EP0531382A1 - N-substituted-1,2,4-triazolone compounds for treatment of cardiovascular disorders - Google Patents

Abstract

The invention relates to a class of N-substituted 1,2,4-triazolone compounds for use in the treatment of cardiovascular disorders. The compounds of particular interest are angiotensin II antagonists of the formula (I), in which R1 is chosen 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, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylethylphenoxyethylphenoxy-substituted , 3,5,5-trimethylhexyl, (2-phenylmethoxy) -1- (phenylmethyl) -E-ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2- (2,5-dimethyloxyphenyl) -2-oxoethyl , 2-phenyl-2- (phenylmethoxy) ethyl, 2- (2,5-dimethyoxy-phenyl) -2-hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonyl-butyl, ethoxycarbonylethyl replaced by benzoyl, 1-benzyoyl-1-methylethyl, acid -1-pentanoic, cyclopropylmethyl, 3-phenyl-2E-propenyl and 3-acetonitryl; 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; in which R3 to R11 each represent a hydrido provided that at least one of the elements R5 and R9 are chosen from COOH, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, (a), (b) and (c), in which R42 and R43 are independently selected from chloro, cyano, nitro, trifluoromethyl, methoxycarbonyl and trifluoromethylsulfonyl. These compounds are particularly useful in the treatment or regulation of hypertension and heart failure.

Description

N-SUBSTITUTED-1,2,4-TRIAZOLONE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS Related Application

This is a continuation-in-part of U.S. Application Ser. No. 07/529,079 filed May 25, 1990.

Field of the Invention

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 1,2,4- triazolones having a biphenylmethyl moiety attached to the nitrogen atom at the four-position of the 1,2,4-triazolone.

Background of the Invention

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

competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [A. T. Chiu et al, European J. Pharmacol., 157, 1321 (1988)]. A family of 1-benzylimidazole-5-acetate derivatives has been shown to have competitive angiotensin II antagonist properties [A. T. Chiu et al, J. Pharmacol. Exp. Ther., 250 (3), 867-874 (1989)]. U.S. Patent No.

4,816,463 to Blankey et al describes a family of 4,5,6,7- tetrahydro-1H-imidazo (4,5-c)-tetrahydro-pyridine

derivatives useful as antihypertensives, some of which are reported to antagonize the binding of labelled angiotensin II to rat adrenal receptor preparation and thus cause a significant decrease in mean arterial blood pressure in conscious hypertensive rats. EP No. 253,310, published 20 January 1988, describes a series of aralkyl imidazole compounds, including in particular a family of biphenylmethyl substituted imidazoles, as antagonists to the angiotensin II receptor. EP No. 323,841 published 12 July 1989 describes four classes of angiotensin II

antagonists, namely, biphenylmethylpyrroles,

biphenylmethylpyrazoles, biphenylmethyl-1,2,3-triazoles and biphenylmethyl 4-substituted-4H-1,2,4-triazoles, including the compound 3,5-dibutyl-4-[(2'-carboxybiphenyl-4- yl)methyl]-4H-1,2,4-triazole. U.S. 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 descrϋes a family of 1,2,4- triazolin-5-one compounds, specifically 2,4-dihydro-4,5- 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-1-piperazinyl)- propyl)-3,4-diethyl-1,2,4-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-1,2,4-triazol-5-one compounds. EP #7,180 published 15 June 1978 describes a family of 1,2-disubstituted-4-alkyl-1,2,4-triazolidine-3, 5- dione 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 N¹- 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 R¹ is selected from polycycloalkyl,

polycycloalkylalkyl, 3-phenylpropyl, 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)-1-(phenylmethyl)- E-ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl,

2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl, acetonitrile, cycloalkenyl, aralkoxycarbonyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, alkylthiothiocarbonyl, arylthiocarbonyl,

arylthiothiocarbonyl, aralkylthiocarbonyl,

alkylthiocarbonyl, aralkylsulfinyl, aralkylsulfonyl and radicals of the formula

wherein each of R¹² and R¹³ is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl,

cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R¹² and R¹³ 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 R¹² and R¹³ 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 R¹² and R¹³ cannot be selected from hydrido and alkyl; wherein each of R² through R¹¹ 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

- wherein X is oxygen atom or sulfur atom;

wherein each of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R¹⁴ and R^{1 5} taken together, R¹⁶ and R¹⁷ taken together and R¹⁸ 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 R¹⁴ and R¹⁵ taken together and each of R¹⁶ and R¹⁷ 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 R³ through R¹¹ may be further

independently selected from hydroxy and acidic moieties of the formula

-Y_nA 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, 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, 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

wherein X is oxygen atom or sulfur atom; wherein R²⁰ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, .aralkyl, aryl, DR²⁵ and

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 R²¹, R²², R²³, R²⁴, R²⁶ and R²⁷ 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 and R²⁷ is further independently selected from amino and amido radicals of the formula

wherein X is oxygen atom or sulfur atom;

wherein each of R²⁸, R²⁹, R³⁰, R³¹ R³² and R³³ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl,

haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R²¹ 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 R²¹ and R²² taken together and each of R²⁶ 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 -Y_nA moiety, is intended to embrace chemical groups which, when attached to any of the R³ through R¹¹ positions of Formula I, confers acidic character to the compound of Formula I. "Acidic character" means proton-donor capability, that is, the capacity of the compound of Formula I to be a proton donor in the presence of a proton-receiving substance such as water. Typically, the acidic group should be selected to have proton-donor capability such that the product compound of Formula I has a pK_a in a range from about one to about twelve. More typically, the Formula I compound would have a pK_a 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 -Y_nA moiety, such carboxyl group would be attached directly to one of the R³ through R¹¹ positions. The Formula I compound may have one -Y_nA moiety attached at one of the R³ through R¹¹ positions, or may have a plurality of such -Y_nA moieties attached at more than one of the R³ through R¹¹ positions, up to a maximum of nine such -Y_nA 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 -Y_nA moiety attached at one of

positions R⁵, R⁶, R⁸ and R⁹ would be expected to have preferred properties, while attachment at R⁵ or R⁹ would be more preferred. 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 pK_a values of the Formula I compound as conferred by the -YnA moiety be in a range from about two to about seven. The -Y_nA moiety may be attached to one of the R³ through R¹¹ positions through any portion of the -Y_nA moiety which results in a Formula I compound being relatively stable and also having a labile or acidic proton to meet the foregoing pK_a criteria. For example, where the -Y_nA 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, 3- phenylpropyl, 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)-1- (phenylmethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenyImethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 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 R¹² and R¹³ is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl,

cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, with the proviso that when X is oxygen atom, then R¹² and R¹³ cannot be selected from hydrido and alkyl; 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, 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, aralkylthiocarbonyl, 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 R³ through R¹¹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo,

haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,

cycloalkynyl, cyano, nitro, carboxyl, 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

_. wherein X is oxygen atom or sulfur atom;

wherein each of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R³ through R¹¹ may be further

independently selected from acidic moieties of the formula

-Y_nA 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 R¹⁹, 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

wherein X is oxygen atom or sulfur atom; wherein R¹⁹ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and DR²³ and 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 R²¹, R²², R²³, R²⁴, R²⁶ 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.

A more preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein R¹ is selected from polycycloalkyl, polycycloalkylalkyl, 3- phenyIpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyl-methyl, hexyl,

ethoxycarbonyImethyl, carboxymethyl, 1-naphthalenyImethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1- (phenyImethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenyImethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropyImethyl,

arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, cycloalkynyl, aralkylsulfonyl and amido radicals of the formula wherein each of R¹² and R¹³ 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, alkoxycarbonyl, 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,

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 y

wherein each of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R³ through R¹¹ may be an acidic moiety further independently selected from acidic moieties of the formula -Y_nA 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 w

wherein each W is independently selected from oxygen atom, sulfur atom and NR³⁸; wherein each of R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl,

cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R³⁴, R³⁵, R³⁶ and R³⁷ may be further independently selected from amino radical of the formula wherein each of R³⁹ and R⁴⁰ is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R³⁹ and R⁴⁰ 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 R⁴⁰ 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 R³⁵ and R³⁶ 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 R³ through R¹¹ or may be attached at any two adjacent positions selected from R³ through R¹¹ so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; 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 R¹ through R¹⁹ 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 wherein X is selected from oxygen atom and sulfur atom; wherein R²⁰ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl and DR²⁵ and

wherein D is selected from oxygen atom and sulfur atom, wherein R²⁵ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R²¹, R²², R²³, R²⁴, R²⁶ 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; R¹ is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenyIpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2- phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonyImethyl, carboxymethyl, 1 -naphthalenyImethyl, 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-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenyImethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropyImethyl,

arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, aralkylsulfonyl and radicals of the formula

wherein each of R¹² and R¹³ 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, cy-anoalkyl, 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 R³ through R¹¹ 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 R³ through R¹¹ may be an acidic moiety further independently selected from acidic moieties of the formula

-Y_nA 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

- wherein each W is independently selected from oxygen atom, sulfur atom and NR³⁸; wherein each of R³⁴, R³⁷ and R³⁸ 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 wherein each of R³⁹ and R⁴⁰ is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R³⁹ and R⁴⁰ 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 R⁴⁰ taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of

carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which

heterocyclic ring may be attached at a single position selected from R³ through R¹¹ or may be attached at any two adjacent positions selected from R³ through R¹¹ so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; 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 R¹⁹, R³⁴ and R³⁷ through R⁴⁰, 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 R¹ is selected from polycycloalkyl. polycycloalkylalkyl, 3-phenyIpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyl- methyl, hexyl, ethoxycarbonylmethyl, carboxymethyl,

1-naphthalenyImethyl, 2-cyclohexylethyl, pentyl,

ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl,

3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenyImethyl)- E-ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl,

2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenyImethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropyImethyl,

arylalkenyl, acetonitrile, aralkylsulfonyl and amido radicals of the formula

wherein each of R¹² and R¹³ 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 R³ through R¹¹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl,

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 of the formula

-Y_nA 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 4

wherein each W is independently selected from oxygen atom, sulfur atom and NR³⁸; wherein each of R³⁴, R³⁷ and R³⁸ 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 R³⁹ 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 a single position selected from R³ through R¹¹ or may be attached at any two adjacent positions selected from R³ through R¹¹ so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; 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 R¹ is selected from adamantyl, adamantylalkyl, 3-phenyIpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2- phenylethyl, 1,1-dimethylethyloxycarbonyImethyl, hexyl, ethoxycarbonyImethyl, carboxymethyl, 1-naphthalenyImethyl, 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-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenyImethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropyImethyl,

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 R¹¹ 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, PO₃H₂,

NHSO₂CF₃, NHSO₂C₆F₅, SO₃H, CONHNH₂, CONHNHSO₂CF₃, CONHOCH₃, CONHOC₂H₅, CONHCF₃, OH, CH₂OH, C₂H₄OH, OPO₃H₂, OSO₃H ,

wherein each of R⁴¹, R⁴² and R⁴³ is independently selected from H, Cl, CN, NO₂, CF₃, C₂F₅, C₃F₇, CHF₂, CH₂F, CO₂CH₃, CO₂C₂H₅, SO₂CH₃, SO₂CF₃ and SO₂C₆F₅; wherein Z is selected from O, S, NR⁴⁴ and CH₂; wherein R⁴⁴ is selected from hydrido, CH₃ and CH₂C₆H₅; and wherein said acidic moiety may be a heterocyclic acidic group attached at any two adjacent positions of R³ through R¹¹ so as to form a fused ring system with one of the phenyl rings of the biphenyl moiety of Formula I, said biphenyl fused ring system selected from

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 R¹ is selected from adamantyl, adamantylmethyl, adamantylethyl, adamantylpropyl, 3-ρhenyIpropyl, 2-oxo-2- phenylethyl, 2-hydroxy-2-phenylethyl, 1,1- dimethylethyloxycarbonyImethyl, hexyl,

ethoxycarbonyImethyl, carboxymethyl, 1-naphthalenyImethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1- (phenyImethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl,

1-oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenyImethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropyImethyl, 3-phenyl- 2E-propenyl and acetonitrile; wherein R² is selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, adamantyl, adamantyImethyl, adamantylethyl, adamantylpropyl, 3 -phenyIpropyl, 2-oxo-2-phenylethyl, 2- hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyImethyl, hexyl, ethoxycarbonyImethyl, carboxymethyl, 1- naphthalenyImethyl, 2-cyclohexylethyl, pentyl,

ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5- trimethylhexyl, (2-phenylmethoxy)-1-(phenyImethyl)-E- ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5- dimethyoxyphenyl)-2-oxoethyl, 2-phenyl-2-

(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenyImethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl- 2E-propenyl, acetonitrile, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, propylthio, butylthio,

1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1- dijnethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,1- difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein at least one of R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂H, SH, PO₃H₂, SO₃H, CONHNH₂,

CONHNHSO₂CF₃, OH,

wherein each of R⁴² and R⁴³ 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.^3.7]dec-2-yl) ethyl, 3-phenyIpropyl,

2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1- dimethylethyloxycarbonylmethyl, hexyl,

ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenyImethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1- (phenyImethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl,

1-oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenyImethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropyImethyl, 3-phenyl- 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 R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂H, SH, PO₃H₂, SO₃H, CONHNH₂, CONHNHSO₂CF₃, OH,

wherein each of R⁴² and R⁴³ 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 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-phenyIpropyl, 2- oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1- dimethylethyloxycarbonyImethyl, hexyl,

ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenyImethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1- (phenyImethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl,

1-oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenyImethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl- 2E-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 R⁹ is hydrido and the other of R⁵ and R⁹ is an acidic group selected from CO₂H and

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:

4'-[(1,3-dibutyl-4,5-dihydro-5-oxo-1H-1,2,4-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'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4'- ylmethyl]-3H-1,2,4-triazol-3-one; 5-butyl-2, 4-dihydro-2- (3-phenyIpropyl) -4- [2 ' - (1H-tetrazol-

5-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'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol- 3-one;

5-butyl-2,4-dihydro-2-(2-hydroxy-2-phenylethyl)-4-[2'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-

3-one;

1,1-dimethylethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4- triazole-1-acetate;

5-butyl-2,4-dihydro-2-hexyl-4-[2'-(1H-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'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-acetate;

3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl) [1,1'- biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-acetic acid;

5-butyl-2,4-dihydro-2-(1-naphthalenyImethyl)-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol- 3-one;

5-butyl-2-(2-cyclohexylethyl)-2,4-dihydro-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-

3-one;

5-butyl-2,4-dihydro-2-pentyl-4-[2'-(1H-tetrazol-5-yl) [1,1'- biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;

ethyl [2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-1-yl]-1- phenylethoxy]acetate;

[2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-1-yl]-1- phenylethoxy] acetic acid;

5-butyl-2,4-dihydro-4-[2'-(1H-tetrazol-5-yl) [1, 1 ' - biphenyl] -4-ylmethyl] -2- (3,5, 5-trimethylhexyl) -3H-1,2, 4- triazol-3-one;

5-butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)-1-

(phenylmethyl)-E-ethenyl]-4-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one; 2-(1-benzoyl-2-phenylethyl)-5-butyl-2,4-dihydro-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-

3-one;

5-butyl-2,4-dihydro-2-(1-oxobutyl)-4-[2'-(1H-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)-2- oxoethyl]-4-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)ethyl]-4- [2'-(1H-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)-2- hydroxyethyl]-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-(2-naphthalenylmethyl)-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-

3-one;

methyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1- pentanoate;

ethyl β-benzoyl-3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4- triazole-1-propanoate;

2-(1-benzyoyl-1-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'-(1H-tetrazol-5-yl) [1,1'- biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-pentanoic acid;

5-butyl-2-(cyclopropylmethyl)-2,4-dihydro-4-[2'-(1H- 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'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-

3-one; and

1-butyl-4,5-dihydro-5-oxo-α-propyl-4-[2'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3- acetonitrile. 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 -CH₂- group. Where the term "alkyl" is used, either alone or within other terms such as "haloalkyl" and "hydroxyalkyl", the term "alkyl" embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl

radicals are "lower alkyl" radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about five carbon 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 dichloromethyl group, or one fluoro atom and one chloro atom, such as a fluoro-chloromethyl group. Examples of a polyhaloalkyl are trifluoromethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl and 2,2,3,3- tetrafluoropropyl groups. The term "difluoroalkyl" embraces alkyl groups having two fluoro atoms substituted on any one or two of the alkyl group carbon atoms. 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 substi- 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 methythion 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. The te.rm "aralkyl" embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenyl- ethyl, phenyIbutyl 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 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 Fcrmula 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 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 pharmaceutically- acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glut-amic, 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. 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.

Synthetic Scheme I shows the preparation of 1,2,4-triazolone 1 from isothiocyanate 2 via N- ethoxycarbonyl thioamide 2. according to the general procedure outlined by Papadopoulos, E. P. and George, B., J. Org. Chern., 41, 3233 (1976). In the first step, N- ethoxycarbonyl thioamide 3 can be prepared from

ethoxycarbonyl isothiocyanate 2 and the corresponding organometallic 4 . The N-ethoxycarbonyl thioamide 3 can be converted to triazolone 1 by the action of the

corresponding hydrazines 5 as described in the reference given above.

Synthetic Scheme II shows the preparation of the alkylating agent 6 from the corresponding precursor 7. When R⁵ equals CO₂CH₃, 7 was purchased from Chemo Dynamics Inc.

Synthetic Scheme III shows the preparation of the alkylating agent precursor 7 where R⁵ equal CN₄C(C₆H₅)₃ from the corresponding methyl ester 7 (R⁵ = CO₂CH₃). In step 1, the methyl ester is converted to the corresponding acid (R⁵ = CO₂H) by the action of sodium

hydroxide/hydrochloric acid. In step 2, the acid is converted to the corresponding acid chloride (R⁵ = COCl) by the action of oxalyl chloride. In step 3, the acid

chloride is converted to the corresponding primary amide (R⁵ = CONH₂) by the action of ammonium. In step 4, the amide is converted to the corresponding nitrile 9 by the action of thionyl chloride at reflux. The nitrile 9 is reacted with trimethyltin azide in toluene at reflux to give the corresponding trimethyltin protected tetrazole 8; deprotection with acetic acid/water and reprotection with triphenylmethyl chloride/triethylamine gives the N-trityl tetrazole 7 (R⁵ = CN₄C(C₆H₅) 3).

Synthetic Scheme IV shows the coupling reaction of the 1,2,4-triazolone 1 with the appropriate alkylating reagent 6 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 6 to give coupled product 11. The trisubstituted 1,2,4- triazolone 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.

Synthetic Scheme V shows the preparation of semicarbazide 14 from bromide 6. 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 6 by treatment with sodium azide.

Synthetic Scheme VI shows the cyclization of 14. to 18 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 11 which may be converted to the corresponding acid 12 or tetrazole 13 by treatment with one of the appropriate reagents as shown in Scheme IV.

The following Ex-amples 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.

4'-[(1, 3-dibutyl-4,5-dihydro-5-oxo-1H-1,2,4-triaznl-4- yl)methyl][1,1'-biphenyl]-2-carboxylic acid

Step 1: Preparation of 2-(p-tolyl)benzoic acid A mixture of 52 g (0.23 mol) of methyl 2-(p- tolyl) 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

(MgS04) and concentrated in vacuo to give 48.7 g (99%) of 2- (p-tolyl) benzoic acid as a white solid: ¹H NMR

(CDCI₃) δ 2.40 (s, 3H), 7.00-8.05 (m, 8H), 10.4-11.4 (broad s, 1H).

Step 2: Preparation of tert-butyl 2-(p-tolyl) 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 2- methylpropene 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 (MgSO₄) and concentrated in vacuo to give 57.2 g (94%) of tert-butyl 2- (p-tolyl) benzoate as a solid: ¹ H 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, 1H).

Step 3; Preparation of 4-bromomethyl-2'-tert- butoxycarbonylbiphenyl

To a mixture of 57 g (0.213 mol) of tert- butyl 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 N- bromosuccinimide 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 (quantitative) of a sample which contained mostly desired product, 4-bromomethyl-2'-tert- 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: ¹H NMR (CDCI₃) δ 1.26(s, 9H), 4.56(s, 2H), 7.2-7.9(m, 8H).

Step 4; Preparation of 4-bromomethyl-2'-tert- butoxycarbonylbiphenyl

The mixture of 11.0 g (0.032 mol) of 4- bromomethyl-2'-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: ¹H NMR (CDCI₃) δ 1.26 (s, 9H), 4.38 (s, 2H), 7.2-7.9 (m, 8H).

Step 5; Preparation of 4-bromomethyl-2'-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-aminomethyl-2'-tert- butoxycarbonylbiphenyl as a yellow oil: ¹H 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'-[[[[2- (1- oxopentyl)hydrazino]carbonyl]amino]methyl] [1,1'- biphenyl]-2-carboxylate To 6.4 mL of IM (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'-tert- butoxycarbonylbiphenyl in 5 mL of methylene chloride along with dropwise addition of 1.5 mL (18.5 mmol) of pyridine. The resulting mixture was stirred at 0ºC 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: ¹H 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 (broad t, 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) δ 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. Step 7: Preparation of tert-butyl 4'-[(3-butyl-4,5- dihydro-5-nxo-1,2,4-triazol-4-yl)methyl] [1,1'-biphenyl]- 2-carboxylate 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 (MgS04) 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-butyl- 1,2, 4-triazolone as an oil: ¹ H 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, 1H).

Step 8: Preparation of tert-hutyl 4'-[ (1 ,3-dibutyl-4,5- dihydro-5-oxo-1H-1,2,4-triazol-4-yl)methyl][1,1'- biphenyl]-2-carboxylate

To 226 mg (0.555 mmol) of the 3-butyl-1,2,4- triazolone from step 7 in 5 mL of N,N-dimethylformamide at about 5°C was added 0.66 mL (0.66 mmol) of 1 M potassium tert-butoxide in tetrahydrofuran. The

resulting solution was stirred at about 5ºC for 20 min, followed by addition of 200 μL (1.76 mmol) of 1- 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 dibutyl-1,2,4-triazolone as an oil: ¹H NMR (CDCI₃) δ 0.8- 1.0 (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'-[(1,3-dibutyl-4,5-dihydro-5- oxo-1H-1,2,4-triazol-4-yl)methyl] [1,1'-biphenyl]-2-carboxylic 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-methanol- acetic 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, 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).

2,5-dibntyl-2,4-dihydro-4-[[2-(1H-tetrazol-5-yl) [1 ,1'- biphenyl]-4'-yl]methyl]-3H-1,2,4-triazol-3-one

Step 1: Preparation of N-ethoxycarbonyl thioyaleramide

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 mL- portions 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 (MgSO₄) 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; ¹H NMR (CDCI₃) δ 0.90(t, J = 7.5 Hz, 3H), 1.20-1.5 (m, 5H), 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). Step 2: Preparation of 5-bntyl-2,4-dihydro-1,2, 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 ether- hexane, and collected by filtration to give 320 mg (76%) of 5-butyl-triazol-3-one as a white solid: ¹H NMR

(CDCl₃) δ 0.85 (t, J = 7.8 Hz, 3H), 1.2-1.4 (m, 2H), 1.55 (quintet, J = 7.8 Hz, 2H), 2.0-3.0 [ m (with t at 2.42, J = 7.8 Hz), 3H], 9.6-11(broad s, 1H).

Step 3: Preparation of N-triphenylmethyl-5-[2-(4'- bromomethylbiphen-2-yl]tetrazole.

A 542.5 g (2.4 mol) sample of methyl 2-(p- tolyl)benzoate (Chemo Dynamics Inc.) was dissolved in 5.5 L of ethanol and treated with 3 L (7.5 mol) of 2.5 N sodium hydroxide. The reaction was stirred overnight at ambient temperature and treated with an additional 480 mL (6.0 mol) of sodium hydroxide; stirring was continued for an additional 24 h and the ethanol removed in vacuo.

The remaining solution was cooled in ice and acidified to pH 1 with hydrochloric acid which caused the product to precipitate; filtration and drying in vacuo gave 510 g (100%) of crude 2-(p-tolyl)benzoic acid: mp 145.0- 147.5°C; NMR (CDCI₃) δ 2.40(s, 3H), 7.17-7.28(m, 4H), 7.35-7.45 (m, 2H), 7.51-7.59 (m, 1H), 7.90-7.97 (m, 1H). The crude acid was suspended in 1 L of toluene and 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, 1H), 5.77(br s, 1H), 7.21-7.53(m, 7H), 7.76-7.83(m, 1H). The crude amide was treated with 1420 mL (19.5 mol) of thionyl chloride at reflux for 3.5 h. The reaction was filtered and thionyl chloride removed in vacuo. The residue was dissolved in 800 mL of toluene and

reconcentrated in vacuo. On standing overnight, the residue crystallized. The crystals were collected and washed with hexane to give 296 g (64%) of 2-(p- tolyDbenzonitrile: 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), 7.58- 7.66(m, 1H), 7.72-7.78(m, 1H). A 286 g (1.48 mol) sample of the crude nitrile was dissolved in 1630 mL 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-[2- (4'-methylbiphen-2-yl]tetrazole: mp 271-272°C (dec);

NMR (DMSO-d₆) 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 N- trimethylstannyl tetrazole was suspended in 4270 mL of toluene and 287 mL of anhydrous tetrahydrofuran (THF) and treated with 63.4 g (173 mol) of anhydrous hydrogen chloride at ambient temperature under nitrogen with stirring. The reaction was allowed to stand overnight and filtered; recrystallization from toluene gave 217 g (62%) of 5-[2-(4'methylbiphen-2-yl)]tetrazole as a solid: mp 149-152°C; NMR (DMSO-d₆) δ2.28(s, 3H), 6.94- 7.02 (m, 2H), 7.08-7.15 (m, 2H), 7.50-7.59 (m, 2H), 7.62- 7.72 (m, 2H). A 200 g (0.85 mol) sample of the tetrazole was suspended in 3.3 L of dichloromethane and treated with 262 g (0.91 mol) of triphenylmethyl chloride and 141 mL (1.0 mol) of -anhydrous triethylamine. The reaction was stirred at reflux for 3 h under nitrogen, washed with water, dried (MgSO4), and concentrated in vacuo. Recrystallization gave 338 g (83%) of N- triphenylmethyl-5-[2-(4'-methylbiphen-2-yl)]tetrazole as a colorless solid: mp 170-173°C; NMR (CDCI₃) δ 2.27 (s, 3H), 6.86-6.96 (m, 8H), 6.98-7.04 (m, 2H), 7.09-7.52 (m, 12H), 7.86-7.94 (m, 1H). The N-triphenylmethyl tetrazole was dissolved in 4260 mL of carbon tetrachloride and treated with 126.4 g (0.71 mol) of N-bromosuccinimide

(NBS) and 11.9 g (49 mmol) of benzoyl peroxide at reflux for 3.5 h. The reaction was filtered and the solvent removed in vacuo. Recrystallization from toluene gave 277 g (59%) of N-triphenylmethyl-5-[2-(4'- bromomethylbiphen-2-yl)]tetrazole as a colorless solid: mp 140-142°C; NMR (CDCI₃) δ 4.39 (s, 2H), 6.85-6.95 (m, 7H), 7.06-7.15 (m, 4H), 7.22-7.43 (m, 9H), 7.45-7.55 (m, 2H), 7.94-8.01 (m, 1H). NMR indicated that this material was only 85% pure; it contained 7% of corresponding dibromo- compound (δ 6.50) and 8% of starting material (δ 2.27); however, no further attempts at purification were made and this mixture was used in all subsequent

alkylation reactions. Step 4; Preparation of 5-butyl-2,4-dihydro-4-[[2-(1- triphenylmethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4'- yl]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 N,N-dimethylformamide was added dropwise 1.8 mL (1.8 mmol) of 1 M potassium tert- butoxide 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 N- triphenylmethyl-5-[2-(4'-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, J = 7.3 Hz, 2H), 4.71 (s, 2H), 6.90 (d, J = 7.2 Hz, 6H), 7.01 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 7.2-7.4(m, 10H), 7.4-7.55 (m, 2H), 7.9-8.0(m, 1H), 9.0 (s, 1H); mass spectrum (FAB) m/e (relative intensity) 624(22), 568(4), 388(30), 382(18), 339(100).

Step 5 : Preparation of 2 , 5-dibntyl-2 , 4-dihydro-4- [ [2 -

( 1-triphenylιrιethyl-1H-tetrazol-5-yl ) [1 , 1 ' -biphenyl ] -4 ' - yl]methyl]-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 N,N- dimethylformamide was added 460 μL (0.46 mmol) of 1 M potassium tert-butoxide in tetrahydrofuran. The resulting solution was stirred at room temperature for 10 min, followed by addition of 150 μL (1.32 mmol) of 1- iodobutane. 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,N'-disubstituted

triazolone as an oil: ¹H 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, J = 7.9 Hz, 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), 6.87- 6.96(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), 7.88- 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-[[2- (1H-tetrazol-5-yl) [1,1'-biphenyl]-4'-yl]methyl]-3H- 1,2,4-triazol-3-nne

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 (MgSO₄) and concentrated in vacuo to give 150 mg (quantitative) of the product compound of example 2 as a solid: ¹H NMR (CDCI₃) 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.

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-[2'-(1- triphenylmethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one

To a solution of 0.4-0.5 mmol of 5-butyl-2,4- dihydro-4-[2'-(1-triphenylmethyl-1H-tetrazol-5-yl) [1,1'- biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one (prepared in example 2, step 4) in 4-5 mL of N,N-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 biphenyl 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 acidified with 3 N hydrochloric acid to about pH 3, and extracted with three 10 mL-portions of chloroform. The combined extracts were dried (MgSO₄) and concentrated in vacuo. The resulting oil or foam solidified upon standing to give the desired tetrazolylbiphenyl 2,5-disubstituted- triazolone.

5-butyl-2,4-dihydro-2-[2-oxo-2-(tricyclo[3,3,1,1,^3,7]dec-1- yl)ethyl]-4-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-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-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 4.5 mL of N,N- 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: ¹H 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 = 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: 552.310.8

5-butyl-2,4-dihydro-2-(3-phenylpropyl)-4-[2'-(1H-tetrazol- 5-yl) [1,1'-biphenyl]-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-triphenyImethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 4.5 mL of N,N- dimethylfoarmamide was reacted with 0.574 mmol of potassium tert -butoxide in tetrahydrofuran and 89 μL (0.583 mmol) of 1-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: ¹H NMR (CDCI₃) δ0.82(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.

5-butyl-2,4-dihydro-2-(2-oxo-2-phenylethyl)-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol- 3-one 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- triphenyImethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 9 mL of N,N- 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), 7.30- 7.65(m, 6H), 7.79(d, J = 7.25 Hz, 1H), 7.86(d, J = 7.25 Hz, 2H); MS (FAB) m/e (relative intensity) 494 (17), 451 (3), 376 (8), 207 (100); HRMS. calcd for M+H: 494.2304. Found: 494.2300.

5-butyl-2 , 4-dihydro-2- (2-hydroxy-2-phenylethyl) -4- [ 2 ' - (1H- tetrazol-5-yl) [1 ,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol- 3-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 (MgSO₄) 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, 1H), 3.85(dd, J = 13.7, 7.7 Hz, 1H), 4.74(br s, 2H), 4.88(q, J = 6 Hz, 1H), 5.54(d, J = 4.8 Hz, 1H), 6.97(d, J = 8.1 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 7.10- 7.40 (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.

L

1,1-dimethylethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl1-4-ylmethyl]-1H-1,2,4- triazole-1-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- triphenyImethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 8 mL of N,N- dimethylformamide was reacted with 0.87 mmol of potassium tert-butoxide in tetrahydrofuran and 141 μL (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: ¹H 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, 1H), 7.48-7.65(m, 2H), 8.02(dd, J = 7.7, 1.2 Hz, 1H); MS (FAB) m/e (relative intensity) 496 (39), 440 (60), 412 (45), 397 (25), 235 (22), 207 (100), 192 (40), 178 (60); HRMS. calcd for M+H: 490.2567. Found: 490.2598.

5-butyl-2,4-dihydro-2-hexyl-4-[2'-(1H-tetrazol-5-yl) [1,1'- biphenyl]-4-ylmethyl]-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'-(1- triphenyImethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 4 mL of N,N- dimethylformamide was reacted with 0.58 mmol of potassium tert-butoxide in tetrahydrofuran and 145 μL (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) δ0.7- 0.9(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, J = 7.26 Hz, 2H), 3.64(t, J = 6.85 Hz, 2H), 4.79 (s, 2H), 7.05 (d, J = 8.06 Hz, 2H), 7.10 (d, J = 8.06 Hz, 2H), 7.45-7.60(m, 2H), 7.60-7.70(m, 2H); HRMS. calcd for M+H: 460.2825. Found: 460.2820. ethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5- yl) [ 1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-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'-(1- triphenylmethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 7 mL of N,N- dimethylformamide was reacted with 1.06 mmol of potassium tert-butoxide in tetrahydrofuran and 147 μL (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. #

3-bntyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl) [1,1'- biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-acetio 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), 7.45- 7.60 (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.

5-butyl-2,4-dihydro-2-(1-naphthalenylmethyl)-4-[2'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol- 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-[2'-(1- triphenylmethyl-1H-tetrazol-5-yl)[1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 4 mL of N,N- dimethylfoirmamide 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: ¹H 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), 7. 80-8 . 0 (m, 2H) , 8. 18-8.3 (m, 1H) ; HRMS . calcd for M+H:

516.2512. Found: 516.2534.

5-butyl-2-(2-cyclohexylethyl)-2,4-dihydro-4-[2'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethvl]-3H-1,2,4-triazol-

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-[2'-(1- triphenyImethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 3 mL of N,N- dimethyIformamide 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: 1H 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, J = 7.65 Hz, 2H), 3.67(t, J = 7.26 Hz, 2H), 4.79(s, 2H), 7.07 (d, J = 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.

5-butyl-2,4-dihydro-2-pentyl-4-[2'-(1H-tetrazol-5-y!)[1,1'-biphenyl]-4-ylmethyl]-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'-(1- triphenyImethyl-1H-tetrazol-5-yl)[1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 3 mL of N,N- dimethylformamide 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 = 7.7 Hz, 2H), 3.64 (t, J = 6.8 Hz, 2H), 4.79(s, 2H), 7.05(d, J = 8.46 Hz, 2H), 7.11 (d, J = 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.

ethyl [ 2- [3-butyl-4 , 5-dihydro-5-oxo-4- [2 ' - (1H-tetrazol-5 -yl) [1 , 1 '-biphenyl] -4-ylmethyl] -1H-1 , 2, 4-triazol-1-yl ] -1-phenylethoxy] acetate

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 μL (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: ¹H NMR (DMSO-d6) δ 0.75 (t, J = 7.66 Hz, 3H), 1.06-1.46 [m (with t at 1.12, J = 7.25 Hz), 7H], 2.31 (t, J = 7.65 Hz, 2H), 3.70-4.20(m, 5H), 4.73(s, 2H), 4.82(d, J = 6.9 Hz, 1H), 6.91(d, J = 8.05. Hz, 2H), 6.95-7.20[m (with d at 7.01, J = 8.06 Hz), 3H], 7.20- 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.

H

[2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-1-yl]-1-phenylethoxy]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 (MgSO₄) 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 (m, 4H), 2.30 (t, J = 8.05 Hz, 2H), 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. 5-butyl-2 , 4-dihydro-4- [ 2 ' - (1H-tetrazol-5-yl) [ 1 , 1 ' - biphenyl]-4-ylmethyl]-2-(3,5,5-trimethylhexyl)-3H-1,2,4- triazol-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-[2'-(1- triphenylmethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 2.5 mL of N,N- dimethylformamide was reacted with 0.43 mmol of potassium tert-butoxide in tetrahydrofuran and 100 mg (0.483 mmol) of 3,5,5-trimethyl-1-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, J = 13.2, 5.7 Hz, 1H), 1.16(dd, J = 13.2, 2.8 Hz, 1H), 1.29(septet, J = 7.25 Hz, 2H), 1.35-1.6(m, 4H), 1.60-1.77(m, 1H), 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, 1H), 7.49 (t, J = 7.25 Hz, 1H), 7.57 (t, J = 7.26 Hz, 1H), 7.86 (d, J = 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.

5-butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)-1- (phenylmethyl)-E-ethenyl]-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one

To a solution of 100 mg (0.136 mmol) of phenacyl trityltetrazolylblphenyl 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 μL (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: ¹H NMR

(CDCI₃) δ 0.74 (t, J = 7.25 Hz, 3H), 1.10 (septet, J = 7.7 Hz, 2H), 1.37 (quintet, J = 7.65 Hz, 2H), 2.12(t, J = 7.25 Hz, 2H), 3.85(s, 2H), 4.63 (s, 2H), 4.74 (s, 2H), 6.73 (d, J = 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 (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.

2- (1-benzoyl-2-phenylethyl) -5-butyl-2, 4-dihydro-4- [ 2 ' - (1H-tetrazol-5-yl) [1, 1 ' -biohenyl] -4-ylmethyl] -3H-1 , 2 , 4-triazol- 3-one

To a solution of 0.24 mL (0.36 mmol) of lithium diisopropylamide (1.5 M in tetr-ahydrofuran, Aldrich) at - 20°C was added a solution of 105 mg (0.143 mmol) of

phenacyl trityltetrazolylblphenyl 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 μL (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 Hz, 3H), 1.00-1.45 (m, 4H), 1.83-2.00 (m, 1H), 2.00-2.20 (m, 1H), 3.36 (dd, J = 13.3, 4.4 Hz, 1H), 3.85 (t, J = 12.9 Hz, 1H), 4.99(dd, J = 10.9, 3.6 Hz, 1H), 5.11 (AB quartet, J = 17.7 Hz, 2H), 7.0-7.7 (m, 14H), 7.90 (d, J = 7.26 Hz, 4H); MS (FAB) m/e (relative intensity) 584 (15), 325 (60), 260 (100), 207 (10); HRMS. calcd for M+H: 584.2774. Found: 584.2794.

5-butyl-2,4-dihydro-2-(1-oxobutyl)-4-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-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'-(1- triphenylmethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 1.5 mL of N,N- dimethylformamide was reacted with 0.26 mmol of potassium tert-butoxide in tetrahydrofuran and 60 μL (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: ¹H NMR (CDCI₃) δ0.89(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(q, J = 7.3

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, 1H), 7.45- 7.65 (m, 2H), 8.05-8.15 (m, 1H); MS (FAB) m/e (relative intensity) 468 (33), 446 (45), 376 (100), 235 (45), 207 (100), 192 (42); HRMS. calcd for M+H: 446.2304. Found: 446.2351.

5-butyl-2,4-dihydro-2-[2- (2 ,5-dimethyoxyphenyl)-2-oxoethyl]-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2 ,4-triazol-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-[2'-(1- triphenyImethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 6 mL of N,N- dimethylformamide 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 to give 110 mg (79%) of the desired product compound as a white solid: ¹H NMR (CDCI₃) δ0.85(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.

5-butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)ethyl]-4- [2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one

To a solution of 148 mg (0.210 mmol) of crude trityl tetrazolylbiphenyl phenylhydroxyethyl triazolone from example 6 in 4 mL of dry tetr-ahydrofuran 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 μL (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, J = 7.25 Hz, 3H), 1.10-1.38 (m, 2H), 1.35 (quintet, J = 7.66 Hz, 2H), 2.34 (t, J = 7.65 Hz, 2H), 3.77 (dd, J = 14.1, 5.44 Hz, 1H), 4.03 (dd, J = 13.7, 8.46 Hz, 1H), 4.21 (d, J = 12.1 Hz, 1H), 4.39 (d, J = 12.1 Hz, 1H), 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.

5-butyl-2,4-dihydro-2-[2-(2,5-dimethyoxyphenyl)-2-hydroxyethyl]-4-[2'-(1H-tetrazol-5-yl)(1,1'-biphenyl]-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 alkylated product was deprotected to give 50 mg

(quantitative) of the desired product compound as a white solid: ¹ H NMR (CDCI₃) δ0.88(t, J = 7.4 Hz, 3H), 1.25- 1.42 (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),

5.13-5.25 (m, 1H), 6.70-6.83 (m, 2H), 6.92-7.00 (m, 1H), 7.05- 7.20 (m, 4H), 7.35-7.43 (m, 1H), 7.45-7.65 (m, 2H), 7.96- 8.08 (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.

5-butyl-2,4-dihydro-2-(2-naphthalenylmethyl)-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,7 ,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'-(1- triphenylmethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 3 mL of N,N- dimethyIformamide 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: ¹H NMR (CDCI₃) δ0.81(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 (25), 207 (100), 192 (30), 178 (35), 141 (100); HRMS.

calcd for M+H: 516.2512. Found: 516.2455.

methyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-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'-(1- triphenyImethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 3 mL of N,N- dimethylfo.rmamide was reacted with 0.3 mmol of potassium tert-butoxide in tetrahydrofuran and 52 μL (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: ¹H NMR (CDCI₃) δ0.89(t, J = 7.3 Hz, 3H), 1.35 (septet, J = 7.5 Hz, 2H), 1.50-1.68 (m, 4H), 1.75 (quintet, J = 8.04 Hz, 2H), 2.32 (t, J = 7.5 Hz, 2H), 2.42 (t, J = 8.0 Hz, 2H), 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, 1H), 7.50-7.68(m, 2H), 8.02(dd, J = 7.7, 1.2 Hz, 1H); 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.

ethyl β-benzoyl-3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biohenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-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 trityltetrazolylblphenyl 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 μL (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 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) δ0.66(t, J = 7.3 Hz, 3H), 0.86(quintet, J = 7.0 Hz, 2H), 1.05(septet, J = 7.2 Hz, 2H), 1.15 (t, J = 6.73 Hz, 3H), 2.27 (t, J = 7.2 Hz, 2H), 2.95(dd, J = 16.3, 6.9 Hz, 1H), 3.14(dd, J = 16.3, 7.2 Hz, 1H), 4.05(q, J = 6.8 Hz, 2H), 4.79(s, 2H), 6.00(t, 3 = 1.3 Hz, 1H), 6.84 (d, J = 8.2 Hz, 2H), 6.99(d, J = 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

2-(1-benzyoyl-1-methylethyl)-5-butyl-2,4-dihydro-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-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'-(1- triphenylmethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 2 mL of N,N- dimethylformamide was reacted with 0.2 mmol of potassium tert-butoxide in tetrahydrofuran and 41 μL (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 = 1.1 Hz, 6H), 6.97(d, J = 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, 1H) .

The alkylated product was deprotected following 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, 3 = 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.

3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-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 (MgSO₄) 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), 11.7- 12.3(br s, 1H); HRMS. calcd for M+H: 476.2410. Found: 476.2411 5-bntyl-2-(cyclopropylmethyl)-2,4-dihydro-4-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-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- triphenyImethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one in 4 mL of N,N- dimethylformamide was reacted at 0°C with 0.39 mmol of potassium tert-butoxide in tetrahydrofur-an and 47 μL (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: ¹H NMR (DMSO-d6) δ 0.28 (q, 3 = 4.8 Hz, 2H), 0.44 (q, J = 5.6 Hz, 2H), 0.79 (t, J = 7.25 Hz, 3H), 1.00-1.08 (m, 1H),

1.24 (septet, J = 7.65 Hz, 2H), 1.42 (quintet, J = 7.25 Hz, 2H), 2.39 (t, J = 7.25 Hz, 2H), 3.54 (d, J = 6.9 Hz, 2H), 4.79 (s, 2H), 7.06 (d, J = 8.05 Hz, 2H), 7.12 (d, J = 8.06 Hz, 2H), 7.45-7.75(m, 4H); HRMS. calcd for M+H: 430.2355.

Found: 430.2395.

5-butyl-2,4-dihydro-2-(3-phenyl-2E-propenyl)-4-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-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'-(1- triphenylmethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one in 3 mL of N,N- dimethylformamide 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, J = 7.25 Hz, 3H), 1.24 (septet, J = 7.66 Hz, 2H), 1.42 (quintet, J = 7.65 Hz, 2H), 2.40 (t, J = 7.65 Hz, 2H), 4.46 (d, J = 5.24 Hz, 2H), 4.82 (s, 2H), 6.31 (dt, J = 16.1, 5.6 Hz, 1H), 6.49 (d, J = 16.1 Hz, 1H), 7.07 (d, J = 8.06 Hz, 2H), 7.15 (d, J = 8.06 Hz, 2H), 7.20-7.75 (m, 9H); MS (FAB) 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.

1-butyl-4.5-dihydro-5-oxo-α-propyl-4-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-aretonitrile

Step 1: Bromination of 2,5-dibutyl-2,4-dihydro-4-[2'- (1H-tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-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 60 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: ¹H 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, 3 = 16.1 Hz, 1H), 6.85-6.95 (m, 6H), 7.01 (d, J = 8.46 Hz, 1H) , 7. 10 (d, J = 8.05 Hz, 2H) , 7 .20-7.40 (m, 10H) , 7 .40- 7 .53 (m, 2H) , 7 .85-7 . 95 (m, 1H) . Step 2; Preparation of 1-butyl-4.5-dihydro-5-oxo-α-propyl-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-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 N,N- dimethyIformamide 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: ¹H NMR (CDCI₃) δ0.75(t, J = 7.25 Hz, 3H), 0.94 (t, J = 7.26 Hz, 3H), 1.15-1.5 (m, 4H), 1.55-1.85(m, 4H), 3.34(dd, J = 8.86, 6.05 Hz, 1H), 3.82(t, 3 = 7.26 Hz, 2H), 4.73 (d, J = 15.7 Hz, 1H), 4.99 (d, J = 15.7 Hz, 1H), 6.85-6.98 (m, 6H), 7.02 (d, J = 8.46 Hz, 2H), 7.11 (d, J = 8.06 Hz, 2H), 7.20-7.40 (m, 10H), 7.4-7.55 (m, 2H), 7.85-7.95 (m, 1H).

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: ¹H NMR (DMSO-d6) δ 0.74 (t, J = 7.3 Hz, 3H), 0.89(t, J = 7. 4 Hz, 3H), 1.29 (quintet, J = 7.3 Hz, 4H), 1.40-1.73 (m, 4H), 3.73 (t, J = 6.96 Hz, 2H), 4.44 (dd, J = 7.9, 5.7 Hz, 1H), 4.91 (AB quartet, J = 16.4 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 7.45- 7.78 (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. BIPLOGICAL EVALUATION

Assay A: Angiotensin ll 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. ¹²⁵l- 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 MgCl₂, 2 mM EDTA, 0.5% bovine serum albumin, 50 mM Tris-HCl, pH 7.5 and ¹²⁵I-AII

(approximately 10⁵ cpm) in the absence or in the presence of unlabelled ligand. The reaction was initiated by the addition of membrane protein and the mixture was

incubated at 25°C for 60 min. The incubation was terminated with ice-cold 50 mM Tris-HCl (pH 7.5) and the mixture was filtered to separate membrane-bound labelled peptide from the free ligand. The incubation tube and filter were washed with ice-cold buffer. Filters were assayed for radioactivity in a Micromedic gamma counter. Nonspecific binding was defined as binding in the presence of 10 μM of unlabelled All. Specific binding 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 ¹²⁵ I-ΑII 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; ln 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 NaHCO₃, 15 KCl, 1.2 NaH₂PO₄, 1.2 MgSO₄, 2.5 CaCl₂, and 11.4 glucose. The preparations were equilibrated for one hour before approximately one gram of passive tension was placed on the rings.

Angiotensin II concentration-response curves were then recorded (3 X 10^-10 to 1 X 10^-5 M). Each concentration of All was allowed to elicit its maximal contraction, and 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 ^-5 M for 5 minutes before challenging with All. Adjacent segments of the same aorta ring were used for all concentration- response curves in the presence or absence of the test antagonist. The effectiveness of the test compound was expressed in terms of pA₂ values and were calculated according to H.O. Schild [Br. J. Pharmacol.

Chemother., 2,189-206 (1947)]. The pA₂ value is the concentration of the antagonist which increases the EC₅₀ value for 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 Tntraduodenal 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 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: ln Vivo Tntragastric 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 as a 30 ng/kg bolus via the venous catheter delivered in a 50 μl 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.

NT = NOT TESTED

¹Assay A: Angiotensin II Binding Activity

²Assay B: In Vitro Vascular Smooth Muscle Response

³Assay C: In Vivo Intraduodenal Pressor Response for compounds of Examples #1* and #2*.

.Assay D : In Vivo Intragastric Pressor Response for Compounds of Example #2-30.

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 pha.rmaceutical 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 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 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 embod.iments, the details of these embodiments are not to be construed as limitations.

Claims

What Is Claimed Is:

1. A compound of Formula I:

wherein m is a number selected from one to four, inclusive; wherein R¹ is selected from polycycloalkyl,

polycycloalkylalkyl, 3-phenyIpropyl, 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)-1-(phenylmethyl)-

E-ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl,

2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl, acetonitrile, cycloalkenyl, aralkoxycarbonyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, alkylthiothiocarbonyl, arylthiocarbonyl,

arylthiothiocarbonyl, aralkylthiocarbonyl,

alkylthiocarbonyl, aralkylsulfinyl, aralkylsulfonyl and radicals of the formula

wherein each of R¹² and R¹³ is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl,

cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R¹² and R¹³ 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 R¹² and R¹³ 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 R¹² and R¹³ cannot be selected from hydrido and alkyl; wherein each of R² through R¹¹ 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

wherein X is oxygen atom or sulfur atom;

wherein each of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R¹⁴ and R¹⁵ taken together, R¹⁶ and R¹⁷ taken together and R¹⁸ 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 R¹⁴ and R¹⁵ taken together and each of R¹⁶ and R¹⁷ 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 R³ through R¹¹ may be further

independently selected from hydroxy and acidic moieties of the formula

-Y_nA 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, 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, 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

wherein X is oxygen atom or sulfur atom; wherein R²⁰ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR²⁵ and

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 R²¹, R²², R²³, R²⁴, R²⁶ and R²⁷ 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 and R²⁷ is further independently selected from amino and amido radicals of the formula

wherein X is oxygen atom or sulfur atom;

wherein each of R²⁸, R²⁹, R³⁰, R³¹ R³² and R³³ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl,

haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R²¹ 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 R²¹ and R²² taken together and each of R²⁶ 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.

2. Compound of Claim 1 wherein m is one;

wherein R¹ is selected from polycycloalkyl,

polycycloalkylalkyl, 3-phenyIpropyl, 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, 1-benzoyl-2-phenylethyl, 1-oxobutyl,

2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-d.imethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 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 R¹² and R¹³ is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl,

cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, with the proviso that when X is oxygen atom, then R¹² and R¹³ cannot be selected from hydrido and alkyl; 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, 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, aralkylthiocarbonyl, 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 R³ through R¹¹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo,

haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,

cycloalkynyl, cyano, nitro, carboxyl, 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 k

wherein X is oxygen atom or sulfur atom;

wherein each of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R³ through R¹¹ may be further

independently selected from acidic moieties of the formula

-Y_nA 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 R¹⁹, 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 wherein X is oxygen atom or sulfur atom; wherein R¹⁹ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and DR²³ and

- 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 R²¹, R²², R²³, R²⁴, R²⁶ 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.

3. Compound of Claim 2 wherein m is one;

wherein R¹ is selected from polycycloalkyl,

polycycloalkylalkyl, 3-phenyIpropyl, 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, 1-benzoyl-2-phenylethyl, 1-oxobutyl,

2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, cycloalkynyl, aralkylsulfonyl and amido radicals of the formula

wherein each of R¹² and R¹³ 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, alkoxycarbonyl, 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,

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

wherein each of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R³ through R¹¹ may be an acidic moiety further independently selected from acidic moieties of the formula -Y_nA 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

wherein each W is independently selected from oxygen atom, sulfur atom and NR³⁸; wherein each of R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl,

cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R³⁴, R³⁵, R³⁶ and R³⁷ may be further independently selected from amino radical of the formula

wherein each of R³⁹ and R⁴⁰ is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R³⁹ and R⁴⁰ 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 R⁴⁰ 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 R³⁵ and R³⁶ 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 R³ through R¹¹ or may be attached at any two adjacent positions selected from R³ through R ¹¹ 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 R¹ through R¹⁹ 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

wherein X is selected from oxygen atom and sulfur atom; wherein R²⁰ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl and DR²⁵ and

wherein D is selected from oxygen atom and sulfur atom, wherein R²⁵ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R²¹, R²², R²³, R²⁴, R²⁶ 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.

4. Compond of Claim 3 wherein m is one; wherein R¹ is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenyIpropyl, 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- (phenyImethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, aralkylsulfonyl and radicals of the formula

wherein each of R¹² and R¹³ 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 R³ through R¹¹ 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 R³ through R¹¹ may be an acidic moiety further independently selected from acidic moieties of the formula

-Y_nA 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

wherein each W is independently selected from oxygen atom, sulfur atom and NR³⁸; wherein each of R³⁴, R³⁷ and R³⁸ 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

wherein each of R³⁹ and R⁴⁰ is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R³⁹ and R⁴⁰ 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 R⁴⁰ taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of

carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which

heterocyclic ring may be attached at a single position selected from R³ through R¹¹ or may be attached at any two adjacent positions selected from R³ through R¹¹ so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; 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 R¹⁹, R³⁴ and R³⁷ through R⁴⁰, 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.

5. Compound of Claim 4 wherein m is one;

wherein R¹ is selected from polycycloalkyl,

polycycloalkylalkyl, 3-phenyIpropyl, 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, 1-benzoyl-2-phenylethyl, 1-oxobutyl,

2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl, acetonitrile, aralkylsulfonyl and amido radicals of the formula

wherein each of R¹² and R¹³ 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 R³ through R¹¹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo,

haloalkyl, cycloalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein each of R³ through R¹¹may be an acidic moiety further independently selected from acidic moieties of the formula

-Y_nA 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

wherein each W is independently selected from oxygen atom, sulfur atom and NR³⁸; wherein each of R³⁴, R³⁷ and R³⁸ 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 where.in each of R³⁹ 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 a single position selected from R³ through R¹¹ or may be attached at any two adjacent positions selected from R³ through R¹¹ so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; 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.

6. Compound of Claim 5 wherein m is one;

wherein R¹ is selected from adamantyl, adamantylalkyl, 3-phenyIpropyl, 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- (phenyImethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-d.imethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl and acetonitrile; where R² is selected from alkyl, hydroxyalkyl, cycioalkyl, 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 R¹¹ 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, PO₃H₂,

NHSO₂CF₃, NHSO₂C₆F₅, SO₃H, CONHNH₂, CONHNHSO₂CF₃, CONHOCH₃, CONHOC₂H₅, CONHCF₃, OH, CH₂OH, C₂H₄OH, OPO₃H₂, OSO₃H,

wherein each of R⁴¹, R⁴² and R⁴³ is independently selected from H, Cl, CN, NO₂, CF₃, C₂F₅, C₃F₇, CHF₂, CH₂F, CO₂CH₃, CO₂C₂H₅, SO₂CH₃, SO₂CF₃ and SO₂C₆F₅; wherein Z is selected from O, S, NR⁴⁴ and CH₂; wherein R⁴⁴ is selected from hydrido, CH₃ and CH₂C₆H₅; and. wherein said acidic moiety may be a heterocyclic acidic group attached at any two adjacent positions of R³ through R¹¹ so as to form a fused ring system with one of the phenyl rings of the biphenyl moiety of Formula I, said biphenyl fused ring system selected from

and the esters, amides and salts of said acidic moieties; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

7. Compound of Claim 6 wherein m is one;

wherein R¹ is selected from adamantyl, adamantylmethyl, adamantylethyl, adamantylpropyl, 3-phenyIpropyl, 2-oxo-2- phenylethyl, 2-hydroxy-2-phenylethyl, 1,1- dimethylethyloxycarbonyImethyl, 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-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl- 2E-propenyl and acetonitrile; wherein R² is selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, isobutyl, tert-butyl, n-pentyl, isopentyl,

neopentyl, adamantyl, adamantylmethyl, adamantylethyl, adamantylpropyl, 3-phenyIpropyl, 2-oxo-2-phenylethyl, 2- hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyImethyl, 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-phenyl-2- (phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl- 2E-propenyl, acetonitrile, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, propylthio, butylthio,

1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1- dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,1- difluoropropyl, 1,1-difluorobutyl and 1, 1-difluoropentyl; wherein at least one of R⁵ , R⁶, R⁸ and R⁹ is an acidic group selected from CO₂H, SH, PO₃H₂, SO₃H, CONHNH₂,

CONHNHSO₂CF₃, OH,

wherein each of R⁴² and R⁴³ 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 R¹ is selected from 2-oxo-2- (tricyclo [3.3.1.1.^3.7]dec-2-yl)ethyl, 3-phenyIpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1- daimethylethyloxycarbonyImethyl, 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-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl- 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 R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂H, SH, PO₃H₂, SO₃H, CONHNH₂, CONHNHSO₂CF₃, . OH,

wherein each of R⁴² and R⁴³ is independently selected from Cl, CN, NO₂, CF₃, CO₂CH₃ and SO₂CF₃; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

9. Compound of Claim 8 wherein m is one;

wherein R¹ is selected from 2-oxo-2-

(tricyclo [3.3.1.I.^3.7]dec-2-yl)ethyl, 3-phenyIpropyl, 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, 1-benzoyl-2-phenylethyl,

1-oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl- 2E-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 R⁹ is hydrido and the other of R⁵ and R⁹ is an acidic group selected from CO₂H and

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

10. Compound of Clam 9 selected from compounds, and their pharmaceutically-acceptable salts, of the group consisting of

4'-[(1,3-dibutyl-4,5-dihydro-5-oxo-1H-1,2,4- 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'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4'- ylirethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-(3-phenylρrqpyl)-4-[2'-(1H- tetrazol-5-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'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4- triazol-3-one; 5-butyl-2,4-dihydro-2-(2-hydroxy-2-phenylethyl)-4-[2'- (1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;

1,1-dimethylethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-acetate;

5-butyl-2,4-dihydro-2-hexyl-4-[2'-(1H-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'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-acetate;

3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-acetic acid; 5-butyl-2,4-dihydro-2-(1-naphthalenylmethyl)-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2-(2-cyclohexylethyl)-2,4-dihydro-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-pentyl-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;ethyl [2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol- 5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-1-yl]- 1-phenylethoxy]acetate;

[2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-l-yl]-1-phenylethoxy]acetic acid;

5-butyl-2,4-dihydro-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-2-(3,5,5-trimethylhexyl)-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)-1- (phenylmethyl)-E-ethenyl]-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;

2-(1-benzoyl-2-phenylethyl)-5-butyl-2,4-dihydro-4-[2'- (1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-(1-oxobutyl)-4-[2'-(1H-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)-2- oxoethyl]-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)ethyl]- 4-[2'-(1H-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)-2- hydroxyethyl]-4-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-(2-naphthalenylmethyl)-4-[2'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4- triazol-3-one;

methyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1- pentanoate;

ethyl β-benzoyl-3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4- triazole-1-proρanoate;

2-(1-benzyoyl-1-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'-(1H-tetrazol-5-yl) [1,1'- biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-pentanoic acid;

5-butyl-2-(cyclopropylmethyl)-2,4-dihydro-4-[2'-(1H-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'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4- triazol-3-one; and

1-butyl-4,5-dihydro-5-oxo-α-propyl-4-[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3- acetonitrile.

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

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

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

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

15. Compound of Claim 10 which is 1,1- dimethylethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol- 5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-acetate.

16. Compound of Claim 10 which is

ethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-acetate.

17. Compound of Claim 10 which is methyl 3- butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-pentanoate.

18. Compound of Claim 10 which is 3-butyl-4,5- dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-pentanoic acid.

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

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

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

22. A pharmaceutical composition comprising a 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:

wherein m is a number selected from one to four, inclusive; wherein R¹ is selected from polycycloalkyl,

polycycloalkylalkyl, 3-phenyIpropyl, 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, 1-benzoyl-2-phenylethyl, 1-oxobutyl,

2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl-

2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl, acetonitrile, cycloalkenyl, aralkoxycarbonyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, alkylthiothiocarbonyl, arylthiocarbonyl,

arylthiothiocarbonyl, aralkylthiocarbonyl,

alkylthiocarbonyl, aralkylsulfinyl, aralkylsulfonyl and radicals of the formula wherein X is oxygen atom or sulfur atom; wherein each of R¹² and R¹³ is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl,

cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R¹² and R¹³ 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 R¹² and R¹³ 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 R¹² and R¹³ cannot be selected from hydrido and alkyl; wherein each of R² through R¹¹ 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

wherein X is oxygen atom or sulfur atom;

wherein each of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R¹⁴ and R^{1 5} taken together, R¹⁶ and R¹⁷ taken together and R¹⁸ 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 R¹⁴ and R¹⁵ taken together and each of R¹⁶ and R¹⁷ 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 R³ through R¹¹ may be further

independently selected from hydroxy and acidic moieties of the formula

-Y_nA 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, 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, 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

wherein X is oxygen atom or sulfur atom; wherein R²⁰ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR²⁵ and

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 R²¹, R²², R²³, R²⁴, R²⁶ and R²⁷ 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 and R²⁷ is further independently selected from amino and amido radicals of the formula

wherein X is oxygen atom or sulfur atom; wherein each of R²⁸, R²⁹, R³⁰, R³¹ R³² and R³³ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl,

haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R²¹ 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 R²¹ and R²² taken together and each of R²⁶ 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.

23. The composition of Claim 22 wherein m is one; wherein R¹ is selected from polycycloalkyl,

polycycloalkylalkyl, 3-phenyIpropyl, 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)-1-(phenyImethyl)- E-ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl,

2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 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 R¹² and R¹³ is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl,

cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, with the proviso that when X is oxygen atom, then R¹² and R¹³ cannot be selected from hydrido and alkyl; 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, 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, aralkylthiocarbonyl, 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 R³ through R¹¹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo,

haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,

cycloalkynyl, cyano, nitro, carboxyl, 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

wherein X is oxygen atom or sulfur atom;

wherein each of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R³ through R¹¹ may be further

independently selected from acidic moieties of the formula -Y_nA 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 R¹⁹, 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

wherein X is oxygen atom or sulfur atom; wherein R¹⁹ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and DR²³ and 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 R²¹, R²², R²³, R²⁴, R²⁶ 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.

24. The composition of Claim 23 wherein m is one; wherein R¹ is selected from polycycloalkyl,

polycycloalkylalkyl, 3-phenyIpropyl, 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)-1-(phenylmethyl)- E-ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl,

2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyi-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, cycloalkynyl, aralkylsulfonyl and amido radicals of the formula

wherein each of R¹² and R¹³ 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, alkoxycarbonyl, 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,

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

wherein each of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R³ through R¹¹ may be an acidic moiety further independently selected from acidic moieties of the formula

-Y_nA 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

wherein each W is independently selected from oxygen atom, sulfur atom and NR³⁸; wherein each of R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl,

cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R³⁴, R³⁵, R³⁶ and R³⁷ may be further independently selected from amino radical of the formula

wherein each of R³⁹ and R⁴⁰ is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R³⁹ and R⁴⁰ 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 R⁴⁰ 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 R³⁵ and R³⁶ 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 R³ through R¹¹ or may be attached at any two adjacent positions selected from R³ through R¹¹ so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; 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 R¹ through R¹⁹ 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

wherein X is selected from oxygen atom and sulfur atom; wherein R²⁰ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl and DR²⁵ and wherein D is selected from oxygen atom and sulfur atom, wherein R²⁵ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R²¹, R²², R²³, R²⁴, R²⁶ 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.

25. The composition of Claim 24 wherein m is one; wherein R! is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenyIpropyl, 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- (phenyImethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, aralkylsulfonyl and radicals of the formula

wherein each of R¹² and R¹³ 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 R³ through R¹¹ 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 R³ through R¹¹ may be an acidic moiety further independently selected from acidic moieties of the formula

-Y_nA 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

wherein each W is independently selected from oxygen atom, sulfur atom and NR³⁸; wherein each of R³⁴, R³⁷ and R³⁸ 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

wherein each of R³⁹ and R⁴⁰ is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R³⁹ and R⁴⁰ 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 R⁴⁰ taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of

carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which

heterocyclic ring may be attached at a single position selected from R³ through R¹¹ or may be attached at any two adjacent positions selected from R³ through R¹¹ so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; 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 R¹⁹, R³⁴ and R³⁷ through R⁴⁰, 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.

26. The composition of Claim 25 wherein m is one; wherein R¹ is selected from polycycloalkyl,

polycycloalkylalkyl, 3-phenyIpropyl, 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)-1-(phenylmethyl)- E-ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl,

2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl, acetonitrile, aralkylsulfonyl and amido radicals of the formula

wherein each of R¹² and R¹³ 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 R³ through R¹¹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo,

haloalkyl, cycloalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl,

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 of the formula

-Y_nA 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

wherein each W is independently selected from oxygen atom, sulfur atom and NR³⁸; wherein each of R³⁴, R³⁷ and R³⁸ 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 R³⁹ 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 a single position selected from R³ through R¹¹ or may be attached at any two adjacent positions selected from R³ through R¹¹ so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; 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.

27. The composition of Claim 26 wherein m is one; wherein R¹ is selected from adamantyl, adamantylalkyl, 3-phenyIpropyl, 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, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyρhenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- 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 R¹¹ 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, PO₃H₂,

NHSO₂CF₃, NHSO₂C₆F5, SO₃H, CONHNH₂, CONHNHSO₂CF₃, CONHOCH₃, CONHOC₂H₅, CONHCF₃, OH, CH₂OH, C₂H₄OH, OPO₃H₂, OSO₃H,

wherein each of R⁴¹, R⁴² and R⁴³ is independently selected from H, Cl, CN, NO₂, CF ₃ , C₂F₅, C₃F₇, CHF₂, CH₂F, CO₂CH₃, CO₂C₂H₅, SO₂CH₃, SO₂CF₃ and SO₂C₆F₅; wherein Z is selected from O, S, NR⁴⁴ and CH₂; wherein R⁴⁴ is selected from hydrido, CH3 and CH₂C₆H_5; and wherein said acidic moiety may be a heterocyclic acidic group attached at any two adjacent positions of R³ through R¹¹ so as to form a fused ring system with one of the phenyl rings of the biphenyl moiety of Formula I, said biphenyl fused ring system selected from

and the esters, amides and salts of said acidic moieties; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

28. The composition of Claim 27 wherein m is one; wherein R¹ is selected from adamantyl,

adamantylmethyl, adamantylethyl, adamantyIpropyl, 3- phenyIpropyl, 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, 1-benzoyl-2-phenylethyl,

1-oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl- 2E-propenyl and acetonitrile; wherein R² is selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,

neopentyl, adamantyl, adamantylmethyl, adamantylethyl, adamantylpropyl, 3-phenyIpropyl, 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, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5- dimethyoxyphenyl)-2-oxoethyl, 2-phenyl-2- (phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl- 2E-propenyl, acetonitrile, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, propylthio, butylthio,

1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1- dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,1- difluoropropyl, 1,1-difluorobutyl and 1,1-difluoropentyl; wherein at least one of R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂H, SH, PO₃H₂, SO₃H, CONHNH₂,

CONHNHSO₂CF₃, OH,

wherein each of R⁴² and R⁴³ is independently selected from Cl, CN, NO₂, CF₃, CO₂CH₃ and SO₂CF₃; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

29. The composition of Claim 28 wherein m is one; wherein R¹ is selected from 2-oxo-2- (tricyclo [3.3.1.1.^3.7] dec-2-yl) ethyl, 3-phenyIpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1- d.imethylethyloxycarbonyImethyl, 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-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl- 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 R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂H, SH, PO₃H₂, SO₃H, CONHNH₂, CONHNHSO₂CF₃, OH,

wherein each of R⁴² and R⁴³ is independently selected from Cl, CN, NO₂, CF₃, CO₂CH₃ and SO₂CF₃; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

30 The composition of Clam 29 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, 2- oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1- dimethylethyloxycarbonyImethyl, 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-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl- 2E-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 R⁹ is hydrido and the other of R⁵ and R⁹ is an acidic group selected from CO₂H and

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

31. The composition of Claim 30 wherein said antagonist compound is selected from compounds, and their pharmaceutically-acceptable salts, of the group consisting of

4'-[(1,3-dibutyl-4,5-dihydro-5-oxo-1H-1,2,4-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'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4'- ylmethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-(3-phenyIpropyl)-4-[2'-(1H-tetrazol- 5-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'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol- 3-one; 5-butyl-2,4-dihydro-2-(2-hydroxy-2-phenylethyl)-4-[2'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-

3-one;

1,1-dimethylethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4- triazole-1-acetate;

5-butyl-2,4-dihydro-2-hexyl-4-[2'-(1H-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'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-acetate;

3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl) [1,1'- biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-acetic acid;

5-butyl-2,4-dihydro-2-(1-naphthalenylmethyl)-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol- 3-one;

5-butyl-2-(2-cyclohexylethyl)-2,4-dihydro-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-

3-one;

5-butyl-2,4-dihydro-2-pentyl-4-[2'-(1H-tetrazol-5-yl) [1,1'- biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;

ethyl [2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-1-yl]-1- phenylethoxy]acetate;

[2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-1-yl]-1- phenylethoxy]acetic acid;

5-butyl-2,4-dihydro-4-[2'-(1H-tetrazol-5-yl) [1,1'- biphenyl]-4-ylmethyl]-2-(3,5,5-trimethylhexyl)-3H-1,2,4- triazol-3-one;

5-butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)-1-

(phenylmethyl)-E-ethenyl]-4-[2'-(1H-tetrazol-5-yl) [1,1'- biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;

2-(1-benzoyl-2-phenylethyl)-5-butyl-2,4-dihydro-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol- 3-one;

5-butyl-2,4-dihydro-2-(1-oxobutyl)-4-[2'-(1H-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)-2- oxoethyl]-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)ethyl]-4- [2'-(1H-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)-2- hydroxyethyl]-4-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-(2-naphthalenylmethyl)-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-

3-one;

methyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1- pentanoate;

ethyl β-benzoyl-3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4- triazole-1-propanoate;

2-(1-benzyoyl-1-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'-(1H-tetrazol-5-yl) [1,1'- biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-pentanoic acid;

5-butyl-2-(cyclopropylmethyl)-2,4-dihydro-4-[2'-(1H- 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'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-

3-one; and

1-butyl-4,5-dihydro-5-oxo-α-propyl-4-[2'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-acetonitrile.

32. A therapeutic method for treating a

circulatory disorder, said method comprising administering to a subject having such disorder a therapeutically- effective amount of an active compound of Formula I :

wherein m is a number selected from one to four,

inclusive; wherein R¹ is selected from polycycloalkyl,

polycycloalkylalkyl, 3-phenyIpropyl, 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, 1-benzoyl-2-phenylethyl, 1-oxobutyl,

2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl, acetonitrile, cycloalkenyl, aralkoxycarbonyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, alkylthiothiocarbonyl, arylthiocarbonyl,

arylthiothiocarbonyl, aralkylthiocarbonyl,

alkylthiocarbonyl, aralkylsulfinyl, aralkylsulfonyl and radicals of the formula wherein each of R¹² and R¹³ is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl,

cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R¹² and R¹³ 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 R¹² and R¹³ 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 R¹² and R¹³ cannot be selected from hydrido and alkyl; wherein each of R² through R¹¹ 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

wherein X is oxygen atom or sulfur atom;

wherein each of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R¹⁴ and R¹⁵ taken together, R¹⁶ and R¹⁷ taken together and R¹⁸ 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 R¹⁴ and R¹⁵ taken together and each of R¹⁶ and R¹⁷ 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 R³ through R¹¹ may be further

independently selected from hydroxy and acidic moieties of the formula -Y_nA 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, 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, 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

wherein X is oxygen atom or sulfur atom; wherein R²⁰ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR²⁵ and 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 R²¹, R²², R²³, R²⁴, R²⁶ and R²⁷ 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 and R²⁷ is further independently selected from amino and amido radicals of the formula

wherein each of R²⁸, R²⁹, R³⁰, R³¹ R³² and R³³ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl,

haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R²¹ 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 R²¹ and R²² taken together and each of R²⁶ 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.

33. The method of Claim 32 wherein m is one; wherein R¹ is selected from polycycloalkyl,

polycycloalkylalkyl, 3-phenyIpropyl, 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)-1-(phenylmethyl)- E-ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl,

2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 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 R¹² and R¹³ is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl,

cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, with the proviso that when X is oxygen atom, then R¹² and R¹³ cannot be selected from hydrido and alkyl; 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, 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, aralkylthiocarbonyl, 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 R³ through R¹¹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo,

haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,

cycloalkynyl, cyano, nitro, carboxyl, 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

wherein X is oxygen atom or sulfur atom;

wherein each of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R³ through R¹¹ may be further

independently selected from acidic moieties of the formula

-Y_nA 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 R¹⁹, 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 wherein X is oxygen atom or sulfur atom; wherein R¹⁹ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, and DR²³ and

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 R²¹, R²², R²³, R²⁴, R²⁶ 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.

34. The method of Claim 33 wherein m is one; wherein R¹ is selected from polycycloalkyl,

polycycloalkylalkyl, 3-phenyIpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyl- methyl, hexyl, ethoxycarbonylmethyl, carboxymethyl,

1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl,

ethoxycarbony.lmethoxyethyl 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-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, cycloalkynyl, aralkylsulfonyl and amido radicals of the formula

wherein each of R¹² and R¹³ 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, alkoxycarbonyl, 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,

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 wherein each of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸ and R¹⁹ is

independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R³ through R¹¹ may be an acidic moiety further independently selected from acidic moieties of the formula

-Y_nA 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

wherein each W is independently selected from oxygen atom, sulfur atom and NR³⁸; wherein each of R³⁴, R³⁵, R³⁶, R³⁷ and R³⁸ is independently selected from hydrido, alkyl, haloalkyl, haloalkylsulfonyl, haloalkylcarbonyl,

cycloalkyl, cycloalkylalkyl, aryl and aralkyl; wherein each of R³⁴, R³ ₅, R³⁶ and R³⁷ may be further independently selected from amino radical of the formula wherein each of R³⁹ and R⁴⁰ is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R³⁹ and R⁴⁰ 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 R⁴⁰ 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 R³⁵ and R³⁶ 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 R³ through R¹¹ or may be attached at any two adjacent positions selected from R³ through R¹¹ so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; 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 R¹ through R¹⁹ 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

wherein X is selected from oxygen atom and sulfur atom;

wherein R²⁰ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl and DR²⁵ and >

wherein D is selected from oxygen atom and sulfur atom, wherein R²⁵ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R²¹, R²², R²³, R²⁴, R²⁶ 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.

35. The method of Claim 34 wherein m is one; R ¹ is selected from polycycloalkyl, polycycloalkylalkyl, 3-phenyIpropyl, 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, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl, acetonitrile, cycloalkenyl, mercaptocarbonyl, aralkylsulfonyl and radicals of the formula

wherein each of R¹² and R¹³ 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 R³ through R¹¹ 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 R³ through R¹¹ may be an acidic moiety further independently selected from acidic moieties of the formula

-Y_nA 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

wherein each W is independently selected from oxygen atom, sulfur atom and NR³⁸; wherein each of R³⁴, R³⁷ and R³⁸ 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 wherein each of R³⁹ and R⁴⁰ is independently selected from hydrido, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R³⁹ and R⁴⁰ 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 R⁴⁰ taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of

carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to about nine ring members, which ring contains at least one hetero atom, selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which

heterocyclic ring may be attached at a single position selected from R³ through R¹¹ or may be attached at any two adjacent positions selected from R³ through R¹¹ so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; 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 R¹⁹, R³⁴ and R³⁷ through R⁴⁰, 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.

36. The method of Claim 35 wherein m is one; wherein R¹ is selected from polycycloalkyl,

polycycloalkylalkyl, 3-phenyIpropyl, 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)-1-(phenyImethyl)- E-ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl,

2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl,

arylalkenyl, acetonitrile, aralkylsulfonyl and amido radicals of the formula

wherein each of R¹² and R¹³ 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 R³ through R¹¹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo,

haloalkyl, cycloalkyl, alkoxy, phenalkyl, phenyl, benzoyl, phenoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl, 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 of the formula

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

wherein each W is independently selected from oxygen atom, sulfur atom and NR³⁸; wherein each of R³⁴, R³⁷ and R³⁸ 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 R³⁹ 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 a single position selected from R³ through R¹¹ or may be attached at any two adjacent positions selected from R³ through R¹¹ so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; 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.

37. The method of Claim 36 wherein m is one; wherein R¹ is selected from adamantyl, adamantylalkyl, 3-phenyIpropyl, 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- (phenyImethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1- oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- 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 R ¹¹ 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, PO₃H₂,

NHSO₂CF₃, NHSO₂C₆F₅, SO₃H, CONHNH₂, CONHNHSO₂CF₃, CONHOCH₃, CONHOC₂H₅, CONHCF₃, OH, CH₂OH, C₂H₄OH, OPO₃H₂, OSO₃H ,

wherein each of R⁴¹, R⁴² and R⁴³ is independently selected from H, Cl, CN, NO₂, CF₃, C₂F₅, C₃F₇, CHF₂, CH₂F, CO₂CH₃, CO₂C₂H₅, SO₂CH₃, SO₂CF₃ and SO₂C₆F₅; wherein Z is selected from O, S, NR⁴⁴ and CH₂; wherein R⁴⁴ is selected from hydrido, CH₃ and CH₂C₆H_5; and wherein said acidic moiety may be a heterocyclic acidic group attached at any two adjacent positions of R³ through R¹¹ so as to form a fused ring system with one of the phenyl rings of the biphenyl moiety of Formula I, said biphenyl fused ring system selected from

and the esters, amides and salts of said acidic moieties; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

38. The method of Claim 37 wherein m is one; wherein R¹ is selected from adamantyl, adamantylmethyl, adamantylethyl, adamantyIpropyl, 3-phenyIpropyl, 2-oxo-2- phenylethyl, 2-hydroxy-2-phenylethyl, 1,1- daimethylethyloxycarbonyImethyl, 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-phenyl- 2-(phenylmethoxy) ethyl, 2-(2 5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl- 2E-propenyl and acetonitrile; wherein R² is selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, isobutyl, tert-butyl, n-pentyl, isopentyl,

neopentyl, adamantyl, adamantylmethyl, adamantylethyl, adamantylpropyl, 3 -phenyIpropyl, 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-(phenyImethyl)-E- ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5- dimethyoxyphenyl)-2-oxoethyl, 2-phenyl-2- (phenylmethoxy) ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, eyelopropylmethyl, 3-phenyl- 2E-propenyl, acetonitrile, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, propylthio, butylthio,

1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1- dimethoxypropyl, 1,1-dimethσxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,1- difluoropropyl, 1,1-difluorobutyl and 1, 1-difluoropentyl; wherein at least one of R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂H, SH, PO₃H₂, SO₃H, CONHNH₂,

CONHNHSO₂CF₃, OH,

wherein each of R⁴² and R⁴³ is independently selected from Cl, CN, NO₂, CF₃, CO₂CH₃ and SO₂CF₃; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

39. The method of Claim 38 wherein m is one; wherein R¹ is selected from 2-oxo-2- (tricyclo[3.3.1.1.^3.7]dec-2-yl) ethyl, 3-phenyIpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1- dimethylethyloxycarbonyImethyl, 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-d.imethyoxyphenyl)-2-oxoethyl, 2-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl- 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 R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂H, SH, PO₃H₂, SO₃H, CONHNH₂, CONHNHSO₂CF₃, OH,

wherein each of R⁴² and R⁴³ is independently selected from Cl, CN, NO₂, CF₃, CO₂CH₃ and SO₂CF₃; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

40. The method of Claim 39 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, 2- oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1- dmethylethyloxycarbonyImethyl, 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-phenyl- 2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2- hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1- methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl- 2E-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 R⁹ is hydrido and the other of R⁵ and R⁹ is an acidic group selected from CO₂H and

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

41. The method of Clam 40 wherein said active compound is selected from compounds, and their

pharmaceutically-acceptable salts, of the group consisting of

4'-[(1,3-dibutyl-4,5-dihydro-5-oxo-1H-1,2,4-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'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4'- ylmethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-(3-phenyIpropyl)-4-[2'-(1H-tetrazol- 5-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'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol- 3-one; 5-butyl-2,4-dihydro-2-(2-hydroxy-2-phenylethyl)-4-[2'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol- 3-one;

1,1-dimethylethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4- triazole-1-acetate;

5-butyl-2,4-dihydro-2-hexyl-4-[2'-(1H-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'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-acetate; 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-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'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol- 3-one;

5-butyl-2-(2-cyclohexylethyl)-2,4-dihydro-4-[2'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol- 3-one;

5-butyl-2,4-dihydro-2-pentyl-4-[2'-(1H-tetrazol-5-yl) [1,1'- biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;

ethyl [2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-1-yl]-1- phenylethoxy]acetate;

[2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-1-yl]-1- phenylethoxy]acetic acid;

5-butyl-2,4-dihydro-4-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-ylmethyl]-2-(3,5,5-trimethylhexyl)-3H-1,2,4- triazol-3-one;

5-butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)-1-

(phenylmethyl)-E-ethenyl]-4-[2'-(1H-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'-(1H- tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol- 3-one;

5-butyl-2, 4-dihydro-2- (1-oxobutyl) -4- [2 ' - (1H-tetrazol-5- yl) [1, 1 '-biphenyl] -4-yMethyl] -3H-1, 2, 4-triazol-3-one; 5-butyl-2,4-dihydro-2-[2-(2,5-dimethyoxyphenyl)-2- oxoethyl]-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-[2-pheny1-2-(phenylmethoxy)ethyl]-4- [2'-(1H-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)-2- hydroxyethyl]-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- ylmethyl]-3H-1,2,4-triazol-3-one;

5-butyl-2,4-dihydro-2-(2-naphthalenylmethyl)-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-

3-one;

methyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5- yl) [1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-l-pentanoate;

ethyl β-benzoyl-3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4- triazole-1-propanoate;

2-(1-benzyoyl-1-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'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-pentanoic acid;

5-butyl-2-(cyclopropylmethyl)-2,4-dihydro-4-[21-(1H- 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'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-

3-one; and

1-butyl-4,5-dihydro-5-oxo-α-propyl-4-[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3- acetonitrile.

42. The method of Clam 32 wherein said circulatory disorder is a cardiovascular disorder.

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

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