IE911801A1 - N-substituted-1,2,4-triazolone compounds for treatment of¹cardiovascular disorders - Google Patents

Description

Non-peptidic N-substituted-1,2,4-triazolone compounds are described for use in treatment of cardiovascular disorders such as hypertension and congestive heart failure. Of particular interest are angiotensin II antagonist compounds provided by 1,2,4triazolones having a biphenylmethyl moiety attached to the nitrogen atom at the four-position of the 1,2,4-triazolone.

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

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

Non-peptidic compounds with angiotensin II antagonist properties are known. For example, the sodium salt of 2-n-butyl-4-chloro-l-(2-chlorobenzyl)imidazole-5 acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [P. C. Wong et al, J. Pharmacol. Exp. Ther. , 242(1), 1-7 (1988)].

Also, the sodium salt of 2-butyl-4-chloro-l- (2nitrobenzyl)imidazole-5-acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [A. T. Chiu et al, European J, Pharmacol,. 157, 1321 (1988)]. A family of l-benzylimidazole-5-acetate derivatives has been shown to have competitive angiotensin II antagonist properties [A. T. Chiu et al, J. Pharmacol . Exp, Ther. . 252(3), 867-874 (1989)]. U.S. Patent No. 4,816,463 to Blankey et al describes a family of 4,5,6,730 tetrahydro-ΙΗ-imidazo(4,5-c)-tetrahydro-pyridine derivatives useful as antihypertensives, some of which are reported to antagonize the binding of labelled angiotensin II to rat adrenal receptor preparation and thus cause a significant decrease in mean arterial blood pressure in conscious hypertensive rats. EP No. 253,310, published 20 January 1988, describes a series of aralkyl imidazole compounds, including in particular a family of c-jbiwi biphenylmethyl substituted imidazoles, as antagonists to the angiotensin II receptor. EP No. 323,841 published 12 July 1989 describes four classes of angiotensin II antagonists, namely, biphenylmethylpyrroles, biphenylmethylpyrazoles, biphenylmethyl-1,2,3-triazoles and biphenylmethyl 4-substituted-4H-l,2,4-triazoles, including the compound 3,5-dibutyl-4-[(2'-carboxybiphenyl-4yl)methyl]-4H-1,2,4-triazole. U.S. Patent No. 4,880,804 to Carini et al describes a family of biphenylmethylbenzimidazole compounds as angiotensin II receptor blockers for use in treatment of hypertension and congestive heart failure.

There are several other families of known compounds having one or two oxo substituents on the triazole ring. For example, East German Patent No. 160,447 published 3 August 1983 describes a family of 1,2,4triazolin-5-one compounds, specifically 2,4-dihydro-4,520 bis(phenylmethyl)-3H-1,2, 4-triazol-3-one, for use as herbicides. Belgian Patent No. 806,146 published 16 October 1972 describes a family of triazolinone compounds, including the compound (3-(4-m-chlorophenyl-l-piperazinyl)propyl)-3,4-diethyl-l,2,4-triazolin-5-one, having tranquilizer, hypotensive and analgesic activities.

Belgian Patent No. 631,842 published 28 February 1963 describes a family of 1,2,4-triazolones having hypnotic, tranquilizer, narcotic, sedative and analgetic activities, which includes a class of 4-N-aralkyl-l,2,4-triazol-5-one compounds. EP #7,180 published 15 June 1978 describes a family of 1,2-disubstituted-4-alkyl-l, 2, 4-triazolidine-3,5dione compounds having a wide variety of activities, such as antiulcer, bronchodilator, antifertility and cardiovascular-related activities which include antihypertensive, antiarrhythmic, platelet aggregation inhibition and smooth muscle activities. EP #283,310 published 18 March 1987 describes a family of N1C-2619/1 diarylmethyl-N2-aminoalkyl-diaza-heterocyclic derivatives for treating cerebral vascular and ischmic diseases and for protecting against anoxia.

DESCRIPTION OF THE INVENTION A class of biphenylalkyl N-substituted-1,2,4 triazolone compounds useful in treating circulatory and cardiovascular disorders is defined by Formula I: wherein m is a number selected from one to four, inclusive; wherein R·'· is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropy1, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyl15 methyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl) 20 E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-l25 methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, aralkoxycarbonyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, alkylthiothiocarbony1, arylthiocarbony1, arylthiothiocarbonyl, aralkylthiocarbonyl, alkylthiocarbonyl, aralkylsulfinyl, aralkylsulfonyl and radicals of the formula X II -CN R12 R13 wherein each of R^2 and r!3 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein 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 which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of 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 which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms, with the proviso that when X is oxygen atom, then R1^ and R1-^ cannot be selected from hydrido and alkyl; wherein each of r2 through R^ is independently selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, aralkoxycarbonyl, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, aroyloxyalkyl, alkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, alkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula -N •R and -NC-R18 R19 wherein X is oxygen atom or sulfur atom; wherein each of R14, R1^, r16, r!7, r!8 and R19 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R^4 and R·'-^ taken together, and R15 * 17 * * 20 * * * * 25 * * * * 30 taken together and R-^-θ and R19 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of R^4 and r!5 taken together and each of R-^-θ and R-*·7 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and wherein each of R^ through R^· may be further independently selected from hydroxy and acidic moieties of the formula -YnA wherein n is a number selected from zero through three, inclusive, and wherein A is an acidic group selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; and wherein any of the foregoing R1 through R19, γ and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, halo, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula X 11 20 / -C-R20 , -N R' R' and -NC-R' R' wherein X is oxygen atom or sulfur atom; wherein R^O is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR25 and C-2619/1 -N R wherein D is selected from oxygen atom and sulfur atom and R23 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R24, R22, R23, R24, R26 and R27 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, aikoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of r21, r22, r23, r24, r26 and r27 j_s further independently selected from amino and amido radicals of the formula 30 -N ‘R -CN and -NCR ‘R wherein X is oxygen atom or sulfur atom; wherein each of R23, R2^, R3^, R34 R32 and R33 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R24 and R22 taken together and each of R23 and R24 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of R24 and R22 taken together and each of R23 and R27 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

Compounds of Formula I would be useful in treating a variety of circulatory disorders including cardiovascular disorders, such as hypertension, congestive heart failure and arteriosclerosis, and to treat other disorders such as glaucoma. These compounds would also be useful as adjunctive therapies. For example, compounds of Formula I may be used in combination with other drugs, such as a diuretic, to treat hypertension. Also, compounds of Formula I could be used in conjunction with certain surgical procedures. For example, these compounds could be used to prevent post-angioplasty re-stenosis. Compounds of Formula I are therapeutically effective in treatment of cardiovascular disorders by acting as antagonists to, or blockers of, the angiotensin II (All) receptor. Compounds of Formula I would be therapeutically effective in treatment of the above-mentioned circulatory and cardiovascular disorders or would be precursors to, or prodrugs of, therapeutically-effective compounds.

The phrase acidic group selected to contain at least one acidic hydrogen atom, as used to define the -YnA moiety, is intended to embrace chemical groups which, when attached to any of the R^ through R^ positions of Formula I, confers acidic character to the compound of Formula I. Acidic character means proton-donor capability, that is, the capacity of the compound of Formula I to be a proton donor in the presence of a proton-receiving substance such as water. Typically, the acidic group should be selected to have proton-donor capability such that the product compound of Formula I has a pKa in a range from about one to about twelve. More typically, the Formula I compound would have a pKa in a range from about two to about seven. An example of an acidic group containing at least one acidic hydrogen atom is carboxyl group (-COOH). Where n is zero and A is -COOH, in the -YnA moiety, such carboxyl group would be attached directly to one of the R^ through R11 positions. The Formula I compound may have one -YnA moiety attached at one of the through R11 positions, or may have a plurality of such -YnA moieties attached at more than one of the R^ through R^·1 positions, up to a maximum of nine such -YnA moieties. There are many examples of acidic groups other than carboxyl group, selectable to contain at least one acidic hydrogen atom. Such other acidic groups may be collectively referred to as bioisosteres of carboxylic acid or referred to as acidic bioisosteres. Specific examples of such acidic bioisosteres are described hereinafter. Compounds of Formula I having the -YnA moiety attached at one of positions R5, R6, R8 and R9 would be expected to have preferred properties, while attachment at R^ or R9 would be more preferred. Compounds of Formula I may have one or more acidic protons and, therefore, may have one or more pKa values. It is preferred, however, that at least one of these pKa values of the Formula I compound as conferred by the -YnA moiety be in a range from about two to about seven. The -YnA moiety may be attached to one of the R8 through R11 positions through any portion of the -YnA moiety which results in a Formula I compound being relatively stable and also having a labile or acidic proton to meet the foregoing pKa criteria. For example, where the -YnA acid moiety is tetrazole, the tetrazole is attached at the ring carbon atom.

A preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein R1 is selected from polycycloalkyl, polycycloalkylalkyl, 3phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyl-methyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5, 5-trimethylhexyl, (2-phenylmethoxy)-l(phenylmethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl5 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, cycloalkynyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, arylthiocarbonyl, arylthiothiocarbonyl, aralkylthiocarbonyl, aralkylsulfonyl and radicals of the formula wherein X is oxygen atom or sulfur atom; wherein each of and is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, with the proviso that when X is oxygen atom, then R1^ and cannot be selected from hydrido and alkyl; wherein R^ Is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, carboxyl, alkylcarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbony1, 5 aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; wherein each of through R^1 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiothiocarbonyl, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl, and amino and amido radicals of the formula R14 and NC-R wherein X is oxygen atom or sulfur atom; wherein each of R·^, r16, r!"\ r!8 and R^-9 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R2 through R1! may be further 5 independently selected from acidic moieties of the formula -YnA wherein n is a number selected from zero through three, inclusive; wherein A is an acidic group selected from acids containing one or more atoms selected from oxygen, sulfur, phosphorus and nitrogen atoms, and wherein said acidic group is selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; and wherein any of the foregoing R1 through R^E Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, halo, haloalkyl, oxo, alkoxy, aryloxy, aralkoxy, alkoxyalkyl·, alkylcarbonyl, alkoxycarbonyl, carboxyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkylthio and alkylthiocarbonyl, and amino and amido radicals of the formula X -N R' R‘ and -NC-R' R‘ wherein X is oxygen atom or sulfur atom; wherein r!9 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and DR22 and R26 -N \r2? wherein D is selected from oxygen atom and sulfur atom, and is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R^l, r22, r23, r24, r26 ancj r27 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

A more preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein R^ is selected from polycycloalkyl, polycycloalkylalkyl, 3phenylpropyl, 2-oxo-2-phenylethy1, 2-hydroxy-2-phenylethy1, 1,1-dimethylethyloxycarbonyl-methyl, hexyl, ethoxycarbonylmethy1, carboxymethyl, 1 -naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-l(phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1oxobutyl, 2-(2, 5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, cycloalkynyl, aralkylsulfonyl and amido radicals of the formula p 12 zR II Z -CN \Ri3 wherein each of R42 and R43 is independently selected from cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein R2 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, aikoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, carboxyl, alkylcarbonyloxy, alkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl; wherein each of R3 through R11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, aikoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, mercapto, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl, and amino and amido radicals of the formula I „ -NC-R18 30 -N and -CN wherein each of R14, r!5, r16, r!7, rI® and R19 is independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R2 through R11 may be an acidic moiety further independently selected from acidic moieties of the formula -YnA wherein n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from W II -OH, -SH, -NR34 *, -C-WH, -S-WH, -S-WH, -P-WH, -P-NH and -P-WH I TK I '35 '36 WR' wherein each W is independently selected from oxygen atom, sulfur atom and NR22 *; wherein each of R24, R22 *, R22, R27 and R22 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R24, R22, R22 and R27 may be further independently selected from amino radical of the formula R' -N •R wherein each of R29 and R4^ is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R29 and R4^ taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein R2^ and R4® taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; wherein each of R22 and R22 may be further independently selected from hydroxy, alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and aralkoxy; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which heterocyclic ring contains at least one hetero atom selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R2 through R^-1 or may be attached at any two adjacent positions selected from R2 through so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; and wherein any of the foregoing R^ through R^-9 and r34 through R40, Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, halo, oxo, haloalkyl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkylthio and alkylthiocarbonyl, and amino and amido radicals of the formula R‘ -C-R20 , -N and -NC-R R' wherein X is selected from oxygen atom and sulfur atom; 10 wherein R2^ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl and DR22 and -N ^R27 wherein D is selected from oxygen atom and sulfur atom, wherein R22 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R2-'-, R22, R22, R2^, R2^ and R27 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

An even more preferred class of compounds consists of those compounds of Formula I wherein m is one; Rl is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 15 oxobutyl, 2-(2,5-dimethyoxyphenyl) -2-oxoethyl, 2-phenyl2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethy1, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-l methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, aralkylsulfonyl and radicals of the formula p 12 /K II X -CN \Ri3 wherein each of R^2 and R^-2 is independently selected from cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein each of R2 is selected from hydrido, alkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, carboxyl, alkylcarbonyloxy, alkylthio, arylthio, aralkylthio, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl; wherein each of R2 through R^-2 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, alkylthio, aralkylthio and mercapto; and wherein each of through R11 may be an acidic moiety 5 further independently selected from acidic moieties of the formula -YnA wherein n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from H W W w 134 II II II -OH, -SH, -NR , -C-WH, -S-WH, -S-WH and -P-WH W WR37 wherein each W is independently selected from oxygen atom, sulfur atom and NR38; wherein each of R34, R3^ and R33 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R34 and R37 may be further independently selected from amino radical of the formula -N ./ ‘R wherein each of R39 and R49 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R39 and R49 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms, and which heterocyclic group may be saturated or partially unsaturated; wherein r39 and R4® taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R^ through R11 or may be attached at any two adjacent positions selected from r3 through R11 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; wherein each of R1 through R1^, R·^4 and R^7 through R4^, Y and A independently may be substituted at any substitutable position with one or more groups selected from alkyl, hydroxy, halo, oxo, haloalkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

A highly preferred class of compounds within Formula I consists of those compounds wherein m is one; wherein r! is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl) E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl 10 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-l methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, aralkylsulfonyl and amido radicals of the formula 0 X II / -CN wherein each of R^2 and R^2 is independently selected from cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl and phenyl; wherein R2 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, alkylthio, arylthio, aralkylthio and arylsulfonyl; wherein each of R2 through R11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl, aikoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein each of R3 through R44 may be an acidic moiety further independently selected from acidic moieties of the formula -YnA wherein n is a number selected from zero through two, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from H w w w I 34 II II II -OH, -SH, -NR , -C-WH, -S-WH, -S-WH and -P-WH 15 W WR37 wherein each W is independently selected from oxygen atom, sulfur atom and NR33; wherein each of R34, R37 and R33 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benzyl; wherein each of R34 and R37 may be further independently selected from amino radical of the formula wherein each of R3^ and R40 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, benzyl and phenyl; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at 5 a single position selected from R2 through R31 or may be attached at any two adjacent positions selected from R2 through R13 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenalkyl and aralkyl; wherein each of R1 through R19, R34 and R37 through R40, Y and A and independently may be substituted at any substitutable position with one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, halo, oxo, haloalkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

An even more highly preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein R2 is selected from adamantyl, adamantylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-230 phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-135 (phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1oxobutyl, 2-(2, 5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2IE 911801 hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-l methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl and acetonitrile; where R2 is selected from alkyl, hydroxyalkyl, cycloalkyl, polycycloalkyl, adamantyl, adamantylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, haloalkyl, alkoxy, phenalkyl, phenyl, phenoxy, phenalkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, alkylthio, phenthio and phenalkylthio; wherein each of R3 through is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, acetyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein each of R3 through R11 may be an acidic moiety further independently selected from acidic moieties consisting of CO2H, CO2CH3, SH, CH2SH, C2H4SH, ΡΟ3Η2ζ NHSO2CF3, NHSO2C6F5z SO3H, CONHNH2, CONHNHSO2CF3, CONHOCH; CONHOC2H5z CONHCF3, OH, CH2OH, C2H4OH, ΟΡΟ3Η2/ OSO3H , wherein each of R44, R42 and R43 is independently selected from H, Cl, CN, NC>2, CF3/ C2F5, C3F7, CHF2/ CH2F, CO2CH3, CO2C2H5, SC>2CH3z SO2CF3 and SO2C6F5; wherein Z is selected from 0, S, NR44 and CH2; wherein R44 is selected from hydrido, CH3 and CH2CgH3. and wherein said acidic moiety may be a heterocyclic acidic group attached at any two adjacent positions of R3 through R44 so as to form a fused ring system with one of the phenyl rings of the biphenyl moiety of Formula I, said biphenyl fused ring system selected from IE 911801 and the esters, amides and salts of said acidic moieties; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

A class of compounds of particular interest consists of those compounds of Formula I wherein m is one; wherein R.1 is selected from adamantyl, adamant ylme thyl, adamantylethyl, adamantylpropyl, 3-phenylpropyl, 2-oxo-2phenylethyl, 2-hydroxy-2-phenylethyl, 1,1dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2- (phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-220 hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl and acetonitrile; wherein R^ is selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec25 butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, adamantyl, adamantylmethyl, adamantylethyl, adamantylpropy1, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethy1, hexyl, ethoxycarbonylmethyl, carboxymethyl, 15 naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethy1)-Eethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,510 dimethyoxyphenyl)-2-oxoethyl, 2-phenyl-2(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethy1, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl15 2E-propenyl, acetonitrile, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, propylthio, butylthio, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,120 difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein at least one of R2, R^, r8 and is an acidic group selected from CO2H, SH, PC>3H2Z SO3H, CONHNH2, CONHNHSO2CF3, OH, wherein each of R42 and R42 is independently selected from Cl, CN, NO2, CF3, CO2CH3 and SO2CF3; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

A class of compounds of more particular interest consists of those compounds of Formula I wherein m is one; wherein R1 is selected from 2-oxo-2(tricyclo[3.3.1.1.2·7]dec-2-yl)ethyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl15 2E-propenyl and 1-cyanobutyl; wherein R2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl, neopentyl, 1-cyanobutyl, propylthio and butylthio; wherein at least one of R2, R6, R8 and R^ is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, wherein each of R42 and R42 is independently selected from Cl, CN, NO2z CF3, CO2CH3 and SO2CF3; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

A class of compounds of even more particular interest consists of those compounds of Formula I wherein m is one; wherein R1 is selected from 2-oxo-2(tricyclo[3.3.1.1.3·7]dec-2-yl)ethyl, 3-phenylpropyl, 2oxo-2-phenylethy1, 2-hydroxy-2-phenylethyl, 1,1IE 911801 dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2- (phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphtha1enylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl and 1-cyanobutyl; wherein R2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, n-pentyl, 1-cyanobutyl, propylthio and butylthio; wherein each of R3, R4, R6, R7, R8, R10 and R11 is hydrido; wherein one of R5 and R8 is hydrido and the other of R3 and R^ is an acidic group selected from CO2H and H or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

A family of specific compounds of particular interest within Formula I consists of compounds, and their pharmaceutically-acceptable salts, of the group of compounds consisting of; 41 -[(1,3-dibutyl-4,5-dihydro-5-oxo-lH-l,2,4-triazol-4 30 yl)methyl][1,1’-biphenyl]-2-carboxylic acid; -butyl-2,4-dihydro-2-[2-oxo-2-(tricyclo[3.3.1.1.3·7]dec-2 yl)ethyl]-4-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4'ylmethyl]-3H-1,2,4-triazol-3-one; -butyl-2,4-dihydro-2-(3-phenylpropyl)-4-[2(lH-tetrazol5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one; 5-butyl-2,4-dihydro-2-(2-oxo-2-phenylethyl)-4-[2'-(1Htetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol5 3-one; -butyl-2,4-dihydro-2-(2-hydroxy-2-phenylethyl)-4-[21 - (1Htetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol3-one; 1,1-dimethylethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H10 tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4 triazole-l-acetate; -butyl-2,4-dihydro-2-hexyl-4-[2'-(lH-tetrazol-5-yl) [1,1'biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one; ethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'- (lH-tetrazol-515 yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-l-acetate; 3-butyl-4,5-dihydro-5-oxo-4-[2'—(lH-tetrazol-5-yl) [1,1'biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-l-acetic acid; 5-butyl-2,4-dihydro-2-(1-naphthalenylmethyl)-4-[2'-(1Htetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol20 3-one; -butyl-2-(2-cyclohexylethyl)-2,4-dihydro-4-[2'-(1Htetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol3-one; -butyl-2,4-dihydro-2-pentyl-4-[2'-(lH-tetrazol-5-yl) [1,1'25 biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one; ethyl [2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-5yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2, 4-triazol-l-yl]-1phenylethoxy]acetate; [2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-5 30 yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-l-yl]-1phenylethoxy]acetic acid; -butyl-2,4-dihydro-4-[2'-(lH-tetrazol-5-yl) [1,1'biphenyl]-4-ylmethyl]-2-(3,5,5-trimethylhexyl)-3H-1,2,4triazol-3-one; -butyl-2, 4-dihydro-2-[2-phenyl-2-(phenylmethoxy)-1(phenylmethyl)-E-ethenyl]-4-[2'-(lH-tetrazol-5-yl) [1,1'biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one; 2- (l-benzoyl-2-phenylethyl)-5-butyl-2, 4-dihydro-4-[2'-(1Htetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol 3- one; -butyl-2,4-dihydro-2-(1-oxobutyl)-4-[2'-(lH-tetrazol-55 yl) [1,1’-biphenyl]-4-ylmethyl]-3H-1, 2,4-triazol-3-one; -butyl-2,4-dihydro-2- [2- (2,5-dimethyoxyphenyl) -2oxoethyl]-4-[2'-(lH-tetrazol-5-yl) [1,1’-biphenyl]-4ylmethyl]-3H-1,2,4-triazol-3-one; -butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)ethyl]-410 [2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4 triazol-3-one; -butyl-2,4-dihydro-2-[2-(2,5-dimethyoxyphenyl)-2hydroxyethyl]-4-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4ylmethyl]-3H-l,2,4-triazol-3-one; -butyl-2,4-dihydro-2-(2-naphthalenylmethyl)-4-[2'- (1Htetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol 3-one; methyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-5yl) [1,1’-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1 20 pentanoate; ethyl p-benzoyl-3-butyl-4,5-dihydro-5-oxo-4-[2'- (1Htetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4triazole-l-propanoate; 2- (1-benzyoyl-l-methylethyl)-5-butyl-2,4-dihydro-4-[2 '- (1H tetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol 3- one; 3-butyl-4,5-dihydro-5-oxo-4-[2’-(lH-tetrazol-5-yl)[1,1'biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-l-pentanoic acid; 5-butyl-2-(cyclopropylmethyl)-2,4-dihydro-4-[2'-(1H30 tetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol 3-one; -butyl-2,4-dihydro-2-(3-phenyl-2E-propenyl)-4-[2'- (1Htetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol 3-one; and l-butyl-4,5-dihydro-5-oxo-a-propyl-4-[2’-(lH-tetrazol-5yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3acetonitrile.

C-2619/1 The term hydrido denotes a single hydrogen atom (H). This hydrido group may be attached, for example, to an oxygen atom to form a hydroxyl group; or, as another example, one hydrido group may be attached to a carbon atom to form a group; or, as another example, two hydrido groups may be attached to a carbon atom to form a -CH2group. Where the term alkyl is used, either alone or within other terms such as haloalkyl and hydroxyalkyl, the term alkyl embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are lower alkyl radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about five carbon atoms. The term cycloalkyl embraces cyclic radicals having three to about ten ring carbon atoms, preferably three to about six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term polycycloalkyl denotes a radical having two or more cycloalkyl rings; for example, two cycloalkyl rings may share a single atom to form a spiroring system, such as a dicyclohexyl-spiro ring system; or an alkylene group of one or more methylene radicals may bridge a cycloalkyl ring to form, for example, an adamantyl group. Preferred polycycloalkyl groups contained 10 to about 20 carbon atoms. The term haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with one or more halo groups, preferably selected from bromo, chloro and fluoro. Specifically embraced by the term haloalkyl are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, for example, may have either a bromo, a chloro, or a fluoro atom within the group. Dihaloalkyl and polyhaloalkyl groups may be substituted with two or more of the same halo groups, or may have a combination of different halo groups. A dihaloalkyl group, for example, may have two fluoro atoms, such as difluoromethyl and difluorobutyl groups, or two chloro atoms, such as a 2bI9/l dichloromethyl group, or one fluoro atom and one chloro atom, such as a fluoro-chloromethyl group. Examples of a polyhaloalkyl are trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl and 2,2,3,35 tetrafluoropropyl groups. The term difluoroalkyl embraces alkyl groups having two fluoro atoms substituted on any one or two of the alkyl group carbon atoms. The terms alkylol and hydroxyalkyl embrace linear or branched alkyl groups having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl groups. The term alkenyl embraces linear or branched radicals having two to about twenty carbon atoms, preferably three to about ten carbon atoms, and containing at least one carbon-carbon double bond, which carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety. The term alkynyl embraces linear or branched radicals having two to about twenty carbon atoms, preferably two to about ten carbon atoms, and containing at least one carbon-carbon triple bond. The term cycloalkenyl embraces cyclic radicals having three to about ten ring carbon atoms including one or more double bonds involving adjacent ring carbons. The terms alkoxy and alkoxyalkyl embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy group. The term alkoxyalkyl also embraces alkyl radicals having two or more alkoxy groups attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl groups. The alkoxy or alkoxyalkyl radicals may be further substi30 tuted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or haloalkoxyalkyl groups. The term alkylthio embraces radicals containing a linear or branched alkyl group, of one to about ten carbon atoms attached to a divalent sulfur atom, such as a methythio group. Preferred aryl groups are those consisting of one, two, or three benzene rings. The term aryl embraces aromatic radicals such as phenyl, naphthyl and biphenyl.

U-2619/1 The term aralkyl embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenyl methyl, phenylethyl, phenylbutyl and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable. The terms aryloxy and arylthio denote radical respectively, aryl groups having an oxygen or sulfur atom through which the radical is attached to a nucleus, examples of which are phenoxy and phenylthio. The terms sulfinyl and sulfonyl, whether used alone or linked to other terms, denotes respectively divalent radicals SO and SO2. The term aralkoxy, alone or within another term, embraces an aryl group attached to an alkoxy group to form, for example, benzyloxy. The term acyl whether used alone, or within a term such as acyloxy, denotes a radical provided by the residue after removal of hydroxyl from an organic acid, examples of such radical being acetyl and benzoyl. Lower alkanoyl is an example of a more prefered sub-class of acyl. The term amido denotes a radical consisting of nitrogen atom attached to a carbonyl group, which radical may be further substituted in the manner described herein. The amido radical can be attached to the nucleus of a compound of the invention through the carbonyl moiety or through the nitrogen atom of the amido radical. The term alkenylalkyl denotes a radical having a double-bond unsaturation site between two carbons, and which radical may consist of only two carbons or may be further substituted with alkyl groups which may optionally contain additional double-bond unsaturation. The term heteroaryl embraces aromatic ring systems containing one or two hetero atoms selected from oxygen, nitrogen and sulfur in a ring system having five or six ring members, examples of which are thienyl, furanyl, pyridinyl, thiazolyl, pyrimidyl and isoxazolyl. Such heteroaryl may be attached as a substituent through a carbon atom of the heteroaryl ring system, or may be attached through a carbon atom of a moiety substituted on a heteroaryl ring-member carbon atom, for example, through the methylene substituent of c-ίϋ 19/i imidazolemethyl moiety. Also, such heteroaryl may be attached through a ring nitrogen atom as long as aromaticity of the heteroaryl moiety is preserved after attachment. For any of the foregoing defined radicals, 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 one unsaturated bond, such as an allyl group, or may have a plurality of unsaturated bonds, with such plurality of bonds either adjacent, such as allene-type structures, or in conjugation, or separated by several saturated carbons.

Compounds of Formula I have been found to inhibit the action of angiotensin II in mammals.

Angiotensin II is a potent vasoconstrictor and participates in the formation of aldosterone which regulates sodium and water balance in mammals. Thus, compounds of Formula I are therapeutically useful in methods for treating hypertension by administering to a hypertensive patient a therapeutically-effective amount of a compound of Formula I. The phrase hypertensive patient means, in this context, a mammalian subject suffering from or afflicted by the effects of hypertension or susceptible to a hypertensive condition if not treated to prevent or control such hypertension.

Also included in the family of compounds of Formula I are optical isomeric forms including diastereoisomers. Further included in this invention are regioisomers of the compounds of Formula I, e.g., compounds having the biphenylalkyl moiety exchanged with the R1 substituent on the triazole ring nitrogen atoms shown in Formula I. Also included in this invention are the C-20i^/l pharmaceutically-acceptable salts of the Formula I compounds. The term pharmaceutically-acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceuticallyacceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric,· pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methansulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N* dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I. <_-Zb ii?/1 IE 91180"* General Synthetic Procedures The compounds of the invention can be synthesized according to the following procedures of Schemes I-VI, wherein each of the R substituents are as defined for Formula I above, except where further noted IE 9118°1 SCHEME I s= :N ./ CO2Et RzMgX ,CO2Et NH2NHR1 R1 Synthetic Scheme I shows the preparation of 1,2,4-triazolone 1 from isothiocyanate 2 via Nethoxycarbonyl thioamide 2 according to the general procedure outlined by Papadopoulos, Ε. P. and George, B., J, Qrg. Chem.. 41, 3233 (1976). In the first step, Nethoxycarbonyl thioamide 2 can be prepared from ethoxycarbonyl isothiocyanate 2 and the corresponding organometallic 4 . The N-ethoxycarbonyl thioamide 2 can be converted to triazolone 1 by the action of the corresponding hydrazines 2 as described in the reference given above. ch3 SCHEME II CH2Br /S /X Synthetic Scheme II shows the preparation of the alkylating agent £ from the corresponding precursor 2. When R5 equals CO2CH3, 7 was purchased from Chemo Dynamics Inc. 44 SCHEME III ch3 ch3 A a I 1. NaOH/HCI 2. (COCI)2 θΗ 3 3. NH3 4. SOCI2 .CN AA R = CO2CH3 AA Me3SnN3 Synthetic Scheme III shows the preparation of the alkylating agent precursor 2 where R2 equal CN4C(C6H5)3 from the correspondinq methyl ester 2 (R^ = CO2CH3). In step 1, the methyl ester is converted to the correspondinq acid (R2 = CO2H) by the action of sodium hydroxide/hydrochloric acid. In step 2, the acid is converted to the correspondinq acid chloride (R2 = COCI) by the action of oxalyl chloride. In step 3, the acid chloride is converted to the correspondinq primary amide (R2 = CONH2) by the action of ammonium. In step 4, the amide is converted to the correspondinq nitrile 2 by the action of thionyl chloride at reflux. The nitrile 2. is reacted with trimethyltin azide in toluene at reflux to give the corresponding trimethyltin protected tetrazole £; deprotection with acetic acid/water and reprotection with triphenylmethyl chloride/triethylamine gives the N-trityl tetrazole 2 (R2 = CN4C(C6H5) 3) .

SCHEME IV N-N U.X KOC(CH3)3 -1 DMF N-N Θ R N K R5 = CN4CPh3 HOAc or_ R5 = CN Me3SnN3 ch2 1 N.B.: R1 may also be hydrido for compound 1 and 11 Synthetic Scheme IV shows the coupling reaction of the 1,2,4-triazolone 1 with the appropriate alkylating reagent ί and subsequent conversion to the compounds of the invention. In the first step, 1 is treated with a base, such as potassium t-butoxide, to generate the corresponding anion 10. Anion 10 is reacted with an alkylating agent £ to give coupled product 11. The trisubstituted 1,2,4triazolone 11 can be subsequently converted to the corresponding acid 12 or tetrazole 13 by treatment with one of the appropriate reagents as shown in Scheme IV.

Alternatively, the compounds of the invention can be synthesized according to the following procedures of Scheme V and VI.

IE 911801 SCHEME V CH2Br NaN3 CHoN 3 7 R5 = CN or CO2C(CH3)3 H2, Pd/C 4 6 Synthetic Scheme V shows the preparation of semicarbazide 14 from bromide Semicarbazide 14 can be prepared from aminomethylbiphenyl 15 and the corresponding hydrazide 16 which can be obtained by treating its ester precursor with hydrazine. Amine 15 can be prepared by hydrogenation of the corresponding azide 17 which can be obtained from its bromide precursor 5 by treatment with sodium azide.

SCHEME VI NaOMe, CH3OH -—> reflux zH N-N R5 = CN or CO2C(CH3)3 KOC(CH3)3, DMF R5 1 9 Synthetic Scheme VI shows the cyclization of 14 to and the subsequent alkylation to 11. In the first step, triazolone 18 can be prepared by dehydration of semicarbazide 14 in alcohol with a base catalyst, such as sodium methoxide. Then triazolone 18 is treated with a base, such as potassium t-butoxide, to generate the corresponding anion 19. Anion 19 is reacted with an alkylating agent 20 to give alkylated product H which may be converted to the corresponding acid 12 or tetrazole 11 by treatment with one of the appropriate reagents as shown in Scheme IV.

The following Examples 1-30 are detailed, descriptions of the methods of preparation of compounds of Formula I. These detailed preparations fall within the scope of, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention. These Examples are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight unless otherwise indicated.

C-2619/1 EXAMPLE #1 N-N 4 ’ — Γ(1.3-dibutyl-4.5-dihydro-5-oxo-lH-l.2.4-triazol-4 yllmethyll Γ1.1'-biphenyl!-2-carboxylic acid Step 1:_Preparation of 2-(p-tolyl)benzoic acid A mixture of 52 g (0.23 mol) of methyl 2-(ptolyl)benzoate (Chemo Dynamics Inc.) and 100 mL (0.25 mol) of 2.5 N aqueous sodium hydroxide solution in 100 mL of methanol was stirred at room temperature for about 6 h, then at reflux for about 6 h. The resulting solution was concentrated in vacuo to half of its original volume. The aqueous solution was acidified with 3 N hydrochloric acid to about pH 3 and extracted with methylene chloride. The extracts were dried (MgSO4) and concentrated in vacuo to give 48.7 g (99%) of 2-(ρ-tolyl)benzoic acid as a white solid: ^H NMR (CDC13) δ 2.40(s, 3H), 7.00-8.05(m, 8H), 10.4-11.4(broad S, IH).

C-2619/1 Step .2:_Preparation of tert-butyl 2-(p-tolvl)benzoate To 48 g (0.226 mol) of 2-(p-tolyl)benzoic acid from step 1 and 5 mL of concentrated sulfuric acid in 100 mL of anhydrous ether cooled in a dry ice-acetone bath was transferred 100 mL of 2-methylpropene. The resulting mixture was agitated on a Parr apparatus at room temperature for about 15 h, and the excess of 2methylpropene was allowed to evaporate at room temperature. The ethereal solution was neutralized with 2.5 N aqueous sodium hydroxide solution, and extracted with three 200 mL-portions of ether. The combined extracts were dried (MgSC>4) and concentrated in vacuo to give 57.2 g (94%) of tert -butyl 2-(p-tolyl) benzoate as a solid: 1H NMR (CDCI3) δ 1.29(s, 9H) , 2.40(s, 3H) , 7.21(s, 4H) , 7.25-7.55(m, 3H), 7.7-7.8(m, IH). step 3:_Preparation ...oi .-lzbromomgPhyl-21 - text 20 but oxycarbonylbipheny1 To a mixture of 57 g (0.213 mol) of tertbutyl 2-(p-tolyl)benzoate from step 2 in 1.7 L of carbon tetrachloride at about 65°C was added 36.4 g (0.204 mol) of N-bromosuccinimide (NBS) and 0.82 g (5 mmol) of azobisisobutyronitrile (AIBN) in one portion. The resulting solution was stirred at reflux for about 6 h followed by addition of another 1.7 g (9.6 mmol) of Nbromosuccinimide and 0.1 g (0.6 mmol) of AIBN. The mixture was stirred at reflux for additional 13 h, and concentrated in vacuo. The residue was dissolved in ethyl acetate-hexane (1:3) and filtered through a pad of silica gel, eluted with ethyl acetate-hexane (1:3) to give 79 g (guantitative) of a sample which contained C-2619/1 mostly desired product, 4-bromomethyl-2tert butoxycarbonylbiphenyl, with a small amount of dibrominated product and starting material. No further purification, however, was attempted and the mixture was used directly in subsequent reactions: -'H NMR (CDCI3) δ 1.26(s, 9H), 4.56(s, 2H), 7.2-7.9(m, 8H).

Step 4: Preparation of 4-azidomethyl-2’- tert 10 butoxycarbonylbiphenyl The mixture of 11.0 g (0.032 mol) of 4bromomethyl-21 - tert -butoxycarbonyl-biphenyl from step 3 and 4.6 g (0.071 mol) of sodium azide in 42 mL of dimethylformamide and 4.2 mL of water was stirred at room temperature for about 24 h and concentrated in vacuo. The residue was extracted with ethyl acetate, and the combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo to give 10 g (quantitative) of 4-azidomethyl-2'- tert -butoxycarbonyl biphenyl as a yellow oil: NMR (CDCI3) δ 1.26 (s, 9H), 4.38(s, 2H), 7.2-7.9(m, 8H).

Step 5: Preparation of 4-aminomethyl-21- tert butoxycarbonylbiphenyl A suspension of 10 g (32 mmol) of the azidomethylbiphenyl from step 4 and 0.6 g of 10% palladium on carbon in 30 mL of absolute ethanol was agitated on a Parr apparatus under a hydrogen atmosphere at 40 psi for about 20 h. The mixture was filtered through a pad of celite and concentrated in vacuo to give 9.2 g (quantitative) of 4-aminomethy1-2'-tert c-2(>vm butoxycarbonylbiphenyl as a yellow oil: H NMR (CDCI3) δ 1.28(s, 9H), 1.71(broad s, 2H), 3.92(s, 2H), 7.2-7.9(m, 8H) .

Step 6: Preparation of tert-butyl 4*-Ι'ΓΓΓ2—(1oxopenty1)hydrazinolcarbonyl!aminolmethyII Γ1.11 biphenyl!-2-carboxylate To 6.4 mL of 1M (6.4 mmol) phosgene in toluene and 5 mL of toluene at 0°C was added dropwise a solution of 1.0 g (3.53 mmol) of 4-aminomethyl-2’- tertbutoxycarbonylbiphenyl in 5 mL of methylene chloride along with dropwise addition of 1.5 mL (18.5 mmol) of 0 pyridine. The resulting mixture was stirred at 0 C for about 30 min, at room temperature for about 1.5'h, and the excess of phosgene was removed under a stream of nitrogen. To the mixture was added 800 mg (6.9 mmol) of valeric acid hydrazide (Lancaster Synthesis), 1.0 mL (12.3 mmol) of pyridine and 2 mL of ether, and the resulting mixture was stirred at room temperature for about 2.5 h. The reaction mixture was concentrated in vacuo, and the residue was chromatographed over silica gel (eluted with isopropanol-hexane, 1:5) to give 780 mg (52%) of semicarbazide as a white solid: NMR (CDCI3) δ 0.86(t, J = 7.2 Hz, 3H), 1.28(s, 9H), 1.20-1.40(m, 2H) , 1.56(quintet, J = 7.2 Hz, 2H) , 2.20 (t, J = 7.5 Hz, 2H), 4.38(d, J = 6 Hz, 2H), 6.27(broadt, 1H), 7.2-7.5(m, 7H), 7.76(dd, J = 7.5, 1.0 Hz, 1H), 7.95-8.05(m, 1H), 8.85(broad s, 1H); 13C NMR (CDCI3) 5 13.7, 22.3, 27.4, 27.7, 33.6, 43.7, 127.0, 128.8, 129.7, 130.7, 132.7, 127.7, 140.7, 141.7, 158.3, 167.9, 173.0.

C-261-9/1 Step. 7;_Preparation of tert-butyl 4Γ(3-butyl-4.5dihydro-5-oxo-l.2,4-triazol-4-yl)methyl! Γ1.11-biphenyl1 2-carboxyIate To 500 mg (1.18 mmol) of the semicarbazide from step 6 in 10 mL of methanol and 5 mL of toluene was added 126 mg (2.33 mmol) of sodium methoxide and the resulting mixture was stirred under vigorous reflux for about 48 h with a moisture trap (molecular sieve, 3A) attached between a condenser and the reaction vessel.

The mixture was acidified with acetic acid and concentrated in vacuo. The residue was dissolved in chloroform and washed with water, saturated sodium bicarbonate and brine. The extract was dried (MgSC>4) and concentrated in vacuo. The residue was chromatographed over silica gel (eluted with ethyl acetate-hexane, 2:1) to give 480 mg (90%) of 3-butyl1,2,4-triazolone as an oil: 4H NMR (CDCI3) δ 0.90 (t, J = 7.2 Hz, 3H), 1.24(s, 9H) , 1.30-1.45(m, 2H), 1.62 (quintet, J = 7.8 Hz, 2H) , 2.43(t, J = 7.5 Hz, 2H) , 4.87(s, 2H), 7.2-7.55(m, 7H), 7.78(dd, J =7.5, 1.2 Hz, IH) .

Step 8: Preparation of tert-butyl.4,-f(l,3-dibutvi-4.5dihydro-5-oxo-lH-l.2,4-triazol-4-yl)methynn, l·' biphenyl1-2-carboxvlate To 226 mg (0.555 mmol) of the 3-butyi-l,2,430 triazolone from step 7 in 5 mL of Ν,Ν-dimethylformamide at about 5°C was added 0.66 mL (0.66 mmol) of 1 M potassium tert-butoxide in tetrahydrofuran. The o resulting solution was stirred at about 5 C for 20 min, followed by addition of 200 ph (1.76 mmol) of 12619/1 ' IE 911801 iodobutane. The mixture was stirred at room temperature for 30 min, quenched with acetic acid and concentrated in vacuo. The residue was chromatographed (eluted with ethyl acetate-hexane, 1:2) to give 210 mg (82%) of dibuty1-1,2,4-triazolone as an oil: '•H NMR (CDCI3) δ 0.81.0(m, 6H), 1.24 (s, 9H), 1.24-1.45 (m, 4H), 1.50-1.68(m, 2H), 1.68-1.80 (m, 2H), 2.41(t, J = 7.5 Hz, 2H), 3.80(t, J = 7.2 Hz, 2H), 4.86(s, 2H), 7.20-7.34[m (with s at 7.28), 5H], 7.35-7.55(m, 2H) , 7.78(dd, J = 7.5, 1.2 Hz, 1H); 13C NMR (CDCI3) δ 14.2, 20.3, 22.8, 26.3, 28.1, 28.5, 31.4, 45.0, 45.6, 127.4, 127.8, 129.7, 130.2, 131.0, 131.2, 133.4, 135.5, 141.8, 142.2, 146.7, 154.6, 168.3; mass spectrum (FAB) m/e (relative intensity) 470(40), 414(100). step 9:_Preparation.of 4'-f ¢1,3~dikutyi-4,5-dihydro.-5r oxo-lH-1,2, 4-triazol-4-yl)methyl1 Ll·,!,'-biphenyl·!-2carboxylic acid To 165 mg (0.356 mmol) of the tert-butyl ester from step 8 in 2 mL of chloroform was added 1 mL (13 mmol) of trifluoroacetic acid (TFA) . The resulting solution was stirred at room temperature for about 15 h, and concentrated in vacuo. The residue was chromatographed over silica gel (ethyl acetate-methanolacetic acid, 85:10:5) to give 152 mg (quantitative) of product compound of example 1 as a solid: 1H NMR (CDCI3) δ 0.75-1.0(m, 6H), 1.2-1.4(m, 4H), 1.52(quintet, J = 7.8 Hz, 2H), 1.69 (quintet, J = 7.5 Hz, 2H), 2.37 (t, J = 7.5 Hz, 2H) , 3.78(t, J = 6.9 Hz, 2H) , 4.85(s, 2H) , 7.12(d, J = 7.8 Hz, 2H), 7.2-7.32(m, 4H), 7.37 (t, J = 7.2 Hz, 1H) , 7.50(t, J = 7.5 Hz, 1H), 7.88(d, J = 7.5 Hz, 1H); 13CNMR (CDCI3) δ 14.11, 14.13, 20.2, 22.6, 26.1, 28.4, -2619/1 31.2, 45.0, 45.7, 127.1, 127.8, 129.6, 130.7, 131.0, 131.4, 132.2, 135.0, 141.5, 142.9, 147.4, 154.5, 172.5; mass spectrum (FAB) m/e (relative intensity) 408(33) , 390(20), 211 (100).

C-2619/1 EXAMPLE #2 2.5-dibutvl-2,4-dihydro-4-ί Γ2-(lH-tetrazol-5_-yl) fl.l'bipbenyl,L-±'-ryl imethy I ] -311-1, 2.4-±piazQlr3rQna Step 1: Preparation of N-ethoxycarbonyl thiovaleramide To 95 ml of 2 M (0.190 mol) butylmagnesium chloride in tetrahydrofuran and 55 mL of anhydrous ether at about -60°C (chloroform-dry ice) was added dropwise 24.4 g (0.162 mol) of ethoxycarbonyl isothiocyanate in 205 mL of anhydrous ether over a period of 2 h. The resulting mixture was stirred cold for about 3 h and allowed to slowly warm to room temperature. The solvent was decanted and the solid was washed with four 50 mLportions of ether. The solid was partitioned between 200 mL of ether and 200 mL of saturated ammonium chloride. The aqueous layer was extracted with two 50 mL-portions of ether and the combined extracts were dried (MgSCM) and concentrated in vacuo . The red oily residue was distilled under reduced pressure to give 18 g (58%) of N-ethoxycarbonyl thiovaleramide as a yellow oil: bp 86 °C/ 1.5 torr; 3H NMR (CDCI3) δ 0.90 (t, J = 7.5 Hz, 3H) , 1.20-1.5(m, 5Η) , 1.65 -1.8(m, 2H) , 3.20(t, J = 7.5 Hz, 2H) , 4.2(q, J = 7.2 Hz, 2H) , 9.2(broad s, 1H) . cwm Step 2: Preparation of 5-butyl-2,4-dihydro-l,2,4 triazol-3-one To 567 mg (3 mmol) of N-ethoxycarbonyl thiovaleramide in 6 mL of absolute ethanol at room temperature was added 190 mL (6 mmol) of 98% hydrazine in 1.5 mL of ethanol. The resulting solution was stirred at about 84°C for 30 min, and concentrated in vacuo. The resulting solid was rinsed with etherhexane, and collected by filtration to give 320 mg (76%) of 5-butyl-triazol-3-one as a white solid: NMR (CDCI3) δ 0.85 (t, J = 7.8 Hz, 3H), 1.2-1.4(m, 2H), 1.55 (quintet, 2 = 7.8 Hz, 2H), 2.0-3.0( m (with t at 2.42, J = 7.8 Hz), 3H], 9.6-ll(broad s, IH).

Step 3: Preparation of N-triphenylmethyl-5-Γ2-(4'bromomethylbiphen-2-yl1 tetrazole.

A 542.5 g (2.4 mol) sample of methyl 2-iptolyl) benzoate (Chemo Dynamics Inc.) was dissolved in 5.5 L of ethanol and treated with 3 L (7.5 mol) of 2.5 N sodium hydroxide. The reaction was stirred overnight at ambient temperature and treated with an additional 480 mL (6.0 mol) of sodium hydroxide; stirring was continued for an additional 24 h and the ethanol removed in vacuo. The remaining solution was cooled in ice and acidified to pH 1 with hydrochloric acid which caused the product to precipitate; filtration and drying in vacuo gave 510 g (100%) of crude 2-(p-tolyl)benzoic acid: mp 145.0147.5°C; NMR (CDCI3) δ 2.40 (s, 3H) , 7.17-7.28 (m, 4H) , 7.35-7.45(m, 2H) , 7.51-7.59(m, IH), 7.90-7.97(m, IH) .

The crude acid was suspended in 1 L of toluene and -2619/1 slowly treated with 400 g (3.15 mol) of oxalyl chloride under nitrogen. The resulting solution was allowed to stir at ambient temperature for 4.5 h and concentrated in vacuo to remove excess oxalyl chloride. The residue was redissolved in 2 L of toluene and treated with 92.8 g (5.46 mol) of anhydrous ammonia. The reaction was filtered and the filtrate concentrated in vacuo producing 424 g (84%) of crude 2-(p-tolyl)benzamide: mp 128-130°C; NMR (CDCI3) δ 2.40(s, 3H) , 5.28(br s, IH) , .77(br s, IH), 7.21-7.53(m, 7H), 7.76-7.83(m, IH). 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 thionyl chloride removed in vacuo. The residue was dissolved in 800 mL of toluene and reconcentrated in vacuo. On standing overnight, the residue crystallized. The crystals were collected and washed with hexane to give 296 g (64%) of 2- (ptolyl)benzonitrile: mp 50.5-52.0°C; NMR (CDCI3) δ 2.42(s, 3H), 7.22-7.34(m, 2H), 7.37-7.52(m, 3H), 7.5820 7.66(m, IH), 7.72-7.78(m, IH) . A 286 g (1.48 mol) sample 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 cooled; filtration gave 600 g of crude N-trimethylstannyl-5-[225 (4'-methylbiphen-2-yl]tetrazole: mp 271-272°C (dec.); NMR (DMSO-dg) δ 0.36 (br t, J = 34 Hz, 9H) , 2.24 (s, 3H) , 6.89-7.06(m, 4H) , 7.35-7.55 (m, 4H) . The crude Ntrimethylstannyl tetrazole was suspended in 4270 mL of toluene and 287 mL of anhydrous tetrahydrofuran (THF) and treated with 63.4 g (173 mol) of anhydrous hydrogen chloride at ambient temperature under nitrogen with stirring. The reaction was allowed to stand overnight and filtered; recrystallization from toluene gave 217 g (62%) of 5-[2-(4'methylbiphen-2-yl)]tetrazole as a 2619/1 solid: mp 149-152°C; NMR (DMSO-d6) 62.28 (s, 3H) , 6.947.02(m, 2H), 7.08-7.15(m, 2H), 7.50-7.59(m, 2H), 7.627.72 (m, 2H). A 200 g (0.85 mol) sample of the tetrazole was suspended in 3.3 L of dichloromethane and treated with 262 g (0.91 mol) of triphenylmethyl chloride and 141 mL (1.0 mol) of anhydrous triethylamine. The reaction was stirred at reflux for 3 h under nitrogen, washed with water, dried (MgSO4), and concentrated in vacuo. Recrystallization gave 338 g (83%) of N10 triphenylmethyl-5-[2-(4'-methylbiphen-2-yl)]tetrazole as a colorless solid: mp 170-173°C; NMR (CDCI3) 6 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, IH). 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' 20 bromomethylbiphen-2-yl)]tetrazole as a colorless solid: mp 140-142°C; NMR (CDCI3) 6 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, IH). NMR indicated that this material was only 85% pure; it contained 7% of corresponding dibromo- compound (6 6.50) and 8% of starting material (6 2.27); however, no further attempts at purification were made and this mixture was used in all subsequent alkylation reactions.

C-?A 1 0/1 Stgp.Jj_Preparation of 5-butyl-2.4-dihydro-4-rr2-(ltriphenylmethyl-lH-tetrazol-5-vl) ri.l'-biphenylWyl!methyl!-3H-1,2,4-triazol-3-one To 247 mg (1.75 mmol) of the 5-butyl-triazol 3-one from step 2 in 17 mL of Ν,Ν-dimethylformamide was added dropwise 1.8 mL (1.8 mmol) of 1 M potassium tertbutoxide in tetrahydrofuran. The resulting light brown solution was stirred at room temperature for 10 min, followed by addition of 952 mg (1.7 mmol) of Ntriphenylmethyl-5-[2-(41-bromomethylbiphen-2 yl)]tetrazole from step 3 in two portions, 30 min apart. The resulting solution was stirred at room temperature for about 1 h, quenched with 160 mL of acetic acid and concentrated in vacuo. The residue was chromatographed (eluted with isopropanol-hexane, 1:7) to give 290 mg (27%) of N-substituted triazolone as a solid: 1H NMR (CDCI3) δ 0.85(t, J = 7.3 Hz, 3H), 1.28(septet, J = 7.5 Hz, 2H), 1.53(quintet, J = 7.7 Hz, 2H), 2.29 (t, 2 = 7.3 Hz, 2H) , 4.71(s, 2H) , 6.90(d, J = 7.2 Hz, 6H) , 7.01(d, 2 = 8.3 Hz, 2H) , 7.12(d, 2 = 8.2 Hz, 2H) , 7.2-7.4(m, 10H), 7.4-7.55(m, 2H), 7.9-8.0(m, IH), 9.0(s, IH); mass spectrum (FAB) m/e (relative intensity) 624(22), 568(4), 388 (30), 382(18), 339(100).

Step 5: Preparation of 2,5-dibutyl-2.4-dihydro-4-ίi2r (l-triphenylmethyl-lH-tetrazol-5-yl) fl, 11-biphenyl!r4Pr yllmethyl!-3H-1,2.4-triazol-3-one To 240 mg (0.389 mmol) of the N-substituted triazolone from step 4 in 4.5 mL of Ν,Νdimethylformamide was added 460 |iL (0.46 mmol) of 1 M potassium tert-butoxide in tetrahydrofuran. The C-2619/1 resulting solution was stirred at room temperature for 10 min, followed by addition of 150 (iL (1.32 mmol) of 1iodobutane. The mixture was stirred at room temperature for about 1 h, quenched with acetic acid and concentrated in vacuo. The residue was filtered through a pad of silica gel (eluted with ethyl acetate-hexane, 1:3) to give 255 mg (97%) of N,Ν'-disubstituted triazolone as an oil: NMR (CDCI3) δ 0.84 (t, J = 7.3 Hz, 3H) , 0.96(t, J = 7.4 Hz, 3H), 1.27(septet, J = 7.3 Hz, 2H), 1.38(septet, J = 7.7 Hz, 2H), 1.50(quintet, 7.9Hz, 2H), 1.75(quintet, J = 7.5 Hz, 2H), 2.28(t, J = 8.0 Hz, 2H) , 3.80(t, J = 7.3 Hz, 2H) , 4.70(S, 2H) , 6.876.96(m, 6H), 7.01(d, J = 8.3 Hz, 2H), 7.11(d, J = 8.3 Hz, 2H) , 7.20-7.40(m, 10H), 7.40-7.53(m, 2H), 7.8815 7.95(m, 1H) ; mass spectrum (FAB) m/e (relative intensity) 680(20), 624(4), 444 (25), 410(20), 395(100), 381(15).

Step 6:_Preparation of 2.5-dibutyl-2.4-dihydro-4-ίf2(lH-tetrazol-5-y1) ί 1.1 ’-biphenyl1-41-vlimethvl!-3H= 1.2.4-triazol-3-one A solution of 245 mg (0.364 mmol) of the N,N' disubstituted triazolone from step 5 in 4 mL of acetic acid and 0.4 mL of water was stirred at room temperature for about 17 h and concentrated in vacuo. The oily residue was dissolved in saturated sodium bicarbonate and washed with three 5 mL-portions of ether-hexane.

The aqueous layer was acidified to about pH 3 whith 3 N hydrochloric acid and extracted with chloroform and ethyl acetate. The combined extracts were dried (MgSOzj) and concentrated in vacuo to give 150 mg (quantitative) of the product compound of example 2 as a solid: 1H NMR C-2619/1 (CDC13) δ 0.85(t, J = 7.1 Hz, 6H), 1.15-1.42(m, 4H), 1.42-1.70[m (with two quintet at 1.50 and 1.61, J = 7.4 and 7.3 Hz), 4H] , 2.34 (t, J = 7.5 Hz, 2H), 3.64 (t, J = 7.2 Hz, 2H), 4.69(s, 2H) , 7.06(q, J = 8.1 Hz, 4H), 7.27(broad s, 1H) , 7.41(d, J = 7.5 Hz, 1H), 7.45-7.65(m, 2H) , 7.82(d, J = 7.2 Hz, 1H); mass spectrum (FAB) m/e (relative intensity) 432(40), 207(100), 178(25); HRMS. calcd for M+H: 432.2512. Found: 432.2510.

C-2619/1 General Procedure: The Reaction of Triazolone with Alkylating Reagent and The Deprotection of Trityl Tetrazole Step 1: Alkylation of 5-butyl-2.4-dihydro-4-Γ2'- (1 5 triphenylmethyl-lH-tetrazol-5-yl) Π.1 *-biphenvll-4ylmethyl]-3H-1.2.4-triazol-3-one To a solution of 0.4-0.5 mmol of 5-butyl-2,4dihydro-4-[ 2 ' — <1-triphenylmethyl-lH-tetrazol-5-yl) [1,1’10 biphenyl]-4-ylmethyl]-3H-1, 2,4-triazol-3-one (prepared in example 2, step 4) in 4-5 mL of Ν,Ν-dimethylformamide was added dropwise 1.2 eqivalent of potassium tert-butoxide (1.0 M in tetrahydrofuran), and the resulting yellow solution was stirred at room temperature for 10 min. To the mixture was added 1.5 eqivalent of an appropriate alkylating reagent dropwise (or in portions, if’ solid).

The resulting solution was stirred at room temperature for 1-5 h, and concentrated in vacuo. The crude product could be purified by silica gel chromatography, eluting with ethyl acetate/hexane, to give pure alkylated product. In most cases, the crude mixture was pure enough, and was used directly for deprotection in step 2.

Step 2: Deprotection of trityl tetrazolyl biphenvl triazolone The alkylated product obtained from step 1 was dissolved in 12 mL of glacial acetic acid and 1.2 mL of water. The resulting solution was stirred at room temperature for 20 h, and concentrated in vacuo. The solid residue was stirred with 5 mL of saturated sodium bicarbonate and 10 mL of ether for 10 min. The ethereal solution was removed and the aqueous layer was washed twice with fresh ether. The resulting aqueous layer was C-2619/1 acidified with 3 N hydrochloric acid to about pH 3, and extracted with three 10 mL-portions of chloroform. The combined extracts were dried (MgSC>4) and concentrated in vacuo. The resulting oil or foam solidified upon standing to give the desired tetrazolylbiphenyl 2,5-disubstitutedtriazolone.

C-2619/1 -butyl-2.4-dihydrc-2- Γ2-οχο-2- (tricyclo f 3.3.1.1 .^-1 dec-iyl)ethyl)-4-Γ2'-(lH-tetrazol-5-yl) f1,1'-biphenyl1-4 'ylmethyl!-3H-1.2,4-triazol-3-one Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 300 mg (0.486 mmol) of 5-butyl-2,4-dihydro-4-[2'-(1 triphenylmethyl-lH-tetrazol-5-yl) [1,1'-biphenyl]-4 ylmethyl]-3H-1,2,4-triazol-3-one in 4.5 mL of N,N15 dimethylformamide was reacted with 0.574 mmol of potassium tert-butoxide in tetrahydrofuran and 150 mg (0.584 mmol) of 1-adamantyl bromomethyl ketone. The alkylated product was deprotected following General Procedure step 2 and the resulting solid was recrystallized from ethyl acetate/hexane to give 180 mg (67%) of the desired product compound as a white solid: -'-H NMR (DMSO-d6) δ 0.77 (t, J = 7.25 Hz, 3H) , 1.22 (m, 2H) , 1.38 (quintet, J = 7.26 Hz, 2H) , 1.67 (br s, 6H) , 1.80(br s, 6H), 1.98(br s, 3H) , 2.37 (t, J = 7.25 Hz, 2H) , 4.76(br s, 2H) , 4.81(br s, 2H) , 6.87(d, J = C-2619/1 8.05 Hz, 2H), 7.14(d, J = 8.06 Hz, 2H), 7.48-7.60(m, 2H), 7.60-7.72 (m, 2H); MS (FAB) m/e (relative intensity) 552(35) 207 (100), 178 (40); HRMS. calcd for M+H: 552.3087.

Found: 552.3108.

C-2619/1 -butvl-2.4-dihydro-2-(3-phenylpropyl)-4-f 2 ’ - (lH-tetrazol5-vl) Γ1,1'-biphenyl]-4-vlmethyll-3H-1,2.4-triazol-3-one Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 300 mg (0.486 mmol) of 5-butyl-2,4-dihydro-4-[2 '- (1triphenylmethyl-lH-tetrazol-5-yl) [1,1’-biphenyl]-4 ylmethyl]-3H-1,2,4-triazol-3-one in 4.5 mL of Ν,Νdimethylformamide was reacted with 0.574 mmol of potassium tert-butoxide in tetrahydrofuran and 89 pL (0.583 mmol) of l-bromo-3-phenylpropane. The alkylated product was deprotected following General Procedure step 2 to give 218 mg (90%) of the desired product compound as a white solid: !h NMR (CDCI3) 80.82(t, J = 7.25 Hz, 3H), 1.27(septet, J= 7.25 Hz, 2H), 1.50 (quintet, J = 7.25 Hz, 2H) , 2.01 (quintet, J = 7.25 Hz, 2H), 2.31(t, J = 7.66 Hz, 2H), 2.59(t, J = 7.65 Hz, 2H), 3.75(t, J = 6.85 Hz, 2H) , 4.71 (br s, 2H), 6.95-7.30(m, 9H), 7.30-7.60(m, 3H), 7.68(d, J =7.25 Hz, 1H); MS (FAB) m/e (relative intensity) 494 (32), 207 (100), 178 (45); HRMS. calcd for M+H: 494.2268. Found: 494.2678.

C-2619/1 -butyl-2.4-dihydro-2-(2-oxo-2-phenylethyl)-4-f2 1 - (1Htetrazol-5-yl) fl.1'-biphenyl)-4-ylmethyll-3H-1,2,4-triazol 3-Qne Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 550 mg (0.972 mmol) of 5-butyl-2,4-dihydro-4-[2’- (1 triphenylmethyl-lH-tetrazol-5-yl) [1,1'-biphenyl]-4ylmethyl]-3H-1,2,4-triazol-3-one in 9 mL of N,N15 dimethylformamide was reacted with 1.14 mmol of potassium tert-butoxide in tetrahydrofuran and 215 mg (1.08 mmol) of 2-bromoacetophenone. A portion of the alkylated product (220 mg, 0.299 mmol) was deprotected following the General Procedure step 2 to give 127 mg (86%) of the desired product compound as a white solid: 1H NMR (CDCI3) δ 0.80 (t, J = 7.25 Hz, 3H), 1.27 (septet, J = 7.7 Hz, 2H), 1.51(quintet, J = 7.26 Hz, 2H) , 2.36(t, J = 7.66 Hz, 2H), 4.74(br s, 2H), 5.17(br s, 2H), 7.02(br s, 4H), 7.307.65 (m, 6H), 7.79(d, J = 7.25 Hz, IH) , 7.86(d, J = 7.25 Hz 2H); MS (FAB) m/e (relative intensity) 494 (17), 451 (3) , C-2619/1 376 (8), 207 (100); HFMS. calcd for M+H: 494.2304. 494.2300.

Found: C-2619/1 EXAMPLE # 6 -butyl-2.4-dihydro-2-(2-hydroxy-2-phenylethyl)-4-Γ21 - (1Htetrazol-5-yl) fl.11-biphenyll -4-ylmethyll-3H-1,2,4-triazol3-one To a solution of 400 mg (0.544 mmol) of trityl tetrazolylbiphenyl ketone from example 5 in 4 mL of methanol and 2 ml of tetrahydrofuran at 0°C was added 25 mg (0.661 mmol) of sodium borohydride in portions. The resulting solution was stirred at 0 °C for 2 h, and quenched with saturated ammonium chloride. Volatiles were removed in vacuo . The aqueous layer was extracted with chloroform, dried (MgSCM) and concentrated in vacuo to give 380 mg (95%) of the desired alcohol. Following the General Procedure step 2, 200 mg (0.271 mmol) of the alcohol obtained from procedure described above was deprotected, and the resulting solid was recrystallized to give 102 mg (76%) of the desired product compound as a white solid: 1H NMR (DMSO-d6) δ 0.77(t, J = 7.25 Hz, 3H), 1.10-1.28(m, 2H), 1.28-1.45(m, 2H), 2.34(t, J = 7.65 Hz, 2H), 3.73(dd, J = 13.7, 6.0 Hz, IH), 3.85(dd, J = 13.7, 7.7 Hz, IH), 4.74(br s, 2H) , 4.88 (q, J = 6 Hz, IH) , 5.54 (d, J = 4.8 Hz, lH) , C-2619/1 6.97(d, J = 8.1 Hz, 2H), 7.04(d, J = 8.4 Hz, 2H), 7.107.40(m, 5H), 7.45-7.60(m, 2H) , 7.60-7.70 (m, 2H) ; MS (FAB) m/e (relative intensity) 496 (5) , 478 (12), 435 (3), 207 (100); HRMS. calcd for M+H: 496.2461. Found: 496.2501.

C-2619/1 EXAMPLE «7 1,1-dimethylethyl 3-butyl-4,5-dihvdro-5-oxo-4-r2'-(1Htetrazol-5-vl) Π,1'-biphenvll-4-vlmethyll-1H-1,2,4triazole-l-acetate Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 450 mg (0.728 mmol) of 5-butyl-2,4-dihydro-4-[2'-(1 triphenylmethyl-lH-tetrazol-5-yl)[1,l'-biphenyl]-4ylmethyl]-3H-1,2,4-triazol-3-one in 8 mL of Ν,Νdimethylformamide was reacted with 0.87 mmol of potassium tert-butoxide in tetrahydrofuran and 141 gL (0.87 mmol) of tert-butyl bromoacetate. A portion of the alkylated product (240 mg, 0.328 mmol) was deprotected following General Procedure step 2 to give 161 mg (78%) of the desired product compound as a white solid: 4H NMR (CDCI3) δ 0.88(t, J = 7.25 Hz, 3H) , 1.35(m, 2H), 1.59(quintet, J = 7.25 Hz, 2H) , 2.43(t, J. = 7.25 Hz, 2H) , 4.43(s, 2H) , 4.78(s, 2H), 7.18(AB quartet, J = 8.5 Hz, 4H), 7.41(d, J = 7.7 Hz, IH), 7.48-7.65(m, 2H), 8.02(dd, 2 = 7.7, 1.2 Hz, IH); MS (FAB) m/e (relative intensity) 496 (39), 440 (60), C-2619/1 412 (45), 397 (25), 235 (22), 207 (100), 192 (40), 178 (60); HRMS. calcd for M+H: 490.2567. Found: 490.2598 C-2619/1 -butyl-2,4-dihydro-2-hexyl-4-Γ21 -(lH-tetrazol-5-yl) Γ1.1 biphenyl1-4-ylmethyl 1 -3H-1.2,4-triazol-3-one Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 250 mg (0.486 mmol) of 5-butyl-2,4-dihydro-4-[2'-(ltriphenylmethyl-lH-tetrazol-5-yl)[1,1’-biphenyl]-4ylmethyl]-3H-1,2,4-triazol-3-one in 4 mL of Ν,Νdimethylformamide was reacted with 0.58 mmol of potassium tert-butoxide in tetrahydrofuran and 145 yL (0.98 mmol) of 1-iodohexane. The alkylated product was deprotected following General Procedure step 2 and the resulting solid was recrystallized to give 127 mg (57%) of the desired product compound as a white solid: 1H NMR (DMSO-d6) δ 0.70.9 (m, 6H) , 1.15-1.32 (m, 8H), 1.41 (q, J = 7.25 Hz, 2H) , 1.5-1.7(m, 2H) , 2.37(t, 2 =7.26 Hz, 2H), 3.64(t, 2 = 6.85 Hz, 2H) , 4.79{s, 2H), 7.05(d, 2 = 8.06 Hz, 2H), 7.10(d, 2 8.06Hz, 2H), 7.45-7.60(m, 2H), 7.60-7.70(m, 2H); HRMS. calcd for M+H: 460.2825. Found: 460.2820.

C-2619/1 EXAMPLE «9 ethyl 3-butvl-.4.5-dihvdrQ-5-oxo-4- Γ2 1 - (lH-tetrazol-5vl) Γ1.1'-biphenyl!-4-ylmethyn-lH-l, 2,4-triazole-l-acetate Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 500 mg (0.81 mmol) of 5-butyl-2,4-dihydro-4-[2'-(1triphenylmethyl-lH-tetrazol-5-yl) [1,1'-biphenyl]-4 ylmethyl]-3H-1,2,4-triazol-3-one in 7 mL of Ν,Νdimethylformamide was reacted with 1.06 mmol of potassium tert-butoxide in tetrahydrofuran and 147 pi (1.33 mmol) of ethyl bromoacetate. The alkylated product was deprotected following General Procedure step 2 to give 336 mg (90%) of the desired product compound as a white solid: 1H NMR (DMSO-d6) δ 0.77 (t, J = 7.65 Hz, 3H) , 1.10-1.30[m (with t at 1.17, J = 6.85 Hz), 5H], 1.41(quintet, J = 7.25 Hz, 2H), 2.39(t, J - 7.65 Hz, 2H), 4.12(q, J = 6.9 Hz, 2H), 4.55(s, 2H) , 4.83(s, 2H) , 7.06(d, J = 8.06 Hz, 2H) , 7.12(d, J = 8.46 Hz, 2H), 7.45-7.75(m, 4H); MS (FAB) m/e (relative intensity) 462 (85), 446 (10), 235 (15), 207 (100), 192 (18); HRMS. calcd for M+H: 462.2254. Found: 462.2277.

C-2619/1 EXAMPLE ¢10 3-butvl-4.5-dihydro-5-oxo-4-Γ2'-(lH-tetrazol-5-yl) fl,l'biphenyl)-4-ylmethyl!-1H-1.2. 4-triazole-l-acetic acid A mixture of 170 mg (0.368 mmol) of ethyl ester from example 9 in 3.4 mL of tetrahydrofuran and 3.4 mL of 2 N aqueous lithium hydroxide was stirred at room temperature for 2 h. Volatiles were removed in vacuo. The aqueous layer was washed with three 4 mL-portions of ether, and acidified with 3 N hydrochloric acid to about pH 3. The mixture was filtered, and the solid was washed with water.

The solid was dried in vacuo to give 100 mg (63%) of the desired product compound. The filtrate was extracted with chloroform, dried (MgSO4), concentrated in vacuo and triturated with ether to give additional 50 mg (31%) of the desired product compound as a white solid: 1H NMR (DMSO-d6) δ 0.78(t, J = 7.25 Hz, 3H), 1.17-1.32(m, 2H), 1.32-1.50(m, 2H) , 2.39(t, J = 7.26 Hz, 2H), 4.43(s, 2H) , 4.82(s, 2H) , 7.06(d, J = 8.06 Hz, 2H), 7.13(d, J = 8.06 Hz, 2H), 7.457.60(m, 2H), 7.58-7.7(m, 2H) ; MS (FAB) m/e (relative intensity) 440 (25), 429 (12); HRMS. calcd for M+H: 434.1941. Found: 434.1977.

C-261'9/1 EXAMPLE #11 -butyl-2,4-dihydro-2-(1-naphthalenvlmethvl)-4- 12'- (1Htetrazol-5-yl) Γ1, 1'-biphenyl]-4-ylmethyl]-3H-1.2.4-triazol3-one Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 250 mg (0.405 mmol) of 5-butyl-2,4-dihydro-4-[2'-(ltriphenylmethyl-lH-tetrazol-5-yl) [1,1'-biphenyl]-4 ylmethyl]-3H-1,2, 4-triazol-3-one in 4 mL of Ν,Νdimethylformamide was reacted with 0.5 mmol of potassium tert-butoxide in tetrahydrofuran and 134 mg (0.606 mmol) of 1-(bromomethyl) naphthalene. The alkylated product was deprotected following General Procedure step 2 to give 159 mg (76%) of the desired product compound as a white solid: 3H NMR (DMSO-d6) δ 0.73 (t, J = 7.25 Hz, 3H) , 1.1-1.25 (m, 2H) , 1.25-1.4(m, 2H) , 2.34(t, J =7.66 Hz, 2H), 4.84(s, 2H) , 5.31(s, 2H) , 7.05(d, J = 8.46 Hz, 2H) , 7.12(d, J = 7.06 Hz, 2H), 7.36(d, J = 6.45 Hz, 1H) , 7.40-7.65(m, 7H), C-2619/1 7.80-8.0(m, 2H), 8.18-8.3(m, IH); HRMS. calcd for M+H: 516.2512. Found: 516.2534. -butvl-2-(2-cyclohexylethvl)-2. 4-dihydro-4-Γ2'-(1H10 tetrazol-5-yl) Γ1, 1'-biphenvll-4-vlmethvll-3H-l,2,4-triazolFollowing the General Procedure for reacting a triazolone with an alkylating agent (described above), 250 mg (0.405 mmol) of 5-butyl-2, 4-dihydro-4-[2'-(1 triphenylmethyl-lH-tetrazol-5-yl)[1,1'-biphenyl]-4 ylmethyl]-3H-1,2,4-triazol-3-one in 3 mL of Ν,Νdimethylf ormamide was reacted with 0.53 mmol of potassium tert-butoxide in tetrahydrofuran and 100 mg (0.523 mmol) of 2-cyclohexyl ethylbromide. The alkylated product was deprotected following General Procedure step 2 to give 165 mg (84%) of the desired product compound as a white solid: lH NMR (DMSO-d6) δ 0.77 (t, J = 7.25 Hz, 3H), 0.8-0.95(m, 2H), 1.0-1.3(m, 6H), 1.3-1.8(m, 9H), 2.37(t, d = 7.65 Hz, 2H), 3.67(t, d = 7.26 Hz, 2H) , 4.79(s, 2H) , 7.07(d, d = C-261r‘-'i 8.46 Hz, 2H), 7.10(d, J = 8.46 Hz, 2H) , 7.45-7.60 (m, 2H), 7.60-7.70(m, 2H); HRMS. calcd for M+H: 486.2981. Found: 486.3012.

EXAMPLE «13 -butvl-2.4-dihydro-2-pentyl-4-Γ2'- (lH-tetrazol-_5_-vl) fl, 1 ’ biphenyl1-4-ylmethyl1-3H-1.2.4-triazol-3-one Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 250 mg (0.41 mmol) of 5-butyl-2,4-dihydro-4-[2'-(1triphenylmethyl-lH-tetrazol-5-yl) [1,1' -biphenyl]-4ylmethyl]-3H-1,2,4-triazol-3-one in 3 mL of Ν,Νdimethylformamide was reacted with 0.53 mmol of potassium tert-butoxide in tetrahydrofuran and 70 mg (0.354 mmol) of 1-iodopetane. The alkylated product was deprotected following General Procedure step 2 to give 110 mg (60%) of the desired product compound as a white solid: 1H NMR (DMSO-d6) δ 0.7-0.9(m, 6H), 1.13-1.32(m, 6H), 1.41(quintet J = 7.2 Hz, 2H), 1.61(quintet, J = 6.9 Hz, 2H), 2.37 (t, J C-261( JE 911801 7.7 Hz, 2H), 3.64(t, 2 = 6.8 Hz, 2H), 4.79(s, 2H) , 7.05(d, = 8.46 Hz, 2H), 7.11(d, 2 = 8.46 Hz, 2H), 7.45-7.6(m, 2H), 7.60-7.7(m, 2H); MS (FAB) m/e (relative intensity) 446 (68), 235 (10), 207 (100), 192 (20), 178 (20); HRMS. calcd for M+H: 446.2668. Found: 446.2705.

C-2619/1 EXAMPLE #14 ethyl ί2-ί3-butyl-4,5-dihydro-5-oxo-4-Γ21- (ΙΗ-tetrazol-5 yl) Π, 1'-biphenvll-4-ylmethvn-1H-1,2, 4-triazol-l-yll-1ohenvlethoxvlacetate To a solution of 160 mg (0.217 mmol) of hydroxyphenethyl trityltetrazolylbiphenyl triazolone obtained from example 6 in 4 mL of dry tetrahydrofuran was added 18 mg (0.45 mmol) of sodium hydride (60% in oil) in one portion, and the resulting suspension was stirred at room temperature for 10 min. After gas evolution was complete, 76 pL (0.866 mmol) of ethyl bromoacetate was added. The resulting solution was stirred at room temperature for 4 h, and quenched with sat ammonium chloride. The mixture was concentrated in vacuo, dissolved in chloroform and washed with water. The aqueous layer was extracted with three 10 mL-portions of chloroform, and the combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude alkylated product. Following the General Procedure step 2 the alkylated product was deprotected to give 105 mg (83%) of the desired product compound as a white solid: NMR (DMSO-d6) δ 0.75 (t, J = C-IW' 7.66 Hz, 3H), 1.06-1.46 [m. (with t at 1.12, 2 = 7.25 Hz), 7H], 2.31(t, 2 = 7.65 Hz, 2H) , 3.70-4.20 (m, 5H) , 4.73(s, 2H), 4.82(d, 2 = 6.9 Hz, IH) , 6.91(d, 2 = 8.05.Hz, 2H), 6.95-7.20[m (with d at 7.01, 2 = 8.06 Hz), 3H], 7.205 7.40(m, 5H), 7.45-7.75(m, 4H); MS (FAB) m/e (relative intensity) 582 (10), 478 (18), 235 (15), 207 (100), 192 (48), 178 (28); HRMS. calcd for M+H: 582.2829. Found: 582.2832.

C-2619/1 EXAMPLE #15 Γ2-f3-butvl-4,5-dihydro-5-oxo-4-Γ21-(lH-tetrazol-5vl) Γ1,11-biphenyl1-4-ylmethyll-1H-1.2,4-triazol-l-yl1-1phenvlethoxv)acetic acid A mixture of 80 mg (0.138 mmol) of ester from example 14 in 1.7 mL of tetrahydrofuran and 1.7 mL of 2 N lithium hydroxide was stirred at room temperature for 3 h. Volatiles were removed in vacuo, and the aqueous solution was washed with three portions of ether. The resulting aqueous solution was acidified with 3 N hydrochloric acid, extracted with chloroform, dried (MgSOq) and concentrated in vacuo. The solid residue was recrystallized from ethyl acetate/hexane to give 72 mg (94%) of the desired product compound as a white solid: 1H NMR (DMSO-d6) δ 0.75 (t, J = 7.26 Hz, 3H), 1.08-1.48 3.70-4.15(m, 4H), 4.65-4.90[m (with s at 4.71), 3H] , 6.88(d, J = 8.06 Hz, 2H), 6.95-7.18[m (with d at 7.01, J = 8.46 Hz), 3H], 7.20-7.40(m, 5H), 7.45-7.75(m, 4H); MS (FAB) m/e (relative intensity) 554 (8), 478 (12), 450 (5), 235 (10), 207 (100), 192 (30), 178 (25); HRMS. calcd for M+H: 554.2516. Found: 554.2536.

C-2619/1 -butvl-2.4-dihydro~4-Γ2'-(lH-tetrazol-5-yl) [1.1*biphenyll-4-ylmethyll-2-(3,5,5-trimethylhexyl)-3H-1.2.4triazol-3-one Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 250 mg (0.405 mmol) of 5-butyl-2,4-dihydro-4-[21 -(1 triphenylmethyl-lH-tetrazol-5-yl) [1,1'-biphenyl]-4 ylmethyl]-3H-1,2, 4-triazol-3-one in 2.5 mL of Ν,Νdimethylformamide was reacted with 0.43 mmol of potassium tert-butoxide in tetrahydrofuran and 100 mg (0.483 mmol) of 3,5,5-trimethyl-l-bromohexane. The alkylated product was deprotected following General Procedure step 2 to give 176 mg (87%) of the desired product compound as a white solid: 1H NMR (CDCI3) δ 0.70-0.95 (m, 15H) , 1.02 (dd, Z = 13.2, 5.7 Hz, IH), 1.16(dd, J= 13.2, 2.8 Hz, IH), 1.29(septet, J= 7.25Hz, 2H), 1.35-1.6(m, 4H), 1.60-1.77(m, IH), 2.36(t, J = 8.06 Hz, 2H) , 3.55-3.75(m, 2H), 4.68(br s, 2H), 7.07 (AB quartet, J = 7.7 Hz, 4H) , 7.40(d, J = 7.7 Hz, IH), 7.49(t, J = 7.25 Hz, IH) , 7.57(t, J = 7.26 Hz, IH), 7.86(d, J = C-2619H 7.25 Hz, 1H); MS (FAB) m/e (relative intensity) 502 (28), 444 (5), 403 (3), 235 (5), 207 (100), 192 (20), 178 (20); HRMS. calcd for M+H: 502.3294. Found: 502.3295.

C-2619/1 -butvl-2.4-dihydro-2-f2-phenvl-2-(phenylmethoxy)-1(phenvlmethyl)-E-ethenvl 1 -4-f21- (lH-tetrazol-5-vl) ΓΙ,!'biPhenvn-4-vlmethyn-3H-1.2,4-triazol-3-one To a solution of 100 mg (0.136 mmol) of phenacyl trityltetrazolylbiphenyl triazolone from example 5 in 1.5 mL of dry tetrahydrofuran was added 10 mg (0.25 mmol) of sodium hydride (60% in oil) and the resulting suspension was stirred at room temperature for 5 min. After gas evolution was complete, 30 yL (0.25 mmol) of benzyl bromide was added. The resulting mixture was stirred at room temperature for 20 h, quenched with ammonium chloride, evaporated and worked up with water and chloroform. The crude was chromatographed over silica gel, eluting with ethyl acetate/hexane, to give 70 mg (56%) of the trityl protected desired product compound as an oil: ^-H NMR (CDCI3) δ 0.74 (t, J = 7.25 Hz, 3H) , 1.10 (septet, 2 = 7.7 Hz, 2H), 1.37(quintet, 2 = 7.65 Hz, 2H), 2.12(t, 2 = 7.25 Hz, 2H), 3.85(s, 2H), 4.63(s, 2H), 4.74(s, 2H) , 6.73(d, 2 = 8.06 Hz, 2H), 6.80-7.00 (m, 8H), 7.08-7.60(m, 27H), 7.93(d, J = 2.0 Hz, 1H).

Following the General Procedure step 2, 70 mg 5 (0.076 mmol) of the alkylated product was deprotected, and the resulting oil was recrystallized from ethyl acetate/ether/hexane to give 46 mg (90%) of the desired product compound as a white solid: 1H NMR (CDCI3) δ 0.78 (t, J = 7.25 Hz, 3H) , 1.18 (septet, J = 7.25 Hz, 2H) , 1.41(quintet, J = 7.7 Hz, 2H) , 2.24 (t, J = 7.7 Hz, 2H), 3.67(s, 2H), 4.50(s, 2H), 4.55 (s, 2H), 6.69(d, J = 8.06 Hz, 2H), 6.91(d, J = 8.46 Hz, 2H), 7.00-7.20 (m, 9H), 7.37 (br s, 5H) , 7.45(td, J = 7.65, 1.2 Hz, 1H) , 7.55(td, J = 7.65, 1.2 Hz, 1H), 7.85(td, J = 7.66, 1.21 Hz, 1H); MS (FAB) m/e (relative intensity) 674 (15), 582 (8), 554 (3), 325 (5), 297 (20), 235 (8), 207 (100), 192 (50), 178 (40); HRMS. calcd for M+H: 674.3243. Found: 674.3302.

C-2619/1 EXAMPLE #18 2- (l-benzoyi-2--phenvlethyl) -5-butvl-2,4-dihvdro-4- Γ 2' — (1Htetrazol-5-yl) Γ1.11-biphenyl!-4-ylmethyl!-3H-1,2,4-triazol3-one To a solution of 0.24 mL (0.36 mmol) of lithium diisopropylamide (1.5 M in tetrahydrofuran, Aldrich) at 20°C was added a solution of 105 mg (0.143 mmol) of phenacyl trityltetrazolylbiphenyl triazolone from example 5 in 2.5 mL of dry tetrahydrofuran via cannula. The resulting solution was stirred cold for 10 min. To the solution was added 25 gL (0.21 mmol) of benzyl bromide, and the resulting solution was stirred at room temperature for 2 h. The reaction was quenched with ammonium chloride, evaporated, and worked up with water and methylene chloride. The crude was chromatographed over silica gel, eluting with ethyl acetate/hexane, to give 106 mg (90%) of the trityl protected desired product. Following the General Procedure step 2 the alkylated product was deprotected to give 60 mg (80%) of the desired product compound as a white solid: 1H NMR (CDCI3) δ 0.75 (t, J - 7.05 C-2619/1 Hz, 3H), 1.00-1.45(m, 4H), 1.83-2.00(m, IH), 3.36(dd, J = 13.3, 4.4 Hz, IH) , 3. IH), 4.99(dd, J = 10.9, 3.6 Hz, IH) , 5. 17.7 Hz, 2H), 7.0-7.7(m, 14H), 7.90(d, (FAB) m/e (relative intensity) 584 (15) (100), 207 (10); HRMS. calcd for M+H: 584.2794.

IH), 2.00-2.20(m 85(t, J = 12.9 Hz 11(AB quartet, J : J = 7.26 Hz, 4H); , 325 (60), 260 584.2774. Found: MS C-2619/1 EXAMPLE. #19 O -butyl-2,4-dihydr0-2-(l-oxobutyl)-4-r2'-GH-tetrazol-5yl) r1.1'-biphenvll-4-vlmethyll -3H-1.2,4-triazol-3-one Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 150 mg (0.243 mmol) of 5-butyl-2,4-dihydro-4-[2'- (1triphenylmethyl-lH-tetrazol-5-yl)[1,1'-biphenyl]-4ylmethyl]-3H-1,2,4-triazol-3-one in 1.5 mL of Ν,Νdimethylformamide was reacted with 0.26 mmol of potassium tert-butoxide in tetrahydrofuran and 60 pL (0.367 mmol) of butyric anhydride. The acylated product was deprotected following General Procedure step 2, the crude product was recrystallized from ethyl acetate/hexane to give 92 mg (85%) of the desired product compound as a white solid: 4H NMR (CDC13) 50.89(t, J = 7.1 Hz, 3H) , 1.00(t, J = 7.26 Hz, 3H), 1.30-1.45(m, 2H) , 1.55-1.70(m, 2H), 1.77 Hz, 2H) , 2.48(t, J = 7.6 Hz, 2H), 2.92(t, J = 7.26 Hz, 2H), 4.84(s, 2H) , 7.18-7.32(m, 4H) , 7.35-7.45(m, IH) , 7.457.65(m, 2H), 8.05-8.15(m, IH); MS (FAB) m/e (relative intensity) 468 (33), 446 (45), 376 (100), 235 (45), 207 C-2619/1 (100), 192 (42); HRMS. calcd for M+H: 446.2304. Found: 446.2351.

EXAMPLE #20 -butvl-2,4-dihvdro-2-Γ2-(2,5-dimethyoxyphenvl)-2oxoethyll-4-F2'-(lH-tetrazol-5-yl) fl. 1'-biphenyl)-410 yImethyΠ -3H-1,2.4-triaziQl-3-one Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 600 mg (0.971 mmol) of 5-butyl-2, 4-dihydro-4-[21 - (1 15 triphenylmethyl-lH-tetrazol-5-yl) [1,1'-biphenyl]-4ylmethyl]-3H-1,2,4-triazol-3-one in 6 mL of N,Ndimethylformamide was reacted with 1.17 mmol of potassium tert-butoxide in tetrahydrofuran and 310 mg (1.20 mmol) of 2,5-dimethoxyphenacyl bromide. The crude product was recrystallized from ethyl acetate/ether/hexane to give 750 mg (97%) of the trityl protected desired product. Following General Procedure step 2, 200 mg of the alkylated product was deprotected, and the crude product was recrystallized C-2619/1 to give 110 mg (79%) of the desired product compound as a white solid: ΧΗ NMR (CDCI3) 5 0.85 (t, J = 7.65 Hz, 3H), 1.32 (septet, J = 7.65 Hz, 2H), 1.58 (quintet, J = 7.65 Hz, 2H), 2.41(t, J = 8.06 Hz, 2H), 3.75(s, 3H), 3.90(s, 3H), 4.82 (s, 2H), 5.15 (s, 2H), 6.92(d, J = 9.27 Hz, 1H), 7.09(dd, J = 8.87, 3.2 Hz, 1H), 7.15(d, J = 8.06 Hz, 2H) , 7.21(d, J = 8.06 Hz, 2H), 7.33-7.6(m, 4H), 7.92(dd, J = 8.06, 1.2 Hz, 1H); MS (FAB) m/e (relative intensity) 576 (13), 554 (38), 207 (100), 165 (63); HRMS. calcd for M+H 554.2516. Found: 554.2567.

C-2619/1 EXAMPLE #21 -butyl-2,4-dihydro-2-i2-phenyl-2-(phenylmethoxy)ethvll-412' - (lH-tetrazol-5-yl)11,1'-biphenyll-4-vlmethyl1-3H-1.2,4triazol-3-one To a solution of 148 mg (0.210 mmol) of crude trityl tetrazolylbiphenyl phenyIhydroxyethyl triazolone from example 6 in 4 mL of dry tetrahydrofuran was added 18 mg (0.201 mmol) of sodium hydride (60% in oil), and the resulting suspension was stirred at room temperature for 5 min. After gas evolution was complete, 50 yL (0.42 mmol) of benzyl bromide was added. The resulting mixture was stirred at room temperature for 1 h, quenched with ammonium chloride, and concentrated in vacuo. The residue was worked up with water and methylene chloride to give 200 mg of the crude alkylated product. Following the General Procedure step 2 the alkylated product was deprotected to give 120 mg (quantitative) of the desired product compound as a white solid: 1H NMR (DMSO-d6) δ 0.75(t, 2 = 7.25 Hz, 3H) , 1.10-1.38(m, 2H), 1.35(quintet, 2 = 7.66 Hz, 2H), 2.34(t, 2 = 7.65 Hz, 2H) , 3.77(dd, 2 = 14.1, 5.44 Hz, IH), 4.03(dd, 2 = 13.7, 8.46 Hz, IH), 4.21(d, 2 = 12.1 Hz, IH), (2 1 π /Ί ΙΕ 911801 4.39(d, J = 12.1 Hz, 1Η), 4.70-4.82[m (with s at 4.76), 4H], 6.99(br s, 4H) , 7.10-7.43(m, 10H), 7.43-7.72(m, 4H); MS (FAB) m/e (relative intensity) 586, 478 (18), 243 (100), 207 (88); HRMS. calcd for M+H: 586.2930. Found: 586.2979.

EXAMPLE #22 -butvl-2,4-dihydro-2-Γ2-(2,5-dimethyoxvphenvl)-2hydroxyethyll-4-Γ21-(lH-tetrazol-5-yl) fl,1'-biphenyl 1^4= ylmethyl!-3H-1,2.4-triazol-3-one To a solution of 250 mg (0.314 mmol) of trityl protected biphenyl dimethoxyphenacyl triazolone from example 21 in 3 mL of methanol and 6 mL of tetrahydrofuran at 0°C was added 16 mg (0.423 mmol) of sodium borohydride in one portion. The resulting solution was stirred cold for 1 h, quenched with ammonium chloride, and evaporated. The residue was chromatographed over silica gel, eluting with ethyl acetate/methylene chloride, 3:1, to give 246 mg (98%) of the trityl protected desired product. Following the General Procedure step 2, 71 mg (0.089 mmol) of the C-2619/1 alkylated product was deprotected to give 50 mg (quantitative) of the desired product compound as a white solid: 1H NMR (CDCI3) 5 0.88 (t, J = 7.4 Hz, 3H), 1.251.42(m, 2H), 1.50-1.63(m, 2H) , 2.42(t, J = 7.4 Hz, 2H) , 3.67(s, 3H), 3.81(s, 3H) , 4.0-4.25(m, 2H) , 4.76(s, 2H) , .13-5.25 (m, 1H), 6.70-6.83(m, 2H), 6.92-7.00(m, 1H), 7.057.20(m, 4H), 7.35-7.43(m, 1H) , 7.45-7.65(m, 2H), 7.968.08(m, 1H); MS (FAB) m/e (relative intensity) 578 (35), 538 (90), 510 (3), 495 (6), 235 (12), 207 (100), 192 (30), 178 (30); HRMS. calcd for M+H: 556.2672. Found: 556.2691. 261Q/' 100 EXAMPLE #23 -butyl-2.4-dihydro-2-(2-naphthalenylmethyl)-4-ί21 - (1Htetrazol-5-yl) fl,1'-biphenyll-4-ylmethyn-3H-1,2,4-triazol3-one Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 150 mg (0.243 mmol) of 5-butyl-2,4-dihydro-4-[2'-(1 triphenylmethyl-lH-tetrazol-5-yl) [1,1'-biphenyl]-4 ylmethyl]-3H-1,2,4-triazol-3-one in 3 mL of Ν,Νdimethylformamide was reacted with 0.3 mmol of potassium tert-butoxide in tetrahydrofuran and 81 mg (0.367 mmol) of 2-(bromomethyl) naphthalene. The alkylated product was deprotected following General Procedure step 2 and the crude product was recrystallized to give 125 mg (quantitative) of the desired product compound as a white solid: ΧΗ NMR (CDCI3) 50.81(t, J = 7.25 Hz, 3H), 1.27 (septet, J = 7.25 Hz, 2H), 1.50(quintet, J = 8.06 Hz, 2H), 2.34(t, J = 7.25 Hz, 2H), 4.69(s, 2H), 5.04(s, 2H), 6.95-7.10(m, 4H) , 7.30-7.60(m, 7H), 7.55-7.8 (m, 5H) ; MS (FAB) m/e (relative intensity) 516 (25), 326 (30), 242 C-2619/1 101 (25), 207 (100), 192 (30), 178 (35), 141 (100); HRMS. calcd for M+H: 516.2512. Found: 516.2455.

EXAMPLE 24 methyl 3-butyl-4,5-dihydro-5-oxo-4-ί 21- (lH-tetrazol-5 10 yl) fl,1'-biphenyll-4-ylmethyl!-1H-1,2,4-triazole-1 pentanoate Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 150 mg (0.243 mmol) of 5-butyl-2,4-dihydro-4-[2'-(ltriphenylmethyl-lH-tetrazol-5-yl) [1,1'-biphenyl]-4 ylmethyl]-3H-1,2,4-triazol-3-one in 3 mL of Ν,Νdimethylformamide was reacted with 0.3 mmol of potassium tert-butoxide in tetrahydrofuran and 52 yL (0.36 mmol) of methyl 5-bromovalerate. The alkylated product was deprotected following General Procedure step 2 to give 115 mg (97%) of the desired product compound as a white solid: iH NMR (CDCI3) 5 0.89(t, 2 = 7.3 Hz, 3H), 1.35(septet, 2 = 7.5 Hz, 2H), 1.50-1.68(m, 4H), 1.75(quintet, 2 = 8.04 Hz, 2H), 2.32(t, 2 = 7.5 Hz, 2H) , 2.42(t, 2 = 8.0 Hz, 2H), C-2619/1 102 3.62(s, 3H), 3.76(t, J =6.8 Hz, 2H) , 4.78(s, 2H) , 7.17(d, J = 7.96 Hz, 2H) , 7.22(d, J = 8.5 Hz, 2H), 7.42(dd, J = 7.4, 1.5 Hz, IH), 7.50-7.68(m, 2H), 8.02(dd, J = 7.7, 1.2 Hz, IH); MS (FAB) m/e (relative intensity) 490 (20), 430 (8), 235 (8), 207 (100), 192 (30), 178 (50); HRMS. calcd for M+H: 490.2567. Found: 490.2570.

C-2619./1 103 ethyl Q-benzoyl-3-butvl-4.5-dihydro-5-oxo-4-f 2'- (IH tetrazol-5-yl) f1,11-biphenyll-4-ylmethyll-1H-1,2,4triazole-l-propanoate To a solution of 0.56 mL (0.84 mmol) of lithium diisopropylamide (1.5 M in tetrahydrofuran, Aldrich) at 78°C was added a solution of 348 mg (0.473 mmol) of phenacyl trityltetrazolylbiphenyl triazolone from example 5 in 2 mL of dry tetrahydrofuran via cannula. The resulting solution was stirred cold for 10 min. To the solution was added 63 |iL (0.568 mmol) of ethyl bromoacetate, and the resulting solution was stirred cold for 15 min, then slowly warmed to -30 °C over a 30-min period. The reaction was quenched with 1 N hydrochloric acid, stirred to room temperature, and worked up with water and methylene chloride. The crude was chromatographed over silica gel, eluting with ethyl acetate/hexane, to give 82 mg (21%) of the trityl protected desired product. Following the General Procedure step 2 the alkylated product was deprotected, and the crude product was chromatographed over C-2619/1 104 silica gel (eluted with isopropanol-hexane-acetic acid, 65:32:3) to give 30 mg (55%) of the desired product compound as a white solid: 1H NMR (DMSO d6) 5 0.66(t, d = 7.3 Hz, 3H), 0.86(quintet, J = 7.0 Hz, 2H), 1.05(septet, J = 7.2 Hz, 2H), 1.15(t, d = 6.73 Hz, 3H), 2.27 (t, d = 7.2 Hz, 2H), 2.95(dd, d = 16.3, 6.9 Hz, 1H) , 3.14(dd, J = 16.3, 7.2 Hz, 1H), 4.05(q, d = 6.8 Hz, 2H) , 4.79(s, 2H), 6.00(t, d = 7.3 Hz, 1H), 6.84{d, d = 8.2 Hz, 2H), 6.99(d, d = 8.0 Hz, 2H), 7.15-7.40(m, 3H), 7.40-7.80(m, 4H), 7.88(d, J= 8.0 Hz, 2H); HRMS. calcd for M+H: 580.2672. Found: 580.2714 C-2619/1 105 EXAMPLE #2 6 2- (1-benzyoyl-l-methylethyl)-5-butyl-2.4-dihydrc-4-Γ2(1Htetrazol-5-yl) Γ1,11-biphenyl!-4-ylmethyll-3H-1.2,4-triazol3- one Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 100 mg (0.162 mmol) of 5-butyl-2,4-dihydro-4-[2'-(1triphenyImethyl-lH-tetrazol-5-yl)[1,l’-biphenyl]-4ylmethyl]-3H-1,2,4-triazol-3-one in 2 mL of N,N15 dimethylformamide was reacted with 0.2 mmol of potassium tert-butoxide in tetrahydrofuran and 41 pL (0.24 mmol) of 2-bromo isobutyrophenone. To the reaction mixture was added 15 mg (0.38 mmol) of sodium hydride (60% in oil), and the resulting mixture was stirred at for 2 h. The mixture was concentrated in vacuo and chromatographed over silica gel (eluting with ethyl acetate-hexane) to give 30 mg (24%) of the trityl protected product: 1H NMR (CDCI3) δ 0.84 (t, J = 7.31 Hz, 3H), 1.18-1.32(m, 2H), 1.47(quintet, J = 7.46 Hz, 2H) , 1.90(s, 6H) , 2.29(t, J = 7.7 Hz, 2H), 4.55(s, 2H) , 6.59(d, J = 8.2 Hz, 2H), 6.89(d, J = 7.7 Hz, 6H), 6.97(d, J C-2619/1 106 = 8.08 Hz, 2H), 7.15-7.48(m, 12H), 7.48-7.55(m, 3H), 7.78(d, J = 7.2 Hz, 2H), 7.90-7.98(m, IH).

The alkylated product was deprotected following 5 the General Procedure step 2 and the crude product was recrystallized to give 16 mg (80%) of the desired product compound as a white solid: 1H NMR (CDCI3) δ 0.85(t, J = 7.25 Hz, 3H) , 1.30(septet, J = 7.6 Hz, 2H), 1.52(quintet, J = 7.25 Hz, 2H) , 1.78(s, 6H) , 2.39(t, J = 8.05 Hz, 2H) , 4.50(s, 2H), 6.55(d, J = 8.06 Hz, 2H) , 6.87(d, J = 8.06 Hz, 2H), 7.15-7.30(m, 2H), 7.30-7.42(m, 2H), 7.45-7.70 (m, 4H) , 7.85-7.95(m, 1H); MS (FAB) m/e (relative intensity) 544 (20), 522 (20), 416 (5), 235 (5), 207 (100), 192 (45), 178 (30); HRMS. calcd for M+H: 522.2617. Found: 522.2658.

C-2619/1 107 EXAMPLE #27 3-butyl-4,5-dihydro-5-oxo-4-Γ21-(lH-tetrazol-5-yl) fl.l’biphenvll-4-ylmethyll-1H-1,2,4-triazole-l-pentanoic acid A mixture of 80 mg (0.163 mmol) of ester from example 24 in 3 mL of tetrahydrofuran and 3 mL of 2 N lithium hydroxide was stirred at room temperature for 2 h. Volatiles were removed in vacuo, and the aqueous solution was washed with three portions of ether. The resulting aqueous solution was acidified with 3 N hydrochloric acid, extracted with chloroform, dried (MgSC>4) and concentrated in vacuo. The solid residue was recrystallized from ethyl acetate/hexane to give 74 mg (94%) of the desired product compound as a white solid: 1H NMR (DMSO-d6) δ 0.78 (t, J = 7.25 Hz, 3H), 1.10-1.53(m, 6H) , 1.63(quintet, J = 8.06 Hz, 2H), 2.22(t, J = 7.25 Hz, 2H) , 2.37(t, J = 7.66 Hz, 2H) , 3.65(t, J - 6.85 Hz, 2H), 4.79(s, 2H), 7.06(d, J = 8.46 Hz, 2H), 7.12(d, J = 8.06 Hz, 2H), 7.45-7.72 (m, 4H), 11.712.3(br s, IH); HRMS. calcd for M+H: 476.2410. Found: 476.2411 ΪΕ 911801 108 -butyl-2-(cyclopropylmethyl)-2.4-dihvdro-4-Γ2(1Htetrazol-5-yl) fl.1'-biphenyll-4-yImethyll-3H-1.2.4-triazol3-one Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 200 mg (0.324 mmol) of 5-butyl-2,4-dihydro-4-[2'-(1 triphenylmethyl-lH-tetrazol-5-yl) [1,1'-biphenyl]-4 ylmethyl]-3H-1,2,4-triazol-3-one in 4 mL of Ν,Νdimethylformamide was reacted at 0°C with 0.39 mmol of potassium tert-butoxide in tetrahydrofuran and 47 pL (0.48 mmol) of bromomethyl cyclopropane for 1.5 h and at room temperature for 2 h. The alkylated product was deprotected following General Procedure step 2 to give 131 mg (94%) of the desired product compound as a white solid: 3H NMR (DMSO-d6) δ 0 .28(q, J = 4 .8 Hz 2H), 0.79(t, J = 7.25 Hz, 3H) , 1.24(septet, J = 7.65 Hz, 2H) , 2H), 2.39(t, J = 7.25 Hz, 2H), 4.79 (s, 2H), 7.06(d, , J = 8.05 2H), 0.44(q, J = 5.6 Hz, 1.00-1.08 (m, 1H) , 1.42(quintet, J = 7.25 Hz, 3.54(d, J = 6.9 Hz, 2H) , C-2619/1 109 2H) , 7.45-7.75(m, 4H); HRMS. calcd for M+H: 430.2355. Found: 430.2395. -butvl-2,4-dihydro-2-(3-phenyl-2E-propenyl)-4-f21 -(1H10 tetrazol-5-yl) Fl,11-biphenyll-4-ylmethyll-3H-1,2,4-triazolr Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 150 mg (0.243 mmol) of 5-butyl-2,4-dihydro-4-[2’-(1triphenylmethyl-lH-tetrazol-5-yl) [1,1'-biphenyl]-4 ylmethyl]-3H-1,2,4-triazol-3-one in 3 mL of Ν,Νdimethylformamide was reacted with 0.3 mmol of potassium tert-butoxide in tetrahydrofuran and 72 mg (0.366 mmol) of cinnamyl bromide. The alkylated product was deprotected following General Procedure step 2 and the crude product was chromatographed over silica gel, eluting with isopropanol/hexane/acetic acid, to give 60 mg (50%) of the desired product compound as a white solid: 1H NMR (DMSO-d6) δ 0.78(t, 2 = 7.25 Hz, 3H), 1.24(septet, 2 = 7.66 Hz, 2H), C-2619/’· IE 911801 110 1.42(quintet, J = 7.65 Hz, 2H), 2.40(t, ϋ = 7.65 Hz, 2H), 4.46(d, J = 5.24 Hz, 2H), 4.82(s, 2H), 6.3l(dt, J = 16.1, 5.6 Hz, IH), 6.49(d, J = 16.1 Hz, IH) , 7.07(d, J = 8.06 Hz 2H), 7.15(d, J = 8.06 Hz, 2H) , 7.20-7.75(m, 9H); MS (FAB) 5 m/e (relative intensity) 492 (38), 464 (3) 376 (3), 243 (12), 207 (87), 178 (20), 117 (100); HRMS. calcd for M+H: 492.2512. Found: 492.2542.

C-2619/1 111 EXAMPLE #3Q 1-butyl-4.5-dihydro-5-oxo-a-propyl-4-12'-(lH-tetrazol-5yl) f1,1'-biphenyl1-4-ylmethyn-1H-1.2.4-triazole-3acetonitrile Step 1;_Bromination of 2»5-dibutyi-2. 4--dihydrQ-4-J2'.c (lH-tetrazol-5-yl) fl,1'-biphenyl!-4-ylmethyl!-3H-1.2,4triazol-3-one A solution of 2.0 g (2.97 mmol) of trityl tetrazolylbiphenyl dibutyl triazolone (prepared in example 2, step 5), 0.63 g (3.56 mmol) of N-bromosuccinimide, and mg (0.36 mmol) of azoisobutyronitrile in 200 mL of degassed carbon tetrachloride was stirred at 65°C for 1 h, cooled and concentrated in vacuo. The residue was chromatographed to give 1.35 g (61%) of bromobutyl triazolone: ΣΗ NMR (CDCI3) δ 0.72 (t, J = 7.65 Hz, 3H) , 0.94(t, J = 7.25 Hz, 3H), 1.10-1.45(m, 3H), 1.75(quintet, J = 7.66 Hz, 2H), 1.95-2.20(m, 2H), 3.83(t, J = 7.25 Hz, 2H), 4.34(t, J = 6.85 Hz, 1H), 4.65(d, J = 15.7 Hz, 1H), 5.12(d, J = 16.1 Hz, 1H), 6.85-6.95(m, 6H), 7.01(d, J = 8.46 Hz, C-2619/1 112 1H), 7.10(d, J = 8.05 Hz, 2H), 7.20-7.40 (m, 10H), 7.407.53(m, 2H), 7.85-7.95(m, IH).

Step 2: Preparation of l-butyl-4.5-dihydro-5-oxo-a5 progylrA-[2'- (lH-tetrazol-ίίτγΙ) [1/1'-biphenyl·!-4-yimethyl·]1H-1,2,4-triazole-3-acetonitrile A mixture of 226 mg (0.3 mmol) of the brominated product from step 1, 38 mg (0.776 mmol) of sodium cyanide, and 0.3 mL of water in 4.5 mL of Ν,Νdimethylformamide was stirred at room temperature for 23 h. The resulting mixture was concentrated in vacuo and chromatographed over silica gel (eluting with ethyl acetate/hexane) to give 178 mg (85%) of cyanobutyl triazolone as a white solid: 4H NMR (CDCI3) 50.75(t, 2 = 7.25 Hz, 3H), 0.94(t, 2 = 7.26 Hz, 3H) , 1.15-1/5(m, 4H), 1.55-1.85(m, 4H) , 3.34(dd, 2 = 8.86, 6.05 Hz, IH) , 3.82(t, = 7.26 Hz, 2H), 4.73(d, 2 = 15.7 Hz, IH), 4.99(d, 2 = .7 Hz, IH), 6.85-6.98 (m, 6H) , 7.02(d, 2 = 8.46 Hz, 2H), 7.11(d, 2 = 8.06 Hz, 2H), 7.20-7.40(m, 10H), 7.4-7.55(m, 2H), 7.85-7.95(m, IH).

Following the General Procedure step 2, 80 mg (0.114 mmol) of the cyanobutyl triazolone was deprotected and chromatographed (eluting with isopropanol/hexane/acetic acid) to give 48 mg (92%) of the desired product compound as a white solid: 4H NMR (DMSO-d6) δ 0.74 (t, 2 = 7.3 Hz, 3H) , 0.89(t, 2 = 7.4 Hz, 3H), 1.29(quintet, 2 = 7.3 Hz, 4H) , 1.40-1.73(m, 4H) , 3.73(t, 2 = 6.96 Hz, 2H) , 4.44(dd, 2 = 7.9, 5.7 Hz, IH) , 4.91(AB quartet, 2 = 16.4 Hz, 2H), 7.10(d, 2 = 8.0 Hz, 2H), 7.18(d, 2 = 8.1 Hz, 2H), 7.457.78 (m, 4H); MS (FAB) m/e (relative intensity) 457 (18), 429 (5), 235 (10), 207 (50), 192 (8), 149 (25), 147 (100); HRMS. calcd for M+H: 457.2464. Found: 457.2521. 113 BIOLOGICAL EVALUATION Assay A:_Angiotensin II Binding Activity Compounds of Formula I were tested for ability to bind to the smooth muscle angiotensin II receptor using a rat uterine membrane preparation. Angiotensin II (All) was purchased from Peninsula Labs. 125 j_ angiotensin II (specific activity of 2200 Ci/mmol) was purchased from Du Pont-New England Nuclear. Other chemicals were obtained from Sigma Chemical Co. This assay was carried out according to the method of Douglas et al (Endocrinology. 106. 120-124 (1980)] . Rat uterine membranes were prepared from fresh tissue. All procedures were carried out at 4°C. Uteri were stripped of fat and homogenized in phosphate-buffered saline at pH 7.4 containing 5 mM EDTA. The homogenate was centrifuged at 1500 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. Assay tubes were charged with 0.25 ml of a solution containing 5 mM MgCl2z 2 mM EDTA, 0.5% bovine serum albumin, 50 mM Tris-HCl, pH 7.5 and 322I-AII (approximately 102 cpm) in the absence or in the presence of unlabelled ligand. The reaction was initiated by the addition of membrane protein and the mixture was incubated at 25°C for 60 min. The incubation was terminated with ice-cold 50 mM Tris-HCl (pH 7.5) and the mixture was filtered to separate membrane-bound labelled peptide from the free ligand. The incubation tube and filter were washed with ice-cold buffer. Filters were assayed for radioactivity in a Micromedic gamma counter. Nonspecific binding was defined as binding in the presence of 10 μΜ of unlabelled All. Specific binding 114 was calculated as total binding minus nonspecific binding. The receptor binding affinity of an All antagonist compound was indicated by the concentration (IC50) of the tested All antagonist which gives 50% displacement of the total specifically bound ^25i-aii from the high affinity All receptor. Binding data were analyzed by a nonlinear least-squares curve fitting program. Results are reported in Table I.

Assay B: In Vitro Vascular Smooth Muscle-Response for All Compounds of Formula I were tested for antagonist activity in rabbit aortic rings. Male New Zealand white rabbits (2-2.5 kg) were sacrificed using an overdose of pentobarbital and exsanguinated via the carotid arteries. The thoracic aorta was removed, cleaned of adherent fat and connective tissue and then cut into 3-mm ring segments. The endothelium was removed from the rings by gently sliding a rolled-up piece of filter paper into the vessel lumen. The rings were then mounted in a water-jacketed tissue bath, maintained at 37°C, between moveable and fixed ends of a stainless steel wire with the moveable end attached to an FT03 Grass transducer coupled to a Model 7D Grass Polygraph for recording isometric force responses. The bath was filled with 20 ml of oxygenated (95% oxygen/5% carbon dioxide) Krebs solution of the following composition (mM): 130 NaCl, 15 NaHC03, 15 KCl, 1.2 NaH2P04, 1.2 MgS04, 2.5 CaCl2z and 11.4 glucose. The preparations were equilibrated for one hour before approximately one gram of passive tension was placed on the rings. Angiotensin II concentration-response curves were then recorded (3 X 10-1θ to 1 X 10-2 M). Each concentration of All was allowed to elicit its maximal contraction, and 115 then All was washed out repeatedly for 30 minutes before rechallenging with a higher concentration of All. Aorta rings were exposed to the test antagonist at 10-2 M for 5 minutes before challenging with All. Adjacent segments of the same aorta ring were used for all concentrationresponse curves in the presence or absence of the test antagonist. The effectiveness of the test compound was expressed in terms of pA2 values and were calculated according to H.O. Schild fBr. J. Pharmacol.

Chemother.. 2,189-206 (1947)]. The pA2 value is the concentration of the antagonist which increases the EC50 value for All by a factor of two. Each test antagonist was evaluated in aorta rings from two rabbits. Results are reported in Table I.

Assay C: In Vivo Intraduodenal Pressor Assay Response for All Antagonists Male Sprague-Dawley rats weighing 225-300 grams were anesthetized with Inactin (100 mg/kg, i.p.) and catheters were implanted into the trachea, femoral artery, femoral vein and duodenum. Arterial pressure was recorded from the femoral artery catheter on a Gould chart recorder (Gould, Cleveland, OH). The femoral vein catheter was used for injections of angiotensin II, mecamylamine and atropine. The tracheal catheter allows for airway patency, and the duodenal catheter was used for intraduodenal (i.d.) administration of test compounds. After surgery, the rats were allowed to equilibrate for 30 minutes. Mecamylamine (3 mg/kg, 0.3 ml/kg) and atropine (400 ug/kg, 0.3 ml/kg) were then given i.v. to produce ganglion blockade. These compounds were administered every 90 minutes throughout the test procedure. Angiotensin II was given in bolus 116 does i.v. (30 ng/kg in saline with 0.5% bovine serum albumin, 0.1 ml/kg) every 10 minutes three times or until the increase in arterial pressure produced was within 3 mmHg for two consecutive All injections. The last two All injections were averaged and were taken as the control All pressor response. Ten minutes after the final control All injection, the test compound (dissolved in sodium bicarbonate) was administered i.d. at a dose of 30 mg/kg in a volume of 0.2 ml. Angiotensin II injections were then given 5, 10, 20, 30, 45, 60, 75, 90, and 120 minutes after administration of the test compound and response of arterial pressure was monitored. The response to All was calculated as percent of the control response and then the percent inhibition is calculated as 100 minus the percent control response. Duration of action of a test compound was defined as the time from peak percent inhibition to 50% of peak. One compound at one dose was tested in each rat. Each test compound was tested in two rats and the values for the two rats were averaged. Results are reported in Table I.

Assay D: In Vivo Intragastric Pressor Assay Response for All Antagonists Male Sprague-Dawley rats weighing 225-300 grams were anesthetized with methohexital (30 mg/kg, i.p.) and catheters were implanted into the femoral artery and vein. The catheters were tunneled subcutaneously to exit dorsally, posterior to the head and between the scapulae.

The catheters were filled with heparin (1000 units/ml of saline). The rats were returned to their cage and allowed regular rat chow and water ad libitum. After full recovery from surgery (3-4 days), rats were placed in Lucite holders and the arterial line was connected to a pressure transducer. Arterial pressure was recorded on a Gould polygraph (mmHg). Angiotensin II was administered 117 as a 30 ng/kg bolus via the venous catheter delivered in a 50 μΐ volume with a 0.2 ml saline flush. The pressor response in mm Hg was measured by the difference from preinjection arterial pressure to the maximum pressure achieved. The All injection was repeated every 10 minutes until three consecutive injections yielded responses within 4 mmHg of each other. These three responses were then averaged and represented the control response to All. The test compound was suspended in 0.5% methylcellulose in water and was administered by gavage. The volume administered was 2 ml/kg body weight. The standard dose was 3 mg/kg. Angiotensin II bolus injections were given at 30, 45, 60, 75, 120, 150, and 180 minutes after gavage. The pressor response to All was measured at each time point. The rats were then returned to their cage for future testing. A minimum of 3 days was allowed between tests. Percent inhibition was calculated for each time point following gavage by the following formula: [(Control Response - Response at time point)/Control Response] X 100. Results are shown in Table I. i Jl 1 118 TABLE I In Vivo and In Vitro Angiotensin II Activity of Coiqpounds of Formula I Test Compound Example # -* Assay A IC50 (nM)2Assay B pA22Assays C and D Inhibition (%) Duration (min.) 10 1* 101 7.0 93 60-100 2* 4.9 9.2 100 >200 2 50 >180 3 25 8.1 NT NT 4 18 8.0 40 180 15 5 7.9 8.5 20 180 6 3.6 8.3 15 . >180 7 16 7.1 20 30 8 8.7 8.9 NT NT 9 9 7.8 NT NT 20 10 91 7.8 NT NT 11 50 7.7 NT NT 12 18 7.9 NT NT 13 5.6 9.0 NT NT 14 180 8.3 NT NT 25 15 30 8.6 40 >180 16 35 7.9 NT NT 17 480 NT NT NT 18 5,800 NT NT NT 19 66 8.2 NT NT 30 20 21 8.0 NT NT 21 280 7.7 NT NT 22 22 8.1 NT NT 23 280 6.5 NT NT 24 4.4 9.4 NT NT 35 25 36 7.8 NT NT C'iUi?/ 1 119 Test Compound 1 Assay A 2Assay B 2Assays C and D Example # IC50 (nM) pA2 Inhibition Duration (%) (min.) 26 43 7.7 NT NT 27 12 8.0 NT NT 28 15 8.0 NT NT 29 290 6.6 NT NT 30 48 7.7 NT NT NT = NOT TESTED ^Assay A: 2Assay B: Angiotensin II Binding Activity In Yitrfi Vascular Smooth Muscle Response 2Assay C: In Vivo Intraduodenal Pressor Response 15 for compounds of Examples #1* and #2*.

Assay D: In Vivo Intragastric Pressor Response for Compounds of Example #2-30. 120 Also embraced within this invention is a class of pharmaceutical compositions comprising one or more compounds of Formula I in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as carrier materials) and, if desired, other active ingredients. The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds of the present invention required to prevent or arrest the progress of the medical condition are readily ascertained by one of ordinary skill in the art. The compounds 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 made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. These may with advantage contain an amount of active ingredient from about 1 to 250 mg, preferably from about 25 to 150 mg. A suitable daily dose for a mammal may vary widely depending on the condition of the patient and other factors. However, a dose of from about 0.1 to 3000 mg/kg body weight, particularly from about 1 to 100 mg/kg body weight, may be appropriate.

The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable 121 carrier. A suitable daily dose is from about 0.1 to 100 mg/kg body weight injected per day in multiple doses depending on the disease being treated. A preferred daily dose would be from about 1 to 30 mg/kg body weight.

Compounds indicated for prophylactic therapy will preferably be administered in a daily dose generally in a range from about 0.1 mg to about 100 mg per kilogram of body weight per day. A more preferred dosage will be a range from about 1 mg to about 100 mg per kilogram of body weight. Most preferred is a dosage in a range from about 1 to about 50 mg per kilogram of body weight per day. A suitable dose can be administered, in multiple sub-doses per day. These sub-doses may be administered in unit dosage forms. Typically, a dose or sub-dose may contain from about 1 mg to about 100 mg of active compound per unit dosage form. A more preferred dosage will contain from about 2 mg to about 50 mg of active compound per unit dosage form. Most preferred is a dosage form containing from about 3 mg to about 25 mg of active compound per unit dose.

The dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex and medical condition of the patient, the severity of the disease, the route of administration, and the particular compound employed, and thus may vary widely.

For therapeutic purposes, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per as., the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl 122 esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.

Claims (42)

What Is Claimed Is:

1. A compound of Formula I: wherein m is a number selected from one to four, inclusive; wherein Rl is selected from polycycloalkyl, 10 polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2. -hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, 15 carboxymethoxyethyl substituted with phenyl, 3. ,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl)E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-220 hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl·, aralkoxycarbonyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, 25 alkylthiothiocarbony1, arylthiocarbonyl, arylthiothiocarbonyl, aralkylthiocarbonyl, alkylthiocarbonyl, aralkylsulfinyl, aralkylsulfonyl and radicals of the formula -CN X / 124 wherein each of R^ 2 and R^- 2 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalky1, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R 32 and R^ 2 taken together may form a heterocyclic group 5 having five to seven ring members including the nitrogen atom of said amino or amido radical and which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially 10 unsaturated; wherein each of R^ 2 and R^ 2 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected 15 from oxygen, nitrogen and sulfur atoms, with the proviso that when X is oxygen atom, then R 12 and R 13 cannot be selected from hydrido and alkyl; wherein each of R 2 through rU is independently selected 20 from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, 25 aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, aralkoxycarbonyl, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, aroyloxyalkyl, 30 alkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, 35 arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, IE 911 BUI 125 aralkylthiocarbonylthio, alkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more 5 ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula 10 wherein X is oxygen atom or sulfur atom; wherein each of R 34 , R^ 2 , R^- 2 , R-*- 7 , R·'· 2 and R^- 9 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R 14 and R 12 taken together, R 12 and 15 R 17 taken together and R 12 and R 19 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, 20 nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated,· wherein each of R 14 and R^ 2 taken together and each of R-'- 2 and R 17 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino 25 or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and wherein each of R 3 through rH may be further 30 independently selected from hydroxy and acidic moieties of the formula -Y n A IE 9118° 1 126 wherein n is a number selected from zero through three, inclusive, and wherein A is an acidic group selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; 5 wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; and wherein any of the foregoing R 1 through R 19 , Y and A 10 groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, halo, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, 15 cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aralkylsulfinyl, 20 aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula ,21 11 20 / -C-R 20 , -N ,22 and -NC-R wherein X is oxygen atom or sulfur atom; wherein R 29 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR^S and -N >27 IE 91180* 127 wherein D is selected from oxygen atom and sulfur atom and R25 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 21 , R 22 , R 23 , R 24 , R 26 and R 27 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of r 21, r22, r 23 z r 24 z r 26 r 27 is further independently selected from amino and amido radicals of the formula -N “R and -NC-R 32 I wherein X is oxygen atom or sulfur atom; wherein each of R 23 , R 2 ^, r30 z r31 r32 and r33 i s independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R 2 ! and R 22 taken together and each of R 23 and R 24 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of R 2 ^ and R 22 taken together and each of R 23 and R 27 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; or a tautomer thereof or a pharmaceutically-acceptable salt thereof. 128

2. Compound of Claim 1 wherein m is one; wherein is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyl5 methyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl) 10 E-ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-l15 methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, cycloalkynyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, arylthiocarbonyl, arylthiothiocarbonyl, aralkylthiocarbonyl, aralkylsulfonyl and radicals of the 20 formula R 12 R 13 wherein X is oxygen atom or sulfur atom; 25 wherein each of R 12 and R^- 2 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, with the proviso that when X is oxygen atom, then R 12 and R 13 cannot be selected from hydrido and alkyl; wherein R 2 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloaikyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, 35 alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, 129 cyanoalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, aikoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, carboxyl, alkylcarbonyloxy, 5 alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, 10 arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl and heteroaryl 15 having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; wherein each of R 3 through R 44 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, 20 haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, aikoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, 25 alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiothiocarbonyl, aralkylthio, aralkylthiocarbonyl, 3D aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl, and amino and amido radicals of the formula IE 911891 -Ν •R 130 -NC-R R 19 wherein X is oxygen atom or sulfur atom; wherein each of R 14 , R 13 , R 1 ^, R 17 , R 13 and R 1 ^ is 5 independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R 3 through R^ may be further 10 independently selected from acidic moieties of the formula -Y n A wherein n is a number selected from zero through three, 15 inclusive; wherein A is an acidic group selected from acids containing one or more atoms selected from oxygen, sulfur, phosphorus and nitrogen atoms, and wherein said acidic group is selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said 20 acidic moieties; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; and wherein any of the foregoing Rl through r19, γ and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, halo, haloalkyl, oxo, 30 alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkylthio and alkylthiocarbonyl, and amino and amido radicals of the formula X 131 11 20 / -C-R 20 , -N R‘ and -NC-R' wherein X is oxygen atom or sulfur atom; wherein r!9 i s selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, 5 aralkyl, aryl, and DR 22 and R 26 -N \r 27 wherein D is selected from oxygen atom and sulfur atom, 10 and R 22 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 21 , R 22 , R 22 , R 24 , R 2 ^ and R 2 ^ is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, 15 carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

3. Compound of Claim 2 wherein m is one; wherein Rl is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethy1, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyl25 methyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl) 30 E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lIE 911801 132 methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, cycloalkynyl, aralkylsulfonyl and amido radicals of the formula II R 12 -CN R 13 wherein each of R^ 3 and R 25 * * * * 30 * * 33 is independently selected from cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, 10 alkoxyalkyl, aralkyl and aryl; wherein R 3 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 15 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalky1, carboxyalkoxyalky1, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, 20 aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, carboxyl, alkylcarbonyloxy, alkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl; 25 wherein each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl·, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, 30 nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, mercapto, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl, and amino and amido radicals of the formula 133 -Ν •R -CN and il ,. NC-R 18 I R 19 wherein each of R 14 , R^ 2 , R 17 , R 12 and R 1 ^ is independently selected from hydrido, alkyl, cycloalkyl, 5 cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R 2 through R^ 1 may be an acidic moiety further independently selected from acidic moieties of the 10 formula -Y n A wherein n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from -OH, -SH, -NR 34 , -C-WH, -S-WH, -Sr wH ' -P-WH, -P-NH and -P-WH '35 '36 WR wherein each W is independently selected from oxygen atom, sulfur atom and NR 22 ; wherein each of R 24 , R 22 , R 22 , R 27 and R 22 is independently selected from hydrido, alkyl, 25 haloalkyl, haloalkylsulfonyl, haloalkylcarbony1, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R 24 , R 22 , R 22 and R 27 may be further independently selected from amino radical of the formula -N Δ1Ί 134 wherein each of R 39 and R 49 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R 39 and R 49 taken together may form a heterocyclic group 5 having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially 10 unsaturated; wherein R 39 and R 49 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen 15 and sulfur atoms; wherein each of R 33 and R 39 may be further independently selected from hydroxy, alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and-aralkoxy; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which heterocyclic ring contains at least one hetero atom 25 selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R^ 3 or may be attached at any two adjacent positions selected 30 from R 3 through R 33 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one 35 or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; It 9Π» υ1 135 and wherein any of the foregoing R 4 through R 4 ^ and R 34 through R 40 , Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl·, halo, oxo, haloalkyl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, aikoxycarbonyl, carboxyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkylthio and alkylthiocarbonyl, and amino and amido radicals of the formula 11 20 / -C-R 20 , -N ,22 and -NC-R' '24 wherein X is selected from oxygen atom and sulfur atom; wherein R 23 is selected from hydrido, alkyl, cycloalkyl, 15 cycloalkylalkyl, aralkyl, aryl and DR 23 and / R 26 -N ^R 27 wherein D is selected from oxygen atom and sulfur atom, 20 wherein R 23 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 24 , R 22 , R 23 , R 24 , R 23 and R 27 is independently selected from hydrido, alkyl, cycloalkyl, 25 cyano, hydroxyalkyl·, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, aikoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt 30 thereof.

4. Compond of Claim 3 wherein m is one; wherein R 4 is selected from polycycloalkyl, polycycloalkylalkyl, 136 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2phenylethy1, 1,1-dimethylethyloxycarbonylmethy1, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl 5. Substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5, 5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl) -E-ethenyl, l-benzoyl-2-phenylethyl, 1oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-210 hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-l methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, aralkylsulfonyl and radicals of the formula „ R 12 II / -CN \ R i3 wherein each of R^ 2 and R^ 3 is independently selected from cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, 20 hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein each of R 2 is selected from hydrido, alkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 25 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, 30 alkoxyalkyl·, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, carboxyl, alkylcarbonyloxy, alkylthio, arylthio, aralkylthio, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl; 35 wherein each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, It 911»01 137 haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, alkylthio, aralkylthio and. mercapto; and wherein each of R 2 through R 11 may be an acidic moiety further independently selected from acidic moieties of the formula -Y n A wherein n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from H W W w I 34 II II II -OH, -SH, -NR , -C-WH, -S-WH, -|-WH and -P-WH 15 W WR 37 wherein each W is independently selected from oxygen atom, sulfur atom and NR 22 ; wherein each of R 24 , R 27 and R 28 is independently selected from hydrido, alkyl, haloalkyl, 20 haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R 24 and R 27 may be further independently selected from amino radical of the formula .39 -N .40 wherein each of R 2 ^ and R 4 0 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein 30 R 2 ^ and R 4 ^ taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms, and which 138 heterocyclic group may be saturated or partially unsaturated; wherein R 3 ^ and R 4 0 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which 5 aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic 10 acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which 15 heterocyclic ring may be attached at a single position selected from R 3 through R 11 or may be attached at any two adjacent positions selected from R 3 through R 31 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of 20 said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; wherein each of R 1 through R 1 ^, r34 and r37 through R 40 , Y and A independently may be substituted at any substitutable position with one or more groups selected from alkyl, hydroxy, halo, oxo, haloalkyl, alkoxycarbonyl, cyano, 30 nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

5. Compound of Claim 4 wherein m is one; wherein Rl is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 139 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl) E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-l methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, aralkylsulfonyl and amido radicals of the formula II -CN ,13 wherein each of R 32 and R 33 is independently selected from cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, 20 phenalkyl and phenyl; wherein R 2 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, 25 alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, 3D aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, alkylthio, arylthio, aralkylthio and arylsulfonyl; wherein each of R 3 through R 33 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, 35 haloalkyl, cycloalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl, 140 alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein each of R 3 through R^ may be an acidic moiety 5 further independently selected from acidic moieties of the formula -Y n A wherein n is a number selected from zero through two, 10 inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from s34 W II -OH, -SH, -NR , -C-WH, -S-WH, -S-WH and -P-WH ΐ WR' 15 wherein each W is independently selected from oxygen atom, sulfur atom and NR 32 ; wherein each of R 34 , R 37 and R 32 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benzyl; wherein each of R 34 and R 37 may be further 20 independently selected from amino radical of the formula -N R 39 R 40 wherein each of R 39 and R 4 0 is independently selected from 25 hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, benzyl and phenyl; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of carboxylic acid may be further 30 selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially lb 141 unsaturated, and which heterocyclic ring may be attached at a single position selected from R 2 through R 6 * * * * 11 * * * * * * * or may be attached at any two adjacent positions selected from R 2 through R 1 ^· so as to form a fused-ring system with one of 5 the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, 10 phenyl, phenalkyl and aralkyl; wherein each of R 1 through R 19 , R 34 and. R 37 through R 40 , Y and A and independently may be substituted at any substitutable position with one or more groups selected 15 from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, halo, oxo, haloalkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy; 20 or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

6. Compound of Claim 5 wherein m is one; wherein Rl is selected from adamantyl, adamantylalkyl, 25 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted 30 with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, 35 ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl and acetonitrile; 142 where R 2 is selected from alkyl, hydroxyalkyl, cycloalkyl, polycycloalkyl, adamantyl, adamantylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalky1, 5 aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, haloalkyl, alkoxy, phenalkyl, phenyl, phenoxy, phenalkoxy, alkoxyalkyl, alkylcarbonyl, aikoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, alkylthio, phenthio and phenalkylthio; wherein each of R 3 through R 44 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, acetyl, aikoxycarbonyl, alkenyl, cyano, nitro, carboxyl, 15 alkylthio and mercapto; and wherein each of R 3 through R 44 may be an acidic moiety further independently selected from acidic moieties consisting of CO2H, CO2CH3, SH, CH2SH, C2H4SH, PO3H2, 20 NHSO2CF3, NHSO2CgF 5z SO3H, CONHNH2, CONHNHSO2CF3, CONHOCH3 CONHOC 2 H 5i CONHCF3, OH, CH2OH, C2H4OH, OPO3H2, OSO3H , It 9Π»υΊ 143 wherein each of R 4 ^·, R 42 and R 42 is independently selected from H, Cl, CN, NO 2 , CF 3/ C 2 F 5 , C3F7, CHF 2/ CH 2 F, CO 2 CH 3 , 5 CO 2 C 2 H5, SO 2 CH 3/ SO 2 CF 3 and SO 2 CgF5,· wherein Z is selected from 0, S, NR 44 and CH2; wherein R 44 is selected from hydrido, CH3 and CH 2 CgH5 ; and wherein said acidic moiety may be a heterocyclic acidic group attached at any two adjacent positions of R 2 through so as to form a fused 10 ring system with one of the phenyl rings of the biphenyl moiety of Formula I, said biphenyl fused ring system selected from 144 and the esters, amides and salts of said acidic moieties; or a tautomer thereof or a pharmaceutically-acceptable salt 5 thereof.

7. Compound of Claim 6 wherein m is one; wherein R 1 is selected from adamantyl, adamantylmethyl, adamantylethyl, adamantylpropy1, 3-phenylpropyl, 2-oxo-210 phenylethyl, 2-hydroxy-2-phenylethyl, 1,1dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted 15 with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2- (phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, 20 ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl and acetonitrile; wherein R 2 i s selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, isobutyl, tert-butyl, n-pentyl, isopentyl, 25 neopentyl, adamantyl, adamantylmethy1, adamantylethyl, adamantylpropyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2Ί81Π 145 hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl)-Eethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5dimethyoxyphenyl)-2-oxoethyl, 2-phenyl-2(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2 hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl, acetonitrile, phenyl, benzyl, phenethyl, cyclohexyl, eyelohexylmethyl, propylthio, butylthio, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,1difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein at least one of R 3 , R®, R® and R 3 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, wherein each of R 43 and R 43 is independently selected from Cl, CN, NO2, CF3, CO2CH3 and SO2CF3; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

8. Compound of Claim 7 wherein m is one; wherein R 1 is selected from 2-oxo-2(tricyclo[3.3.1.1. 3 · 7 ]dec-2-yl)ethyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1IE 911801 146 dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted 5 with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, 1 -benzoy1-2-phenylethy1, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2- (phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, 10 ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl and 1-cyanobutyl; wherein R 2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl, neopentyl, 15 1-cyanobutyl, propylthio and butylthio; wherein at least one of R 2 , R 8 , R 8 and R^ is an acidic group selected from CO 2 H, SH, PO 3 H 2< SO 3 H, CONHNH 2/ CONHNHSO 2 CF 3 ,. OH, wherein each of R 42 and R 42 is independently selected from Cl, CN, NO 2 , CF 3 , CO 2 CH 3 and SO 2 CF 3 ; or a tautomer thereof or a pharmaceutically-acceptable salt 25 thereof.

9. Compound of Claim 8 wherein m is one; wherein Rl is selected from 2-oxo-2(tricyclo[3.3.1.1. 3 - 7 ]dec-2-yl)ethyl, 3-phenylpropyl, 230 oxo-2-phenylethyl, 2-hydroxy-2-phenylethy1, 1,1dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted It 911801 147 with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2- (phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-25 hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl and 1-cyanobutyl; wherein R 2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl·, 10. 4-methylbutyl, n-pentyl, 1-cyanobutyl, propylthio and butylthio; wherein each of R 3 , R 4 , R 8 , R 7 , R 8 , R 19 and R 11 is hydrido; wherein one of R 3 and R 9 is hydrido and the other of R 3 and R 9 is an acidic group selected from CO2H and H or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

10. Compound of Claim 9 selected from compounds, and their pharmaceutically-acceptable salts, of the group consisting of 4 ’ - [ (1,3-dibutyl-4,5-dihydro-5-oxo-lH-l,2,425 triazol-4-yl) methyl ] [1,1’ -biphenyl] -2-carboxylic acid; 5-butyl-2,4 -dihydro-2- [ 2-oxo-2- (t ricyclo [3.3.1.1. 3 · 7 ] dec2-yl)ethyl]-4-[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4'ylmethyl]-3H-1,2,4-triazol-3-one; 30 5-butyl-2,4-dihydro-2- (3-phenylpropyl) -4- [2' - (1Htetrazol-5-yl) [1,1’-biphenyl] -4-ylmethyl] -3H-1,2,4triazol-3-one; 5-butyl-2,4-dihydro-2- (2-oxo-2-phenylethyl) -4- [2 ’ - (1Htetrazol-5-yl) [1,1' -biphenyl] -4-ylmethyl] -3H-1,2,435 triazol-3-one; 148 5-butyl-2,4-dihydro-2- (2-hydroxy-2 -phenylethyl) -4- [2' (lH-tetrazol-5-yl) [1,l'-biphenyl]-4-ylmethyl]-3H-1,2,4trlazol-3-one; 1,1-dimethylethyl 3-butyl-4,5-dihydro-5-oxo-4- [2' - (1H5 tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4triazole-l-acetate; 5-butyl-2,4 -dihydro-2 -hexyl-4- [2' - (lH-tetrazol-5yl) [1,1' -biphenyl] -4-ylmethyl] -3H-1,2,4-triazol-3-one; ethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'- (ΙΗ-tetrazol-510 yl) [1,1' -biphenyl] -4-ylmethyl] -1H-1,2,4-triazole-lacetate; 3- butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-5-yl)[1,1'· biphenyl] -4-ylmethyl] -1H-1,2,4-triazole-l-acetic acid; 5-butyl-2,4-dihydro-2- (1-naphthaleny lmethyl) -4- [2' - (1H15 tetrazol-5-yl) [1,1'-biphenyl] -4-ylmethyl] -3H-1,2,4triazol-3-one; 5-butyl-2- (2-cyclohexylethyl) -2,4-dihydro-4- [2' - (1Htetrazol-5-yl) [1,1' -biphenyl] -4-ylmethyl] -3H-1,2,4triazol-3-one; 20 5-butyl-2,4-dihydro-2-pentyl-4- [2' - (lH-tetrazol-5yl) [1,1' -biphenyl] -4-ylmethyl] -3H-1,2,4-triazol-3-one; ethyl [2- [3-butyl-4,5-dihydro-5-oxo-4- [2 ’ - (lH-tetrazol5-yl) [1,1' -biphenyl] -4-ylmethyl] -1H-1,2,4-triazol-l-yl] 1- phenylethoxy]acetate; 25 [2- [ 3-butyl-4,5-dihydro-5-oxo-4- [2' - (lH-tetrazol-5yl) [1,1'-biphenyl] -4-ylmethyl] -1H-1,2,4-triazol-l-yl] -1 phenylethoxy]acetic acid; 5-butyl-2,4-dihydro-4-[2'-(lH-tetrazol-5-yl)[1,1'biphenyl] -4-ylmethyl] -2- (3,5,5-trimethylhexyl) -3H-1,2,4 30 triazol-3-one; 5-butyl-2,4-dihydro-2- [2-phenyl-2- (phenylmethoxy) -1(phenylmethyl) -E-ethenyl] -4- [2' - (lH-tetrazol-5-yl) [1,1' biphenyl] -4-ylmethyl] -3H-1,2,4-triazol-3-one; 2- (l-benzoyl-2-phenylethyl) -5-butyl-2,4-dihydro-4- [2' 35 (lH-tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4triazol-3-one; 5-butyl-2,4-dihydro-2- (1-oxabutyl) -4- [2' - (lH-tetrazol-5 yl) [1,1' -biphenyl] -4-ylmethyl] -3H-1,2,4-triazol-3-one; 5-butyl-2,4-dihydro-2- [2-(2,5-dimethyoxyphenyl) -240 oxoethyl] -4- [2' - (lH-tetrazol-5-yl) [1,1' -biphenyl] -4y lmethyl]-3H-1,2,4-triazol-3-one; 5-butyl-2,4-dihydro-2- [2-phenyl-2- (phenylmethoxy) ethyl] 4- [2' - (lH-tetrazol-5-yl) [1,1' -biphenyl] -4-ylmethyl] -3H1,2,4-triazol-3-one; ΙΕ νπβυι 149 5-butyl-2,4-dihydro-2- [2- (2,5-dimethyoxyphenyl) -2hydroxyethyl]-4-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4ylmethyl]-3H-1,2,4-triazol-3-one; 5-butyl-2,4-dihydro-2- (2-naphthalenylmethyl) -4- [2' - (1H5 tetrazol-5-yl) [1,1' -biphenyl] -4-ylmethyl] -3H-1,2,4triazol-3-one; methyl 3-butyl-4,5-dihydro-5-oxo-4-[2'- (lH-tetrazol-5yl) [1,1' -biphenyl] -4-ylmethyl] -1H-1,2,4-triazole-lpentanoate; 10 ethyl p-benzoyl-3-butyl-4,5-dihydro-5-oxo-4- [2' - (1Htetrazol-5-yl) [1,1'-biphenyl] -4-ylmethyl] -1H-1,2,4triazole-l-propanoate; 2- (1-benzyoyl-l-methylethyl) -5-butyl-2,4-dihydro-4- [2' (lH-tetrazol-5-yl) [1,1'-biphenyl] -4-ylmethyl] -3H-1,2,415 triazol-3-one; 3- butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-5-yl) [1,1'biphenyl] -4-ylmethyl] -1H-1,2,4-triazole-l-pentanoic acid; 5-butyl-2- (cyclopropylmethyl) -2,4-dihydro-4- [2' - (1H20 tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4triazol-3-one; 5-butyl-2,4-dihydro-2- (3-phenyl-2E-propenyl) -4- [2' - (1Htetrazol-5-yl) [1,1' -biphenyl] -4-ylmethyl] -3H-1,2,4triazol-3-one; and 25 1-butyl-4,5-dihydro-5-oxo-a-propyl-4-[2'-(lH-tetrazol-5yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3acetonitrile.

11. Compound of Claim 10 which is 5-butyl-2,430 dihydro-2-pentyl-4-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4ylmethyl]-3H-1,2,4-triazol-3-one.

12. Compound of Claim 10 which is 5-butyl-2,4dihydro-2-hexyl-4-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-435 ylmethyl]-3H-1,2,4-triazol-3-one.

13. Compound of Claim 10 which is 5-butyl-2-(2cyclohexylethyl)-2,4-dihydro-4-[2'-(lH-tetrazol-5-yl) [1,1'biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one. C-2619/1 150

14. Compound of Claim 10 which is 5-butyl-2(cyclopropylmethyl) -2, 4-dihydro-4-[2'-(lH-tetrazol-5yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one. 5 15. Compound of Claim 10 which is 1,1dimethylethyl 3-butyl-4, 5-dihydro-5-oxo-4-[2'-(lH-tetrazol 5-yl)[1,1'-biphenyl]-4-ylmethyl]-lH-l,2,4-triazole-lacetate. 10 16. Compound of Claim 10 which is ethyl 3-butyl-4,5-dihydro-5-oxo-4-[2’-(lH-tetrazol-5yl)[1,1’-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-l-acetate 17. Compound of Claim 10 which is methyl 315 butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-5-yl) [1,1’ — biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-l-pentanoate. 18. Compound of Claim 10 which is 3-butyl-4,5dihydro-5-oxo-4-[2'-(lH-tetrazoi-5-yl)[1,1'-biphenyl]-420 ylmethyl]-1H-1,2,4-triazole-l-pentanoic acid. 19. Compound of Claim 10 which is 5-butyl-2,4dihydro-2-(3-phenylpropyl)-4-[2'-(lH-tetrazol-5-yl) [1,1' biphenyl]-4-ylmethyl]-3H-1,2, 4-triazol-3-one. 20. Compound of Claim 10 which is 5-butyl-2,4dihydro-2-(2-oxo-2-phenylethyl)-4-[2'- (lH-tetrazol-5yl) [1,1' -biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one. 30 21. Compound of Claim 10 which is 5-butyl-2,4dihydro-2-(2-hydroxy-2-phenylethyl)-4-[2'-(lH-tetrazol-5 yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one. C-2619/1 22. A pharmaceutical composition comprising a 151 therapeutically-effective amount of an angiotensin II antagonist compound and a pharmaceutically-acceptable carrier or diluent, said antagonist compound selected from a family of compounds of Formula I: R 7 (I) wherein m is a number selected from one to four, inclusive; wherein Rl is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl) E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2-(phenylmethoxy)ethyl, 2-(2, 5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, aralkoxycarbonyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, alkylthiothiocarbonyl, arylthiocarbony1, arylthiothiocarbony1, aralkylthiocarbony1, alkylthiocarbonyl, aralkylsulfinyl, aralkylsulfonyl and radicals of the formula C-2019/1 152 wherein X is oxygen atom or sulfur atom; 5 wherein each of R 12 and R^ 2 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein r!2 and R^ 2 taken together may form a heterocyclic group having five to seven ring members including the nitrogen 10 atom of said amino or amido radical and which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of R 12 and R 12 taken together may

15. Form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms, with the proviso

16. 20 that when X is oxygen atom, then R 12 and R 13 cannot be selected from hydrido and alkyl; wherein each of R 2 through R 1 · 1 is independently selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, 25 cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl·, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, 30 cyanoalkyl, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, aralkoxycarbonyl, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, aroyloxyalkyl, alkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, 35 alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, C-26i9/l 153 alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, alkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula -N •R -CN and X II „ -NC-R 18 •R wherein X is oxygen atom or sulfur atom; wherein each of R 34 , R^ 2 , R^ 8 , R^ 7 , R 28 and R^· 2 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R 24 and R^ 2 taken together, R^· 8 and rI 7 taken together and R^ 8 and r!9 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of R 14 and R·'· 2 taken together and each of R 38 and R^ 7 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; L-26i9/l IE 9118U1 154 and wherein each of R 3 through R 11 may be further independently selected from hydroxy and acidic moieties of the formula -Y n A wherein n is a number selected from zero through three, inclusive, and wherein A is an acidic group selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; and wherein any of the foregoing R 1 through R 13 , Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, halo, oxo, alkoxy, aryloxy, aralkoxy, araikylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula and -NC-R 23 wherein X is oxygen atom or sulfur atom; wherein R 3 ^ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, 35 aralkyl, aryl, DR 33 and C-2619/i 155 -N R wherein D is selected from oxygen atom and sulfur atom and R 25 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 23 , R 22 , R 23 , R 24 , R 26 and R 27 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of r 21, r 22, r 23 z r 24 z r 26 R 27 is further independently selected from amino and amido radicals of the formula -N >28 ιί R 30 II / ‘R -CN and -NC-R wherein X is oxygen atom or sulfur atom; 20 wherein each of R 23 , R 29 , R 39 , R 33 R 32 and R 33 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R 23 and R 22 taken together and each of R 23 25 and R 24 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which 30 heterocyclic group may be saturated or partially unsaturated; wherein each of R 23 and R 22 taken together and each of R 23 and R 27 taken together may form an aromatic heterocyclic group having five ring members including the Zfrl 9/1 156 nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; or a tautomer thereof or a 5 pharmaceutically-acceptable salt thereof.

17. 23. The composition of Claim 22 wherein m is one; wherein Rl is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 10 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 15 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl) E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl) -2-oxoethyl, 2-phenyl 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, 20 ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, cycloalkynyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, arylthiocarbonyl, arylthiothiocarbonyl, 25 aralkylthiocarbony1, aralkylsulfonyl and radicals of the formula 30 wherein X is oxygen atom or sulfur atom; wherein each of R^- 2 and R-*- 3 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, with the proviso that when X is oxygen atom, then R 12 and R 13 cannot 35 be selected from hydrido and alkyl; u-ztj'iy/i 157 wherein R 2 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, 5 alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, 10 alkynyl, cycloalkynyl, cyano, carboxyl, alkylcarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, 15 arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, 20 alkylsulfonyl, aralkylsulfonyl, arylsulfonyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; wherein each of R 3 through rH is independently selected 25 from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, 30 mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, 35 arylthiothiocarbonyl, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfonyl, C-2619/1 158 aralkylsulfonyl and arylsulfonyl, and amino and amido radicals of the formula -N •R and -NC-R 18 wherein X is oxygen atom or sulfur atom; wherein each of R^ 4 , R^· 2 , R^ 2 , R^ 7 , R 22 and R^ 9 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R 2 through may be further independently selected from acidic moieties of the formula -Y n A wherein n is a number selected from zero through three, inclusive; wherein A is an acidic group selected from acids containing one or more atoms selected from oxygen, sulfur, 20 phosphorus and nitrogen atoms, and wherein said acidic group is selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, 25 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^ through R^ 9 , Y and A 30 groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, halo, haloalkyl, oxo, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, cyano, nitro, alkylsulfonyl, 35 haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, C-2biy/l 159 alkylthio and alkylthiocarbonyl, and amino and amido radicals of the formula ,21 -C-R 20 , -N ,22 and -NC-R' 124 wherein X is oxygen atom or sulfur atom; wherein R^ 3 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and DR 33 and -N wherein D is selected from oxygen atom and sulfur atom, and R 33 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 3 -*-, 15 R 33 , R 33 , R 34 , R 3 ® and R 37 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl ; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

18. 24. The composition of Claim 23 wherein m is

19. 25 one; wherein R^ is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, 30 ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl) E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyle-26i’y/i IE 9118° 4 160 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-l methylethyl, 1-pentanoic acid, cyclopropylmethyl, 5 arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, cycloalkynyl, aralkylsulfonyl and amido radicals of the formula wherein each of R^ 2 and R 33 is independently selected from cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; 15 wherein R 2 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, 20 aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, carboxyl, alkylcarbonyloxy, 25 alkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl; wherein each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, 30 haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, 35 mercapto, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl, and amino and amido radicals of the formula C-2019/1 161 -N R 16 and R 17 II -NC-R 18 R 19 wherein each of R^- 4 , R^ 3 , r16, r! 7 , R 3 - 3 and R 1 ^ is 5 independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R 3 through R 11 may be an acidic moiety 10 further independently selected from acidic moieties of the formula -Y n A 15 wherein n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from -OH, -SH, -NR , -C-WH, -S-WH, -β-WH, -P-WH, -P-NH and -P-WH WR’ R 35 R 36 5- 37 wherein each W is independently selected from oxygen atom, sulfur atom and NR 33 ; wherein each of R 34 , R 33 , R 33 , R 37 25 and R 33 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R 34 , R 33 , R 33 and R 37 may be further independently selected from amino radical of the formula -N R 39 R 40 C-2619/1 162 wherein each of R 39 and R 49 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein 5 R 39 and R 49 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which 10 heterocyclic group may be saturated or partially unsaturated; wherein R 39 and R 49 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more 15 hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; wherein each of R 33 and R 33 may be further independently selected from hydroxy, alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and aralkoxy; and the amide, ester and salt derivatives of said acidic 20 groups ; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, 25 which heterocyclic ring contains at least one hetero atom selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R 33 30 or may be attached at any two adjacent positions selected from R 3 through R 33 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; 35 wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; C-2619/1 163 and wherein any of the foregoing Rl through R 3 ^ and R 34 through R 40 , Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, halo, oxo, haloalkyl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkylthio and alkylthiocarbonyl, and amino and amido radicals of the formula X II 20 / -C-R , -N .21 ‘R and -NC-R' R' wherein X is selected from oxygen atom and sulfur atom; wherein R 2 ^ is selected from hydrido, alkyl, cycloalkyl, 15 cycloalkylalkyl, aralkyl, aryl and DR 22 and / R 25 26 -N \r 27 wherein D is selected from oxygen atom and sulfur atom, 20 wherein R 22 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 23 , R 22 , R 23 , R 24 , R 28 and R 27 is independently selected from hydrido, alkyl, cycloalkyl, 25 cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt 30 thereof. 25. The composition of Claim 24 wherein m is one; wherein R 3 is selected from polycycloalkyl, C-2619/1 164 polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 5 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5, 5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1oxobutyl, 2-(2, 5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl10 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethy1, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-l methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, 15 aralkylsulfonyl and radicals of the formula 0 A II / -CN ,13 wherein each of R 12 and R 13 is independently selected from 20 cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein each of R 2 is selected from hydrido, alkyl, 25 polycycloalkyl·, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalky1, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, 30 alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, carboxyl, alkylcarbonyloxy, alkylthio, arylthio, araikylthio, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl; C-2619/1 165 wherein each of R 2 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, 5 alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, alkylthio, aralkylthio and mercapto; and wherein each of R 2 through rH may be an acidic moiety further independently selected from acidic moieties of the 10 formula -Y n A wherein n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and 15 bioisosteres of carboxylic acid selected from ,34 -OH, -SH, -NR , -C-WH, -S-WH, -S-WH and -P-WH WR' wherein each W is independently selected from oxygen atom, 20 sulfur atom and NR 22 ; wherein each of R 24 , R 27 and R 22 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R 24 and R 27 may be further independently selected from amino 25 radical of the formula -N R 39 R 40 wherein each of R 29 and R 49 is independently selected from 30 hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R 29 and R 49 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may C-2619/1 166 further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms, and which heterocyclic group may be saturated or partially unsaturated; wherein R 39 and R 49 taken together may form an 5 aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and the amide, ester and salt derivatives 10 of said acidic groups; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen 15 atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R 33 or may be attached at any two adjacent positions selected from R 3 through R 33 so as to 20 form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one 25 or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; wherein each of R 1 through R 19 , R 34 and R 37 through R 40 , Y and A independently may be substituted at any substitutable 30 position with one or more groups selected from alkyl, hydroxy, halo, oxo, haloalkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy; 35 or a tautomer thereof or a pharmaceutically-acceptable salt thereof. C-2619/1 167

20. 26. The composition of Claim 25 wherein m is one; wherein R 3 is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyl5 methyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl) 10 E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-l 15 methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, aralkylsulfonyl and amido radicals of the formula R 12 0 / R II / -CN \ Rl3 wherein each of R 32 and R 33 is independently selected from cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, phenalkyl and phenyl; 25 wherein R 2 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, 30 aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, alkylthio, arylthio, aralkylthio and arylsulfonyl; C-2619/1 168 wherein each of R 3 through R^· is independently selected from hydrido, hydroxy, alkyl, hydroxyalky1, halo, haloalkyl, cycloalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl, 5 alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein each of R 3 through R 34 may be an acidic moiety further independently selected from acidic moieties of the 10 formula -Y n A wherein n is a number selected from zero through two, inclusive; wherein A is selected from carboxylic acid and 15 bioisosteres of carboxylic acid selected from ,34 W II -OH, -SH, -NR , -C-WH, -S-WH, -S-WH and -P-WH T WR' wherein each W is independently selected from oxygen atom, sulfur atom and NR 32 ; wherein each of R 34 , R 37 and R 32 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benzyl; wherein each of R 34 and R 37 may be further independently selected from amino radical of the formula -N wherein said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of wherein each of R 39 and R 49 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, 30 alkoxyalkyl, benzyl and phenyl; and the amide, ester and salt derivatives of said acidic groups; C-2619/1 169 heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially 5 unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R 27 * * * * * 33 or may be attached at any two adjacent positions selected from R 3 through R 33 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and 10 salt derivatives of said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenalkyl and aralkyl; wherein each of R 3 through R 19 , R 34 * * and R 37 * through R 40 , Y and A and independently may be substituted at any substitutable position with one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, halo, 20 oxo, haloalkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy; or a tautomer thereof or a pharmaceutically-acceptable salt 25 thereof.

21. 27. The composition of Claim 26 wherein m is one; wherein R 3 is selected from adamantyl, adamantylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-230 phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1 -naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-135 (phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1oxobutyl, 2-(2, 5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2- (phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, C-2619/1 170 ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl and acetonitrile; 5 where R 2 is selected from alkyl, hydroxyalkyl, cycloalkyl, polycycloalkyl, adamantyl, adamantylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, 10 cyanoalkyl, haloalkyl, alkoxy, phenalkyl, phenyl, phenoxy, phenalkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, alkylthio, phenthio and phenalkylthio; 15 wherein each of R 3 through R 33 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, acetyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein each of R 3 through R 33 may be an acidic moiety further independently selected from acidic moieties consisting of CO2H, CO2CH3, SH, CH 2 SH, C2H4SH, PO3H2, NHSO2CF3, NHSO2CgF5 z SO3H, CONHNH 2 , CONHNHSO2CF3, CONHOCH; 25 CONHOC2H5, CONHCF3, OH, CH2OH, C2H4OH, OPO3H2, OSO3H , C-2619/1 171 wherein each of R 41 , R 42 and R 43 is independently selected from H, Cl, CN, NO 2 , CF 3< C 2 F 5 , C3F7, CHF 2/ CH 2 F, CO 2 CH 3 , 5 CO 2 C 2 H5, SO 2 CH 3/ SO 2 CF3 and SO 2 CgF5; wherein Z is selected from 0, S, NR 44 and CH2; wherein R 44 is selected from hydrido, CH3 and CH 2 CgH5 ; and wherein said acidic moiety may be a heterocyclic acidic group attached at any two adjacent positions of R 3 through R 11 so as to form a fused 10 ring system with one of the phenyl rings of the biphenyl moiety of Formula I, said biphenyl fused ring system selected from C-2619/1 172 and the esters, amides and salts of said acidic moieties; or a tautomer thereof or a pharmaceutically-acceptable salt 5 thereof.

22. 28. The composition of Claim 27 wherein m is one; wherein R 1 is selected from adamantyl, 10 adamantylmethyl, adamantylethy1, adamantylpropy1, 3phenylpropy1, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl·, pentyl, ethoxycarbonylmethoxyethyl 15 substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl) -E-ethenyl, 1-benzoyl-2-phenylethy 1, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2- (phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-220 hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl and acetonitrile; wherein R 2 is selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec25 butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, adamantyl, adamantylmethyl, adamantylethy1, C-2619/1 173 adamantylpropyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1naphthalenylmethyl, 2-cyclohexylethyl, pentyl, 5 ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl)-Eethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5dimethyoxyphenyl)-2-oxoethyl, 2-pheny1-210 (phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethy1, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl, acetonitrile, phenyl, benzyl, phenethyl, 15 cyclohexyl, cyclohexylmethyl, propylthio, butylthio, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,1difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; 20 wherein at least one of R 3 , R 6 , R 8 and R 3 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, wherein each of R 42 and R 43 is independently selected from Cl, CN, NO2, CF3, CO2CH3 and SO2CF3; or a tautomer thereof or a pharmaceutically-acceptable salt 30 thereof.

23. 29. The composition of Claim 28 wherein m is one; wherein Rl is selected from 2-oxo-2(tricyclo[3.3.1.1. 3 · 7 ]dec-2-yl)ethyl, 3-phenylpropyl, C-2619/1 174 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl 5 substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-l(phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2- (phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-210 hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl and 1-cyanobutyl; wherein R 2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 15 4-methylbutyl, tert-butyl, n-pentyl, neopentyl, 1-cyanobutyl, propylthio and butylthio; wherein at least one of R 3 , R 8 , R 8 and R^ is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO 2CF3, OH, wherein each of R 42 and R 43 is independently selected from Cl, CN, NO2/ CF3, CO2CH3 and SO2CF3; 25 or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

24. 30 The composition of Claim 29 wherein m is one; wherein R 4 is selected from 2-oxo-230 (tricyclo[3.3.1.1. 3 · 7 ]dec-2-yl)ethyl, 3-phenylpropyl, 2oxo-2-phenylethy1, 2-hydroxy-2-phenylethy1, 1,1dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl C-2619/1 175 substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, <2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl5 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl and 1-cyanobutyl; wherein R 2 is selected from 10 ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, n-pentyl, 1-cyanobutyl, propylthio and butylthio; wherein each of R 3 , R 4 , R 6 , R 7 , R 8 , R 10 and R 11 is hydrido; wherein one of R 3 and R 9 is hydrido and the other of R 2 and R 9 is an acidic group selected from CO2H 15 and H N—N or a tautomer thereof or a pharmaceutically-acceptable salt 20 thereof.

25. 31. The composition of Claim 30 wherein said antagonist compound is selected from compounds, and their pharmaceutically-acceptable salts, of the group consisting 25 of 4 1 -[(1,3-dibutyl-4, 5-dihydro-5-oxo-lH-l,2,4-triazol-4 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 5-butyl-2,4-dihydro-2-[2-oxo-2-(tricyclo[3.3.1.1. 3 · 7 ]dec-2 yl)ethyl]-4-[2 1 -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4'30 ylmethyl]-3H-1,2,4-triazol-3-one; 5-butyl-2,4-dihydro-2-(3-phenylpropyl)-4-[2'-(lH-tetrazol5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one; 5-butyl-2,4-dihydro-2-(2-oxo-2-phenylethyl)-4-[2'-(1Htetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol35 3-one; C-2619/1 176 5-butyl-2,4-dihydro-2-(2-hydroxy-2-phenylethyl)-4-[2'-(1Htetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol3-one; 1,1-dimethylethyl 3-butyl-4, 5-dihydro-5-oxo-4-[2'- (1H5 tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4triazole-l-acetate; 5-butyl-2,4-dihydro-2-hexyl-4-[2'-(lH-tetrazol-5-yl) [1,1'biphenyl]-4-ylmethyl]-3H-1,2, 4-triazol-3-one; ethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-510 yl)[1,1’-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-l-acetate; 3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-5-yl) [1,1'biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-l-acetic acid; 5-butyl-2,4-dihydro-2-(1-naphthalenylmethyl)-4-[2'-(1Htetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol15 3-one; 5-butyl-2-(2-cyclohexylethyl)-2,4-dihydro-4- [2'- (1Htetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol3-one; 5-butyl-2,4-dihydro-2-pentyl-4-[2'-(lH-tetrazol-5-yl) [1,1'20 biphenyl]-4-ylmethyl]-3H-1,2, 4-triazol-3-one; ethyl [2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-5yl)[1,1’-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-l-yl]-1phenylethoxy]acetate; [2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-525 yl) [1,1 ’-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-l-yl]-1phenylethoxy]acetic acid; 5-butyl-2,4-dihydro-4-[2'-(lH-tetrazol-5-yl)[1,1'biphenyl]-4-ylmethyl]-2-(3,5, 5-trimethylhexyl)-3H-1,2,4triazol-3-one; 30 5-butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)-1(phenylmethyl)-E-ethenyl]-4-[2’-(lH-tetrazol-5-yl)[1,1'biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one; 2-(l-benzoyl-2-phenylethyl) -5-butyl-2,4-dihydro-4-[2'- (1Htetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol 35 3-one; 5-butyl-2,4-dihydro-2-(1-oxobutyl)-4-[2'-(lH-tetrazol-5yl) [1,1 ’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one; 111 5-butyl-2,4-dihydro-2-[2-(2,5-dimethyoxyphenyl)-2oxoethyl]-4-[2’-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4ylmethyl]-3H-1,2,4-triazol-3-one; 5-butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)ethyl]-45 [2 1 - (lH-tetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4triazol-3-one; 5-butyl-2,4-dihydro-2-[2-(2,5-dimethyoxyphenyl)-2hydroxyethyl]-4-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4ylmethyl]-3H-l,2,4-triazol-3-one; 10 5-butyl-2,4-dihydro-2-(2-naphthalenylmethyl)-4- [2'- (1Htetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol3-one; methyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-5 yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2, 4-triazole-1 15 pentanoate; ethyl p-benzoyl-3-butyl-4,5-dihydro-5-oxo-4-[2'- (1Htetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4triazole-l-propanoate; 2- (1-benzyoyl-l-methylethyl)-5-butyl-2,4-dihydro-4-[2'- (1H20 tetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol3- one; 3-butyl-4,5-dihydro-5-oxo-4-[2 1 -(lH-tetrazol-5-yl)[1,1'biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-l-pentanoic acid; 5-butyl-2-(cyclopropylmethyl)-2,4-dihydro-4-[2'- (1H25 tetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol3-one; 5-butyl-2,4-dihydro-2-(3-phenyl-2E-propenyl)-4-[2'- (1Htetrazol-5-yl) [1, 1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol3-one; and 30 1-butyl-4,5-dihydro-5-oxo-a-propyl-4-[2 1 -(lH-tetrazol-5yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2, 4-triazole-3acetonitrile. C-2619/1

26. 32. A therapeutic method for treating a 178 circulatory disorder, said method comprising administering to a subject having such disorder a therapeuticallyeffective amount of an active compound of Formula I: R 7 (I) wherein m is a number selected from one to four, inclusive; wherein R 3 is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-pbenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl· substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl) E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, aralkoxycarbonyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, alkylthiothiocarbonyl, arylthiocarbonyl, arylthiothiocarbonyl, aralkylthiocarbonyl, alkylthiocarbonyl, aralkylsulfinyl, aralkylsulfonyl and radicals of the formula C-2619/1 179 X II R 12 -CN R 13 wherein each of R^- 2 and r!3 £ s independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl·, 5 cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R 12 and R 12 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and which heterocyclic group may further contain one or more hetero atoms as ring 10 members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of R 12 and R 12 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido 15 radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms, with the proviso that when X is oxygen atom, then R 12 and R 13 cannot be selected from hydrido and alkyl; wherein each of R 2 through rH is independently selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloaikyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, 25 alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, aralkoxycarbonyl, alkoxyalkyl, alkylcarbonyl, 30 alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, aroyloxyalkyl, alkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, 35 alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, C-2619/1 180 arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, 5 aralkylthiocarbonylthio, alkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, 10 and amino and amido radicals of the formula -N ‘R and -NC-R 18 wherein X is oxygen atom or sulfur atom; 15 wherein each of R 34 , R 33 , R 33 , R 37 , R 33 and R 39 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R 34 and R 33 taken together, R 33 and R 37 taken together and R 33 and R 39 taken together may form 20 a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may 25 be saturated or partially unsaturated; wherein each of R 34 and R 33 taken together and each of R 33 and R 37 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may 3D further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and wherein each of R 3 through R 33 may be further independently selected from hydroxy and acidic moieties of 35 the formula C-2619/1 •Ε 911801 181 -Y n A wherein n is a number selected from zero through three, 5 inclusive, and wherein A is an acidic group selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, 10 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^ through R^ 9 , Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, 15 alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, halo, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, 20 aralkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur 25 and nitrogen atoms, and amino and amido radicals of the formula ,21 -C-R 20 , -N “R' and -NC-R' '24 30 wherein X is oxygen atom or sulfur atom; wherein R 29 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR 22 and C-2619/1 182 -Ν .27 wherein D is selected from oxygen atom and sulfur atom and R 25 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 2 ·'·, R 22 , R 23 , R 24 , R 23 and R 27 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of r21, r22, r23 ; r24, r26 an d r27 j_ s further independently selected from amino and amido radicals of the formula ,30 -N R -CN and -NC-R R wherein each of R 23 , R 23 , R 3 ®, R 33 · R 32 and R 33 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R 21 and R 22 taken together and each of R 23 and R 24 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein each of R 21 and R 22 taken together and each of R 26 and R 27 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen c-2019/i 183 and sulfur atoms; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

27. 33. The method of Claim 32 wherein m is one; 5 wherein R 3 is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, 10 ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl) E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl15 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, cycloalkynyl, 20 mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, arylthiocarbonyl, arylthiothiocarbonyl, aralkylthiocarbonyl, aralkylsulfonyl and radicals of the formula wherein X is oxygen atom or sulfur atom; wherein each of R 33 and R 33 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, 30 cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, with the proviso that when X is oxygen atom, then R 32 and R 33 cannot be selected from hydrido and alkyl; wherein R 3 is selected from hydrido, alkyl, hydroxyalkyl, 35 halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, C-2619/i 184 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, 5 aralkoxy, alkoxyalkyl, alkylcarbonyl, aikoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, carboxyl, alkylcarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, 10 alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, 15 aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; wherein each of R 3 through R 44 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl·, 25 aikoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, 30 alkylthiothiocarbonyl, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiothiocarbonyl, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, 35 aralkylthiocarbonylthio, mercapto, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl, and amino and amido radicals of the formula C-2619/1 X -N 185 V -CN and -NC-R 18 wherein X is oxygen atom or sulfur atom; wherein each of R 34 , R 32 , R 38 , R 37 , R 38 and R 39 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R 3 through R 33 may be further independently selected from acidic moieties of the formula wherein n is a number selected from zero through three, inclusive; wherein A is an acidic group selected from acids containing one or more atoms selected from oxygen, sulfur, phosphorus and nitrogen atoms, and wherein said acidic group is selected to contain at least one acidic hydrogen atom, and the amide, ester and salt derivatives of said acidic moieties; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms; and wherein any of the foregoing R 3 through R 39 , Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, halo, haloalkyl, oxo, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkylthio and alkylthiocarbonyl, and amino and amido radicals of the formula C-2619/i X 186 X 11 20 / -C-R 20 , -N R' and -NC-R' wherein X is oxygen atom or sulfur atom; wherein R^ 9 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, 5 aralkyl, aryl, and DR 22 and wherein D is selected from oxygen atom and sulfur atom, 10 and R 22 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 23 , R 22 , R 23 , R 24 , R 26 and R 27 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, 15 carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

28. 34. The method of Claim 33 wherein m is one; wherein Rl is selected from polycycloaikyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 25 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 30 3,5 , 5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl)E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, 187 ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-l methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl·, mercaptocarbonyl, cycloalkynyl, aralkylsulfonyl and amido radicals of the 5 formula R 12 R 13 wherein each of R 32 and R 33 is independently selected from 10 cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein R 2 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, 15 polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, 20 aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, carboxyl, alkylcarbonyloxy, alkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl; wherein each of R 3 through R 11 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, 30 alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, mercapto, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl, and amino and amido radicals of the formula c-xo 19/1 R 16 188 II 18 -NC-R 18 u wherein each of R 44 , R 43 , R 43 , R 47 , R 4 ® and R 4 ^ is independently selected from hydrido, alkyl, cycloalkyl, 5 cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; -N / „ .CN and wherein each of R 3 through R 44 may be an acidic moiety further independently selected from acidic moieties of the 10 formula -Y n A wherein n is a number selected from zero through three, 15 inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from -OH, -SH, -NR 34 , -C-WH, -S-WH, -S-WH, -P-WH, -P-NH and -P-WH '35 ,36 WR’ wherein each W is independently selected from oxygen atom, sulfur atom and NR 3 ®; wherein each of R 34 , R 33 , R 33 , R 37 and R 3 ® is independently selected from hydrido, alkyl, 25 haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R 34 , R 33 , r 33 and R 37 may be further independently selected from amino radical of the formula -N ./ .39 C-2619/1 189 wherein each of R 39 and R 4(3 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R 39 and R 49 taken together may form a heterocyclic group 5 having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially 10 unsaturated; wherein R 39 and R 49 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen 15 and sulfur atoms; wherein each of R 35 and R 38 may be further independently selected from hydroxy, alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and aralkoxy; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which heterocyclic ring contains at least one hetero atom 25 selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R 33 or may be attached at any two adjacent positions selected 30 from R 3 through R 33 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one

29. 35 or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; C-2619/1 190 and wherein any of the foregoing R 3 through R 39 and R 34 through R 40 , Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, alkenyl, aralkyl, hydroxyalkyl, halo, oxo, haloalkyl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkylthio and alkylthiocarbonyl, and amino and amido radicals of the formula X -N R' R‘ and -NC-R' R‘ wherein X is selected from oxygen atom and sulfur atom; wherein R 39 is selected from hydrido, alkyl, cycloalkyl, 15 cycloalkylalkyl, aralkyl, aryl and DR 32 and .26 -N •R wherein D is selected from oxygen atom and sulfur atom, 20 wherein R 32 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 33 , R 33 , R 33 , R 34 , R 32 * and R 37 is independently selected from hydrido, alkyl, cycloalkyl, 25 cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt 30 thereof. 35. The method of Claim 34 wherein m is one; R^ is selected from polycycloalkyl, polycycloalkylalkyl, c-Zbiv/ ί 191 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1oxobutyl, 2-(2, 5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethy1, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-l methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, aralkylsulfonyl and radicals of the formula II -CN R 12 R 13 wherein each of R^ 2 and R 33 is independently selected from cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, 20 hydroxyalkyl·, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl ; wherein each of R 2 is selected from hydrido, alkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 25 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalky1, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, 30 alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, carboxyl, alkylcarbonyloxy, alkylthio, arylthio, araikylthio, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl; 35 wherein each of R 3 through rH is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, C-2619/1 192 haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, alkylthio, aralkylthio and mercapto; and wherein each of R 3 through R 33 may be an acidic moiety further independently selected from acidic moieties of the formula -Y n A wherein n is a number selected from zero through three, inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from ,34 W II -OH, -SH, -NR , -C-WH, -S-WH, -S-WH and -P-WH T WR' wherein each W is independently selected from oxygen atom, sulfur atom and NR 33 ; wherein each of R 34 , R 37 and R 33 is independently selected from hydrido, alkyl, haloalkyl, 20 haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R 34 and R 37 may be further independently selected from amino radical of the formula R· wherein each of R 39 and R 49 is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein 30 R 39 and R 49 taken together may form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms, and which C-2619/1 193 heterocyclic group may be saturated or partially unsaturated; wherein R 39 and R 49 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which 5 aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic 10 acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which 15 heterocyclic ring may be attached at a single position selected from R 3 through R 33 or may be attached at any two adjacent positions selected from R 3 through R 36 33 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of 20 said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; wherein each of R 3 through R 39 , R 34 and R 37 through R 49 , Y and A independently may be substituted at any substitutable position with one or more groups selected from alkyl, hydroxy, halo, oxo, haloalkyl, alkoxycarbonyl, cyano, 30 nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

30. 36. The method of Claim 35 wherein m is one; wherein R 3 is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethy1, ei Jt i 194 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1- naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl) E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-l methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, aralkylsulfonyl and amido radicals of the formula wherein each of R^· 2 and R^ 3 is independently selected from cycloalkyl, cyano, amino, hydroxyalkyl, alkoxyalkyl, 20 phenalkyl and phenyl; wherein R 2 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, polycycloaikyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, 25 alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, 30 aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, alkylthio, arylthio, aralkylthio and arylsulfonyl; wherein each of R 3 through is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, 35 haloalkyl, cycloalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl, 195 alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein each of R 3 through R 11 may be an acidic moiety 5 further independently selected from acidic moieties of the formula -Y n A wherein n is a number selected from zero through two, 10 inclusive; wherein A is selected from carboxylic acid and bioisosteres of carboxylic acid selected from -OH, -SH, -NR 34 , -C-WH, -S-WH, -S-WH and -P-WH WR' 15 wherein each W is independently selected from oxygen atom, sulfur atom and NR 33 ; wherein each of R 34 , R 37 and R 33 is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benzyl; wherein each of R 34 and R 37 may be further 20 independently selected from amino radical of the formula R39 -N ‘R wherein each of R 3 ^ and R 4 ^ is independently selected from 25 hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, benzyl and phenyl; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of carboxylic acid may be further 30 selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially 196 unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R 33 or may be attached at any two adjacent positions selected from R 3 through R 33 so as to form a fused-ring system with one of 5 the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, 10 phenyl, phenalkyl and aralkyl; wherein each of R 3 through R 39 , R 34 and R 37 through R 40 , Y and A and independently may be substituted at any substitutable position with one or more groups selected 15 from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, halo, oxo, haloalkyl, alkoxycarbonyl, cyano, nitro, alkylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy; 20 or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

31. 37. The method of Claim 36 wherein m is one; wherein R 3 is selected from adamantyl, adamantylalkyl, 25 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2phenylethyl, 1,1-dimethylethyloxycarbonyImethy1, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted 30 with phenyl, 3,5, 5-trimethylhexyl, (2-phenylmethoxy)-1(phenyImethy1)-E-ethenyl, l-benzoyl-2-phenylethyl, 1oxobutyl, 2-(2, 5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, 35 ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl and acetonitrile; L-i.oiy/1 197 where R 2 is selected from alkyl, hydroxyalkyl, cycloalkyl, polycycloalkyl, adamantyl, adamantylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylalkoxyalkyl, carboxyalkoxyalkyl, 5 aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, haloalkyl, alkoxy, phenalkyl, phenyl, phenoxy, phenalkoxy, alkoxyalkyl, alkylcarbonyl, aikoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyl, cycloalkenyl, alkynyl, alkylthio, phenthio and phenalkylthio; wherein each of R 3 through R 44 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, acetyl, aikoxycarbonyl, alkenyl, cyano, nitro, carboxyl, 15 alkylthio and mercapto; and wherein each of R 3 through R 44 may be an acidic moiety further independently selected from acidic moieties consisting of CO2H, CO2CH3, SH, CH2SH, C2H4SH, PO3H2, 20 NHSO2CF3, NHSO2CgF5 z SO3H, CONHNH2, CONHNHSO2CF3, CONHOCH3 CONHOC2H5, CONHCF3, OH, CH2OH, C2H4OH, OPO3H2, OSO3H , '4-0 i > / 1 198 wherein each of R 43 , R 42 and R 43 is independently selected from H, Cl, CN, N0 2 , CF3, C 2 F 5 , C3F7, CHF 2/ CH 2 F, CO 2 CH3, 5 CO 2 C 2 H5, SO 2 CH3, SO 2 CF3 and SO 2 CgF5,· wherein Z is selected from 0, S, NR 44 and CH2; wherein R 44 is selected from hydrido, CH3 and CH2CgH5 ; and wherein said acidic moiety may be a heterocyclic acidic group attached at any two adjacent positions of R 3 through R 33 so as to form a fused 10 ring system with one of the phenyl rings of the biphenyl moiety of Formula I, said biphenyl fused ring system selected from C_-i >/ 1 IE 9Ή8θ 4 199 and the esters, amides and salts of said acidic moieties; or a tautomer thereof or a pharmaceutically-acceptable salt 5 thereof.

32. 38. The method of Claim 37 wherein m is one; wherein R 3 is selected from adamantyl, adamantylmethyl, adamantylethyl, adamantylpropyl, 3-phenylpropyl, 2-oxo-2 10 phenylethyl, 2-hydroxy-2-phenylethyl, 1,1dimethylethyloxycarbonylmethy1, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted 15 with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2- (phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, 20 ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl and acetonitrile; wherein R 2 is selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, isobutyl, tert-butyl, n-pentyl, isopentyl, 25 neopentyl, adamantyl, adamantylmethyl, adamantylethyl, adamantylpropyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2<. -ί,υ ι >/1 200 hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbony lmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, 5 carboxymethoxyethyl substituted with phenyl, 3,5,5trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl)-Eethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5dimethyoxyphenyl)-2-oxoethyl, 2-phenyl-2(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-210 hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl, acetonitrile, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, propylthio, butylthio, 15 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,1difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein at least one of R 2 , R 8 , R 8 and R 9 is an acidic 20 group selected from CO 2 H, SH, PO3H 2> SO3H, CONHNH 2/ CONHNHSO 2 CF 3 , OH, 25 wherein each of R 42 and R 43 is independently selected from Cl, CN, NO 2 , CF3, CO2CH3 and SO 2 CF 3 ; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

33. 39. The method of Claim 38 wherein m is one; wherein R 1 is selected from 2-oxo-2(tricyclo[3.3.1.1. 3 - 7 ]dec-2-yl) ethyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1e-rtOi yy i 201 dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted 5 with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2- (phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2hydroxyethy1, 2-naphthalenylmethyl, methoxycarbonylbutyl, 10 ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl and 1-cyanobutyl; wherein R 2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl, neopentyl, 15 1-cyanobutyl, propylthio and butylthio; wherein at least one of R 3 , R 6 , R 8 and R^ is an acidic group selected from CO 2 H, SH, PO3H 2/ SO3H, CONHNH 2 , C0NHNHSO 2 CF3, ΌΗ, wherein each of R 42 and R 43 is independently selected from Cl, CN, NO2, CF3, CO2CH3 and SO2CF3; or a tautomer thereof or a pharmaceutically-acceptable salt 25 thereof.

34. 40. The method of Claim 39 wherein m is one; wherein R^ is selected from 2-oxo-2(tricyclo[3.3.1.1. 3 · 7 ]dec-2-yl)ethyl, 3-phenylpropyl, 230 oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted 202 with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1(phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl2- (phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-25 hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-lmethylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl2E-propenyl and 1-cyanobutyl; wherein R 2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 10 4-methylbutyl, n-pentyl, 1-cyanobutyl, propylthio and butylthio; wherein each of R 2 , R 4 , r6, R 7 , R 2 , r!0 and R 11 is hydrido; wherein one of R 5 and R 9 is hydrido and the other of R 2 and R 9 is an acidic group selected from CO 2 H and H or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

35. 41. The method of Claim 40 wherein said active compound is selected from compounds, and their pharmaceutically-acceptable salts, of the group consisting of 25 4'-[(1,3-dibutyl-4,5-dihydro-5-oxo-lH-l,2,4-triazol-4yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 5-buty1-2, 4-dihydro-2-[2-oxo-2-(tricyclo[3.3.1.1. 3 · 7 ]dec-2 yl)ethyl]-4-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4'ylmethyl]-3H-1,2,4-triazol-3-one; 30 5-butyl-2,4-dihydro-2-(3-phenylpropyl)-4-[2'—(lH-tetrazol5-yl) [1,1 '-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one; 5-butyl-2,4-dihydro-2-(2-oxo-2-phenylethyl)-4-[2'-(1Htetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol3-one; 203 5-butyl-2,4-dihydro-2-(2-hydroxy-2-phenylethyl)-4-[2’-(1Htetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol3-one; 1,1-dimethylethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H5 tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4triazole-l-acetate; 5-butyl-2,4-dihydro-2-hexyl-4-[2'-(lH-tetrazol-5-yl)[1,1'biphenyl]-4-ylmethyl]-3H-1,2, 4-triazol-3-one; ethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-510 yl)[1,1’-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-l-acetate; 3-butyl-4,5-dihydro-5-oxo-4-[2’-(lH-tetrazol-5-yl)[1,1'biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-l-acetic acid; 5-butyl-2,4-dihydro-2-(1-naphthalenylmethyl)-4-[2'-(1Htetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol15 3-one; 5-butyl-2-(2-cyclohexylethyl)-2,4-dihydro-4-[2'-(1Htetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol3-one; 5-butyl-2,4-dihydro-2-pentyl-4-[2'-(lH-tetrazol-5-yl) [1,1' — 20 biphenyl]-4-ylmethyl]-3H-1,2, 4-triazol-3-one; ethyl [2- [3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-5yl)[1,1’-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-l-yl]-1phenylethoxy]acetate; [2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-525 yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-l-yl]-1phenylethoxy]acetic acid; 5-butyl-2,4-dihydro-4-[2'-(lH-tetrazol-5-yl)[1,1'biphenyl]-4-ylmethyl]-2-(3,5, 5-trimethylhexyl)-3H-1,2,4triazol-3-one; 30 5-butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)-1(phenylmethyl)-E-ethenyl]-4-[2’-(lH-tetrazol-5-yl)[1,1'biphenyl]-4-ylmethyl]-3H-1,2, 4-triazol-3-one; 2-(l-benzoyl-2-phenylethyl)-5-butyl-2,4-dihydro-4-[2'- (1Htetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol 35 3-one; 5-butyl-2,4-dihydro-2-(1-oxobutyl)-4-[2'-(lH-tetrazol-5yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one; •Ε 911801 204 5-butyl-2,4-dihydro-2-[2-(2,5-dimethyoxyphenyl)-2oxoethyl]-4-[2 1 -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4ylmethyl]-3H-1,2,4-triazol-3-one; 5-butyl-2, 4-dihydro-2- [2-phenyl-2- (phenylmethoxy) ethyl] -45 [2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2, 4 triazol-3-one; 5-buty1-2,4-dihydro-2-[2-(2,5-dimethyoxyphenyl)-2hydroxyethyl]-4-[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4ylmethyl]-3H-1,2,4-triazol-3-one; 10 5-butyl-2,4-dihydro-2-(2-naphthalenylmethyl)-4-[2'- (1Htetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol 3-one; methyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-5yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-l 15 pentanoate; ethyl p-benzoyl-3-butyl-4,5-dihydro-5-oxo-4-[2‘- (1Htetrazol-5-yl)[1,l'-biphenyl]-4-ylmethyl]-1H-1,2,4triazole-l-propanoate; 2- (1-benzyoyl-l-methylethyl)-5-butyl-2,4-dihydro-4-[2'- (IH 20 tetrazol-5-yl) [1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol 3- one; 3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol-5-yl) [1,1'biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-l-pentanoic acid; 5-butyl-2-(cyclopropylmethyl) -2,4-dihydro-4-[2 1 - (1H25 tetrazol-5-yl)[1,1’-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol 3-one; 5-butyl-2,4-dihydro-2-(3-phenyl-2E-propenyl)-4- [2'- (1Htetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol 3-one; and 30 l-butyl-4,5-dihydro-5-oxo-a-propyl-4-[2 1 -(lH-tetrazol-5yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3acetonitrile.

36. 42. The method of Claim 32 wherein said 35 circulatory disorder is a cardiovascular disorder.

37. 43. The method of Claim 42 wherein said cardiovascular disorder is hypertension. 205

38. 44. The method of Claim 42 wherein said cardiovascular disorder is congestive heart failure.

39. 45. A compound as claimed in Claim 1, substantially as hereinbefore described and exemplified.

40. 46. A pharmaceutical composition according to Claim 22, substantially as hereinbefore described.

41. 47. A process for preparing a compound as claimed in Claim 1, substantially as hereinbefore described and exemplified .

42. 48. A compound as claimed in Claim 1, whenever prepared by a process claimed in Claim 47.