4H -CH? CH? -N '-NH * 425 cn4h single bond- H CH3 H 426 cn4h single bond H C2 H5 H and *

B is incorporated in A 338

Another preferred class of specific conjugates of the invention is provided by conjugates formed from an AII antagonist biphenylmethyl-1H-substituted 1,2,4-triazole compound attached to a cleavable glutamyl residue. Each conjugate of this class contains a linker moiety which bonds a terminal carboxylic acid moiety to the triazole moiety of the AII antagonist compound with the 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- # 8324, as shown in Table VI, can generally be prepared according to the procedures of Example # 427. 339 \. (I.e.

Example 427

N-acetyl-L-glutamic acid, 5- (5-butyl-1- [2 '- (1H-tetrazol-5-yl) -1', 1'-biphenyl-4-ylmethyl-1H-1,2,4- yl] acetic acid hydrazide

Step 1; Preparation of 5- [4- (5-Butyl-3-hydrazinylcarbonylmethyl-1,2,4-triazol-1-yl) methyl] -1'-biphenyl] -2-ylmethyl-1H-tetrazole

Under nitrogen, 8.34 g (20 mmol) of the compound of Example 7 are dissolved in 200 ml of absolute methanol at -10 ° C (ice / methanol) and treated dropwise with 3.0 g ( 215 mmol) of thionyl chloride. After the addition is complete, the reaction is allowed to warm to room temperature for 2 hours before stirring at reflux overnight. All volatiles were removed in vacuo and the residue was redissolved in 100 ml of methanol. Under nitrogen, 20 g (265 mmol) of anhydrous hydrazine are added and the reaction is stirred at reflux overnight. Concentration in vacuo gives rise to the crude product; Purification by chromatography on silica gel affords 5- [4 '- [(5-butyl-3-hydrazinylcarbonylmethyl-1,2,4-triazol-1-yl) methyl] 1'-biphenyl] -2-yl] methyl-1H-tetrazole.

Step 2: Preparation of N-acetyl-L-alutamic acid. 5-yl) -1-biphenyl-4-ylmethyl-1H-1,2,4-triazol-3-yl] acetyl} hydrazide To a solution of 10.0 g 45 g (34.5 mmol) of N-BOC-L-glutamic acid α-tert-butyl ester (BACHEM) in 100 ml of methylene chloride under nitrogen is added 3.5 g (17.0 mol) -cyclohexylcarbodiimide (DCC). The reaction is allowed to stir for 2 hours 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 concentrated in vacuo. Purification by silica gel chromatography (Waters Prep-500A) yielding the pure material by thin layer chromatography (TLC). This material is redissolved in 100 ml of methylene chloride under nitrogen and cooled to 0øC before the addition of 135 ml of TFA. The stirred reaction is allowed to warm to room temperature and concentrated in vacuo. The crude product is dissolved in 80 ml of acetonitrile / water (1: 1) and the pH adjusted to 9 with K 2 CO 3. The solution is cooled to 0øC and 1.1 ml (11 ml) is added. mmol) of acetic anhydride and 11 ml (11 mmol) of 1 M K2 CO3 during this course of reaction the pH is maintained at 9 ° C and the reaction temperature maintained below 5 ° C. After the last addition, the reaction is allowed to warm to room temperature overnight. The pH was adjusted to 4 with 3M HCl and the reaction was concentrated to 300 mL. Purification by reverse phase chromatography (Waters Delta Prep-3000) gave 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] acetyl] hydrazide. 341

Εχ. # ALB Ξ P 428 single bond -NH- HH COCH3 429 single bond -NH- HH C0CH2C1 430 single bond -NH- HH COC4H9 431 single bond -NH- H CH3 COCH3 432 single bond -NH- H C2H5 COCH3 433 single bond - NH-HHH 434 single bond -NH- H ch3 H

Εχ. # ALBEP 435 single bond -NH- H C2K5 H 436 single bond -NHCH2CH2- HH COCH3 437 single bond -NHCH2CH2- HH COCH2 Cl 438 single bond -NHCH2CK2- HH COC4H9 439 single bond -NHCH2CK2- H CH3 COCH3 440 single bond -NHCH2CH2 - H C 2 H 5 COCH 3 441 single bond -NHCH 2 CH 2 -HHH 442 single bond -NHCH 2 CH 2 -H CH 3 H 443 single bond -NHCH 2 CH 2 -H c 2 h 5 H 444 single bond / EX. #

BE P 446 single bond N-Η K COC4H9 447 single bond N-H CH3 COCK 3 448 single bond H-2 5 5 COCH 3 449 single bond

-N- * H

450 single bond -N-H CH3 H 451 single bond /

-NH-C2H5 H 452 CH2 -NH- Η H COCH2C1 453 CH2 -NH- Η H COC 4H9 454 CH2 -NH- H CH3 COCH3 344

Ex. ## STR10 ## 459 CH2 -NH- H C2 H5 H 459 CH-2 -NHCH2 CH2 -HH COCK3 460 CH2 -NHCH2 CH2 - HH COCH2C1 461 ch2 -NHCH2CH2- HH COC4H9 462 ch2 -NHCH2CH2- H CH3 COCH3 463 ch2 -NHCH2CH2- H C2H5 COCH3 464 CH2 -NHCH2CH2- HHH 465 ck2 · -NHCH2CH2- H C2H5 H 345Ex . #

## STR2 ## ## STR8 ## ## STR8 ## ## STR3 ## embedded image CH3 C2 H5 COCH3 472 CH2

-N- * H 473 ch2

-NH-CH3 H 474 CH2 R3 -N -N-

H C2 H5 H 346 Εχ. # AL Ξ EP 475 CH2CH2 -NH- HH COCH3 476 CH2CH2 -NH- HH COCH2C1 477 CH2CH2 -NH- HH COC4H9 478 CH2CH2 -NH- H CK3 COCH3 479 CH2CH2 -NH- H c2h5 COCH3 480 CH2CK2 -NH- HHH 481 CH2CH2 - NH- H CH3 H 482 CH2CH2 -NH- H c2h5 h 483 CH2CH2 -NHCH2CH2- HH COCH3 484 CH2CH2 -NHCH2CH2- HH COCH2C1 485 CH2CH2 -NHCH2CH2- HH COC4H9 486 CH2CH2 -NHCH2CH2- H CH3 COCH3 487 CH2CH2 -NHCH2CH2- H C2H5 COCH3 Ex. # 34

Λ Λ Λ 493 CH 2 CH 2 -NHCH 2 CH 2 - Η C 2 K 5 Η 491 CKH 2 CH 2 - Η CHH 49 492 CH 2 CH 2 --Ν Ν - Η Η COCH 2 C 1 Λ '493 CH 2 CH 2 -COCH3 494 CH2CH2 -O-CH3 COCH3 495 CH2CH2 CH3 CHO 496 CH2CH2 -O

Ν- * Η Η Εχ. #

THE

L

B E

P 497 498 499 500 501 502 503 504 505 506 507 CH2CH2

(N) C3 H6 (n) C3 H6 (n) C3 H6 (n) C3 H6 (n) C3 H6 (n)

-NH-NH-NH-NH-NH-NH-NH-NH-NH-NHCH2CH2-

H

H

H

H

H

H

H

H

H

H 2½ 5

H

H

H CH3 C2H5

H CH3 c2h5

H COCH 3 COCH 2 C 1 COC 4 H 9 COCH 3 COCK 3

H

H

H COCH3 349

Εχ. # A

LB E P

I

(N) C 3 H 6 (n) C 3 H 6 (n) C 3 H 6 (n) C 3 H 6 (n) C 3 H 6 (n)

-NHCH 2 CH 2 -H

-NKCH2CH2 -H

-NKCH2CH2 -H

-NHCH 2 CH 2 -H

-NHCH 2 CH 2 -H

-NHCH 2 CH 2 -H

-NHCH2 CH2 -

517 C3 H6 (η) C3 H6 (n) C3 H6 (n) C3 H6 (n) C3 H6 (n) C3 H6 (n) C4H8 (η) C4H8 (η) C4H8 (η) C4H8 (η) C4H8 (η) C4H8 (η)

L BE

-CH 2 CH 3 -COCH 3 COCH 3 H C 2 H 5 * CH 3 CH 2 CH 2 CH 3 CH 2 COCH 3 COCH 3 COCH 2 C 1 COC 4 H 9 COCH 3 COCH 3 351 Εχ. ## EQU1 ## embedded image ## STR8 ## ## STR3 ## embedded image ## STR8 ## embedded image ## STR8 ## STR3 ## STR8 ## STR8 ## STR8 ## STR8 # (Η) -NHCH2CH2-H CH3 coch3 535 C4H8 (η) -NHCH2CH2- H C2K5 COCH3 536 C4H8 (η) -NHCH2CH2- HHH 537 C4H8 (η) -NHCH2CH2- HH ) -NHCH 2 CH 2 -H ch 3 H 538 C 4 H 8 (η) -NHCH 2 CH 2 -H C 2 H 5 H 539 C 4 H 8 (η)

Ex. #

THE

L

B E

P 540 C 4 H 8 (n) 541 C 4 H 8 (n)

COCH2C1 COC4H9 542 C4H8 (n) 543 C4K8 (n)

COCH3 COCH3 544 C4 H8 (n) / -

H 545 C 4 K 8 (n) / -

H 546 C 4 H 8 (n) / -

H 547

-NH-

H H COCH 3. # Α L Β Ε 548 -ΝΗ- Η Η COCH2C1 «V 549

W -ΝΗ- C4HH 550 550

CH3 COCH3 551 -O- C2 H5 COCH3 * 552

eur-lex.europa.eu eur-lex.europa.eu

-ΝΗ- Η CH3 Η 554

-CHHΗ-555 -NHCH₂CH₂-CHHΗ

354Εχ. # A

L BE

P 556

-NHCH 2 CH 2 - Η H

COCH2Cl 557

-NHCH2CH2 - Η H CCC4H9 558 -NHCH2CH2- H CH3 COCH3 559 -NHCH2CH2- K C2H5 COCH3 ^ 560

-NHCH 2 CH 2 - Η H

H 561 -NHCH 2 CH 2 -H CH 3

H 562

W -NHCH2 CH2 --H C2 H5

H 563

N, N-dimethylformamide

H COCH3 355 ΕΧ. #

A L B E

P 564 565 566 567 568 569 570 571

COCH2 Cl COC4 H9 COCH3 COCH3 H H H COCH3 356

THE

L B E P -CHR \ -NH-H H C0CH2C1

-CHrAH H COCH4

-NH-NH-NH-H CH3 COCK 3 H C2 H5 COCH3

H

-CH

-NH- H CH3 H -NH- H C2 H5 K -NHCH2 CH2 - Η H COCH3

357Ex. # A

L BE

P 580 (CH 3)

-NHCH 2 CH 2 - Η H

COCH2Cl 581

-NHCH2 CH2 - Η H CCX3 4H9 582 583 584 585 586 587

-NHCH 2 CH 2 -H CH 3 -NHCH 2 CH 2 -K C 2 H 5

-NHCH2CH2- Η H -NHCK2CH2- H CH3 -NHCH2CH2- H C2H5

-NH-H CCCH3 COCH3

K

H

H COCH3 358

Εχ. # A

L B E

P \

• * 588 589 590 591 592 593 594 595

COCH2Cl CCX: 4H9 COCH3 COCH3 H -CH2-

-NH-CH3

H

H C2 H5

H

Η H COCH 3

359Ex. # A

L BE

P 596 -ch2ch2- -NH-

H H COCH 2 Cl 597 -ch 2ch 2 4 -NH-

Η H COCH4 598 -ch2ch; COCH3 600 -CH 2 CH 2 - 4 - NH - H - C H H COCH 3 600 - CH 2 CH 2 - 4 - NH -

H H

H 601 602 603 - CH 2 CH 3 - (CH 2 CH 2)

-NHCH 2 CH 2 -H

H

H

H COCH3 -W / 360Εχ. #

THE

L B E

P 604 605 606 607 608 609 610 -CH 2 CH 2 -CH 2 CH 2 CH 2 -CH 2 CH 2 CH 2 - P -NHCH2CH2- H C2H5 --CH2CHf - NHCH2CH2 - Η H - CH2CHf - NKCH2CH2 - H CH3 - CH2CH2 --- NH - CH2CH2 - H C2H5

COCH2 Cl CCC4 H9 CCCH3 COCH3

H

H 611 -ch2ch

-N- *

H COCH3 361 Εχ. #

THE

L

B E

P 612 613 614 615 616 617 613

N- [N- N-

Η H

Η H H CH3 H C2K5

H K CH3 H C2 H5 COCH2 C1 COC4 H9 COCH3 COCH3

H

H

H 619 CHF -NH-

H

H COCH3 Εχ. #

THE

L

B E

P 620 621 622 623 624 625 626 627

-NH-NH-NH-NH-NH-NH-NH-

H H

Η H H CH3 H C2H5

Η H H CK 3 H C 2 H 5

-NHCH 2 CH 2 -H

H

COCH 2 Cl COC 4 H 9 COCK 3 COCH 3

H

H

H COCH3

363Ex. # A

L

B E

P 628 629 630 631 632 633 «ν '634 635

-NRCH2CK2- KK

CCCH2CI

-NHCH2CH2- K H -NKCH2CH2- H CH3 -NKCH2CK2- H C2H5

-NHCH2CH2 - Η H -NHCK2CK2- H CH3 -NKCK2CH2- H C2K5 N-N-

H CCC 4H 9 CCC 3 CCCH 3

H

K

H COCH3 364Εχ. #

THE

L BE

P 636 637 638 639 640 641 642 643

COCH2 Cl COC4 H9 COCH3 COCH3 H H H COCH3 -NH- H H Εχ. #

THE

L B Ξ

P 644

\ / -ch2-ch2-

5 -NH- Η H COCH2 Cl 645

CHF-CHf-NH-H H COCH4 646

CH? -NH- H CK3 CGCH 3 647

V / -CH 2 -CH 2 -NH- H C 2 H 5 COCH 3 648

CHFCHf -NH- Η H

H 649

CHFCHf -NH-H CH 3

H 650

CHFCHF &quot; -NH- H C2 H5

H 651

CH 2 -CH 2 -

-NHCH 2 CH 2 -H

H COCH3 366

366 Εχ · # A

LB E P 652

k -CHRCHr -NHCH2CH2- H H COCH2C1 653 -CHRCH1 -NHCK2CH2-H H CCC4H9 654 CH3 -CHF -NKCH2CH2- H CH3 COCH3 655 -γ1 -NHCH2 CH2 --H C2 H5 COCH3 657

CH 2 -NHCH 2 CH 2 -H CH 3 H 656

CHCHCH -N -NHCH₂CH₂- Η H

H 658

λ / CHf-CHf--NHCH 2 CH 2 -H C 2 H 5 h 659

CH 2 -CH 2 CH 3

THE

L B E

P C0CH2 Cl

CH 2 -CH 2 -NH-N H CCC 4 H 9

CHO-CH, - CH3 CH3 COCK3

-NH-. N-C2 H5 COCH3

CH, -CHO-N-N- [H

H

H

CH 2 CN

H

-CH2-NH-

H H C0CH3 368 ΕΧ. #

THE

L BE

P 668 669 670 671 672 673 674 675

-NH- H -NH- H -NH- H -NH- H -NH- H -NH- H -NH- H -NHCH2CH2- H

H

H CH3 C2H5

H CH3 C2K5

H COCH2 C1 COC4 H9 COCH3 COCH3

H

H

H COCH3 369 Ec. #

THE

L BE

P 676 677 678 679 680 681 682

-NHCH2CH2- Η H -NHCH2CH2- Η H -NHCH2CK2- H CH3 -NHCH2CH2- H C2H5 -NHCH2CH2- Η H -NHCH2CH2- H CH3 -NKCH2CH2- H C2H5

COCH 2 Cl COC 4 H 9 COCK 3 COCH 3

H

H

H 683

-N- *

H COCH3 370 &quot; Sv &

Εχ. # A

L BE

P 684 685 686 687 688 689 690

N-N-N-N-N-

-N-N-N-N-N-

Η H

Η H H CH3 H C2H5

* H H CH3 H C2 H5 COCH2 C1 COC4 H9 COCH3 COCH3

H

H

H 691

-NH- C H H COCH 3 692 -NH- H H COCH 2 Cl 693 -NH- H H COC 4 H 9 694. -NH- H CH3 COCH3 695 -NH- H C2H5 COCH3 696 -NH- H H 697 -NH- H CH3 H 698 -NH- H C2H5 H 699 J ^ T -NHCH2CH2- H H COCH3 700 -NHCH2CH2- Η Η COCH2C1 372B Ξ

P

-NHCH 2 CH 2 -NHCH 2 CH 2 -NHCH 2 CH 2 -NHCH 2 CH 2 -NHCH 2 CH 2 -NHCH 2 CH 2 -NHCH 2 CH 2 -NHCH 2 CH 2 -NHCH 2 CH 2 -NHCH 2 CH 2 -NHCH 2 CH 2 -NHCH 2 CH 2 - - N - (-) - N - (

Η H COC 4 H 9 H CH 3 H C 2 H 5

Η H H CH3 H C2H5

H

Η H

Η H - COCH 3 COCH 3

H

H

H CCCH3 COCH2C1 CCC4H9 373 Ex. # Β Ε ρ 710 JP = T V / Η CH3 COCH3 711 Η C2H5 COCH3 712 Η Η 713 Ρ Τ Η CH3 Η 714 JP = T ΛΛ Η C2K5 Η 715

-COCH3 716 -CH.

JPCT -ΝΗ- Η Η COCH2C1 717

-CH

-PCT -ΝΗ- Η COC 4Η9 718

-CH

JPT -ΝΗ- Η CH3 COCH3 374 Ex. # Βε ρ 719 -CH. -CONH 3 720 -CH. jpcr

-NH- Η H 721 -CH.

JPzT -NH-

H CH 3 H 722 -CH.

JPPT-NH-

H C2 H5 723 -CH. -Per -NHCH2 CH2 - Η H COCH3 724 -CH. -NHCH 2 CH 2 - Η H COCH 2 Cl 725

-CH -NHCH2 CH2 - Η H COC4 H9 726

-CH-CHCH2 -CH2 -CH3 -COCH3 727

-CH-NHCH 2 CH 2 -H C 2 H 5 COCH 3 Εχ. #

THE

L

B E

P 728

-CH

-NHCH 2 CH 2 - Η H

H 729 -CH, -NHCH 2 CH 2 -H CH 3

H 730

-CH-NCH2 CH2 CH2 H

K 731 -CH.

/ - N - HN_I COCH3 732

-CH 2 -NH -CH

-CH

/ -S -N-Η H COC 4 H 9 734 -CH. -NH-CH3 COCH3 735 -CH. -N- N

H C2 H5 COCH3 376 Εχ. #

THE

L B

E P 736 737 738 739 740 741 742 743

- N - N - [[

-NH- H -NH- H -NH- H -NH- H -NH-

H

Η H

CH3 H

C 2 H 5 H H COCH 3 H C 0 C H 2 Cl H COC 4 H 9 CH 3 COCH 3 C 2 H 5 COCH 3 377

Κ. L A p p

744 -CHzCH -N -NH-

H Η H 745 -ch2ch2- -NH- K CH3h 746 -ch2ch2-

-PZT -NK-

H C2 H5 H 747 -ch2ch2

-NKCH 2 CH 2 -K

H CCCH3 748 -ch2ch2 -NHCH2CH2- Η H C0CH2C1 749 -ch2ch2 -NHCH2CH2- Η H CCC4H9 750 -ch2ch2 -NKCH2CH2- H CH3 COCH3 751 -ch2ch j. -NHCH2 CH2 --H C2 H5 C CCH3 752 -C

-NHCH 2 CH 2 - Η H

378Εχ. # A

L-BE 753 754 755 756 757 758 759 760

-NHCH 2 CH 2 -H CH 3

H -NHCH 2 CH 2 --H C 2 H 5

H

H COCH3

Η H C0CH2 Cl -N-Η HN_t

H CH 3 -N-H C 2 H 5 -NN * N C t C 4 H 9 COCH 3 COCH 3

Η H

379Εχ. # A

L B E P 761 762 763 764 765 766 767 768

-N-H-_t

-NH- H CH3 K - c2 H5 η H COCH3 H C0 C H2 C H H COC4 H9 CH3 COCH3 C2 H5 COCH3

Η H

380 Ex. # A

L B E

P 769 770 771 772 773 774 775 776 777 778

-NH- H CH 3 -NH- H C 2 H 5

-NHCH 2 CH 2 - Η H

-NH- Η H

-NH- Η H -NH- H CH3 -NH- H C2H5 -hCH2CH2- h h -NHCH2CH2- ΗCH3 -NHCH2CH2-

H

H COCH 3 COCH 2 Cl COC 4 H 9 COCH 3 coch 3

H

H

C2 H5 H

381Ex · # A

L BE 779 780 781 782 783 784, 785 786

-N-N-

-N

-N- N - N - N - N - N

N-

H COCH3

H H

H K H CH 3 C 2 H 5 Η H CH 3 COCH 2 Cl CCC 4 H 9 COCH 3 COCH 3

H

H

H C2H5 H 382 m w Εχ · #

B E 787 788 789 790 791 792 793 794 795 CH2CH2 -nk- h h CH2CH2 -nh- H h jzcr

CH 2 CH 2 - - n - CH 2 CH 2 - - NH - CH 2 CH 2 - - - - H C 2 H 5 CH 2 CH 2 -

CH 2 CH 2 -NHCH 2 CH 2 - Η H COCH 3 COCH 2 C 1 CCC 4 H 9 COCH 3 COCH 3

H

H

H COCH3

383ΕΧ. # A

L BE 796

CH 2 CH 2 -NHCH 2 CH 2 - Η H COCH 2 Cl 797

CH2CH2- -NHCH2CH2- Η H COC4H9 798 jppt CH2CH2- -NHCH2CH2- H CH3 COCH3 799 CH2CH2- -NHCK2CH2- H C2H5 COCH3 800

CH 2 CH 2 -NHCH 2 CH 2 - Η H

H 801 CH 2 CH 2 -NHCH 2 CH 2 -H CH 3

H 802

JPPT CH 2 CH 2 -NHCH 2 CH 2 -H C 2 H 5

H 803

SpT CH2CH2 * M *

-N

H COCH3 384Εχ. #

THE

L B E P 804 805 806 807 808 809 810 811

-N-N- [N-

-NH- H H COCH 2 Cl 1 Η H CCC 4 H 9 H CH 3 COCK 3 H C 2 H 5 COCH 3

Η H

H CH3 H

H C2 H5 H

H

H COCH3 812 813 814 815 816 817 818

Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η C2H5 Η 819 ch2-

-CH-CH-CH 2 CH 2 -

386Ex. # A 820 -CH. 821 822 823 824 825 826 827

CH 2 -CH 2 -CH 2 -CH 2 -CH

-CH CH 2 -NHCH 2 CH 2 - Η K CCC 4 H 9

-CHOH-4 &quot; 2 -NHCH 2 CH 2 -H CH 3 COCH 3

&quot; -CH2 OH-CH2-NHCH2-CH2-H C2 H5 COCH3

-CH

CH JPZT &quot; 2 -NHCK 2 CH 2 - Η H

-CH

-NHCH 2 CH 2 -H CH 3 H

-CH

-CH2 -NHCH2 CH2 --H C2 H5 H CH2 -CH2 -NHCHOCH3

387 Εχ. # A

L BE

P 828 ch2-

-C H

H H COO2 Cl 829 CH, -

-CH

Η H COC4H9 830 831 832

N-

H CH3 H C2H5

* H CCCH3 COCH3

H 833

-CH2-

Η ch3 η 834 CH,

-CH

-N-

H 2 h 5 h

BIOLOGICAL EVALUATION In order to identify suitable angiotensin II antagonists for use as the first component of the conjugate of the invention, certain compounds of Examples 1-17 were evaluated differently in three biological assays (Assays &quot; A &quot;, &quot; B &quot; &quot; C &quot;). In a fourth trial, the blood pressure lowering effects of the conjugate of Example 18 (Test &quot; D &quot;) were evaluated.

Assay A: Angiotensin II Binding Activity

The compounds of Formula I were tested for the ability to bind to the angiotensin II receptor of smooth muscles using a rat uterine membrane preparation. Angiotensin II (AII) was purchased from 125

Peninsula Labs. Α-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. 106, 120-124 (1980)]. Rat uterine membranes were prepared from fresh tissue. All procedures were carried out at 4 ° C. The 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 x g for 20 min, and the supernatant was recentrifuged at 100,000 x 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. The test tubes were loaded with 0.25 ml of a solution containing 5 nM MgCl2, 2 mM EDTA, 0.5% bovine serum albumin, 50 mM Tris-HCl, pH 7.5 and I-AII (about 5

10 cpm) in the absence or presence of unlabeled ligand. The reaction was started by addition of membrane protein and the mixture was incubated at 25 ° C for 60 min. The incubation was quenched with ice cold 50 mM Tris-HCl (pH 7.5) and the mixture was filtered to separate the bound peptide bound to the free ligand membrane. The incubation tube and the filter were washed with ice-cold buffer. Filters were assayed for radioactivity in a Micro-meter gamma counter. Non-specific binding was defined as binding in the presence of 10 μg of unlabeled AII. The specific binding was calculated as the total binding minus the nonspecific binding. The receptor binding affinity of an AII antagonist compound was indicated by the concentration (Cl) of the tested AII antagonist 125, which gave 50% displacement of the specifically bound total I-AII of the high affinity AII receptor. Binding data were analyzed by means of a non-linear least squares curve fitting program. The results are shown in Table VII.

Assay B: Vascular Flat Muscle Response In Vitro relative

to the IIA

The compounds of Formula I were tested for antagonistic activity in rabbit aortic rings. Male New Zealand white rabbits (2-2.5 kg) were sacrificed using an excessive dose of pentobarbital and bled through the carotid arteries. The thoracic aorta was removed, cleaned of adherent fat and connective tissue, and then cut into 3 mm annular segments. The endothelium was removed from the rings by gentle sliding of a piece of filter paper wrapped within the lumen of the vessel. The rings were then placed in a wrapped tissue bath maintained at 37øC between mobile and fixed ends of a movable end stainless steel wire attached to a Grass FT03 transducer coupled to a Grass Model 7D polygraph for isometric strength responses. The bath was filled with 20 ml of oxygenated Krebs solution (95% oxygen / 5% carbon dioxide) having the following composition (mM): NaCl, NaHCO 3> 15.15 KCl, 1.2 NaH 2 PO 4, 1 , 2 MgSO 4, 2.5 CaCl 2, and 11.4 glucose. The preparations were equilibrated for approximately one hour before a gram of passive voltage was placed in the rings. The angiotensin II-response concentration curves were in. (3 x 10 to 1 x 10 M). Each AII concentration was allowed to cause its maximum contraction, and then the AII was washed away repeatedly for 30 minutes prior to challenge with a higher concentration of AII. The. -5

The aortic rings were exposed to the 10 M test antagonist for 5 minutes prior to challenge with AII. Adjacent segments of the same aortic annulus were used for all concentration-response curves in the presence or absence of the test antagonist. The efficacy of the test compound was expressed in terms of pA2 values and were calculated according to H.O. Schild. J. Pharmacol. Chemother., 2, 189-206 (1947)]. The pA2 value is the concentration of the antagonist which increases the value of CE5α to AII by a factor of 2. Each test antagonist was evaluated in aortic rings from two rabbits. The results are shown in Table VII.

Test C: Response to Intxaduodenal In Vivo Reagent Assay

to AII antagonists.

Male Sprague-Dawley rats weighing 225-300 g were anesthetized with Inactin (100 mg / kg, i.p.) and catheters were implanted in the trachea, femoral artery, femoral vein and duodenum. Blood pressure was recorded from the artery catheter 392

femoralnum Gould graph recorder (Gould, Cleveland, OH). The femoral vein catheter was used for angio-tensin II, mecamylamine and atropine injections. The tracheal catheter allowed clearance of the airways, and the duodenal catheter was used for intraduodenal administration (i.d.) of the test compounds. After surgery, the rats were allowed to equilibrate for 30 minutes. Macaroylamine (3 mg / kg, 0.3 ml / kg) and atropine (400 μg / kg, 0.3 ml / kg) were then administered i.v. to produce ganglia blockage. These compounds were administered every 90 minutes throughout the entire test procedure. Angiotensin II was given as an iv bolus dose (30 ng / kg in saline with 0.5% bovine serum albumin, 0.1 mg / kg) in 10 minutes three times or until the increase in blood pressure produced to be within 3 mmHg during two consecutive injections of AII. The mean of the last two injections of AII was calculated and was taken as the pressure response to the control AII. Ten minutes after the final control AII injection, the test compound (dissolved in sodium bicarbonate) was given i.d. at a dose of 3, 10, 30 or 100 mg / kg in a volume of 0.2 ml. Angiotensin II injections were then administered 5, 10, 20, 30, 45, 60, 75, 90 and 120 minutes after administration of the test compound and the blood pressure response was monitored. The response to the IIA was calculated as a percentage of the control response and then the percent inhibition was calculated as 100 minus the percentage of the control response. The duration of action of the test compound was defined as the time from the peak of percent inhibition to 50% of the peak. A compound was tested in a given dose in each rat. Each test compound was tested in two rats and the mean values were calculated for the two rats. The results are shown in Table VII. 393

TABLE VII

Activity of Compounds of the Invention on Anqiotensin II In Vivo and In Vitro

Test Compound Example # 1 Assay A CI5 0 (nM) 2 Assay B Pa2 Dose (mg / kg) 3 Assay C Inhibition (%) Duration (min) 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 1 300 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 17 4.0 8.64 / 8.40 NT NT NT 9 970 6.14 / 6.09 NT NT NT 19 12,000 5.18 / 5.35 NT NT NT 394

3 Assay c Inhibition Duration (%) (min) 1 2

Compound A Test A Test CI5Q pA2 Dose

Example # (nM) (mg / kg)

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 1 400 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 3 700 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 \ 395

Test Compound Example # 1 Test IC50 (nM) A 2 Assay B pa2 Dose (mg / kg) 3 Assay C Inhibition (%) Duration (min) 47 2 1 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 3 100 6.02 NT NT NT 55 80 6.56 / 7.13 NT NT NT 56 5.09 / 8 , 35 NT NT NT 57 2 300 6.00 NT NT NT 58 140 6.45 / 6.57 NT NT NT 59 120 7.23 / 7.59 NT NT NT 60 2 200 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 3 100 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

Test Compound Example # 1 Assay A IC50 (nM) 2 Assay B pa2 Dose (mg / kg) 3 Assay C Inhibition (%) Duration (min) 74 6.5 8.56 / 8.39 NT NT NT 75 570 6.00 / 5.45 NT NT NT 76 5 400 5.52 / 5.78 NT NT NT 77 15 000 5.77 NT NT NT 78 480 6.41 / 6.35 NT NT NT

ΝΤ = NOT TESTED * Unobserved antagonist activity up to 10 μια of the test compound.

Assay A: Angiotensin II Binding Activity 2

Assay B: Vascular Flat Muscle Response

In Vitro 3

C / D Assay: In Vitro Press Response (test compounds administered intraduodenally, except for the compounds of Examples # 3, # 26 and # 30, which were given intragastrically).

Test D:

In Vivo Effects of Chronic Conjugate Infusion of the Invention

A conjugate of the invention, as synthesized in Example 79, was evaluated biologically by an in vivo assay to determine the ability of the conjugate to selectively inhibit renal action and thereby control blood pressure. This live experiment was conducted to characterize the effects of the conjugate of Example 79 on spontaneously hypertensive rats (REH) by acute iv administration and by chronic iv administration. The compound of Example 18 or the saline vehicle was infused continuously for four days in REH. The mean arterial pressure (Gould Chart Recorder, model 3800) was measured; pressure transducer Statham P23Db) through a catheter placed in the femoral artery between 10:00 A.M. and 2:00 P.M. each day. The conjugate of Example 79 (10 mg / hr) or the saline solution was infused through a catheter into the jugular vein with a Harvard infusion pump. After administration of the conjugate of Example 79, a decrease in mean arterial pressure was then observed as compared to the saline vehicle control as reported in Table VIII and also in Figure 1. A test was conducted to determine whether the conjugate of Example 79 would antagonize vascular, non-renal angiotensin II reactants. In this test, the AII was administered by injection &quot; bolus &quot; (100 ng / kg) to the REH rats (as previously described) on the day of control and on days 1, 3 and 4, during the infusion of conjugate. No evidence was observed regarding antagonism to angiotensin II receptors, since similar pressor responses to angiotensin II injections were observed on the control day and on days 1, 3 and 4 of the conjugate infusion of Example 79 (see Figure 2). Tachycardia was observed on day 1 of the conjugate infusion, but the heart rate returned to the control level over the next three days (see Figure 3).

TABLE VIII

Effect of Example # 79 Conjugate on Pressure

Time (days): Control 1 2 3 4 Conjugate of Ex. # 18 (10 mg / hr) PAM (mm Hg): 183 159 155 154 166 (SD) ± 5 ± 7 ± 4 ± 6 ± 9 TABLE IX Effect of (10 mg / hr) 31 30 29 25 (SD) ± 4 ± 6 ± 5 ± 3 TABLE X Effect Example 10: Time (days): Control 1 2 3 4 Conjugate of Example # 18 (10 mg / hr) Beats / min: 352 395 352 344 374 (SD) ± 9 ± 21 ± 12 ± 22 ± 20 399

Also encompassed by this invention is a class of pharmaceutical compositions comprising one or more conjugates comprising a first component selected from angiotensin II antagonist compounds of Formula I, attached to a second component provided by an enzyme cleavable portion. Such pharmaceutical compositions further comprise one or more pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as "vehicle") 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 that route, and at a dose effective for the intended treatment. Therapeutically effective doses of a conjugate of the present invention required to prevent or stop the progress of the medical condition are readily calculated by one skilled in the art. The conjugates and composition may, for example, be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.

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 prepared 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 advantageously contain an amount of conjugate ranging from about 1 to 250 mg, preferably from about 25 to 150 mg. A suitable daily dose for a human can vary widely depending on the situation of the patient and other factors. However, a dose ranging from about 0.1 to 3000 mg / kg body weight, particularly from about 1 to 100 mg / kg body weight, may be appropriate. 400

The conjugate may also be administered by injection as a composition in which, for example, saline, dextrose or water solutions may be used as an appropriate vehicle. An appropriate daily dose ranges from about 0.1 to 100 mg / kg of the injected body weight per day in multiple doses depending on the disease to be treated. A preferred daily dose may range from about 1 to 30 mg / kg body weight. Conjugates indicated for prophylactic therapy will preferably be administered in a daily dose ranging generally from about 0.1 mg to about 100 mg per kilogram of body weight per day. A more preferred dosage will range from about 1 mg to about 100 mg per kilogram of body weight. Most preferred is a dosage ranging from about 1 to about 50 mg per kilogram of body weight per day. An appropriate dose may 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 dosage unit form. A more preferred dosage will contain from about 2 mg to about 50 mg of the active compound per dosage unit form. Most preferred is a dosage form containing from about 3 mg to about 25 mg of active compound per dosage unit. The dosage regimen for treating a disease condition with the conjugates and / or compositions of this invention is selected according to a number 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 used, thus exhibiting a very broad variation.

For therapeutic purposes, the conjugates of this invention are usually combined with one or more adjuvants suitable for the indicated route of administration. If administered per os. the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, alkyl esters of cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acid, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then compressed or encapsulated for convenient administration. Such capsules or tablets may contain a sustained release formulation as may be provided in a hydroxypropylmethylcellulose conjugate dispersion. 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 carriers or diluents mentioned for use in 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 solutions, and / or various solutions plug. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

While this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations. Various equivalents, variations and modifications may be made without departing from the spirit and scope of the present invention, and it should be understood that such equivalent embodiments are part of this invention.

Claims (23)

Claims 1-. A process for the preparation of a conjugate comprising a residue of a biphenylalkyl-1 H-substituted-1,2,4-triazole angiotensin II antagonist compound, wherein said conjugate is renal selective, especially a conjugate comprising a first and second residues, wherein the first and second residues are linked together by a cleavable bond, wherein said first residue is provided by a biphenyl-β-substituted-1-angiotensin II antagonist compound , 2,4-triazole, and wherein said second residue is capable of being cleaved from the selectivity of the first residue in the kidney, particularly a conjugate wherein said first and second residues are provided by precursor compounds, wherein the compound precursor of one of said first and second residues has a carboxylic acid moiety that can react and the precursor of the other of said first and second residues has a moiety amino group which may be reacted or a moiety convertible to an amino moiety that can react, whereby a cleavable bond may be formed between said carboxylic acid moiety and said amino moiety; characterized in that a reaction is carried out between the precursors of the first and second residues, wherein one of the precursors must contain a reactive acid moiety, and the other precursor must contain a reactive amino moiety, so as to obtain a conjugate having a cleavable bond, wherein any of the precursors of the first and second residues may contain such acidic or reactive amino moieties. 23. A process according to claim 1, wherein a conjugate wherein said compound is derived from an angiotensin II antagonist is selected from the class of compounds defined by Formula I: wherein m represents a number selected from one to four, inclusive; Wherein each of R to R 2 is independently selected from hydrogen, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl alkoxycarbonyloxy, alkylcarbonylalkyl, alkoxycarbonylalkyl, aralkyloxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylcarbonylthio, alkylcarbonylthio, alkylcarbonylthio, alkylcarbonylthio, alkylcarbonyloxyalkyl, , alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, 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 have one or more ring atoms selected from oxygen, sulfur and nitrogen, and wherein each of R 1 through R 11 may additionally be independently selected from amino and starch radicals of the formula: ???????? R 12 X ???????? R 14 ????? -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -NH- Wherein X represents an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R to R 2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R 1 and R 1 taken together, R 1 and R 1 taken together, R 1 and R 17 taken together, R 19 and R 2 taken together and R 5 and R taken together may form a heterocyclic group having five to seven ring members including nitrogen atom of said amino or amido radical and wherein the heterocyclic group may additionally contain one or more heteroatoms as ring members selected from 405,405 oxygen, nitrogen and sulfur and wherein the heterocyclic group may be saturated or partially unsaturated; wherein each of R and R13 taken together, R14 and R15 taken together, R120. 2122 and R taken together and R and R taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and wherein the heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; And wherein each of R to R may also be independently selected from hydrogen and haloalkyl, and from acidic moieties of the formula: -YnA wherein n is a number selected from zero to three, inclusive, and wherein A represents 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 represents 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 ; And wherein any of the aforementioned R, Y, and A groups having a substitutable position may be substituted by 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, 406 alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulphonyl, aralkylsulfinyl, aralkylsulphonyl, arylsulfinyl, arylsulphonyl, arylsulphonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen, and nitrogen or amide radicals of the formula: wherein X is selected from an oxygen atom and a compound of the formula: and sulfur atom; wherein each of R 1, R 2, R 2, R 2, R 2 is selected from hydrogen, alkyl, cycloalkyl, Cycloalkylalkyl, aralkyl, aryl, DR and R 31 wherein D is selected from an oxygen atom and a sulfur atom and R is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl ; wherein each of R25, R26, R27, R28, R29, R31 and R32 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl , arylsulfinyl, arylsulphonyl, haloalkylsulfinyl, haloalkylsulphonyl, aralkyl and aryl, and wherein each of R1, R2, R3, R4, R5 and R40 And is also independently selected from amino and starch radicals of the formula: ???????? R33 ????? ## STR3 ## wherein X is an oxygen atom or a sulfur atom; Wherein each of R 1, R 2, R 3, R 4, R 5, R 5 and R 7 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl , alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; wherein each of R 2 and R 3 taken together and each of R 2 and R taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical , wherein the heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur atoms and wherein the heterocyclic group may be saturated or partially unsaturated; wherein each of R and R taken together and each of R and R taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and wherein the heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; with the proviso that at least one of said substituents R 1 to R 2, and A contains a primary or secondary amino terminus or a moiety convertible to a primary or secondary amino terminus; 408 or a tautomer thereof or a pharmaceutically acceptable salt thereof; 3 â. A process according to Claim 2, characterized in that a conjugate is prepared in which m represents one; wherein each of R1 to 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 alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, alkylthiothiocarbonylthio, arylthio, arylthiocarbonylthio, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthioocandrbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylthiocarbonyl, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiothiocarbonyl, ar aralkylsulfonyl, arylsulfinyl, arylsulfonyl, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl, wherein each of said heteroaralkyl groups is optionally substituted with one or more substituents selected from halogen, containing heteroaryl and cycloheteroalkyl groups have one or more ring heteroatoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 to R11 may additionally be independently selected from amino and amido radicals of the formula: 409 R1 2 3 4 5 6 7 8 9 10 11 X R 12 / &quot; R 15 R 18 X R 19 X R 21 11 / &quot;## STR2 ## wherein R 1 is selected from the group consisting of: wherein R 1, R 2, R 3, R 4, wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; wherein each of R 10 through R 24 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; And wherein each of R 1 to R 2 may also be independently selected from hydrogen and haloalkyl, and from 4 acidic moieties of the formula: wherein n is a number selected from zero to 7 three, inclusive; and wherein A represents 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 in order to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; in which Y represents 410 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; 1 2 4 and wherein any of the aforementioned groups R to R, Y and A having a substitutable position may be substituted by one or more groups selected from alkyl, alkenyl, aralkyl, hydroxyalkyl, trifluoromethyl, difluoroalkyl alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercaptocarbonyl, alkylthio, alkylthiocarbonyl, and amino or amido radicals of the formula: ???????? wherein X is selected from an oxygen atom and a sulfur atom; wherein each of R¹, R², R², R² and R² is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and DR30 and R31 / -N wherein D is selected from an atom oxygen and a sulfur atom, and R 30 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R25, R26, R27, R28, R29, R31 and R32 is independently selected from hydrogen, alkyl, 411 cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R 1, R 2, R 3, R 4, R 5, R 4 and R 5 is also independently selected from amino and amido radicals of the formula: 33 X 35 X / -N II / II '37 -CN and -NC-R 34 R Wherein X is selected from an oxygen atom or a sulfur atom; wherein each of R through R is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; with the proviso that at least one of said 11 to R, Y and A substituents contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. 4a. A process according to Claim 3, characterized in that a conjugate in which m is one is prepared; wherein each of R1 to R11 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkoxycarbonyl, 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 cycloheteroalkylcarbonylalkyl groups, wherein each of said heteroaryl and cycloheteroalkyl containing groups has one or more ring-selected heteroatoms R 2 and R 2 are each independently selected from amino and amido radicals of the formula: wherein R 1 through R 11 are independently selected from amino and amido radicals of the formula: 13 XR &quot;## STR1 ## wherein R 1, R 2, R 3 and R 4 are independently selected from the group consisting of: and OCN .21 wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R1 to R2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; And wherein each of R to R may also be independently selected from hydrogen and haloalkyl, and from acidic moieties of the formula: wherein n is a number selected from zero to three, inclusive; wherein A is selected a. from a carboxylic acid and carboxylic acid bioisosters selected from: II-WH, -S-WH, II -S-WH, II-P-NH and -P-WH W -P-WH, R 41 WR 42 wherein each W is independently selected from one. . R 3, R 4, R 5 and R 6 are independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and isopropylsulfonyl; 39 40 41 42 aralkyl; wherein each of R 1, R 2, R 3 and R 4 may also be independently selected from an amino radical of the formula: Wherein each of R1 and R2 is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl. And wherein R and R taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, wherein the heterocyclic group may additionally contain one or more heteroatoms as members of ring selected from oxygen, nitrogen and sulfur atoms and wherein the heterocyclic group may be saturated or partially unsaturated; wherein R and R taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and wherein the aromatic heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from of oxygen, nitrogen and sulfur; wherein each of R3 and R4 may also be independently selected from hydroxy, alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and aralkoxy; and the amide, ester and salt derivatives of said acidic groups; wherein said carboxylic acid bioisostere may also be selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, wherein the ring contains at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, wherein said heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and wherein the heterocyclic ring may be attached at a single position selected from R to R or may be attached to any two adjacent positions selected from R 3 through R 11 so as to form a ring system condensed with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; 415 wherein Y represents a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; And wherein any of the above-referenced R, 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 or amido radicals of the formula: wherein X is selected from an oxygen atom and a sulfur atom; wherein each of R 1, R 2, R 3, R 2 and R 3 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl and DR and R 31 / -N wherein D is selected from oxygen atom and a sulfur atom, wherein R is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 25, R 26, R 27, R 28, R 29, R 31 and R 32 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl groups; with the proviso that at least one of said substituents R 1 to R 2, Y and A contains a primary or secondary ammo terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. . A process according to Claim 4, characterized in that a conjugate in which 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, alkylcarboxyl, alkoxycarbonyl , alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl groups, wherein each of said heteroaryl and cycloheteroalkyl containing groups have one or more ring heteroatoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 to R11 may additionally be independently selected from amino and amido radicals of the formula: ## STR1 ## 2 n "RR" 18 "_ 19 RXRX 1 &quot;## STR1 ## wherein X is selected from the group consisting of: wherein X is selected from the group consisting of: an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; wherein each of R 12 through R 24 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; Wherein each of R to R 1 is independently selected from hydrogen, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl cycloalkenyl, alkynyl, cycloalkyl, cyano, nitro, carboxyl, alkylthio, aralkylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulphonyl, arylsulfinyl, arylsulphonyl and heteroaryl groups having one or more ring atoms selected from oxygen, sulfur and nitrogen; And wherein each of R to R may also be independently selected from the acidic moieties of the formula: wherein η is a number selected from zero to three, inclusive; wherein A is selected from a carboxylic acid and carboxylic acid bioisosters selected from: -OH, -SH, -NHB, -NR39, -C-WH, -S-WH, Wherein each W is independently selected from an oxygen atom, a sulfur atom and NR, in each of R, R and R and independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aral-. 3 9 4 2 kg; wherein each of R 1 and R 2 may also be optionally selected from an amino radical of the formula: wherein each of R 3 and R 4 is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R and R taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, wherein the heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur atoms and wherein the heterocyclic group may be saturated or partially unsaturated; wherein R 44 and R 45 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and wherein the aromatic heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from of oxygen, nitrogen and sulfur; and the amide, ester and salt derivatives of said acidic groups; wherein said carboxylic acid bioisostere may also be selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, wherein the ring contains at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, wherein said heterocyclic ring may be saturated, fully unsaturated, or partially unsaturated, and wherein the heterocyclic ring may be attached at a single position selected from or may be attached to any two adjacent positions Are selected from R to R to form a ring system condensed with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y represents a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; and wherein each of R1 to R11, Y and A may be independently 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 aralkyl groups; with the proviso that at least one of said 1,2-R, R, Y and A substituents contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. 63. A process according to Claim 5, characterized in that a conjugate in which 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, phenalkoxy, phenylthio, phenalkylthio, aral alkoxycarbonyl, 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 ring heteroatoms selected from oxygen, sulfur and nitrogen, and wherein each of R1 to R3-1 may additionally be independently selected from amino and starch radicals of the formula: / R 2, R 2, R 2, R 2, R 2, R 2, R 2, R 3, R 4, Wherein X is selected from an oxygen atom or a sulfur atom; and wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; wherein each of R 12 through R 24 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl and phenyl; Wherein each of R to R 2 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkoxy, alkoxyalkyl, alkylcarbonyl alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio, mercapto and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; And wherein each of R to R may be an acidic moiety also independently selected from acyclic moieties of the formula: -Y n A 422 wherein n represents a number selected from zero to two, inclusive; and wherein A is selected from a carboxylic acid and carboxylic acid bioisosters selected from: -NR 39, -C-WH, -S-WH, -S-WH II wherein each W is independently selected from oxygen, sulfur and NR , in each of 394243, R1, R2 and R3 are independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benzyl; wherein each of R3 and R4 may also be independently selected from an amino radical of the formula: wherein each of R3 and R4 is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, benzyl and phenyl; and the amide, ester and salt derivatives of said acidic groups; wherein said carboxylic acid bioisostere may also be selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, wherein the ring contains at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, wherein said heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and wherein the heterocyclic ring may be attached at a single position selected from 3 '. . R to R or may be attached to any two adjacent positions. 3 - 11 are selected from R to R so as to form a ring system fused to one of the phenyl rings of the biphenyl moiety of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y represents a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenalkyl and aralkyl; and wherein each of R1 to R3, Y and A may be independently 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; with the proviso that at least one of said R 1 substituents to R 1, Y and A contains a primary or secondary amino terminus or a moiety convertible to a primary or secondary amino terminus; or a tautomer or a pharmaceutically acceptable salt thereof. 7a. A process according to Claim 6, characterized in that a conjugate in which m is ura; 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, aralkylcarbonyloxyalkyl, aralkylcarbonyloxyalkyl, phthalimido, phthalimidoalkyl, tetrazole, tetrazolealkyl, alkylthio, cycloalkylthio, and radicals amino and amido groups of the formula: ???????? R12 ???????? R14 ????? R15 - * CH2 CH2 - R17 R18 X R19 X R21 R23 X &quot; (CH 2) n-2 &quot; N-C-N, N-20 &quot; And wherein X is selected from an oxygen atom or a sulfur atom; and wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R to R1 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl and phenyl; Wherein each of R 1 to R 2 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkoxy, alkoxyalkyl, acetyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; 425 And wherein each of R 1 to R 2 may be an acidic moiety also independently selected from acylic moieties consisting of CO 2 H, CH 2 CH 2, SH, CH 2 SH, CH 3 CH 2, CH 3 CH 2, CH 2 CH 3, CH 2 CH 2 CH 3, so3h, conhnh2, conhnhso2cf3 / conhoch3, CONHOC2H5, conhcf3, oh, ch2oh, c2h4oh, opo3h2, oso3h, wherein each of R 46, R 47 and R 47 is independently selected from H, Cl, CN, NO 2, CF 3, C 2 F 5, CH 3 F 7, CH 2 CH 2, CH 2 CH 3, C 2 H 2 '5' SO 2 CH 3, SO 2 CF 3 and SO 2 C 6 F 5; wherein Z is selected from O, S, NR, and CH 2; wherein R 1 is selected from hydrogen, CH 2 and m wherein said acidic moiety may be an heterocyclic acidic group attached to any two adjacent positions selected from R 1 to R 2 in order to form a ring which includes one of the phenyl rings of the biphenyl moiety of Formula I, said biphenyl condensed ring system being selected from and the amide, ester and salt derivatives of said acidic moieties; with the proviso that at least one of said R 1 to R 2 substituents contains a primary or secondary amino terminal moiety or a moiety convertible at a primary or secondary amino terminus; or a tautomer or a pharmaceutically acceptable salt thereof. A process according to claim 7, characterized in that a conjugate in which m is one; wherein each of R 1 and R 2 is independently selected from amino, aminomethyl, aminoethyl, aminopropyl, CH 2 OH, CH 2 OCOCH 3, CH 2 C 1, Cl, CH 2 OCH (CH 3) 2, I, CH 2, CH 2 CO 2 h, CH (CH 3) CO 2 h, , C H, -CH 2 OCOCH 2 CH 2 -CO2CH3, -CONH2, -CONHCH3, CON (CH3) 2 ' -OC 2 NHCON 2 C 2 H 5. -CH 2 NHC 2 H 3, -CH 2 NHC 2 CH 3, -CH 2 NHC 2 CH 3, -CH 2 NHC 2 CH 3 (CH 3) 2, -CH 2 NHC H 2 C 4 H 9, -CH 2 NHC 2 O-adamantyl, -CH 2 NHC 2 - (1-naphthyl), -CH 2 NHCONHCH 3, -CH 2 NHCONHC H 2, -CH 2 NHCH 3 CH 3, - CH 2 NHCONH (1-adamantyl), -CH 2 CH 2 -CH 2 CH 2 -CO 2 NCH 2 CO 2 -NH 2, -CH 2 CH 2 CH 2 CO 2 H, -CH 2 CH 2 F, - CH 2 CH 2 CH 3, -CH 2 CH 3 CH 3, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 F 2, -CH 2 CH 2 F, -CH 2 CH 2 F, -CH 2 CH 2 -, -CH 2 -, -CH 2 - (O &gt;, CH 2 Cl, NO 2, CF 3, CH 2 OH, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl , 428 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 3 11 1,1-difluoropentyl; and wherein each of R 1 to R 2 and R 5 is hydrogen, with the proviso that at least one of R 1, R 2, R 3 and R 4 represents an acidic group selected from CO 2, SH, PO 3, SO 3, conhnh2, conhnhso2cf3, OH, H | Wherein each of R and R is independently selected from Cl, CN, NO 2, CF 3 'CO 2 CH 3 and SO 2 CF 3; with the proviso that at least one of said R1 to R11 substituents contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. 93. A process according to Claim 8, characterized in that a conjugate in which 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, 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, 429 1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein R is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n -pentyl and neopentyl; wherein each of R 3, R 4, R 6, R 7, R 5 and R 7 is hydrogen; in one of RS and R 9 represents hydrogen and the other of R 1 and R 2 represents an acidic group selected from CO 2 H, SH, P 3 H 2 'SO 3 H / CONHNH 2, CONHNHSO 2 CF 3, OH, Wherein each of R1 and R2 is independently selected from Cl, CN, NO2, CF3, CO2 CH2, and SO2 CF3; with the proviso that at least one of said R 1 to R 3 substituents contains a primary or secondary amino terminus or a moiety convertible to a primary or secondary amino terminus; or a tautomer or a pharmaceutically acceptable salt thereof. loa A process according to Claim 1, characterized in that a conjugate is prepared wherein said second residue forms an enzymatically cleavable amide bond of the kidney with the residue of said angiotensin II antagonist compound. according to Claim 1, characterized in that a conjugate is prepared in which said second residue is provided by a compound of Formula II: 1a. Process of the C-G / 50 GCCH_CH_CH R Γ 2β 2α / N (II) Wherein each of R and R may be independently selected from hydrogen, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein G is selected from hydroxy, halo, mercapto, -OR, -SR, and wherein each of R1, R2 and R3 is independently selected from hydrogen and ; with the proviso that said compound of Formula II is selected such that formation of a cleavable amide bond occurs at the carbonyl portion attached to the carbon of the gamma position of said compound of Formula II. A process according to Claim 11, characterized in that a conjugate in which each substituent G is hydroxy is prepared. 13. A process according to Claim 12, characterized in that a conjugate is prepared wherein each R5 and R6 substituent is hydroxy; wherein R is hydrogen; selected from O -CR55 55. wherein R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and chloromethyl. 14 a. A process according to Claim 13, characterized in that a conjugate is prepared in which said second residue is: 15a. A process according to Claim 1, characterized in that a conjugate is prepared in which said first residue is a biphenylalkyl-1 H-substituted-1,2,4-triazole angiotensin II antagonist compound containing a primary or secondary amino terminal portion selected from amino and linear or branched aminoalkyl moieties containing linear or branched alkyl groups selected from aminomethyl, aminoethyl, aminopropyl, amino-isopropyl, amino-butyl, amino-sec -butyl, amino-isobutyl, amino- butyl, aminopentyl, amino-isopentyl and amino-neopentyl. A compound according to Claim 1, characterized in that a conjugate is prepared wherein said first residue is provided by a 432 antagonist compound angiotensin II of biphenylalkyl-1 H-substituted 1,2,4-triazole containing a moiety convertible to a primary or secondary amino terminal portion. 17a. A process according to Claim 16, characterized in that a conjugate is prepared in which said moiety which can be converted to an amino terminal portion is a carboxylic acid group which may react with an amino moiety of a diamino terminated linker group in order to providing an amino terminal portion which can then be further reacted with a carboxylic acid moiety of a compound providing said second residue so as to form a hydrolysable amide bond. A process according to Claim 17, characterized in that a conjugate is prepared wherein said diamino terminated linker is a divalent radical of Formula III: â € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ- between R200 and R201 may be independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, haloalkyl, amino, monoalkylamino, dialkylamino, cyanoamino, carboxyalkyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl groups; and wherein n is zero or a number selected from three to seven inclusive. 433 A process according to Claim 18, characterized in that a conjugate is prepared wherein each of R200 and R201 represents hydrogen. 20 ^. A process according to Claim 17, characterized in that a conjugate is prepared wherein said diamino terminated linker group is a divalent radical of Formula IV: wherein each of Q and T represents one or more groups independently selected from wherein each of R3 to R4 may be independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl groups. 2a. A process according to Claim 20, characterized in that a conjugate is prepared wherein said diamino terminated linker group is a divalent radical of Formula V: Wherein each of R and R is independently selected from hydrogen, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxy, carboxy alkyl and alkanoyl; and wherein each of p and q represents a number independently selected from one to six, inclusive; with the proviso that when each of R and R3 is selected from halo, hydroxy, amino, monoalkylamino and dialkylamino, then the carbon to which R or R is attached in Formula V is not adjacent to an atom of nitrogen of Formula V. 22a. A process according to Claim 21, characterized in that a conjugate is prepared wherein each of R¹ and R² is independently selected from hydrogen, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q represents a number independently selected from two to four, inclusive. 435 233. A process according to claim 22, wherein a conjugate wherein each of R 20 and R 20 is independently selected from hydrogen, amino, monoalkylamino and carboxy; and wherein each of p and q represents a number independently selected from the two and three numbers. 24a. A process according to Claim 23, characterized in that a conjugate is prepared wherein each of R3 and R4 is hydrogen; and wherein each of p and q represents two. 25â. A process according to Claim 17, characterized in that a conjugate is prepared wherein said diamino terminated linker group is a divalent radical of Formula VI: Wherein each of R1 to R3 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, aryl, haloalkyl, amino, monoalkylamino, dialkylamino, cyanoamino , carboxyalkyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; and wherein p represents a number selected from one to six inclusive. 26. A process according to Claim 25, characterized in that a conjugate is prepared in which each of 436 Wherein R1 and R2 represent hydrogen; wherein each of R 2 and R 2 is independently selected from hydrogen, alkyl, phenalkyl, phenyl, alkoxyalkyl, hydroxyalkyl, haloalkyl and carboxyalkyl; and wherein p represents two or three. 27a. A process according to Claim 26, characterized in that a conjugate is prepared wherein each of R 1 and R 2 represents hydrogen; wherein each of R 2 and R 2 is independently selected from hydrogen and alkyl; and wherein p represents two. 28 ^. A process according to Claim 27, characterized in that a conjugate is prepared in which each of 2X4 2X5 2X6 2X7 between R1, R2, R3 and R8 represents hydrogen; and wherein p represents two. 29ã. A process according to Claim 9 for preparing a conjugate wherein said angiotensin II antagonist compound is selected from the group consisting of: 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; 437 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-butyryl-sec-butyl-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-tert-butyl-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-butyryl-3-cyclohexyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-But-1-3-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; 438 4 '- [(5-Butyl-3-cyclohexanoyl-1H-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-1H-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- -amide; 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; 439 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; λ 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] (Ι, Ι'-biphenyl] -2-carboxylic acid; , 4 '- [(3,5-di-isopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] sec-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid 4 '- ((3,5-diisobutyl-1H 4 '- [(3,5-di-tert-butyl-1H-1,2,4-triazol-1-yl) methyl] -1,1,4- 2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid 440 4 '- [(3,5-di-pentyl-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] 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-butyryl-3-aminoethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] tetrazole; 5- [4 '- [(5-butyryl-3-aminopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] tetrazole; 5- [4 '- [(5-butyryl-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] B] phenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-butyl-5- (4-aminomethylphenylmethyl) -1 H -1,2,4-triazol-1- methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 - [[(3-Butyl-5- (4-aminomethylphenyl) 5- [4 '- [[(3-butyl-5- (4-aminoethylphenyl) -1H-benzofuran- -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] (4-aminocyclohexylethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl- -biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-but-5- (4-aminomethylcyclohexyl) 1 H -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 (4-aminoethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] -1- [4 '- [ biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [(5-Butyl-3-carboxy-1H-1,2,4-triazol-1-yl) methyl] [1 , 4 '- [(5-butyl-3-carboxymethyl-1H-1,2,4-triazol-1-yl) methyl] - [ 5 - [4 - [(5-Butyl-3-carboxyethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2H-tetrazole; 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-butyryl-3-carboxybutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2H] -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] 5 - [4 '- [[(3-butyl-5- (4-carboxymethylphenylmethyl) -1H-1,2,4-triazol-1-yl) -1H-tetrazole; 5 - [4 '- [[(3-butyl-5- (4-carboxymethylphenyl) -1H-1,2,3-thiadiazolyl] 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- 4-carboxycyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; (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-but-5- (4-carboxyethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl ] [1,1'-biphenyl] -2-yl] -1H-tetrazole A process according to Claim 19, characterized in that a conjugate is prepared which is 5 - [[4 '- [ 5-dibutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] carbonyl-hydrazide. according to Claim 15, characterized in that a conjugate which is N-acetyl-N - [[5-butyl] -1 - [[2 '- (1H-tetrazol-5-yl) [1,17- -biphenyl] -4-yl] methyl] -1H-1,2,4-triazol-3-yl] methyl] -L-glutamine A process according to claim 19, which is 5- [5-butyl-1 - [[2 '- (1H-tetrazol-5-yl) [1,1'-biphenyl] -4-yl] methyl] -1H-1,2,4 -tri-azol-3-yl] acetylhydrazide of N-acetyl-L-glutamic acid. A process for the preparation of a pharmaceutical composition, characterized in that one or more pharmaceutically acceptable carriers or diluents are included in said pharmaceutical composition and a therapeutically effective amount is a renal selective conjugate, wherein said conjugate comprises a residue of a angiotensin II of bife-nylalkyl-1H-substituted-1,2,4-triazole, wherein said conjugate is renal selective, especially a conjugate comprising a first and a second residue, wherein the first and 444 444 second residues are linked together by a cleavable bond, wherein said first residue is provided by a biphenylalkyl-1H-substituted-1,2,4-triazole angiotensin II antagonist compound, and wherein said the second residue is capable of being cleaved from the selectivity of the first residue in the kidney, particularly a conjugate 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 portion reactable carboxylic acid and the precursor of the other of said first and second residues has an amino moiety that can react or a moiety convertible to an amino moiety that can react, whereby a cleavable bond may be formed between said carboxylic acid moiety and said amino moiety. 34a. A process according to Claim 33, characterized in that a composition is prepared wherein said angiotensin II antagonist compound is selected from a class of compounds defined by Formula I: four, inclusive; wherein each of R 1 through R 11 is independently selected from hydrogen, alkyl, hydroxyalkyl, halo, Cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkyloxycarbonylalkyl, alkoxycarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylthiocarbonyl, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, aralkylthiothiocarbonyl, aralkylthiothiocarbonylthio, mercapto, alkylsulfinyl, alkylsulphonyl, aralkylsulfinyl, arylthiothiocarbonyl, aralkylthiothiocarbonyl, aralkylthiothiocarbonyl, aralkylthiothiocarbonyl, aralkylthiothiocarbonyl, arylsulfonyl, arylsulfonyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, and cycloheteroalkylcarbonylalkyl groups, wherein each of said heteroaryl and cyclohetero-containing groups has one or more ring moieties selected from oxygen, sulfur and nitrogen atoms, and wherein each of R 1 through R 11 may additionally be independently selected from amino and amido radicals of the formula: and R 12 X R 14 X / -CH 2 -CH 2 -R 2 N 1 R 18 X R 19 X R 21 B 23 X 1 &quot; / &quot; / 1 &quot; -CH2-N-C-N, V ° -CH2-OCN and -R22 -tCH2 + n-COR wherein X represents an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R to R 2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein R 12 and R 13 taken together are R 16 and R 17 taken together, R 19 and R 20 taken together and R 2 and R 3 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and wherein the heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur atoms and wherein the the heterocyclic group may be saturated or partially unsaturated; wherein each of R 13 and R 21 taken together, R 2 and R 3 taken together, R 20 2122 and R taken together and R 5 and R taken together may form an aromatic heterocyclic group having five ring members including nitrogen atom of said amino or amido radical and wherein the heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; And wherein each of R to R may also be independently selected from hydrogen and haloalkyl, and from acidic moieties of the formula: -YnA 447 wherein n represents a number selected from zero to three inclusive, and wherein A represents 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 represents 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; And wherein any of the aforementioned groups R to R, Y and A having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, trifluoromethyl cycloalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, alkylthio, alkylthiocarbonyl, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, arylsulfinyl, arylsulfinyl, arylsulphonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino or starch radicals of the formula: ???????? - Wherein X is selected from an oxygen atom and a sulfur atom; wherein each of R 1, R 2, R 3, R 4 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and DR wherein D is selected from an oxygen atom and a sulfur atom and R 30 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 25, R 26, R 27, R 28, R 29, R 29 and R 32 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxy, alkylsulfinyl, alkylsulphonyl, arylsulfinyl, arylsulphonyl, haloalkylsulfinyl, haloalkylsulphonyl, aralkyl and aryl, and wherein each of R1, R2, R3, R4, R4, R3 and R4 are the same. R 2 is also independently selected from amino and amido radicals of the formula: and -NC-R -N .33 .34 XR &quot; Wherein X is an oxygen atom or a sulfur atom; wherein each of R33, R34, R3, R36, R37 and R38 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; wherein each of R² and R² taken together and each of R² and R² taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido , wherein the heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur atoms and wherein the heterocyclic group may be saturated or partially unsaturated; wherein each of R 26 and R 27 taken together and each of R 5 and R taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and wherein the heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; with the proviso that at least one of said substituents up to R, Y and A contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer thereof or a pharmaceutically acceptable salt thereof; 35â. A process according to Claim 34, characterized in that a composition is prepared in which m represents one; wherein each of R1 to R1 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, 450 arylthiocarbonyl, arylcarbonylthio, ariltiocarboniloxi, arylthio- carboniltio, ariltiotiocarbonilo, ariltiotiocarboniltio, aral- alkylthio, aralquiltiocarbonilo, aralquilcarboniltio, aralquiltio- carbonyloxy, aralquiltiocarboniltio, aralquiltiotiocarbonilo, aralquiltiotiocarboniltio, mercapto, alkylthio, alquilsul- fonilo, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, ftalimidoalquilo, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl, wherein each of said heteroaryl and cycloheteroalkyl containing groups has one or more ring heteroatoms selected from oxygen atoms, Sulfur and nitrogen, and wherein each of R to R may additionally be independently selected from amino and starch radicals of the formula: ???????? R 12 -N 2 n -fCH 2 n. 13 XR &quot; / CN: R 16, R 16, R 16, R 16, Wherein X is selected from an oxygen atom or a sulfur atom; and wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; 12 R244. wherein each of R is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; And wherein each of R to R may also be independently selected from hydrogen and haloalkyl, and from acidic moieties of the formula: wherein n is a number selected from zero to three, inclusive ; and wherein A represents 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 so as to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y represents 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 ; Any of the aforementioned groups R to R, Y and A having a substitutable position may be substituted by one or more groups selected from alkyl, alkenyl, aralkyl, hydroxyalkyl, trifluoromethyl, difluoroalkyl alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercaptocarbonyl, alkylthio, alkylthiocarbonyl, and amino or amido radicals of the formula: Wherein X is selected from an oxygen atom and a sulfur atom; wherein each of R25, R26, R27, R28 and R29 is selected from hydrogen, alkyl, cycloalkyl, • cycloalkylalkyl, aralkyl, aryl, and DR and R31 / -N3 wherein D is selected from from an oxygen atom and a sulfur atom, and R is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R25, R26, R27, R28, R29, R31 and R32 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R25, R26, R27, R28, R29, R31 and R32 is also independently selected from amino and amido radicals of the formula: and -NC- N.333.34 XR &quot; Wherein X is selected from an oxygen atom or a sulfur atom; wherein each of R through R is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; with the proviso that at least one of said substituents R 1 to R 2, Y and A contains a primary or secondary amino terminus or a moiety convertible to a primary or secondary amino terminus; or a tautomer or a pharmaceutically acceptable salt thereof. 36a. A process according to Claim 35, characterized in that a composition is prepared in which m represents one; wherein each of R1 to 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 cycloheteroalkylcarbonylalkyl groups, wherein each of said heteroaryl and cycloheteroalkyl-containing groups has a or more selected ring heteroatoms those from oxygen, sulfur and nitrogen atoms, and wherein each of R to R may additionally be independently selected from amino and amido radicals of the formula: R 12 X R 14 - * CH 2h; / N V3 f &quot; / Η -CH CN R15 R18 X R19 X R21 - + CH2 h5 1 &quot; N-C-N, V ° &quot; -OCH2-, -CH2-, -CH2-, -CH2-, -CH2-, -CH2-, -CH2-, -CH2- a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R to R 2 'is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; And wherein each of R to R may also be independently selected from hydrogen and haloalkyl, and from acidic moieties of the formula: wherein n is a number selected from zero to three, inclusive; wherein A is selected from a carboxylic acid and carboxylic acid bioisosters selected from: 455 -OH, -SH, NR, W-I -C-WH, -S-WH, w-1-WH, 1-W-WH, I-W-P-NH and -P-WH .41 wherein each W is independently selected from an oxygen atom, a sulfur atom and NR 43 in each of R 39 and R 40 is independently selected from R 1, R 2, R 2, R 2, R 3 and R 4 independently of one another is selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and 9 aralkyl; wherein each of R 1, R 1 and R 1 may also be independently selected from an amino radical of the formula: Wherein each of R1 and R2 is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl. And wherein R and R taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, wherein the heterocyclic group may additionally contain one or more heteroatoms as members of ring selected from oxygen, nitrogen and sulfur atoms and wherein the heterocyclic group may be saturated or partially unsaturated; wherein R and R taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and wherein the aromatic heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from of oxygen, nitrogen and sulfur; in 456 which each of R 40 and R 41 may also be independently selected from hydroxy, alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and aralkoxy; and the amide, ester and salt derivatives of said acidic groups; wherein said carboxylic acid bioisostere may also be selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, wherein the ring contains at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, wherein said heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and wherein the heterocyclic ring may be attached at a single position selected from 3 ', R 1 to R 2 or may be attached to any two adjacent positions selected from R to R so as to form a ring system fused to one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y represents a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; 1, 24 and wherein any of the above-referenced R, 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 or amido radicals of the formula: Wherein X is selected from an oxygen atom and a .25.26 .27.28 sulfur atom; wherein each of R 29 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl and DR wherein D is selected from an oxygen atom and a The sulfur atom, wherein R is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; ,  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ25, 27, 28, 29, 31, 32, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl groups; with the proviso that at least one of said substituents 1-24. . . -. R 2 to R 3, Y and A contain a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. 458 37ã. A process according to Claim 36, characterized in that a composition is prepared wherein m is 12 μm; wherein each of R and R 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, alkylsulfinyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl groups, wherein each of said heteroaryl and cycloheteroalkyl containing groups have one or more ring heteroatoms selected from oxygen, sulfur and nitrogen, and wherein each of R 1 through R 11 may additionally be independently selected from amino and amido radicals of the formula: ???????? R 2 ????? / CNV * x * - (- CH 4 - NC-R 2 n-117 16 R 18 X 19 -tCH 2 N-C-N -CH 2 n .20 XR &quot; wherein X is selected from an oxygen atom or a sulfur atom; χ 459 wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R1 to R3 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; Wherein each of R1 to R3 is independently selected from hydrogen, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl alkenyl, cycloalkenyl, alkynyl, cycloalkyl, cyano, nitro, carboxyl, alkylthio, aralkylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulphonyl, arylsulfinyl, arylsulphonyl and heteroaryl groups having one or more ring atoms selected from of oxygen, sulfur and nitrogen atoms; And wherein each of R to R may also be independently selected from acidic moieties of the formula: -YnA wherein n represents a number selected from zero to three, inclusive; wherein A is selected from a carboxylic acid and carboxylic acid bioisosters selected from: HW W W | II -OH, -SH, -NR 39, -C-WH, -S-WH, -S-WH and -P-WH W wherein each W is independently selected from an oxygen atom , a sulfur atom and NR 39 in each of R 2, R 3 and R 4 is independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aryl; 2 kg; wherein each of R 1 and R 2 may also be optionally selected from an amino radical of the formula: wherein each of R 1 and R 2 is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R and R taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, wherein the heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur atoms and wherein the heterocyclic group may be saturated or partially unsaturated; wherein R and R taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and wherein the aromatic heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from of oxygen, nitrogen and sulfur; and the amide, ester and salt derivatives of said acidic groups; wherein said carboxylic acid bioisostere may also be selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, wherein the ring contains at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, wherein said heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and wherein the heterocyclic ring may be attached at a single position selected from 311 ·. R to R or may be attached to any two adjacent positions selected from R to R so as to form a ring system condensed with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y represents a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; may be substitutable with alkyl, cyclo-trifluoromethyl, alkylsulfonyl, aryloxy and aral- and wherein each of R1 to R11, Y and A independently are independently in any position one or more groups selected from alkyl, cycloalkylalkyl, hydroxy, oxo, difluoroalkyl, alkoxycarbonyl, cyano, nitro, haloalkylsulfonyl, aryl, aralkyl, alkoxy, coxy; with the proviso that at least one of said substituents R 1 to R 2, Y and A contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminus; or a tautomer or a pharmaceutically acceptable salt thereof. 38. A composition according to Claim 37, characterized in that a composition is prepared wherein m is 12 μm; wherein each of R1 and R2 is independently 462 selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, benzoyl, phenoxy, phenoxyalkyl, phenalkoxy, phenylthio, phenalkylthio, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl alkoxycarbonylalkyl, aralkyloxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, phthalimido, phthalimidoxyalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloalkyl, cycloalkylthio, cycloalkylthio, -heteroalkylalkyl and cycloheteroalkylcarbonylalkyl, wherein each of said heteroaryl and cycloheteroalkyl containing groups has one or more ring heteroatoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 to R11 may additionally be independently selected from amino radicals and of the formula: R 12 X R 14 X / &quot;## STR2 ## wherein R 1 is hydrogen, R17 R18 X R19 X R21 R23 X 1 &quot; / &quot; / 1 &quot; N-C-N, NR 20 OCN and 2 n R 22 -N-COR 2 n wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; wherein each of R3 and R3 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl and phenyl; wherein each of R 3 through R 11 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl alkenyl, cyano, nitro, carboxyl, alkylthio, mercapto and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; and wherein each of R 3 through R 4 may be an acidic moiety also independently selected from acyclic moieties of the formula: wherein n represents a number selected from zero to two, inclusive; and wherein A is selected from a carboxylic acid and carboxylic acid bioisosters selected from: wherein R 1 is selected from a carboxylic acid and carboxylic acid bioisosters selected from: Wherein each W is independently selected from an oxygen atom, a sulfur atom and NR, in each of R1, R2, R3 and R4 is selected from the group consisting of hydrogen, and independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benzyl; wherein each of R 39 and R 41 may also independently be from an amino radical of the formula: wherein each of R 1 and R 2 is independently selected from hydrogen, , cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, benzyl and phenyl; and the amide, ester and salt derivatives of said acidic groups; wherein said carboxylic acid bioisostere may also be selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, wherein the ring contains at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, wherein said heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and wherein the heterocyclic ring may be attached at a single position selected from 3 '. . R 2 to R 2 may be attached to any two adjacent positions. Are selected from R to R so as to form a ring system condensed 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; wherein Y represents a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenalkyl and aralkyl; And wherein each of R to R, Y and A may be independently 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; with the proviso that at least one of said substituents R 1 to R 2, Y and A contains a primary or secondary ammo terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. 39a. A process according to Claim 38, characterized in that a composition is prepared wherein m is 12 μm; 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 alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, phthalimido, phthalimidoalkyl, tetrazole, tetrazolealkyl, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, alkylthio, , cycloalkylthio, and amino and amido radicals of the formula: ???????? N 2 -fCH 2 ???????? R 13 X R 14 &quot; / CNN * X II - (-CH NC-R 2 n, J 17, R 18 X 19 - 19 - N - COR 2 n 22 Wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; cycloalkyl, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl, and phenyl; R 2 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl and phenyl; Wherein each of R to R 2 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkoxy, alkoxyalkyl, acetyl alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein each of R 3 through R 11 may be an acidic moiety also independently selected from acylic moieties consisting of CO 2 H, NH 2 SO 3 CF 3, SO 3 H, CO 2 CH 3, CONHNH SH, CH 2 SH, CH 2 SH 4, P03 H 2 ' -CONHNHSO2CF3, CONHOCH CONHOCHc, CONHCF-, OH, CH_OH, CΗΗΟΗΟΗ, OPOHH,, OSOHH, 25 3 2 '467 467 Wherein each of R¹, R² and R² is independently selected from H, Cl, CN, NO₂, CF,, C₂F,, CF5H ^, CHF₂, CH₂F, CO₂CH,, CO₂C₂H,, SO₂CH,, CF3 and SC2C4; wherein Z is selected from O, S, NR and CH 2; wherein R49 is selected from hydrogen, CH3 and CH2 CgH5; and wherein said acidic moiety may be an acidic heterocyclic group attached to any two adjacent positions selected from R to R so as to form a fused ring system which includes one of the phenyl rings of the biphenyl moiety of Formula I , said biphenyl condensed ring system being selected from and the amide, ester and salt derivatives of said acidic moieties; with the proviso that at least one of said κ substituents even contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. 40a. A process according to Claim 39, characterized in that a composition is prepared in which m represents 12 μm; wherein each of R1 and R2 is independently selected from amino, aminomethyl, aminoethyl, aminopropyl, 469 -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CO 2 H, CH (CH 3) CO 2 H, νο 2, Cl, I Η / -CH 2 OCOCH 2 CH a -CO 2 CH 3. -CH 2 NHC 2 CH 3, -CH 2 NHCH 2 CH 3, -CH 2 NHC 2 CH 2 (CH 3) 2, -CH 2 NHC 2 C 4 H 9, -CH 2 NHC 2 O-adamantyl, - CH 2 NHCONHC 3 H 7, -CH 2 NHCONHC 4 Hg, -CH 2 NHCONHCH (CH 3) 2, -CH 2 NHCONH (1-naphthyl), -CH 2 NHCONH (1-adamantyl), CO H, -CH 2 CH 2 -CO CH 2 CH 2 CO 2 H, -CH 2 CH 2 F, -CH 2 OCONHCH 3, -CH 2 OCSHCH 3, -CH 2 NHCSOC 3 H 7, -CH 2 CH 2 CH 2 F, -CH 2 ONO 2, -CH 2 CH 2 CH 2, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-propyl, n-butyl, n-butyl, n- phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl, 1-oxopentyl, 1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, halo, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl, and 1,1-difluoropentyl; and wherein each of R 1 to R 2 is hydrogen, with the proviso that at least one of R 4, 470 R 9 and R 8 represent an acidic group selected from CO 2 H, SH, CO 3 H 2, SO 3 H, CONHNH 2, COOHNHSO 2 CF 3, OH, Wherein each of R¹ and R² is independently selected from Cl, CN, NO₂, CF & &, co2ch3 and so2cf3; with the proviso that at least one of said R1 to R11 substituents contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. 41 *. A process according to Claim 40, characterized in that a composition is prepared wherein m represents one; wherein R 1 is selected from amino, aminomethyl, aminoethyl, aminopropyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxo-pentyl, 1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1- pentyl, hydroxyalkyl, halo, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein R is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl and neopentyl; wherein each of R 1, R 4, R 5, R 8, R 9 and R 9 are hydrogen; in one of R1 and R2 is 471 Hydrogen and the other of R 1 and R 2 represents an acidic group selected from CC> 2H, SH, P03H2 'SO3H' CONHNH2, CONH2 SO3, OH, Wherein each of R¹ and R² is independently selected from Cl, CN, NO₂, CF,, CO₂CH e and SO₂CF;; with the proviso that at least one of said R¹ to R contem substituents contains a primary or secondary ammo terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. 42. A process according to Claim 41, characterized in that a composition is prepared wherein said second residue forms an enzymatically cleavable amide bond of the kidney to the residue of said angiotensin II antagonist compound. 433. A process according to Claim 33, characterized in that a composition is prepared wherein said second residue is provided by a compound of Formula II: The C-G (II) GC 50 CH 2 CH 2 -CH Wherein each of R and R may be independently selected from hydrogen, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein G is selected from hydroxyl, halo, mercapto, -OR, -SR and / or wherein each of R1, R2 and R3 is independently selected from hydrogen and alkyl; with the proviso that said compound of Formula II is selected such that formation of a cleavable amide bond occurs at the carbonyl portion attached to the carbon of the gamma position of said compound of Formula II. 44 *. A process according to Claim 43, characterized in that a composition is prepared wherein each substituent G is hydroxy. 45 *. A process according to Claim 44, characterized in that a composition is prepared wherein each substituent G is hydroxy; wherein R 50 is hydrogen; and wherein R 51 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl , n-hexyl and chloromethyl. 463. A process according to Claim 45, characterized in that a composition is prepared wherein said second residue is: 3 O 47. A process according to Claim 33 for preparing a composition wherein said first residue is a biphenylalkyl-1 H-substituted-1,2,4-triazole angiotensin II antagonist compound containing a primary amino terminal portion or amino groups selected from amino and linear or branched aminoalkyl moieties containing linear or branched alkyl groups selected from aminomethyl, aminoethyl, aminopropyl, amino-isopropyl, amino-butyl, amino-sec-butyl, amino-isobutyl, tert-butyl, aminopentyl, amino-isopentyl and amino-neopentyl. 483. A process according to claim 33 for preparing a composition wherein said first residue is provided by a biphenylalkyl-1 H-substituted 1,2,4-triazole angiotensin II antagonist compound containing a convertible moiety in a primary or secondary amino terminal portion. 474 49â. A process according to Claim 48, characterized in that a composition is prepared in which said portion which can be converted to an amino terminal portion is a carboxylic acid group which may react with an amino moiety of a diamino terminated linker group in order to providing an amino terminal portion which can then be further reacted with a carboxylic acid moiety of a compound providing said second residue so as to form a hydrolysable amide bond. 50à. A process according to Claim 49, characterized in that a composition is prepared in which said diamino terminated linker group is a divalent radical of Formula III: wherein R 1, R 2, R 3, R 4, wherein each of R200 and R201 may be independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, haloalkyl, amino, monoalkylamino, dialkylamino, cyanoamino, carboxyalkyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl and wherein n is zero or a number selected from three to seven, inclusive. A process according to Claim 50, characterized in that a composition is prepared wherein each of R200 and R201 represents hydrogen. The composition of Claim 49, wherein said composition is a compound of the formula: diamino terminated linker group is a divalent radical of Formula IV: -N (TV) J wherein each of Q and T represents one or more groups independently selected from each of R¹ to R² can be independently cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl. 53a. A process according to Claim 52, characterized in that a composition is prepared wherein said diamino terminated linker group is a divalent radical of Formula V: wherein each of R1 and R2 is independently selected from hydrogen, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q represents a number independently selected from one to six, inclusive; with the proviso that when each of R3 and R3 is selected from halo, hydroxy, amino, monoal-. ·. . And the dialkylamino, then the carbon to which R or R is attached in Formula V is not adjacent to a nitrogen atom of Formula V. 54a. A process according to Claim 53, characterized in that a composition is prepared wherein each of R1 and R2 is independently selected from hydrogen, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q represents a number independently selected from two to four, inclusive. 55 *. A process according to Claim 54, characterized in that a composition is prepared wherein each of R and R is independently selected from hydrogen, amino, monoalkylamino and carboxy; and wherein each of p and q represents a number independently selected from the two and three numbers. 56a. A process according to Claim 55, characterized in that a composition is prepared wherein each of R 202 and R 203 represents hydrogen; and wherein each of p and q represents two. 57a. A process according to Claim 49, characterized in that a composition is prepared in which said diamino terminated linker group is a divalent radical of Formula VI: wherein each of R 21 to R 21, is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, aryl, haloalkyl, amino, monoalkylamino, dialkylamino, cyanoamino, carboxyalkyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl; and wherein p represents a number selected from one to six inclusive. 58. A process according to claim 57, wherein a composition wherein R 21 and R 21 each represent hydrogen; wherein each of R 2 and R 2 is independently selected from 478 hydrogen, alkyl, phenalkyl, phenyl, alkoxyalkyl, hydroxyalkyl, haloalkyl and carboxyalkyl; and wherein p represents two or three. 59a. A process according to Claim 58, characterized in that a composition is prepared wherein each of R 1 and R 2 represents hydrogen; wherein each of R 21 and R 21 is independently selected from hydrogen and alkyl; and wherein p represents two. 60â. A process according to Claim 59, characterized in that a composition is prepared wherein each of R 1, R 2, R 3 and R 4 represents hydrogen; and wherein p represents two. 6ia. A process according to Claim 41, characterized in that a composition is prepared wherein said angiotensin II antagonist compound is selected from the group consisting of: 4 '- [3,5-dibutyl-1 H -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; 479 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-sec-butyl-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-tert-butyl-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; 480 4 '- [(5-Butyl-3-cyclohexanoyl-1H-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-phenyl-ethyl-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-1H-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- -amide; 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; 481 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-diisopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(3,5-di-sec-butyl-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-di-tert-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 482 4 '- [(3,5-di-pentyl-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] 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] 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] , 5 '- [4' - [[(3-butyl-5- (4-aminomethylphenylmethyl) -1H-1,2,4-triazol-1-yl] 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] -α-tetrazole; 5- [4 - [[(3-Butyl-5- (4-aminoethylphenyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1 -biphenyl] -2-yl] -α-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 5- [4 '- [[(3-butyl-5- (4-aminocyclohex-1-yl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -α-tetrazole; 5 '[4' - [[(3-Butyl -5- (4-aminomethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -α-tetrazole; 5- [ 4 '- [[(3-butyl-5- (4-aminomethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] (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] -α-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] -β-tetrazole ; 5- [4 '- [(5-Butyl-3-carboxypropyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2- [1] -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] - [1,17-biphenyl] -2-yl] 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] 5- [4 '- [[(3-butyl-5- (4-carboxymethylphenylmethyl) -1H-1,2,4-triazol-1-yl] -1H-tetrazole; -yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 - [[(3-Butyl-5- (4-carboxymethylphenyl) -1H- 4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; -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 (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-triazole -1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole A process according to Claim 51, characterized in that a composition is prepared wherein said conjugate is 5 - [[4 '- [(3,5-dibutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] carbonylhydrazide N-acetylglutamic acid. A process according to claim 47, wherein said conjugate is N 2 -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. A composition according to Claim 51, wherein said conjugate is 5- (5-butyl-1 - [[2 '- (1H-tetrazol-5-yl) '-biphenyl-4-yl] methyl] -1H-1,2,4-triazol-3-yl] acetylhydrazide A method for the treatment of N-acetyl-L-glutamic acid. a circulatory disorder, in particular related to hypertension, in particular chronic hypertension, or in particular a disorder due to sodium retention, in particular congestive heart failure, cirrhosis and nephrosis, comprising administering to a patient affected by, or susceptible to, , 486 wherein said conjugate comprises a residue of a biphenylalkyl-1H-substituted-1,2,4-triazole angiotensin II antagonist compound, in particular a conjugate comprising a compound of formula first and second residues, wherein the first and second residues are linked to one another by a cleavable bond, wherein said first residue is provided by a 1-substituted biphenylalkyl-1H-angiotensin II antagonist compound, 2,4-triazole, and wherein said second residue is capable of being cleaved from the selectivity of the first residue in the kidney, particularly a conjugate 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 reactive carboxylic acid moiety and the precursor of the other of said first and second residues is an amino group which can react or a moiety convertible to an amino moiety which can react, whereby a cleavable bond may be formed between said carboxylic acid moiety and said amino moiety; the dosage range of conjugate being from 0.1 to 3000 mg per kilogram of body weight per day, particularly from about 1 to about 100 mg / kg / day, orally, or from about 0.1 to about of 100 mg / kg / day by injection. 66a. A method according to Claim 61, characterized in that a conjugate is used wherein said angiotensin II antagonist compound is selected from a class of compounds defined by Formula I: 487 wherein m represents a number selected from one to four, inclusive; wherein each of up to is independently selected from hydrogen, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl,. alkoxycarbonyl, alkoxycarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxy-alkyl, alkoxycarbonylalkyl, cycloalkylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptothiocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, alkylthiocarbonyl, alkylthiocarbonyloxy, alkylthiocarbonyloxy, alkylthiothiocarbonyl, alkylthiothiocarbonyl, alkylthiothiocarbonyl, arylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthiocarbonylthio, aralkylthiothiocarbonyl, aralkylthiothiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, aralkylthiocarbonylthio, sulphonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, and cycloheteroalkylcarbonylalkyl, wherein each of said heteroaryl and cyclohetero-containing groups, 488 have one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R to R may additionally be independently selected from amino and amido radicals of the formula: R 12 X R14 X - + CH2 CH2 / - R 2, R 3, R 4, R 4, R 4, R 4, R 4, R 5, N-C- / N, &quot; OCN and 2 n R22 1 &quot; wherein X represents an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R to R 2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R1 and R2 taken together, R2 and R3 taken together, R2 and R3 taken together, R2 and R3 taken together and R2 and R3 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and wherein the heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur and wherein the heterocyclic group may be saturated or partially unsaturated; wherein each of R13 taken together, R and R are taken together, R 489 And R 2 and R 3 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and wherein the heterocyclic group may additionally contain one or more more heteroatoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and wherein each of R 1 to R 11 may also be independently selected from hydrogen and haloalkyl, and from acyl moieties of the formula: -YA n wherein n is a number selected from from zero to three, inclusive, and wherein A represents 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 represents 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 ; And wherein any of the foregoing R, Y and A groups above mentioned having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, trifluoromethyl, 6-difluoroalkyl, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, carboxy, mercapto , mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, 490 aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino or starch radicals of the formula: and -NC-R 28 Wherein X is selected from an oxygen atom and a sulfur atom; wherein each of R2, R28, R27, R2, and R6 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR30 and R31 / -N32 where D is selected from from an oxygen atom and a sulfur atom and R 30 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 25, R 26, R 27, R 28, R 29, R 29 and R 32 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxy, alkylsulfonyl, arylsulfinyl, arylsulfinyl, arylsulphonyl, haloalkylsulfinyl, haloalkylsulphonyl, aralkyl and wherein each of R¹, R², R², R², R², R² and R² is also independently selected from amino and starch radicals of the formula: / -CN / 35 R X and II Wherein X is an oxygen atom or a sulfur atom; cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl groups; wherein each of taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical, wherein the heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen atoms, nitrogen and sulfur and wherein the heterocyclic group may be saturated or partially unsaturated; wherein each of R3 and R3 taken together and each of R4 and R4 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and wherein the the heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; with the proviso that at least one of said 11 to R, Y and A substituents contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer thereof or a pharmaceutically acceptable salt thereof; 492 67â. 6. A method according to Claim 66, characterized in that a conjugate in which m is one; wherein each of R1 to 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 alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arthiothio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiothiocarbonyl, ar alkylthio, alkylthio, alkylthio, alkylthio, heteroarylalkyl, heteroarylalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl, wherein each of said heteroarylalkyl, cycloalkylalkyl, cycloalkylalkyl, aralkylsulfonyl, aralkylsulfonyl, arylsulfonyl, phthalimidoalkyl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl groups. containing heteroaryl and cycloheteroalkyl groups have one or more ring heteroatoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 to R11 may additionally be independently selected from amino and amido radicals of the formula: J, 12 X R14 X II j II 2 n. - * 082 * Η CN, HC-R16, 13 R15 R17 493 R18 X N "C R / N,--CH 2 'n 20 21 X R &quot; Wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; R 24 each wherein R 15 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; And wherein each of R to R may also be independently selected from hydrogen and haloalkyl, and from acidic moieties of the formula: wherein n is a number selected from zero to three, inclusive; and wherein A represents 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 so as to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y represents 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 ; 494 124 and wherein any of the above-referenced R, Y, and A groups having a substitutable position may be substituted by one or more groups selected from alkyl, alkenyl, aralkyl, hydroxyalkyl, trifluoromethyl, difluoroalkyl alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercaptocarbonyl, alkylthio, alkylthiocarbonyl, and amino or amido radicals of the formula: ???????? . wherein X is selected from an oxygen atom and a sulfur atom; wherein each of R 1, R 2, R 3, R 4 and R 9 are as defined above. . R is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and DR30 and R31 / -N wherein D is selected from an oxygen atom and a sulfur atom, and R3 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 25, R 26, R 27, R 28, R 29, R 29 and R 32 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkanoyloxy, carboxy, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R25, R26, R27, R28, R29, R31 and R32 is also independently selected from amino and amido radicals of the formula: CN X 37 and -NC-R? 34 .36 wherein X is selected from an oxygen atom or a sulfur atom; Wherein each of R through R 2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; with the proviso that at least one of said substituents 1 24. . R and Y contain a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. 68s. 7. A method according to Claim 67, characterized in that a conjugate in which m is one; wherein each of R1 to R3 is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarboxyl, 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 cycloheteroalkylcarbonylalkyl groups, wherein each of said heteroaryl and cycloheteroalkyl containing groups has one or more heteroatoms selected ring from oxygen, sulfur and nitrogen atoms, and wherein each of R 1 through R 11 may additionally be independently selected from amino and amido radicals of the formula: X R14 &quot; / CNV * X II -fCH, * - NC-R 2 n, J. 17 16 R 18 X R / N, -CH 2 n R 20 X R &quot; Wherein X is selected from an oxygen atom or a sulfur atom; and wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R to R 2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; And wherein each of R to R may also be independently selected from hydrogen and haloalkyl, and from acidic moieties of the formula: wherein n is a number selected from zero to three, inclusive; wherein A is selected from a carboxylic acid and carboxylic acid bioisosters selected from: C 1 -CH 2, Wherein each W is independently selected from an oxygen atom, a hydrogen atom, a C1-4 alkyl group, sulfur and NR, in each of 39, 40, 41, 42, 43, R 3, R 4, R 5, R 4, R 5 and R 6 are independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl ; wherein each of R 1, R 2, R 3 and R 4 may also be independently selected from an amino radical of the formula: R 44 Wherein each of R1 and R2 is independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R3 and R4 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, wherein the heterocyclic group may additionally contain one or more heteroatoms 498 as ring members selected from oxygen, nitrogen and sulfur atoms and wherein the heterocyclic group may be saturated or partially unsaturated; wherein R and R taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and wherein the aromatic heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from of oxygen, nitrogen and sulfur; wherein each of R 40 and R 41 may also be independently selected from hydroxy, alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and aralkoxy; and the amide, ester and salt derivatives of said acidic groups; wherein said carboxylic acid bioisostere may also be selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, wherein the ring contains at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, wherein said heterocyclic ring may be saturated, fully unsaturated, or partially unsaturated, and wherein the heterocyclic ring may be attached at a single position selected from or may be attached to any two adjacent positions -. . Are selected from R to R so as to form a ring system fused to one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y represents a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; 124 and in which any of the groups R to R, Y and A, referred to, having a replaceable position, may be substituted 499 by one or more groups selected from alkyl, difluoroalkyl, alkenyl, aralkyl, hydroxyalkyl, trifluoromethyl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkoxycarbonyl, carboxy, mercaptocarbonyl, alkylthio, alkylthiocarbonyl, and amino or amido radicals of the formula: II 2Θ and -NC-R R 26 Wherein X is selected from an oxygen atom and a sulfur atom; wherein each of R1, R2, R3, R4 and R7 is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl and DR and R31 / -N wherein D is selected from an oxygen atom and a sulfur atom, wherein R is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R25, R26, R27, R28, R29, R31 and R32 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl aralkyl and aryl; with the proviso that at least one of said substituents R 1 to R 2, Y and A contains a primary amino terminal portion or 500 secondary or a portion convertible into a primary or secondary amino terminal portion; or a tautomer or a pharmaceutically acceptable salt thereof. 69a. 7. A method according to Claim 68, characterized in that a conjugate in which m is one; wherein each of R¹ and R² is independently selected from alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aryl, aryl, aroyl, aryloxy, aryloxyalkyl, aralkoxy, alkoxyalkyl, alkylcarbonyl , alkoxycarbonyl, alkenyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, carboxyalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, mercaptocarbonyl, mercaptoalkyl, alkoxycarbonyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, alkylsulfinyl alkylsulphonyl, aralkylsulfinyl, arylsulfinyl, arylsulfonyl, phthalimido, phthalimidoalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl and cycloheteroalkylcarbonylalkyl, wherein each of said heteroaryl and cycloalkyl groups -heteroalkyl groups have one or more ring heteroatoms selected from oxygen, sulfur and nitrogen atoms, and wherein each of R1 to R11 may additionally be independently selected from amino and amido radicals of the formula: -CH 2 CN / -CH2-n-CH2-n-NCH2 -CH2 -CH2- Wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; wherein each of R 12 through R 24 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; Wherein each of R to R 2 is independently selected from hydrogen, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, cyano, nitro, carboxyl, alkylthio, aralkylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulphonyl, arylsulfinyl, arylsulphonyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; And wherein each of R 2 to R 3 may also be independently selected from acidic moieties of the formula: wherein n represents a number selected from zero to three, inclusive; wherein A is selected from a carboxylic acid and carboxylic acid bioisosters selected from: wherein R 1 is selected from a carboxylic acid and carboxylic acid bioisosters selected from: Wherein each W is independently selected from an oxygen atom, a sulfur atom and NR43, in each of R3, R4 and R4 is independently selected from the group consisting of: selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R 1 and R 2 may also be optionally selected from an amino radical of the formula: wherein each of R 1 and R 2 is independently selected from hydrogen, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, and aryl, and wherein R and R taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical , wherein the heterocyclic group may additionally contain one or more heteroatoms as ring members selected from oxygen, nitrogen and sulfur atoms and wherein the heterocyclic group may be saturated or partially unsaturated; wherein R and R taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said 503 an amino radical and wherein the aromatic heterocyclic group may additionally contain one or more heteroatoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and the amide, ester and salt derivatives of said acidic groups; wherein said carboxylic acid bioisostere may also be selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, wherein the ring contains at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, wherein said heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and wherein the heterocyclic ring may be attached at a single position selected from 3 '. R to R or may be attached to any two adjacent positions selected from R to R so as to form a ring system condensed with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y represents a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; may be substitutable with alkyl, cyclo-trifluoromethyl, alkylsulfonyl, aryloxy and aral-11 and wherein each of R 1 to R 2, Y and A independently are independently in any position one or more groups selected from alkyl, cycloalkylalkyl, hydroxy, oxo, difluoroalkyl, alkoxycarbonyl, cyano, nitro, haloalkylsulfonyl, aryl, aralkyl, alkoxy, coxy; with the proviso that at least one of said 24, R to R, Y and A substituents contains a primary amino terminal moiety or 504 secondary or a portion convertible into a primary or secondary amino terminal portion; or a tautomer or a pharmaceutically acceptable salt thereof. 70a. 7. A method according to Claim 69, characterized in that a conjugate in which 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, phenalkoxy, phenylthio, phenalkylthio, aral alkoxycarbonyl, 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 ring heteroatoms selected from Oxygen, sulfur and nitrogen, and wherein each of R to R may additionally be and are independently selected from amino and amido radicals of the formula: ???????? R 12 ???????? / CN -fCH NC-R 2 η I 117 16 R18 X R / N,--CH 2 'n 20 X R &quot; / OCN \ 21 22 23 R X -N-COR 2 n 24 505 wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; Wherein each of R to R 2 is independently selected from hydrogen, alkyl, cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl and phenyl; Wherein each of R 1 to R 2 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkoxy, alkoxyalkyl, alkylcarbonyl , alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio, mercapto and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; And wherein each of R to R may be an acidic moiety also independently selected from acyl moieties of the formula: wherein n is a number selected from zero to two, inclusive; and wherein A is selected from a carboxylic acid and carboxylic acid bioisosters selected from: HI 39 -OH, -SH, -NR, W ··C-WH, -S-WH, w W II II S-WH and -P-WH II | l 42 W WR 506 wherein each W is independently selected from an oxygen atom, a sulfur atom and NR43, in each of R1, R2 and R3 is independently selected from hydrogen, alkyl, haloalkyl, haloalkylsulfonyl, halo - carbonyl, cycloalkyl, phenyl and benzyl; wherein each of R 3 and R 2 may also be independently selected from an amino radical of the formula: wherein each of R 3 and R 4 is independently selected from from hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, benzyl and phenyl; and the amide, ester and salt derivatives of said acidic groups; wherein said carboxylic acid bioisostere may also be selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, wherein the ring contains at least one heteroatom selected from oxygen atoms, sulfur and nitrogen, wherein said heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and wherein the heterocyclic ring may be attached at a single position selected from R to R 11 or may be attached at any two adjacent positions; 11 are selected from R to R so as to form a ring system condensed 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; 507 wherein Y represents a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenalkyl and aralkyl; And wherein each of R to R, Y and A may be independently substituted at any substitutable position with one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, oxo, trifluoromethyl, difluoroalkyl, alkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy; with the proviso that at least one of said substituents 1 &gt; R and Y contain a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. 7iâ. A method according to Claim 70, characterized in that a conjugate in which m is one; wherein each of R 1 and R 2 is independently selected from alkyl, aminoalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, benzoyl, phenoxy, phenoxyalkyl, phenalkyloxy, phenylthio, phenalkylthio alkoxycarbonyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkylcarbonyloxyalkyl, phthalimido, phthalimidoalkyl, tetrazole, aralkoxycarbonyl, aralkoxycarbonylalkyl, aralkoxycarbonylalkyl, aralkyloxycarbonylalkyl, aralkyloxycarbonylalkyl, aralkylcarbonyloxyalkyl, phthalimidoalkyl, tetrazole, aralkoxycarbonyl, aralkoxycarbonyl, , tetrazolealkyl, alkylthio, cycloalkylthio, and amino and amido radicals of the formula: 508.12 XR &quot; / 14-fCH3 CN 15.13 R 2 n R18 X R19 X | &quot; / &quot; / N-C-N, Wherein X is selected from an oxygen atom or a sulfur atom; wherein each n is a number independently selected from zero to six, inclusive; selective, wherein each of R 1 to R 2 is independently dependent on hydrogen, alkyl, cycloalkyl, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl and phenyl; Wherein each of R to R 2 is independently selected from hydrogen, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkoxy, alkoxyalkyl, acetyl alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; And wherein each of R 1 to R 2 may be an acidic moiety also independently selected from acylic moieties consisting of CO 2 H, CO 2 C 3 'SH' CH 2 SH 'C 2 H 4 SH' P 3 H 2 'nhso 2' 3 ', NH 2 C 6 F 5, SO 3 H, CH 2 CH 2 , conhnhso2cf3, conhoch3, CONHOC2H5, CONHCF3, OH, CH20H, C2H4OH, 0P03H2, 0S03H, 509 Ν · / Ν / Η / Η and / Ν Η , 46 II (I.e. R 47  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒCH2 C6 H5 and R48 is independently CHF, From R to R so as to form a fused ring system which includes one of the phenyl rings of the biphenyl moiety of Formula selected from H, Cl, CN, NC> 2, CF 3, C 2 F 5, C 3 F 7, , co2ch3, co2c2h5, so2ch3 (selected from O, S, NR2R3, hydrogenated, CH2 SO4 CF3 and CH and SO2 C6 F5; I, said biphenyl condensed ring system being selected from and the amide, ester and salt derivatives of said acidic moieties; with the proviso that at least one of said R1 to R substituents contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. 72â. 7. A method according to Claim 71, characterized in that a conjugate in which m is one; wherein each of R1 and R2 is independently selected from amino, aminomethyl, aminoethyl, aminopropyl, CH2 OH, N-N-CH2-CH2CH2CH2H, CH (CH3) co2h, no2, Cl, 1H, -CH2OCOCH2CH2 -CON2 CH3, -CONH2, -CONKCH3, CON (CH3) 2, -CH2 -NHCO2 -C2 H5, -CH2 NH2 -CH2NHCO2CH3, -CH2NHCO2C3, -CH2NHCO2C3H7, -CH2NHC02CH2 (CH3) 2, -CH2NHC02C4H9, -CH2NHC02-adamantyl / -CH NHCO- (1-naphthyl), -CH2 NHCONHCH2, -CH2 NHCONH2, -CH 2 NHCONH 3 H 7, -CH 2 NHCONHC 4 Hg, -CH 2 NHCONH 4 Hg, -CH 2 NHCONHCH (CH 2), -CH 2 NHCONH (1-naphthyl), -CH 2 NHCONH (1-adamantyl), CO 2 H, -CH 2 CH 2 -COO, -CH 2 CH 2 CH 3, -CH 2 CH 2 CH 2 CH 2, -CH 2 CH 2 F, - CH 2 OCONHCH 3, -CH 2 OCSHCH 3, -CH 2 NHCSOCH 3, -CH 2 CH 2 CH 2 F, -CH 2 ONO 2, -CH 2 SH, -CH 2 OH, Cl, NO 2, CF 2, CH 2 OH, 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 3 11-1,1-difluoropentyl; and wherein each of R1 to R5 is hydrogen, with the proviso that at least one of R1, R2, R 2 and R 3 represent an acidic group selected from CO 2 H, SH, CO 3 H 2, SO 3 H, CONHNH 2, COOHNHSO 2 CF 3, Wherein each of R1 and R2 is independently selected from Cl, CN, NO2, CF3, CO2 CH2 and SC> 2 CF3; with the proviso that at least one of said R1 to R11 substituents contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. 73a. A method according to claim 72, characterized in that a conjugate in which 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, 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 R 2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n -pentyl and neopentyl; wherein each of R 3, R 4, R 8, R 7, R 8, R 10, and R 19 is hydrogen; in one of R1 and R2 is hydrogen and the other of R 5 and R 9 represents an acidic group selected from CO 2 H, SH, CO 3 H 2, SO 3 H, CONHNH 2, COOHNHSO 2 CF 3, wherein each of e is independently selected from Cl, CN, NO 2, CF 3, CO 2 CH 3 and SO 2 CF 3; with the proviso that at least one of said R 1 to R 2 substituents contains a primary or secondary amino terminal moiety or a moiety convertible to a primary or secondary amino terminal moiety; or a tautomer or a pharmaceutically acceptable salt thereof. 74â. A method according to Claim 73, characterized in that a conjugate is used wherein said second residue forms an enzymatically cleavable amide bond of the kidney with the residue of said angiotensin II antagonist compound. 75â. A method according to Claim 65, characterized in that a conjugate is used wherein said second residue is provided by a compound of Formula II: (II) II-C-G &quot; Wherein each of R¹ and R² may be independently selected from hydrogen, alkylcarbonyl, alkoxycarbonyl, alkoxyalkyl, hydroxyalkyl and haloalkyl; and wherein G is selected from hydroxy, halo, mercapto, -OR, -SR and / or wherein each of R¹, R² and R² is independently selected from hydrogen and alkyl; with the proviso that said compound of Formula II is selected such that formation of a cleavable amide bond occurs at the carbonyl portion attached to the carbon of the gamma position of said compound of Formula II. 7 6a. 7. A method according to Claim 75, characterized in that a conjugate in which each G substituent is hydroxy. 77a. A method according to Claim 76, characterized in that a conjugate in which each G substituent is hydroxy; wherein R3 is hydrogen; and wherein R3 is selected from 515 Wherein R is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, n-hexyl and chloromethyl. 3. A method according to Claim 77, characterized in that a conjugate is used wherein said second residue is: -CCH-CH-CHNHCCH- (CH2) 3 O 733. A method according to claim 65, characterized in that a conjugate is used wherein said first residue is a biphenyl-alkyl-1H-substituted-1,2,4-triazole angiotensin II antagonist compound containing a primary or secondary amino terminal moiety selected from amino and straight or branched aminoalkyl moieties containing linear or branched alkyl groups selected from amino, ethyl, aminopropyl, amino-isopropyl, aminobutyl, amino-sec -butyl, amino- isobutyl, amino-tert-butyl, aminopentyl, amino-isopentyl and amino-neopentyl. 803. A method according to Claim 65, characterized in that a conjugate is used wherein said first residue is provided by a biphenylalkyl-1H-substituted-1,2,4-triazole angiotensin II antagonist compound containing a portion convertible to a primary or secondary amino terminal portion. 516 81 '. A method according to claim 80, characterized in that a conjugate is used in which said portion which can be converted to an amino terminal portion is a carboxylic acid group which may react with an amino moiety of a diamino terminated linker group of to provide an amino terminal portion which can then be further reacted with a carboxylic acid moiety of a compound providing said second residue to form a hydrolyzable amide linkage. 82â. A method according to Claim 81, characterized in that a conjugate in which said diamino terminated linker is a divalent radical of Formula III: in which: each of R200 and R201 may be independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, aryl, haloalkyl, amino, monoalkylamino, dialkylamino, cyanoamino, carboxyalkyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl groups; and wherein n is zero or a number selected from three to seven inclusive. 83â. A method according to claim 82, characterized in that a conjugate is used wherein each of 200-201. ,. R 2 and R 3 are hydrogen. S4a. A method according to Claim 81, characterized in that a conjugate is used in which said group 517 The diamine terminated linker is a divalent radical of Formula IV: wherein each of Q and T represents one or more groups independently selected from R202 and R202, Wherein each of R 1 to R 2 may be independently selected from hydrogen, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl, alkanoyl, alkenyl, cycloalkenyl and alkynyl. 8 5a. A method according to claim 84, characterized in that a conjugate is used in which said diamino terminated linker group is a divalent radical of Formula V: Wherein each of R1 and R2 is independently selected from hydrogen, hydroxy, alkyl, phenalkyl, phenyl, alkoxy, benzyloxy, phenoxy, alkoxyalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; and wherein each of p and q represents a number independently selected from one to six, inclusive; with the proviso that when each of R3 and R7 is selected from halo, hydroxy, amino, mono-dialkylamino and dialkylamino, then the carbon to which R or R3 is attached in Formula V is not adjacent to a nitrogen atom of Formula V. 86a. A method according to Claim 85, characterized in that a conjugate in which each of R 20 and R 20 is independently selected from hydrogen, hydroxy, alkyl, alkoxy, amino, monoalkylamino, carboxy, carboxyalkyl and alkanoyl ; and wherein each of p and q represents a number independently selected from two to four, inclusive. 87 a. 5. A method according to Claim 86, characterized in that a conjugate is used in which each of 519 R 2 and R 3 are independently selected from hydrogen, amino, monoalkylamino and carboxy; and wherein each of p and q represents a number independently selected from the two and three numbers. 38-. A method according to claim 87, characterized in that a conjugate is used wherein each of R20 and R20 is hydrogen; and wherein each of p and q represents two. 89â. A method according to claim 81, characterized in that a conjugate is used wherein said diamino terminated linker is a divalent radical of Formula VI: (VI) 214 217 wherein each of R through R is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aralkyl, aryl, haloalkyl, amino, monoalkylamino, dialkylamino, cyanoamino, carboxyalkyl, alkylsulfinyl, alkylsulphonyl, arylsulfinyl and arylsulphonyl; and wherein p represents a number selected from one to six inclusive. 90â. 5. A method according to claim 89, characterized in that a conjugate in which each of "214" 215 is used. . ..,. R² and R³ represent hydrogen; wherein each of R2 and R3 is independently selected from hydrogen, 520 alkyl, phenalkyl, phenyl, alkoxyalkyl, hydroxyalkyl, haloalkyl and carboxyalkyl; and wherein p represents two or three. 9a. A method according to Claim 90, characterized in that a conjugate in which each of R 21 and R 21 is hydrogen; wherein each of R 21 and R 217 is independently selected from hydrogen and alkyl; and wherein p represents two. 92â. A method according to Claim 91, characterized in that a conjugate is used wherein each of R 21, R 21, R 21 and R 21 are hydrogen; and where p represents two. 93d. A method according to Claim 73, characterized in that a conjugate is used wherein said angiotensin II antagonist compound is selected from the group consisting of: 4 '- [3,5-dibutyl-1 H -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; 521 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-sec-butyl-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-tert-butyl-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-butyryl-3-cyclohexyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(5-butyryl-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-butyryl-3-cyclohexanoyl-1H-1,2,4-triazol-1-yl) methyl] - [1,1'-biphenyl] -2-carboxylic acid; 522 4 '- [(5-Butyl-3- (1-oxo-2-cyclohexylethyl) -1H-1,2,4-triazol-1-yl) methyl] [(1', 2'-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-1H-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- -amide; 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; 523 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-diisopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(3,5-di-sec-butyl-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-di-tert-butyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-carboxylic acid; 4 '- [(3,5-di-pentyl-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- [1H-tetrazole] [4 '- [ 5-butyl-3-aminomethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -tetrazole 5- [4 '- [ (5-butyryl-3-aminoethyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2H-tetrazole 5- [4'- [(5-butyl-3-aminopropyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] -α-tetrazole; - [(5-butyl-3-aminobutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2- [1] -β-Tetrazole; '- [[(3-butyl-5- (4-aminophenyl) -1H-1,2,4-triazol-1-yl] methyl] - [1,1'-biphenyl] -2-yl] tetrazole; 5- [4 '- [[(3-butyl-5- (4-aminophenylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] - 2-yl] -α-tetrazole; 5- [4 '- [[(3-Butyl-5- (4-aminophenylethyl) -1H-1,2,4-triazol-1-yl] methyl] [Î ±, 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] -α-tetrazole; 5- [4 '- [[(3-Butyl-5- (4-aminocyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] 1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-Butyl-5- (4-aminocyclohexylmethyl) -1 H -1,2,4-triazol- 5 - [4 '- [[(3-butyl-5- (4-aminocyclohexylethyl) -1H-1,2,4-thiadiazol- 1,2-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 5- [4 '- [[(3-But- 5- [4 '- [[(2-Aminoethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] 3-butyl] -5- (4-aminomethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -β-tetrazole; "[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-1 H -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] 5- [4 '- [[(3-butyl-5- (4-carboxymethylphenylmethyl) -1H-1,2,4-triazol-1-yl) -1H-tetrazole; 5- [4 '- [[(3-butyl-5- (4-carboxymethylphenyl) -1H-1,2,3,4-tetrahydro- 5- [4 '- [[(3-butyl-5- (4-carboxyethylphenyl) -piperazin-4-yl] -methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 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; (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'-CC (3-butyl) -5- (4-carboxymethylcyclohexylmethyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -1H-tetrazole; 527 5- [4 '- [[(3-Butyl-5- (4-carboxymethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] -1,1'-biphenyl ] -2-yl] -α-tetrazole and 5- [4 '- [[(3-butyl-5- (4-carboxyethylcyclohexyl) -1H-1,2,4-triazol-1-yl] methyl] [1,1'-biphenyl] -2-yl] -β-tetrazole The method of Claim 83, wherein a selective renal conjugate is 5 - [[4 ' - [(3,5-dibutyl-1H-1,2,4-triazol-1-yl) methyl] [1,1'-biphenyl] -2-yl] carbonylhydrazide of N-acetylglutamic acid. A method according to claim 79, characterized in that a selective renal 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: A method according to Claim 83, by using a selective renal conjugate which is 5- [5-butyl] -1 - [[2 '- (1H-tetrazol-5-yl) [1,1'-biphenyl] -4-yl] methyl] -1- N, N-acetyl-L-glutamic acid, N-acetyl-L-glutamic acid. 1991 act Λ. PEREIRA 0A CftDá * Q »n * OêcU &lt; ta Pwptie &amp; aè mawMKãl RUA VTCXOR CORDON. 10 A *