WO1991019715A1

WO1991019715A1 - 1H-SUBSTITUTED-IMIDAZO[4,5-d]PYRIDAZINE COMPOUNDS FOR TREATMENT OF CARDIOVASCULAR DISORDERS

Info

Publication number: WO1991019715A1
Application number: PCT/US1991/003907
Authority: WO
Inventors: Philippe R. Bovy; Timothy S. Chamberlain; Joe T. Collins
Original assignee: G.D. Searle & Co.
Priority date: 1990-06-15
Filing date: 1991-06-07
Publication date: 1991-12-26
Also published as: AU7983691A

Abstract

A class of 1H-substituted-imidazo (4,5-d) pyridazine compounds is described for use in treatment of circulatory disorders. Compounds of particular interest are angiotensin II antagonists of the formula (I). These compounds are particularly useful in treatment or control of circulatory and cardiovascular disorders such as hypertension and congestive heart failure.

Description

1H-SUBSTITUTED-IMIDAZO [4,5-d,PYRIPAZINE COMPOUNDS

FOR TREATMENT OF CARDIOVASCULAR DISORDERS

Field of the Invention

Non-peptidic 1H-substituted-imidazo [4, 5-d] pyridazine compounds are described for use in treatment of circulatory and cardiovascular disorders such as

hypertension and congestive heart failure. Of particular interest are angiotensin II antagonist compounds provided by imidazo [4, 5-d]pyridazine having a biphenylmethyl moiety attached to the N-1 position of the imidazo-pyridazine heterocycle. 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, an octapeptide which is the primary active species of this system. Angiotensin II is a potent vasoconstrictor agent and also produces other physiological effects such as promoting aldosterone secretion, promoting sodium and fluid retention, inhibiting renin secretion, increasing sympathetic nervous system activity, increasing vasopressin secretion, causing positive cardiac inotropic effect and modulating other hormonal systems.

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 l-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.

Several families of imidazo-pyridazine derivatives have been synthesized. For example, alkaline hydrolysis of 1,2,5-thiadiazole-3,4-dicarboxylic acid bishydrazide followed by a cyclization step in the presence of formic acid produced 4,7-dihydroxy- and 4,7- dichloro[4,5-d]pyridazine derivatives [I. Sekikawa,

J. Heterocyclic Chem., 6, 129-130 (1969)]. Also synthesis of imidazo-pyridazine nucleoside analogues has been

described. For example, ring closure of an imidazole nucleoside produced the compound 1-(β-D- ribofuranosyl)imidazo[4,5-d]pyridazine-4,7-dione [C.

Tapiero et al, J. of Carbohydrates Nucleosides Nucleotides,3(3), 191-195 (1976)]. In a study of chemical modification of antibiotic nucleosides, the compound 1-(2,3,5-tri-O- benzoyl-β-D-ribofuranosyl) imidazo- [4, 5-d]pyridazine4,7 (5H, 7H)dione was synthesized [P.D. Cook et al, J.

Heterocyclic Chem., 15, 1 (1978)]. A series of substituted imidazo (4, 5-d)pyridazines has been studied for

pharmacological properties [G. G. Ferguson et al, J. Pharm. Sci., 59(11), 1584-1586 (1970)]. A family of 4-substituted imidazo [4, 5-d]pyridazines, including several 4-amino- and 4-alkylamino-1-benzyl-7-chloroimidazo [4, 5-d]pyridazines, has been prepared for antitumor evaluation [J.A. Carbon, J, Am. Chem. Soc. 80, 6083-6088 (1958)]. In view of the antitumor activity of 5-amino-7-hydroxy-v- triazolo[d]pyrimidine, several 4,7-disubstituted

imidazo [4, 5-d]pyridazines were synthesized including the compound 4, 7-bisethylmercapto-1-ethylimidazo [4,5-d]pyridazine [R. N. Castle et al, J. Org. Chem.. 23, 1534-1538 (1958)]. Based on the antimalarial activity of certain quinoline derivatives, a family of ω-dialkylaminoalkylaminoimidazo [4, 5-d]pyridazines was synthesized including, typically, the compound 4-(3- dimethylaminopropylamino)-7-chloro-1-(tetrahydro-2'-pyranyl)imidazo[4,5-d]pyridazine [N. R. Patel et al,

J. Heterocyclic Chem.. 5, 13-24 (1968)].

Certain imidazo-pyridazine compounds have been described for treatment of cardiovascular disorders. For example, EP #184,738, published 18 June 1986, describes a family of 2-naphthyl-substituted imidazo [4,5-d]pyridazin-4- on compounds having antithrombotic, cardiotonic and hypotensive properties. Japanese Patent #065,202,

published 18 March 1987, describes a family of imidazo heterocyclic carbostyril derivatives useful as cardiotonic, hypotensive and antiinflammatory agents. U.S. Patent No. 4,656,171 describes certain 2-phenyl-imidazo-pyridazines for use as cardiotonics, including a benzyloxy-substituted 2-phenyl-imidazole [4, 5-c]pyridazine. U.S. Patent No.

4,722,929 describes 2-aryl-imidazo-pyridazine compounds for use as cardiotonics, including a benzyloxy-substituted 2-phenyl-4-chloro-imidazo[4,5-d] pyridazine. EP #399,731 published 28 November 1990 describes several different families of imidazopyridines and imidazodiazines as angiotensin II antagonists including, in particular, the compounds methyl 4'-[(2-butyl-4-hydroxy-3H-imidazo [4,5-d]pyridazin-3-yl)methyl]biphenyl-2-carboxylate and 2-butyl-4-hydroxy-3[(2'(1H-tetrazol-5-yl) biphenyl-4-yl) methyl]-3H-imidazo[4,5-d]pyridazine. EP #400,974 published 5 December 1990 describes several families of imidazo-fused sixmembered heterocyclics as angiotensin II antagonists including, in particular 7-methyl-2-7propyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine.

EP #420,237 published 3 April 1991 describes

biphenylmethane imidazopyridine compounds for use as angiotensin II antagonists.

DESCRIPTION OF THE INVENTION

A class of 1H-substituted-imidazo [4,5-d]pyridazine 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 each of R¹ through R¹¹ and R³⁹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, .

alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, formyl, alkylcarbonyloxy,

cycloalkylalkoxy, alkoxyalkoxy, mercaptocarbonyl,

mercaptothiocarbonyl, alkoxycarbonyloxy, aroyloxy,

alkylaminocarbonyloxy, arylaminocarbonyloxy, 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 each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is

independently selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R¹² and R¹³ taken together, R¹⁴ and R¹⁵ taken together and R¹⁶ and R¹⁷ taken together may each form a heterocyclic group having five to seven ring members including at least one carbon atom ring member and the nitrogen atom of said amino or amido radical as a ring member, and which

heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein R¹² and R¹³ taken

together and R¹⁴ and R¹⁵ taken together may form an

aromatic heterocyclic group having five ring members including at least one carbon atom ring member and the nitrogen atom of said amino or amido radical as a ring member 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 acidic moieties of the formula

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, wherein said Y_nA group is further characterized in being a radical

containing a free carboxylic acid group or being a radical which is a bioisostere of said free carboxylic acid group, 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 Y is further selected from

and -CH=CH-, wherein R¹⁸ is selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbonyl; and wherein any of the foregoing R¹ through R¹⁸, R³⁹, Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, halo, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy,

alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercapto, mercaptocarbonyl, alkylthio, arylthio,

alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl,

aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl,

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

wherein X is selected from oxygen atom and sulfur atom; wherein R¹⁹ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR²⁴ and

wherein D is selected from oxygen atom, nitrogen atom and sulfur atom and R²⁴ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R²⁰, R²¹, R²², R²³, R²⁵ and R²⁶ 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 R²⁰' R²¹' R²², R²³, R²⁵ and R²⁶ is further independently selected from amino and amido radicals of the formula

wherein each of R²⁷, R²⁸, R²⁹, R³⁰, R³¹ and R³² is

independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein R²⁰ and R²¹ taken together and R²² and R²³ taken together may each form a heterocyclic group having five to seven ring members including at least one carbon atom ring member and the nitrogen atom of said amino or amido radical as a ring member, 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 R²⁰ and R²¹ taken together and R²⁵ and R²⁶ taken together may each form an aromatic heterocyclic group having five ring members including at least one carbon atom ring member and the nitrogen atom of said amino or amido radical as a ring member, 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 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. It is understood that, if R¹ and R² of Formula I have different values from each other, two regioisomers can be obtained which fall within the scope of the present invention either as individual compounds or as their mixture in all ratios.

Preferred compounds of Formula I are all characterized in having a substituent, other than hydrido, at each of the R¹ and R² positions of the imidazopyridazine ring. Such substituents are selected from the

aforementioned R¹ and R² groups. Compounds having alkyl groups, especially lower alkyl groups at the R³⁹ position, are particularly useful as angiotensin II antagonists. 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 RH positions. The Formula I compound may have one -Y_nA moiety attached at one of the R³ through R ^{1 1} 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 -YnA moiety attached at one of

positions R⁵, R⁶, R⁸ and R⁹ would be expected to have preferred properties, while attachment at R⁵ or R⁹ would be more preferred. Compounds of Formula I may have one or more acidic protons and, therefore, may have one or more pK_a values. It is preferred, however, that at least one of these pK_a values of the Formula I compound as conferred by the -Y_nA 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 each of R¹ through R¹¹ and R³⁹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, cycloalkoxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, formyl,

alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,

cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy,

mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio,

alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl,

aralkylthiocarbonylthio, aralkylthiocarbonyl,

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 each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is

independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, 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, wherein said Y_nA group is further characterized in being a radical containing a free carboxylic acid group or being a radical which is a bioisostere of said free

carboxylic acid group, 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; or wherein Y is one or more groups selected from

and -CH=CH-, wherein R¹⁸ is selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl,

alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbonyl; and wherein any of the foregoing R¹ through R¹⁸, R³⁹, Y and A groups having a substitutable position may be substituted by one or more groups selected from alkyl, halo, alkenyl, aralkyl, hydroxyalkyl, trifluoromethyl, difluoroalkyl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercaptocarbonyl, alkylthio, alkylthiocarbonyl, and amino and amido radicals of the formula

wherein X is selected from oxygen atom and sulfur atom; wherein R¹⁹ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl; wherein each of R²⁰, R²¹, R²² and R²³ is independently selected from hydrido, alkyl, cycloalkyl, cyano,

hydroxyalkyl, haloalkyl, cycloalkylakyl, 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 each of R¹ and R² is independently selected from hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkyloxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, formyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy,

mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, 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 each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is

independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl,

monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein R³⁹ is selected from linear or branched alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, arylalkyl and

alkylcycloalkylalkyl, and wherein any one of the foregoing R³⁹ substituents having a substitutable position may be substituted with one or more substituents selected from alkyl, haloalkyl, halo, nitro, cyano, aryl, arylamino, alkylamino, alkylarylamino, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio,

arylsulfinyl and arylsulfonyl; and wherein each of R³ through R¹¹ is independently

selected from hydrido, linear or branched alkyl (C₁-C₁₀), linear or branched alkenyl (C₂-C₁₀), linear or branched alkynyl (C₂-C₁₀), cycloalkyl (C₃-C₁₀), cycloalkenyl (C₃-C₁₀), cycloalkylalkyl (C₄-C₁₀), aryl, arylalkyl, alkylaryl, halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl, and wherein at least one of the R³ to R¹¹ substituents is a carboxylic acid radical of the formula

wherein R³³ is selected from hydrido, linear or branched alkyl (C₁-C₁₀,), linear or branched alkenyl (C₂-C₁₀), linear or branched alkynyl (C₂-C₁₀), cycloalkyl (C₃-C₁₀),

cycloalkenyl (C₃-C₁₀), cycloalkylalkyl (C₄-C₁₀) and

cycloalkenylalkyl (C₄-C₁₀); or wherein said R³ through R^{1 1} substituent is a bioisostere of a free carboxylic acid having a pK_a in a range from about two to about ten, said bioisostere being selected from sulfenic acid, sulfinic acid, sulfonic acid, sulfonyl carboxamide, sulfonamides, hydroxamic acid, hydroxamate, aminotetrazole, phosphorus- containing and thiophosphorus-containing acids selected from

wherein W is selected from O, S and N-R⁴⁰; wherein each of R³⁴, R³⁵' R³⁶ and R⁴⁰ is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyl and R³⁷-N-R³⁸, wherein R³⁷ and R³⁸ can be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl and alkanoyl; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic groups containing 5 to 7 atoms of which one or more heterocyclic ring atoms are selected from oxygen and nitrogen, which heterocyclic group has an ionizable proton with a pk_a in a range from about two to about ten; 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 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 said bioisostere of carboxylic acid may be further selected from substituted amino groups of the formula

NH-R⁴⁶

wherein R⁴⁶ is selected from alkylsulfonyl, arylsulfonyl, fluoroalkylsulfonyl, fluoroarylsulfonyl,

fluoroalkylcarbonyl, fluoroarylcarbonyl and CO-R⁴¹ wherein R⁴¹ is selected from hydrido, linear or branched alkyl (C₁- C₁₀,), linear or branched alkenyl (C₂-C₁₀), linear or branched alkynyl (C₂-C₁₀), cycloalkyl (C₃-C₁₀), cycloalkenyl (C₃-C₁₀), cycloalkylalkyl (C₄-C₁₀) and cycloalkenylalkyl (C₄-C₁₀); wherein any of the foregoing R³³ through R³⁸, R⁴⁰, R⁴¹ and R⁴⁶ substituents having a substitutable position may be substituted with one or more substituents selected from alkyl, haloalkyl, halo, nitro, cyano, aryl, arylalkyl, alkylaryl, hydroxyl, alkoxy, aryloxy, alkylthio,

alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

Examples of heterocyclic groups which can be used as bioisosteres of carboxylic acid include:

A

wherein each of R⁴², R⁴³ and R⁴⁴ 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, NR⁴⁵ and CH₂ , wherein R⁴⁵ is selected from hydrido, CH₃ and CH₂C₆H₅ . Examples of fused ring systems which include the phenyl rings of Formula I are as follows:

An even more highly preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein R¹ and R² is independently selected from hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl,

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

cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthic, aralkylthio, aralkylthiocarbonylthio, mercapto,

alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl,

wherein each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is

monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; 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 at least one of R³ through R¹¹ is an acidic moiety 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,

NHCN₄H and

and wherein said acidic moiety may further be a

heterocyclic acidic group attached at any two adjacent positions of R³ through R¹¹ so as to form a fused ring system to include one of the phenyl rings of the biphenyl moiety of Formula I, said 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 each of R^ and R² is independently selected from hydroxy, amino, aminomethyl, aminoethyl,

dimethylaminoethylamino, methyl, ethyl, n-propyl,

isopropyl, n-butyl, secbutyl, isobutyl, tertbutyl, n-pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, hydroxyalkyl, halo, methylthio, propylthio, isopropylthio, cyclohexylthio, methoxy, ethoxy, isopropoxy, phenoxy, cyclohexyloxy, methoxymethoxy, methoxy-1-ethyloxy, cyano, formyl, acetyloxy,

ethylcarbonyloxy, n-propylcarbonyloxy,

isopropylcarbonyloxy, n-butylcarbonyloxy, sec-butylcarbonyloxy, iso-butylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy,

isopentylcarbonyloxy, n-hexylcarbonyloxy, benzyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,

cycloheptyloxy, isopropanoyloxy, benzoyloxy,

methylaminocarbonyloxy, isopropylaminocarbonyloxy and phenylaminocarbonyloxy; wherein R³⁹ is selected from hydrido, linear or branched alkyl (C₁-C₁₀), linear or branched alkenyl (C₂-C₁₀), linear or branched alkynyl (C₂-C₁₀), cycloalkyl (C₃-C₁₀),

cycloalkenyl (C₃-C₁₀), cycloalkylalkyl (C₄-C₁₀) and cycloalkenylalkyl (C₄-C₁₀); wherein at least one of R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂H, SH, PO₃H₂, SO₃H, CONHNH₂,

CONHNHSO₂CF₃, OH, NHSO₂CH₃, NHSO₂CF₃, NHCOCF₃, CONHSO₂C₆,H₅, CONHOH, CONHOCH₃, CONHSO₂CH₃,

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 each of R¹ and R² is independently selected from hydroxy, amino, aminomethyl, aminoethyl,

dimethylaminoethylamino, methyl, ethyl, n-propyl,

isopropyl, n-butyl, secbutyl, isobutyl, n-pentyl, phenyl, benzyl, 1-hydroxyalkyl, halo, methylthio, propylthio, methoxymethoxy, methoxy-1-ethyloxy, acetyloxy,

ethylcarbonyloxy, n-propylcarbonyloxy,

cycloheptyloxy, isopropanoyloxy, benzoyloxy,

methylaminocarbonyloxy, isopropylaminocarbonyloxy and phenylaminocarbonyloxy; wherein R³⁹ is selected from n-propyl, n-butyl, n-pentyl, propylthio and propoxy; wherein each of R³, R⁴, R⁶, R⁷, R⁸, R¹⁰ and R¹¹ is hydrido; wherein one of R⁵ and R⁹ is. an acidic group selected from CO₂H and tetrazole and the other of R⁵ and R⁹ is hydrido; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

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 "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 substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or haloalkoxyalkyl groups. The term "alkylthio" embraces radicals containing a linear or branched alkyl group, of one to about ten carbon atoms attached to a divalent sulfur atom, such as a methythio group. 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 term "aralkyl" embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, phenylbutyl and diphenylethyl. The terms "benzyl" and "phenylmethyl" are interchangeable. The terms

"aryloxy" and "arylthio" denote radical respectively, aryl groups having an oxygen or sulfur atom through which the radical is attached to a nucleus, examples of which are phenoxy and phenylthio. The terms "sulfinyl" and

"sulfonyl", whether used alone or linked to other terms, denotes respectively divalent radicals SO and SO₂- The term "aralkoxy", alone or within another term, embraces an aryl group attached to an alkoxy group to form, for example, benzyloxy. The term "acyl" whether used alone, or within a term such as acyloxy, denotes a radical provided by the residue after removal of hydroxyl from an organic acid, examples of such radical being acetyl and benzoyl. "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 the effects of hypertension or susceptible to a hypertensive condition if not treated to prevent or control such hypertension.

Included within the family of compounds of

Formula I are the tautomeric forms of the described

compounds . Examples of tautomeric forms which are included in the family of compounds of Formula I are as follows:

Also included in the invention are compounds which are optical isomeric forms, including

diastereoisomers, of the compounds of Formula I . Further included within the invention are the regioisomers of compounds of Formula I where the biphenylalkyl group is attached to the nitrogen atom at the three-position of the imidazo-pyridine ring system of Formula I. Further included within the invention are the pharmaceutically- acceptable salts of compounds of Formula I. The term

"pharmaceutically-acceptable salts" embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic,

cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methansulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic,

β-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline,

diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the

appropriate acid or base with the compound of Formula I. A family of specific compounds of particular interest within Formula I is provided by compounds, and their pharmaceutically-acceptable salts, of the group consisting of:

4'-[(2-butyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-dichloro-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-difluoro-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-dibromo-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-1H-imidazo[4,5-d]pyridazin-1-yl-4,7-diol)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-dithio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-dimethoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-diethoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazin1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-dicyclohexyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-buty1-4,7-dibenzyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-dimethyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-diethyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-dicyclohehyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diphenyl-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-di(phenylethyl)-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diamino-1H-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-bis(2-dimethylaminoethylamino)-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-butyl-4,7-bis(3-dimethylaminopropylamino)-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-butyl-4,7-dimethylthio-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-diethylthio-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-diisopropylthio-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-buty1-4,7-dicyclohexylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diphenylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-dibenzylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-diisopropanoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-dicyclohexanoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dicyano-1H-imidazo[4,5-d]pyridazin-1¬yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-buty1-4,7-di-(formyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-di-(1,1-dimethoxy-isopropyl)-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2¬carboxylic acid;

4'-[(2-butyl-4,7-di-(1-oxo-butyl)-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-di-(1-oxo-cyclohexyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazin¬1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-methyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin¬1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-ethyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin¬1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-buty1-4-propy1-7-hydroxy-1H-imidazo[4,5-d]pyridazin¬l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-cyclohexyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-methoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5¬d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-fluoro-7-hydroxy-1H-imidazo[4,5-d]pyridazm¬l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-buty1-4-bromo-7-hydroxy-1H-imidazo[4,5-d]pyridazin¬l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-isopropyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-phenoxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-benzyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-butyl-4-(3-dimethylaminopropylamino)-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-butyl-4-methylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-ethylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-isopropylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-cyclohexylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-phenylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-benzylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-acetyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-cyclohexanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-(methoxymethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-(methoxy-1-ethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-formyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-buty1-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl] -2 -carboxylic acid;

4'-[(2-butyl-4-(1-oxo-butyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-(1-oxo-cyclohexyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-dichloro-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-4,7-difluoro-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-dibromo-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-1H-imidazo[4,5-d]pyridazin-1-yl-4,7-diol)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-4,7-dithio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-4,7-dimethoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-diethoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dicyclohexyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxy.lic acid;

4'-[(2-methyl-4,7-dibenzyloxy-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-dimethyl-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-diethyl-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-dicyclohehyl-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-diphenyl-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-4,7-di(phenylethyl)-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-diamino-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic .acid;

4'-[(2-methyl-4,7-bis(2-dimethylaminoethylamino)-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-4,7-bis(3-dimethylaminopropylamino)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-dimethylthio-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-diethylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-dicyclohexylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-diphenylthio-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-dibenzylthio-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-4,7-diisopropanoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-dicyclohexanoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dicyano-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-di-(formyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-di-(1,1-dimethoxy-isopropyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-4,7-di-(1-oxo-butyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-di-(1-oxo-cyclohexyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4-methyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-ethyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-cyclohexyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-methoxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-fluoro-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-bromo-7-hydroxy-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4-isopropyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-phenoxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-benzyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-phenyl-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4-(3-dimethylaminopropylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4-methylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-ethylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-isopropylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-cyclohexylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-phenylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-benzylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-acetyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-cyclohexanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-(methoxymethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-4-(methoxy-1-ethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4-formyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4-(1-oxo-butyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-(1-oxo-cyclohexyl)-7-hydrσxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-dichloro-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-difluoro-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dibromo-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-1H-imidazo[4,5-d]pyridazin-1-yl-4,7- diol)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-dithio-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-dimethoxy-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-diethoxy-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-diisopropyloxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dicyclohexyloxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isoprσpyl-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-dibenzylσxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropy1-4,7-dimethyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-diethyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dicyclohehyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diphenyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-di(phenylethyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diamino-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-bis(2-dimethylaminoethylamino)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-bis(3-dimethylaminopropylamino)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-dimethylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diethylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dicyclohexylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diphenylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropy1-4,7-dibenzylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diisopropanoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dicyclohexanoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-dicyano-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-di-(formyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-di-(1,1-dimethoxy-isopropyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-di-(1-oxo-butyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-di-(1-oxo-cyclohexyl)-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-chloro-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-methyl-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-ethyl-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-propyl-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-isopropyl-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-cyclohexyl-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-methoxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropy1-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4, 5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-fluoro-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-bromo-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-isopropyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-phenoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-benzyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-(3-dimethylaminopropylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-methylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-ethylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-isopropylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-cyclohexylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-phenylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-benzylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-acetyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-cyclohexanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-(methoxymethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-(methoxy-1-ethyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-formyl-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-bipherιyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-isopropyl-4-(1-oxo-butyl)-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-(1-oxo-cyclohexyl)-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-isopropyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-dichloro-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-difluoro-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-dibromo-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-1H-imidazo[4,5-d]pyridazin-1-yl-4,7-diol)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-dithio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-dimethoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-diethoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopenty1-4,7-dicyclohexyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-dibenzyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dimethyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-diethyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dicyclohehyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diphenyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-di(phenylethyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diamino-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-bis(2-dimethylaminoethylamino)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-bis(3-dimethylaminopropylamino)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-dimethylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diethylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dicyclohexylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diphenylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dibenzylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diacetyloxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diisopropanoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dibenzoyloxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dicyclohexanoyloxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-bis(methoxy-1-ethyloxy)-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-neopentyl-4,7-dicyano-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-di-(formyl)-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-di-(1,1-dimethoxy-isopropyl)-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-neopentyl-4,7-di-(1-oxo-butyl)-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-di-(1-oxo-cyclohexyl)-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-methyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-ethyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-cyclohexyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-methoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphejιyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-fluoro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-bromo-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-isopropyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-phenoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-benzyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4-(3-dimethylaminopropylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4-methylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-ethylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-isopropylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4 '- [ (2-neopentyl-4-cyclohexylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-phenylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-benzylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-acetyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-isopropanoyloxy-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-neopentyl-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-cyclohexanoyloxy-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-neopentyl-4-(methoxymethyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-neopentyl-4-(methoxy-1-ethyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-neopentyl-4-cyano-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-formyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4-(1-oxo-butyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-(1-oxo-cyclohexyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-dichloro-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-difluoro-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dibromo-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-1H-imidazo[4,5-d]pyridazin-1-yl-4,7-diol)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexy1-4,7-dithio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-dimethoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-diethoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-dicyclohexyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-dibenzyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dimethyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-diethyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dicyclohehyl-1H-imidazo[4,5-d]pyridazin-1-yl) methyl] [1, 1 ' -biphenyl] -2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diphenyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-di(phenylethyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-bis(2-dimethylaminoethylamino)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-bis(3-dimethylaminopropylamino)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dimethylthio-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diethylthio-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diisopropylthio-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dicyclohexylthio-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diphenylthio-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dibenzylthio-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diacetyloxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diisopropanoyloxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dibenzoyloxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dicyclohexanoyloxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-dicyano-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-di-(formyl)-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-di-(1,1-dimethoxy-isopropyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-cyclohexyl-4,7-di-(1-oxo-butyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-di-(1-oxo-cyclohexyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-methyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-ethyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-cyclohexyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-methoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-fluoro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-bromo-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-isopropyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-phenoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-benzyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-(3-dimethylaminopropylamino)-7-hydroxy- 1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-cyclohexyl-4-methylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-ethylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-isopropylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-cyclohexylthio-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-cyclohexyl-4-phenylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-benzylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-acetyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-isopropanoyloxy-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-cyclohexanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4-(methoxymethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4-(methoxy-1-ethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-formyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4-(1-oxo-butyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4-(1-oxo-cyclohexyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-buty1-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dichloro-1H-imidazo[4,5-d]pyridazine;

2-buty1-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-difluoro-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibromo-1H-imidazo[4,5-d]pyridazine;

2-buty1-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol;

2-buty1-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dithio-1H-imidazo[4,5-d]pyridazine;

2-buty1-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethoxy-1H-imidazo[4,5-d]pyridazine;

2-buty1-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diethoxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexyloxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzyloxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethyl-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diethyl-1H-imidazo[4-,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dicyclohehyl-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diphenyl-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-di(phenylethyl)-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diamino-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1H- imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(3-dimethylaminopropylamino)-1H- imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethylthio-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diethylthio-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexylthio-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenylthio-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzylthio-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropanoyloxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexanoyloxy-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyano-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-di-(formyl)-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-di-(1,1-dimethoxy-isopropyl)-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-di-(1-oxo-butyl)-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-ethyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-methoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-fluoro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-bromo-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-isopropyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-phenoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-benzyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-methylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-ethylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-.

yl]methyl]-4-benzylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-acetyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(methoxymethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(methoxy-1-ethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-formyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(1-oxo-butyl)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(1-oxo-cyclohexyl)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-.

yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dichloro-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-difluoro-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dibromo-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dithio-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethoxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diethoxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexyloxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzyloxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethyl-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diethyl-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-diisopropyl-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-dicyclohehyl-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-diphenyl-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-di(phenylethyl)-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-diamino-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-bis(2-dimethylaminoethylamino)-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-bis(3-dimethylaminopropylamino)-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-dimethylthio-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-diethylthio-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-diisopropylthio-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-dicyclohexylthio-1H-imidazo[4,5-d]pyridazine

2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-diphenylthio-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-dibenzylthio-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-diacetyloxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-diisopropanoyloxy-1H-imidazo[4,5-d]pyridazine

2-methyl-1-[ 2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4 7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dicyclohexanoyloxy-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dicyano-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-di-(formyl)-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-di-(1,1-dimethoxy-isopropyl)-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-di-(1-oxo-butyl)-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-ethyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-methoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-fluoro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-bromo-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-benzyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-methylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-ethylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-isopropylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyclohexylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-phenylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-.

yl]methyl]-4-benzylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-acetyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(methoxymethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(methoxy-1-ethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-formyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(1-oxo-butyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(1-oxo-cyclohexyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dichloro-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-difluoro-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibromo-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dithio-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethoxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diethoxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexyloxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzyloxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethyl-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diethyl-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dicyclohehyl-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diphenyl-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-di(phenylethyl)-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diamino-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1H- imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(3-dimethylaminopropylamino)-1H- imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dimethylthio-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diethylthio-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexylthio-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenylthio-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzylthio-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropanoyloxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexanoyloxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyano-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-di-(formyl)-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-di-(1,1-dimethoxy-isopropyl)-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-di-(1-oxo-butyl)-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-ethyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-methoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-fluoro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-bromo-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-isopropyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-phenoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-benzyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl] -4- (3-dimethylaminoethylamino) -7-hydroxy-1H¬imidazo [4, 5-d]pyridazine;

2-isopropyl-1- [ [2 ' - (1H-tetrazol-5-yl) [1, 1 ' -biphenyl] -4¬yl]methyl] -4-methylthio-7-hydroxy-1H-imidazo [4, 5 ¬d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-ethylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-benzylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-acetyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(methoxymethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(methoxy-1-ethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-formyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(1-oxo-butyl)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(1-oxo-cyclohexyl)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dichloro-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-difluoro-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dibromo-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dithio-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethoxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diethoxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexyloxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzyloxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethyl-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diethyl-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohehyl-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2•-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenyl-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-di(phenylethyl)-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diamino-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(3-dimethylaminopropylamino)-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethylthio-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diethylthio-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexylthio-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenylthio-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzylthio-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropanoyloxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dicyclohexanoyloxy-1H-imidazo[4,5- d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5- d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- y1]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5- d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dicyano-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-di-(formyl)-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-di-(1,1-dimethoxy-isopropyl)-1H-imidazo[4,5- d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-di-(1-oxo-butyl)-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-ethyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropyl-7-hydroxy-1H-imidazo[4,5¬d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-methoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-fluoro-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-bromo-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-benzyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-methylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-ethylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-isopropylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyclohexylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-phenylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-benzylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-acetyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(methoxymethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(methoxy-1-ethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-formyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(1-oxo-butyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(1-oxo-cyclohexyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dichloro-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-difluoro-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibromo-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dithio-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethoxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diethoxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexyloxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzyloxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethy1-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diethyl-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dicyclohehyl-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diphenyl-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-di(phenylethyl)-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diamino-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1H- imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(3-dimethylaminopropylamino)-1H- imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dimethylthio-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diethylthio-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexylthio-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenylthio-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzylthio-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropanoyloxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexanoyloxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyano-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-di-(formyl)-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-di-(1,1-dimethoxy-isopropyl)-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-di-(1-oxo-butyl)-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-ethyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-methoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-fluoro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-bromo-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-isopropyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyclohexyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-phenoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-benzyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-methylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-ethylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-benzylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-acetyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-y1]methyl]-4-benzoy1oxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(methoxymethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(methoxy-1-ethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-formyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(1-oxo-butyl)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(1-oxo-cyclohexyl)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- .

yl]methyl]-7-propyl-4-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[2'(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-pentanoyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyclohexanecarbonyloxy-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-7-(2,2-dimethylpropanoyloxy)-4-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(2,2-dimethylpropanoyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis-(2,2-dimethylpropanoyloxy)-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenylacetylchloride-7-hydroxy-1H-imidazo[4,5-d]pyridazine; and

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyl-1H-imidazo[4,5-d]pyridazine. Another family of specific compounds of more particular interest within Formula I. is provided by compounds, and their pharmaceutically-acceptable salts, of the group consisting of the following:

4'-[(2-butyl-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazin¬l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-diphenyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-di(phenylethyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-buty1-4,7-bis(3-dimethylaminopropylamino)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-diisopropyIthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diphenylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-di-(formyl)-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-methyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-fluoro-7-hydroxy-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-benzyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-isopropylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-phenylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-1H-imidazo[4,5-d]pyridazin-1-yl-4,7-diol)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-4,7-dithio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methy1-4,7-dimethoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-dimethyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-diphenyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-4,7-di(phenylethyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methy1-4,7-bis(3-dimethylaminopropylamino)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4*-[(2-methyl-4,7-diphenylthio-1H-imidazo[4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-di-(formyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-methyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-propy1-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-fluoro-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-benzyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-phenyl-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-methyl-4-isopropylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-phenylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-dichloro-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-1H-imidazo[4,5-d]pyridazin-1-yl-4,7-diol)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-dithio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazin¬l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-dimethyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diphenyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-di(phenylethyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-bis(3-dimethylaminopropylamino)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4,7-diphenylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropy1-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-di-(formyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-methyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-fluoro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-benzyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-isopropylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-phenylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-isopropanoyloxy-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-neopentyl-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-1H-imidazo[4,5-d]pyridazin-1-yl-4,7- diol)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-dithio-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-dimethoxy-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-diisopropyloxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-dimethyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-diphenyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopenty1-4,7-di(phenylethyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-bis(3-dimethylaminopropylamino)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diphenylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-di-(formyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4-methyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-fluoro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl].-2-carboxylic acid; 4'-[(2-neopentyl-4-benzyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4-isopropylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-phenylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dichloro-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-1H-imidazo[4,5-d]pyridazin-1-yl-4,7- diol)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-dithio-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-dimethoxy-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-diisopropyloxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic. acid; 4'-[(2-cyclohexyl-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-dimethyl-1H-imidazo[4,5-d]pyridazin- 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-diisopropyl-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diphenyl-1H-imidazo[4,5-d]pyridazin- l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-di(phenylethyl)-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-bis(3-dimethylaminopropylamino)-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-cyclohexyl-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-diphenylthio-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-di-(formyl)-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-methyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-fluoro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-benzyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4-isopropylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-phenylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dichloro-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4¬yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dithio-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diethoxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dicyclohexyloxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dimethyl-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diphenyl-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzylthio-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4¬yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5¬d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1- [ [2 ' - (1H-tetrazol-5-yl) [1, 1 ' -biphenyl] -4-yl]methyl] -4-isopropyl-7-hydroxy-1H~imidazo [4, 5 -d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-methoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-ethylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-benzylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl] -4-isopropanoyloxy-7-hydroxy-IH-imidazo [4, 5 -d]pyridazine;

2-butyl-1- [ [2 ' - (1H-tetrazol-5-yl) [1, 1 ' -biphenyl] -4 -yl]methyl] -4-benzoyloxy-7-hydroxy-IH-imidazo [4, 5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diethoxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dicyclohexyloxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dimethyl-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenyl-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzylthio-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yljmethyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyano-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-¬yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-methoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-ethylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-benzylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-acetyloxy-7-hydroxy-1H-imidazo[4,5¬d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxy-1-ethyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dichloro-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-dithio-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexyloxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenoxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethyl-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl] methyl] -4, 7-diisopropyl-1H-imidazo [4, 5-d]pyridazine;

2-isopropyl-1-[ [2 ' - (1H-tetrazol-5-yl) [1, 1 ' -biphenyl] -4-yl] methyl] -4, 7-diphenyl-1H-imidazo [4, 5-d] pyridazine;

2-isopropyl-1-[ [2 ' - (1H-tetrazol-5-yl) [1, 1 ' -biphenyl] -4-yl]methyl] -4, 7-bis (2-dimethylaminoethylamino) -1H- imidazo [4, 5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzylthio-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-methoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-ethylthio-7-hydroxy-1H-imidazo[4,5d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-benzylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-acetyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(methoxy-1-ethyloxy)-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dichloro-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropyloxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyclohexyloxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenoxy-1H-imidazo'[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethyl-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenyl-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzylthio-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1-,1'-biphenyl]-4-yl]methyl]-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyano-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyclohexyl-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-methoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-ethylthio-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-neopentyl-1-[[2*-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dichloro-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dimethyl-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropyl-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diphenyl-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diisopropylthio-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzylthio-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dicyano-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-isopropyl-7-hydroxy-1H-imidazo[4,5d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-cyclohexyl-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-methoxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-ethylthio-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-acetyloxy-7-hydroxy-1H-imidazo[4,5¬d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(methoxy-1-ethyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine; and

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyano-7-hydroxy-1H-imidazo[4,5-d]pyridazine.

Another family of specific compounds of more particular interest within Formula I consists of compounds, and their pharmaceutically-acceptable salts, of the group consisting of :

4'-[(2-buty1-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-buty1-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl) methyl] [1, 1 ' -biphenyl] -2-carboxylic acid;

4'-[(2-butyl-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-butyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2¬carboxylic acid;

4'-[(2-butyl-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methyl-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1H- imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-methyl-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1- yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-isopropyl-4-chloro-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-propyl-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5- d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-(2-dimethylaminoethylamino)-7-hydroxy- 1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2- carboxylic acid;

4'-[(2-isopropyl-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic' acid; 4'-[(2-neopentyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4 ,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl] [1, 1 '-biphenyl] -2-carboxylic acid; 4 ' - [ (2-cyclohexyl-4-propyl-7-hydroxy-1H-imidazo [4, 5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-cyclohexyl-4-isopropanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4¬yl]methyl]-4,7-dichloro-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxymethyloxy).-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-acetyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-dichloro-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-acetyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2*-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-acetyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5¬d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-chloro-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-acetyloxy-7-hydroxy-1Hτimidazo[4,5- d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-benzoyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-7-propyl-4-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- y1]methyl]-4-cyclohexanecarbony1oxy-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-7-(2,2-dimethylpropanoyloxy)-4-hydroxy-1H- imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyl-1H-imidazo[4,5-d]pyridazine.

Another family of compounds of more particular interest within Formula I is provided by compounds, and their pharmaceutically-acceptable salts, of the group consisting of the following: 4'-[(2-butyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-buty1-1H-imidazo[4,5-d]pyridazin-1-yl-4,7-diol)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-methy1-1H-imidazo[4,5-d]pyridazin-1-y1-4,7-diol)methyl][1,1'-biphenyl]-2-carboxylic acid;

4'-[(2-neopentyl-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine-4, 7-diol;

2-butyl-1-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4¬yl]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydrox--1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-acetyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine; 2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diethoxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine;

2-cyclohexyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine;2-butye-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-7-propyl-4-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-pentanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexanecarbonyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-7-(2,2-dimethylpropanoyloxy)-4-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-4,7-bis-(2,2-dimethylpropanoyloxy)-1H-imidazo[4,5-d]pyridazine;

GENERAL SYNTHETIC PROCEDURES

The compounds of the invention can be synthesized in accordance to the following procedures which are modeled upon a subset of biphenylmethyl carboxylic acid or biphenylmethyl tetrazole compounds of the family of compounds of Formula I. The reactions are performed in a solvent appropriate to the reagent and material employed and suitable to the transformation being performed. Some of the steps will involve reagents and substrates with functionality that will require protection. For the synthetic description and examples which follow,

abbreviations which have been used have the following meanings :

CHCl₃ = chloroform

DMF = dimethylformamide

DMSO = dimethylsulfoxide

g = gram

MeOH = methanol

min = minute

h = hour

mol = mole

mmol = millimole

mw = molecular weight

TLC = thin layer chromatography

Trt = trityl

AIBN = 2,2'-azobisisobutyronitrile

KtBuO = potassium t-butoxide

Other abbreviations may be explained in the text,

In Scheme 1, as a first step, there is shown bromination of a biphenylcarboxylic ester 1 with N-bromosuccinimide in the presence of AIBN in a suitable solvent such as carbon tetrachloride. The resulting benzyl bromide 2 is used to alkylate a 4, 5-dicarboxyimidazole 3 . A variety of solvents can be used to perform this

alkylation reaction, including alcohols, dimethylformamide, acetonitrile and water. This alkylation reaction is performed in the presence of at least one quivalent of a base. Among the bases that can be used are trialkylamines, potassium t-butoxide, sodium methoxide, sodium hydride, potassium and cesium carbonates. The choice of the base will be guided by the acidity of the imidazole proton to be abstracted. The reaction is normally brought about at temperatures ranging from 0°C to 120°C. The pyridazines ϋ are obtained by a cyclocondensation reaction between the imidazole 4 and hydrazine. Depending on the reactivity of the imidazole 5, a stoichiometric or an excess quantity of the hydrazine is used and the reaction occurs at a

temperature which may vary from below room temperature to the reflux temperature of the reaction medium. The reaction solvent can either be an inert solvent or one of the reagents. The free acid ϋ is obtained from the corresponding ester 5 by treatment with TFA in

dichloromethane when R is a t-butyl group or by treatment with potassium hydroxide when R is a methyl group. An excess quantity of either TFA or KOH is used and the temperature may vary from below room temperature to the reflux temperature of the reaction medium.

In Scheme 2, a biphenylcarboxylic acid ester 7 is converted to the cyanoderivative 8 by a method described by J. A. Krynitsky et al [Org. Synth. Coll., 2, 698 (1955) ] and J. Cason [Org. Synth. Coll.. 2, 169 (1955)]. The acid obtained by saponification of ester 2 is transformed into the acid chloride which in turn is converted into the primary carboxamide eventually dehydrated to cyano

derivative 8. The cyano derivative & is reacted by a 1,3-dipolar cycloaddition with trialkyltin azide to produce the corresponding tetrazole R as described by K. Sisido et al [J. Organometal. Chem., 22, 337-46 (1971)]. The reaction is advantageously performed with an excess of the

trialkyltin azide in refluxing toluene or dimethylformamide as inert solvent. The N-(trimethyl-stannyl)tetrazole 9 can be converted to the free tetrazole by bubbling dry gaseous hydrochloric acid in an ethereal or alcoholic solution. Intermediate free tetrazole is reacted with an

aralkylhalide, such as trityl chloride, which will provide a removable protecting group for the tetrazole. This reaction is best performed with trityl chloride in an inert solvent such as dichloromethane in the presence of at least one equivalent of a non-nucleophilic base such as pyridine or a trialkylamine. The bromination of 10 into the benzyl bromide 11 is performed with N-bromosuccinimide in the presence of AIBN in an inert solvent such as carbon tetrachloride, the reaction medium being heated at a temperature from 40°C to reflux of the solvent used.

In Scheme 3, the bromomethylbiphenyl tetrazole 11 is used to alkylate a 4,5-dicarboxyimidazole 12. A variety of solvents can be used to perform this alkylation reaction including alcohols, dimethylformamide,

acetonitrile and water. This alkylation reaction is best performed in the presence of at least one equivalent of a base. Among the bases that can be used are trialkylamines, potassium t-butoxide, sodium methoxide, sodium hydride, potassium and cesium carbonates. The choice of the base will be guided by the activity of the imidazole proton to be abstracted. The reaction is normally brought about at temperatures ranging from about 0°C to about 120°C. The pyridazines 12. are obtained by a cyclocondensation reaction between the imidazole and hydrazine. Depending on the reactivity of the imidazole 15., a stoichiometric or an excess quantity of the hydrazine is used and the reaction occurs at a temperature which may vary .from below room temperature to the reflux temperature of the reaction solvent. The reaction may be performed neat or in the presence of an inert solvent such as dimethylformamide, ethanol or toluene. The desired free tetrazole derivative 16 is obtained by removal of the protecting group. The deprotection reaction can be performed thermally at temperatures from about 50°C to about 150°C or preferably at a lower temperature in the presence of aqueous acetic acid.

Scheme 4 is a diagram illustrating methods that lead to modification of the substituents R¹ and R². For example, when each of R¹ and R² is a chloro substituent, compound 12 can be substituted by nucleophiles such as amines, aminoalkyls, thiol, hydroxy and alkoxy groups. A compound of formula 18 is obtained when compound 17 is heated in presence of a thiolate salt in a polar solvent such as water or dimethylformamide. If hydroxide ion is used as the nucleophilic species, the diol IB. is formed which can be subsequently converted into a dialkoxy compound 20 by treatment with a halide, alkyItosylate or alkylmesylate. The reaction is preferably performed in the presence of at least one equivalent of a base which can be organic, e.g., a carbonate or bicarbonate of an alkali or alkaline earth metal. Depending on the reactivity of the alkylating agent, a stoichiometric or an excess quantity is used, and the reaction occurs at a temperature which may vary from about 0°C to reflux temperature of the reaction medium.

Scheme 5 describes the preparation of 4- or

7-hydroxy pyridazine derivatives. As a first step is shown the preparation of the 2-butyl-4,5-dimethoxycarbonyl-imidazole. According to the Maquenne procedure [Snyder et al, Org. Synth.. 1947, 22,65] the starting material, tartaric acid, is treated sequentially by fuming nitric acid, ammonia and valeraldehyde. The intermediate diacid is directly converted to the dimethylester 22 by the use of hydrochloric acid (gas) or sulfuric acid in methanol. In the second step, the diester is treated with a reducing agent, preferentially a metallic hydride like

diisobutylaluminum hydride to give, by partial reduction the adehyde-ester derivative 22. The adehyde-ester 22 can be alkylated by the bromomethyl biphenyl tetrazole 11 (prepared in Scheme 2). A variety of solvents can be used to perform this alkylation reaction including alcohols, dimethylformamide, acetonitrile and water. This alkylation reaction is best performed in the presence of at least one equivalent of a base. Among the bases that can be used are trialkylamines, potassium t-butoxide, sodium methoxide, sodium hydride, potassium and cesium carbonates. The choice of the base will be guided by the activity of the imidazole proton to be abstracted. The reaction is normally brought about at temperatures ranging from about 0°C to about 120°C. This reaction gave a mixture of the tetrasubstituted imidazoles 24 and 25, isomeric by the position of the aldehyde and carbomethoxy groups on the imidazole nucleus. The isomers can be separated by crystallization or by a chromatographic method. The pyridazines 26 and 27 are obtained by a cyclocondensation reaction between the imidazole and hydrazine. Depending on the reactivity of the imidazole, 24 or 25, a stoichiometic or an excess quantity of the hydrazine is used and the reaction occurs at a temperature which may vary from below room temperature to the reflux temperature of the reaction solvent. The reaction may be performed neat or in the presence of an inert solvent such as dimethylformamide, chloroform, isopropanol, ethanol or toluene. The

cyclization reaction may be catalyzed by the use of a base such as trialkylamines or alcoholates. The desired free tetrazole derivative is obtained by removal of the protecting group. The deprotection reaction can be performed thermally at temperatures from about 50°C to about 150°C in a variety of solvents including methanol, ethanol, isopropanol, dimethylformamide or chloroform, or preferably at a lower temperature in the presence of aqueous acetic acid.

Scheme 6 describes an alternative preparation of hydroxy-pyridazine, particularly suitable for the 7-hydroxy isomers 27. As a first step, is shown the preparation of 2-butyl-4,5-dimethoxycarbonyl-imidazole. According to the Maquenne procedure the starting material, tartaric acid, is treated sequentially by fuming nitric acid, ammonia and valeraldehyde. The intermediate diacid is directly converted to the dimethylester 22 by the use of

hydrochloric acid (gas) in methanol. In the second step, several equivalents of a metallic hydride are used to reduce one of the ester function of 22 to the corresponding primary alcohol 28 Preferentially 3 equivalents of lithium triethylborohydride ("superhydride") in an inert solvent such as an ether or a cyclic ether such as

tetrahydro furane are used. After acidic aqueous workup, the alcohol-ester 28 is isolated in good yield. This alcohol ester 28 can be alkylated by the bromomethyl biphenyl tetrazole 11 (prepared in Scheme 2). A variety of solvents can be used to perform this alkylation reaction, including alcohols, dimethylformamide, acetonitrile and water. This alkylation reaction is performed in the presence of at least one equivalent of a base. Among the bases that can be used are trialkylamines, potassium t-butoxide, sodium methoxide, sodium hydride, potassium and cesium carbonates. The choice of the base will be guided by the acidity of the imidazole proton to be abstracted. The alkylation reaction results in the formation of a mixture of alkylated imidazoles 29 and 30 The treatment of this mixture with an oxidizing system such as pyridinium chlorochromate in dichloromethane, lead tetraacetate in pyridine or, preferentially manganese dioxide in

dichloromethane or acetonitrile. The temperature may vary from below room temperature to the reflux temperature of the reaction mixture. The reaction is normally brought about at temperatures ranging from 0°C to 120°C. This oxidative process produces preferentially the adehyde 29 which can be easily separated by a chromatographic procedure or by crystallization. The pyridazine 22 is obtained by a cyclocondensation reaction between the imidazole 2A and hydrazine. A stoichiometric quantity or preferentially an excess of the hydrazine can be used and the reaction occurs at a temperature which may vary from below room temperature to the reflux temperature of the reaction medium. The reaction solvent can either be an inert solvent or one of the reagents. The desired derivative 22 is obtained directly from the reaction mixture.

Scheme 7 describes a general procedure for preparation of ester derivatives.

A solution of 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis-hydroxy-1H-imidazo[4,5-d]pyridazine and a non nucleophilic base, preferentially a trialkylamine, and more preferentially triethylamine in a polar solvent such as acetonitrile or DMF is stirred at 25°C and 1 equivalent of the desired acid chloride. The reaction is monitored by TLC and/or HPLC. Several more equivalents (up to 5 equivalents total) may be added, depending whether the mono or the disubstituted product is desired. After aqueous work up the products of the reaction can be separated and purified by preparative reverse-phase, high-pressure liquid chromatography

(RPHPLC) .

The following examples are provided to

illustrate the present invention and are not intended to limit the scope thereof. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures expressed are in degrees centigrade.

Example 1

4'-[[2-butyl-1H-imidazo.4.5-dlpyridazin-1-yl]methyl]-[1,1'- biphenyl]- 2- carboxylic acid:

The target compound was prepared through the intermediates described in steps below:

Step 1: 2-n-butyl-1H-imidazole-4,5-dicarboxylic acid, dimethyl ester:

The starting diacid (Lancaster, 32g, mw = 212.2, 0.15 mol) was suspended in 500 mL methanol. Dry hydrogen chloride was bubbled into the reaction mixture for two hours. Toward the end of the first hour, the solid went into solution and the reaction mixture was stirred 60 hr at 25°C. The solvent was removed under vacuum and water was added to the residue. The mixture was made basic by addition of potassium

carbonate at 0 C. The brown oil which formed was extracted with ethyl acetate, dried over potassium carbonate and concentrated. The material obtained weighed 25g and was homogeneous by TLC (SiO₂. MeOH-CHCl₃/1-5).

1H NMR (CDCI₃, δ ppm) : 9.9 (bs,1H); 3.8 (s, 6H); 2.65 (m, 2H); 1.6 (m, 2H) ; 1.25 (m, 2H) ; 0.8 (m, 3H). Step 2 : 1 -[2-(trimethylsilyl)ethoxylmethyl-2-n-butyl-1H- imidazole-4,5-dicarboxylic acid, dimethyl ester:

The diester (23g, mw = 240, 96 mmol) was dissolved in 300 mL DMF. Potassium t-butoxide (100 mL of a IM solution in dry THF) was added through a syringe. The solution was stirred for 15 min at 25°C. [2-(trimethylsilyl)- ethoxy]methyl chloride (SEM-chloride, 18.6 mL, 1.1 eq, mw 166, d=0.94) was added and a precipitate formed instantly . The reaction was stirred for 90 min at 25°C. The solvent was removed and the residue partitioned between ethyl acetate and water. The organic extract was dried over K₂CO₃ and concentrated. By TLC (SiO₂, MeOH-CHCl₃/1-10) a single major spot was observed. This crude product (38g, ) was used in subsequent steps without further purification.

XH NMR (CDCI₃, δ ppm) : 5.5 (s, 2H, N-CH₂-O); 3.95 (s, 6H, CO₂CH₃); 3.5 (t, 2H, C-CH₂-O); 2.9 ( t, 2H, C-CH₂-C); 1.75 (m, 2H, C-CH₂-C); 1.4 ( m, 2H, C-CH₂-C); 0.95 ( t, 3H, CH₃-C); 0.85 ( t, 2H, C-CH₂-Si); 0.0 (s, 9H, CH₃-Si).

NB. When purification was necessary, the compound was purified using a Waters Prep 500 and two silicagel

cartridges. The mobile phase was 30-70/EtOAc-Hexane.

Samples were collected and analyzed by TLC (same solvent system).

Step 3: 1-[2-(trimethylsilyl)ethoxylmethyl-2-n-butyl-4,5-di-(hydroxymethyl)-1H-imidazole: The protected diester prepared above (10g, mw = 370, 0.027 mol) was dissolved in 50 mL dry diethyl ether. The

resulting solution was slowly added through an addition funnel to a solution of lithium aluminium hydride (LAH, 100 mL of a IM solution in diethyl ether) cooled in an

ice/water bath. After 2h stirring at 0-5°C, a precipitate was observed and the reaction mixture was stirred at 25°C for one more hour. The excess of LAH was decomposed by adding 3.77 mL of water, 3.77 mL 15% sodium hydroxide, and 11.3 mL water. The resulting mixture was filtered and the remaining gummy salts were washed with 300 mL tetrahydrofuran. The filtrate and tetrahydrofuran washing were combined and concentrated. The remaining oil weighed 7 g. 1H NMR (CDCl₃, δ ppm) : 5.3(s, 2H, N-CH₂-O); 4.65 (s, 2H, C- CH₂-O); 4.55 (s, 2H, C-CH₂-O);3.55 (t, 2H, C-CH₂-O) ; 2.7 (t, 2H, C-CH₂-C); 1.75 ( m, 2H, C-CH₂-C); 1.45 ( m, 2H, CCH₂-C); 0.95 ( t, 3H, CH₃-C); 0.9 ( t, 2H, C-CH₂-Si) ; 0.0 (s, 9H, CH₃-Si).

Step 4: 2-n-butyl-4,5-di-(hydroxymethyl)-1H-imidazole: The protected diol (7g) was dissolved in 50 mL 3N HCl and 50 mL ethanol. The solution was refluxed for 3 hours and the azeotrope then removed by distillation under vacuum. Water (50 mL) was added and the pH was brought to basicity (pH 9 ) with potassium carbonate. The precipitate was collected and dried under vacuum to yield 3.4g (85% yield) of the deprotected diol.

¹H NMR (DMSO-d₆, δ ppm) : 11.5 (bs, 1H); 4.2 (bs, 4H); 2.45

(t, 2H); 1.6 (m, 2H); 1.3 (m, 2H); 1.85 (t, 3H).

Step 5: 4 '- [[2-butyl-4, 5-bis (hydroxymethyl) -1H-imidazol-1- yl]methyl]-[1,1'-bi-phenyl]-2-carboxylic acid, methyl ester: Potassium t-butoxide (62 mL of 1 M solution in THF) was added to a solution of diol 4 (11.4g, mw = 184, 0.062 mol) in 300 mL DMF under a nitrogen blanket and the resulting solution stirred at 25°C for 15 minutes. The 4'-(bromomethyl)-[1,1'-biphenyl]-2-carboxylic acid, methyl ester (20.8g, 1.1 eq, MW 305, 68 mmol) was added and the reaction was stirred for two hours at 25°C. The solvents were removed and the residue partitioned between water and ethyl acetate. The residue from the ethyl acetate extract (20g.) was chromatographed on silicagel with 5% methanol in ethyl acetate. The desired diol (9g) was obtained as a solid.

1H NMR (CDCl3 , δ ppm): 7.85 (d, 1H); 7.5 (t, 1H); 7.4 (t, 1H); 7.35 (d, 1H) ; 7.3(d,2H); 7.0 (d, 2H); 5.25 (s,2H); 4.5 +4.6 (s + s, 2H + 2H); 3.65 (s, 3H); 3.3 (bs, 2H);

2.60 (t, 2H); 1.65 (m, 2H); 1.35 (m, 2H); 0.85 (t, 3H). MS (calcd C₂₄H₂₈N₂O₄, found M+H⁺) : 408.5, 409.

Step 6 : 4'-[[2-butyl-4.5-bis(carboxaldehyde)-1H-imidazol-1-yl]methyl]-[1,1'-biphenyl]-2-carboxylic acid methyl ester:

The dihydroxymethyl-imidazole (mw = 408; 1.5g; 3.67 mmol) was dissolved in 40 mL anhydrous pyridine. Lead

tetraacetate (mw=443; 3.91g; 8.8 mmol; 2.5 eq) was added and the mixture was stirred at 25°C for 4h. Volatiles were removed in vacuum and the residue was partitioned between potassium carbonate and ethyl acetate. The organic phase was dried and concentrated. This yielded 0.7g of the desired dialdehyde as an oil.

1H NMR (CDCl3, δ ppm): 10.35 (s, 1H); 10.1 (s, 1H); 7.85 (d, 1H); 7.6 (t, 1H) ; 7.5 (t, 1H); 7.4 (d, 1H) ; 7.3 (d, 2H); 7.1 (d, 2H); 5.7 (s, 2H); 3.60 (s, 3H); 2.7 (t, 2H, C-CH₂-C); 1.65 (m, 2H, C-CH₂-C); 1.30 ( m, 2H); 0.95 (t, 3H).

Step 7: 4'-[[2-butyl-1H-imidazo[4 ,5-d]pyridazin-1-yl]methyl]-[1,1'-biphenyl]-2-carboxylic acid, methyl ester:

A solution of 200 mg (0.5 mmol) of the imidazole in 2 mL ethanol were added to 25 mg (0.5 mmol) hydrazine in 2.5 mL ethanol. After stirring at 25°C for 2h and at 40°C for 4h, the solvent and volatiles were removed. The crude was analyzed by TLC and NMR. The crude was chromatographed on SiO₂ with 5% ethanol in chloroform. The fractions

containing a product with R_f = 0.1 (SiO₂, 5% ethanol in chloroform) were pooled and concentrated in vacuo. About 40 mg of the desired compound was isolated as a yellow oil. 1H NMR (CDCI3, δ ppm): 10.4( s, 1H); 10.2 (s, 1H) ; 7.95 (d, 1H); 7.55 (t, 1H); 7.45 (t, 1H); 7.3 (d+d,2H+1H); 7.1 (d, 2H); 5.47 (s, 2H); 3.65 (s, 3H); 3.0 ( t, 2H, C-CH₂-C); 1.95 (m, 2H, C-CH₂-C); 1.50 (m, 2H); 1.0 (t, 3H).

Step 8: 4'-[[2-butyl-1H-imidazo[4.5-d]pyridazin-1- yl]methyl]-[1,1'-biphenyl]-2- carboxylic acid:

The product isolated from the previous step was hydrolyzed in 5 mL 2.5 N sodium hydroxide and 5 mL ethanol and stirred at 25°C for 6-8h. The azeotrope was distilled off and the residue acidified to pH = 3. The resulting solid was collected and dried (m.p. = 188.2-190.7°C).

¹HNMR (CDCI3. δ ppm) : 10.5 (s, 1H) ; 10.3 (s, 1H) ; 8 (d, 1H); 7.55 (t, 1H); 7.45 (d+t, 2H+1H); 7.3 (d, 1H) ; 7.05 (d, 2H);

5.45 (s, 2H); 2.95 (t, 2H, C-CH₂-C); 1.85 (m, 2H, C-CH₂-C);

1.45 (m, 2H); 0.95 (t, 3H) .

MS (calcd C₂₃H₂₂N₄O₂ + H⁺, found M + H⁺) : 387.1821,

387.1775, Δ = 4.6.

Example 2

4'-[[2-butyl-1H-imidazo[4.5-d]pyridazin-1-yl-4.7-diol]methyl]-[1,1'-biphenyl]- 2- carboxylic acid:

Step 1: 4'-[[2-butyl-4,5-bis(methoxycarbonyl)-1H-imidazol-1-yl]methy!]-[1,1'- biphenyl]- 2- carboxylic acid, t-butyl ester:

The imidazole (1.2g, 5 mmol) was dissolved in 20 mL dry DMF, and 5 mL of a IM solution of tBuOK in THF was added. The reaction mixture was stirred for 0.5h at 25°C and cooled in a ice bath. The 4'-(bromomethyl)-[1,1'-biphenyl]-2-carboxylic acid, t-butyl ester (2.3g, 5 mmol) was added and the reaction was stirred for two hours, during which time the temperature rose from 0 to 25°C, and then stirred for 16 more hours at 25°C. The solvents were removed and the residue partitioned between water and ethyl acetate. The residue from the ethyl acetate extract (5g) was chromatographed on silicagel with 5% methanol in ethyl acetate. The fractions containing the main product (R_f = 0.4 on SiO₂, Hex:EtOAc 1:1) were pooled and concentrated. A white solid (3.7g) was obtained which was identified as the desired material by 1H NMR.

¹H NMR ( CDCI3 , δ ppm): 7.8 (d, 1H); 7.65 (t, 1H); 7.6 (t, 1H); 7.25 (d, 1H); 7.25 (d,2H); 7.0 (d, 2H); 5.45 (s,2H); 3.95 + 3.9 (s + s, 3H + 3H); 2.7 (t, 2H); 1.75 (m, 2H); 1.35 (m, 2H); 1.25 (s, 9H) ; 0.9 (t, 3H). Step 2: 4 '- [[2-butyl-1H-imidazo [4.5-d]pyridazin-1-yl-4,7- diol]methyl]-[1,1'- diphenyl - 2- carboxylic acid. t-butγl ester:

The ester prepared above (1.3g, 2.6 mmol) and anhydrous hydrazine (82 mg, 2.6 mmol) were mixed in 5 mL methanol and refluxed for 2h. TLC indicated incomplete reaction. An aliquot of hydrazine (4uL) were added and the mixture stirred at 100°C for 2h. After cooling at 25°C, a white precipitate (220 mg) was filtered and washed with cold methanol which was recrystallized from acetone/ethyl acetate (150 mg, m.p. = 206.5-206.8°C).

1H NMR (CD3OD , δ ppm): 7.6 (d, 1H) ; 7.4 (t, 1H); 7.3 (t, 1H); 7.2 (d, 1H); 7.5 (s, 4H); 5.7 (s,2H); 2.75 (t, 2H); 1.6 (m, 2H); 1.25 (m, 2H); 1.05 (s, 9H); 0.8 (t, 3H).

FABMS (calcd C₂₇H₃₀N₄O₄, found M + Li⁺) 474.23, 481.

Step 3 : 4 ' - [[2-butyl-1H-imιidazo [4 , 5-d]pyridazin-1-yl-4 , 7- diol]methyl]-[1,1'-biphenyl]- 2- carboxylic acid:

The t-butyl ester prepared above was dissolved in a mixture of 5 mL TFA and 5 mL dichloromethane and stirred at 25°C for 12 h. The volatiles were removed in vacuo and the resulting oil triturated with diethyl ether to provide a white solid ( m.p. = 248.3-248.5)

1H NMR ( CD₃OD , δ ppm): 8.1 (d, 1H); 7.64 (t, 1H) ; 7.5 (t, 1H); 7.35 (d, 1H) ; 7.3 (d, 2H); 7.2 (d,2H); 5.9 (s,2H);

3.05 (t, 2H); 1.7 (m, 2H); 1.4 (m, 2H); 0.95 (t, 3H).

FABMS (calcd C₂₃H₂₀N₄O₄ + H⁺, found M + H⁺, exact mass) : 419.1719, 419.1937, Δ = 1.8. Example 3.

2-butyl-4,7-dichloro-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine:

Step 1: 2-Butyl-4.7-dihydroxyimidazo[4.5-d]pyridazine:

2-Butyl-imidazole-4,5-carboxylic acid dimethyl ester (1.9 g, 7.9 mmol) and 5 mL anhydrous hydrazine were mixed and stirred at 120°C for 20h. The remaining excess of hydrazine was eliminated in vacuo and the remaining solid

recrystallized from methanol (60 mL).

¹HNMR (DMSO-d₆ & CDCI₃, δ ppm): 6 (bs, exchangeable); 2.8 (t, 2H); 1.8 (m, 2H) ; 1.35 (m, 2H); 0.95 (t, 3H).

FABMS (calcd C₉H₁₂N₄O₂ + H⁺, found M+H⁺, exact mass) :

209.1039, 209.1050, Δ = 1.1.

Step 2: 2-Butyl-4.7-dichloroimidazo[4.5-d]pyridazine:

2-Butyl-4,7-dihydroxyimidazo[4,5-d]pyridazine (320 mg, 1.5 mmol), 320 uL N,N-dimethylaniline and 8 mL phosphorus oxychloride were mixed together and stirred under an argon atmosphere for 1h. The excess phosphorus oxychloride was removed under reduced pressure and the syrupy residue was cooled and poured into 50 mL of ice water while stirring. This solution was extracted with chloroform and the residue (0.5g tan solid) after drying and removal of solvent was purified on a silicagel column (elution 5% methanol in chloroform). The fractions containing the main product (Rf = 0.36, 10% methanol in chloroform) were pooled and concentrated to a solid (300 mg) which was recrystallized from ethyl acetate (m. p. = 207.2-209.6°C).

FABMS (calcd C₉H₁₂N₄O₂ + H⁺, found M+H⁺) : 245, 245.1, dichloro isotopic pattern.

Elemental Analysis (calcd C₉H₁₂N₄O₂ , found) : C, 44. 10, 44. 14; H, 4. 11, 4.12; N, 22.58, 22.78.

Step 3: N-triphenγlmethγl-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- (ptolyl)benzoic acid: mp 145.0-147.5°C; NMR (CDCI₃) δ2.40

(s, 3H), 7.17-7.28 (m, 4H), 7.35-7.45 (m, 2H) , 7.51-7.59 (m, 1H), 7.90-7.97 (m, 1H). The crude acid was suspended in 1 L of toluene and slowly treated with 400 g (3.15 mol) of oxalyl chloride under nitrogen. The reaction was allowed to stir at ambient temperature for 4.5 h and concentrated in vacuo to remove excess oxalyl chloride. The residue was redissolved in 2 L of toluene and treated with 92.8 g (5.46 mol) of anhydrous ammonia. The reaction was filtered and the filtrate concentrated in vacuo

producing 424 g (84%) of crude 2-(p-tolyl)benzamide: mp 128-130°C; NMR (CDCI₃) δ2.40 (s, 3H) , 5.28 (br s, 1H), 5.77 (br s, 1H) , 7.21-7.53 (m, 7H) , 7.76-7.83 (m, 1H). The crude amide was treated with 1420 mL (19.5 mol) of thionyl chloride at reflux for 3.5 h. The reaction was filtered and the thionyl chloride removed in vacuo. The residue was dissolved in 800 mL of toluene and reconcentrated in vacuo. On standing overnight, the residue crystallized. The crystals were collected and washed with hexane to give 296 g (64%) of 2-(p-tolyl)benzonitrile: mp 50.5-52.0°C; NMR (CDCI₃) 62.42 (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 286g (1.48 mol) sample of the crude nitrile was dissolved in 1630 mL of toluene and treated with 377g (1.8 mol) of

trimethyltinazide at reflux for 24 h. The reaction was cooled; filtration gave 60Og of crude N-trimethylstannyl-5- [2-(4'-methylbiphen-2-yl]tetrazole: mp 271-272°C (dec.); NMR (DMSO-d₆) δ0.36 (br t, J=34 Hz, 9H), 2.24 (s, 3H),

6.89-7.06 (m, 4H), 7.35-7.55 (m, 4H). The crude N-trimethylstannyl tetrazole was suspended in 4270 mL of toluene and 287 mL of anhydrous tetrahydrofuran (THF) and treated with 63.4g (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 217g (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 200g (0.85 mol) sample of the tetrazole was suspended in 3.3 L of dichloromethane and treated with 262g (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 338g (83%) of N-triphenylmethyl-5-[2-(4'-methylbiphen-2-yl)]tetrazole as a colorless solid: mp 170-173°C; NMR (CDCI3) δ2.27 (s,

3H), 6.86-6.96 (m, 8H), 6.98-7.04 (m, 2H) , 7.09-7.52 (m, 12H), 7.86-7.94 (m, 1H). The N-triphenylmethyl tetrazole was dissolved in 4260 mL of carbon tetrachloride and treated with 126.4g (0.71 mol) of N-bromosuccinimide (NBS) and 11.9g (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 277g (59%) of N-triphenylmethyl-5-[2-(4'-bromomethylbiphen-2- yl)]tetrazole as a colorless solid: mp 140-142°C; NMR (CDCl₃) 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 : 2-butyl-1-{2'-[N-triphenγlmethyl-1H-tetrazol-5- yl)-[1,1'-biphenyl]-4-yl]methyl}-1H-imidazo[4,5-d]pyridazine-4,7-dichloro:

An aliquot of 200 mg of the 2-butyl-4,7-dichloroimidazo[4,5-d]pyridazine (mw 245; 0.8 mmol) was dissolved in 5 mL dry dimethyl formamide. Potassium t-butoxide (0.8mL; 1M solution) was added and the solution stirred at 25°C for 15 minutes. An equimolar amount of (N-triphenylmethyl-5-[2(4'-bromomethyl-biphenyl)]tetrazole (650 mg; MW 557; purity 70%) was added at 0°C and the resulting solution was stirred at 25 C for 3 hours. After removal of the solvents under vacuum, the residue was chromatographed on silicagel with hexane/ethyl acetate 2/1 and the main product isolated (R^f = 0.5 in hexane/ethyl acetate 2/1) and identified by NMR.

FABMS (calcd C₄₂H₃₄N₈C₁₂, found M + Li⁺) : 720.7, 727

(dichloro isotopic pattern). Step 5: 2-butyl-1-{2'-[1H-tetrazol-5-yl)-[1,1'-biphenyl]- 4-yl]methyl}-1H-imidazo[4.5-d]pyridazine-4,7-dich!oro:

The product (100 mg) obtained above is stirred in 25 ml of 10% water in acetic acid for 10 hours at 25°C. The solid remaining after lyophylization was triturated under diethylether and filtered (m.p. = 218-219°C). This compound was suitable for further transformations.

FABMS (calcd C₂₃H₂₀N₈C₁₂, found M + H⁺) : 479.3, 479

(dichloro isotopic pattern).

Example 4

2-butyl-1-{2'-[1H-tetrazol-5-yl)-[1,1'-biphenyl]-4- yl]methyl}-1H-imidazo[4,5-d]pyridazine-4,7-diol:

Step 1: 2-butyl-1-(2'-[N-triphenylmethyI-1H-tetrazol-5- yl)-[1,1'-hiphenyl]-4-yl]methyl}-1H-imiriazo-4,5- dicarboxylic acid methyl ester:

An aliquot of 3g of the 2-butyl-imidazole-4,5-carboxylic acid dimethyl ester (mw 240; 12.5 mmol) was dissolved in 50 mL dry dimethyl formamide. Potassium t-butoxide (12.7 mL; 1M solution) was added and the solution stirred at 25 C for 10 minutes. An equimolar amount of (N-triphenylmethyl-5- [2(4'-bromomethyl-biphenyl)]tetrazole (8.5g; MW 571; 15.1 mmol; purity 80%) was added and the resulting solution was stirred at 25°C for 15h. After removal of the solvents under vacuum, the residue was partitioned between

chloroform and water. The organic extract after drying and concentration was chromatographed on silicagel with

chloroform/ethyl acetate 95/5 and the main product isolated (5.5g; 60 % yield) and identified by NMR.

1HNMR (CDCI₃, δ ppm) : 7.95-6.75 (unresolved signals; 23 H); 5.3 (s, 2H); 3.95 ( s, 3H); 3.73 (s, 3H); 2.6 (t, 2H); 1.6 (m, 2H) ; 1.3 (m, 2H) ; 0 . 85 (t, 3H) . Step 2; 2-bυtyl-1-{2'-[1H-tetrazol-5-yl)-[1,1'-biphenyl]- 4-yl]methyl}-1H-imidiazo-4,5-dicarboxylic acid methyl ester:

The compound isolated above (2g, 2.7 mmol) was dissolved in 100 mL methanol and heated at reflux. Two equivalents of hydrazine hydrate (mw = 50; 270 mg; 5.4 mmol) in solution in 20 mL methanol were slowly added. The reaction mixture was refluxed for 2 hours, and the solvent removed under vacuum. TLC indicated a complex mixture of products. The residue was taken up in ethyl acetate and a remaining insoluble was removed by filtration. To the filtrate, hexane was added to yield a second solid which was filtered and dried. The second solid (m. p. = 113.4-115.8°C) was identified by NMR and MS as the desired product.

1HNMR (CDCI₃, δ ppm) : 7.65 (m; 4 H); 5.4 (s, 2H); 3.8 ( s, 3H); 3.7 (s, 3H); 2.65 (t, 2H); 1.55 (m, 2H); 1.3 (m, 2H); 0.95 (t, 3H).

FABMS (calcd C₂₅H₂₆N₆O₄, found M + H⁺) : 474, 475.

Step 3; 2-butyl-1-(2'-[1H-tetrazol-5-yl)-[1,1'-biphenyl]- 4-yl]methyl}-1H-imidazo[4,5-d]pyridazine-4.7-diol:

2-butyl-1-{2'-[1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]methyl}-1H-imidazo-4,5-dicarboxylic acid methyl ester

(650 mg, 1.4 mmol) and 137 mg hydrazine hydrate (2.8 mmol) were combined in isopropanol and refluxed for 72h. The solvent was removed, the residue washed with some ether and the residual solid ( m.p. = 163.3-177.3°C) was collected. ¹HNMR (CDCI₃, δ ppm) : 7.65 (m; 1H); 7.4 (m, 2H); 7.25 (m, 1H); 7.1 (d, 2H); 7.0 (d, 2H); 5.7 (s, 2H); 2.7 (t, 2H);

1.6 (m, 2H); 1.3 (m, 2H); 0.85 (t, 3H).

MS (calcd C23H₂2N8O2, found M + H⁺) : 442, 443. Example 5

2-butyl-4 , 7-diethoxy-1- {2 ' -[1H-tetrazol-5-yl) - [ 1 , 1 ' - biphenyl]-4-yl]methyl}-1H-imidazo [ 4 , 5-d]pyridazine :

Step 1: 1-Benzyl-2-butyl-4,7-diethoxyimidazo[4.5- d]pyridazine:

An aliquot of 210 mg of the 2-butyl-4,7- dichloroimidazo[4,5-d]pyridazine (mw 245; 0.85 mmol) was dissolved in sodium methanolate in methanol (0.8 mL; 1M solution) and 120 uL of benzyl bromide (1 mmol) was added. The solution was stirred at 25.C for 96h. The solution was filtered, the solvent was removed and 2 equivalents of sodium ethoxide in ethanol were added and the resulting solution was stirred at 25°C for 3 days. After removal of the solvents under vacuum, the residue was chromatographed on silicagel with hexane/ethyl acetate 3/2 and the main product isolated .

Step 2: 2-butyl-4,7-diethoxyimidazo[4.5-d]pyridazine:

The 1-benzyl-2-butyl-4,7-diethoxyimidazo[4,5-d]pyridazine (350 mg, 1 mmol) was suspended in ammonia and sodium was added by portions until persistence of blue color. Ammonium chloride and ammonia evaporated. The reaction mixture was partitioned between dichloromethane and water, the organic phase collected, dried (potassium carbonate) and

concentrated. The resulting product (250 mg) was used in the next step without further purification.

Step 3: 2-butyl-1-{2'-[1H-tetrazol-5-yl)-[1,1'-biphenyl]- 4-yl]methyl}-1H-imidazo[4.5-d]pyridazine-4.7-diethoxy:

An aliquot of 250 mg of the 2-butyl-4,7-diethoxyimidazo[4,5-d]pyridazine (mw 264; 0.9 mmol) was dissolved in 5 mL dry dimethylformamide. Potassium t-butoxide (0.8 mL; IM solution) was added and the solution stirred at 25ºC for 15 minutes. An equimolar amount of (N-triphenylmethyl-5-[2(4'-bromomethyl-biphenyl)]tetrazole (891 mg; MW 557; purity 70%) was added at 0°C and the resulting solution was stirred at 25°C for 13h and at 40°C for 96h. After removal of the solvents under vacuum and aqueous work-up, the residue was chromatographed on silicagel with hexane/ethyl acetate 9/1 and the main product isolated (120 mg). This material was dissolved in 90% acetic acid and stirred for 24h at 25°C. The acetic acid was removed under vacuum and the resulting glassy residue stirred in 50 mL hexane for 3 days. The hexane was decanted and the solid purified by SiO₂ chromatography eluted with dichloromethane (95)/ethanol (5) and

dichloromethane (95) /ethanol (4.9)/acetic acid (0.1). The sharp peak was collected and the solvent evaporated under reduced pressure. The colorless oil was stirred four days in hexane and solidified. The compound collected (66 mg) was identified by NMR and MS .

Elemental Analysis (calcd C₂₇H₃₀N₈O₂, found): C, 65.04, 64.32; H, 6.06, 6.01; N, 22.47, 21.25. EXAMPLE #6

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4.5-d ] pyridazine

Step 1: Preparation of 2-butyl-1-[2'-(N-triohenylmethyl- 1H-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]-4-(1- oxobutyl)-5-methoxy carbonyl-1H-imidazole.

The diester 2-butyl-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl] 4,5-bis

methoxycarbonyl-1H-imidazole (7.5 g, 10.3 mL) was dissolved in toluene, cooled to 0°C, and then a runny gel consisting of a mixture of propylmagnesium chloride (10 mL of 2 M solution in ether 20.6 mmol) and triethylamine (61.9 mmol, 8.63 mL) at 0°C was added dropwise in 4 mL increments every 5 minutes until it had been used up. The reaction mixture was stirred at ~0°C under argon for 1 1/2h and a 4N HCl was added. The residue was concentrated in vacuo. The residue was extracted from H₂O with EtOAc, the combined EtOAc layers dried and evaporated to give 7.66 g of a

yellow/orange glass (10% yield). This crude material was purified on a chromatography column of silica gel eluted with a mixture of hexane/ethylacetate (4v/iv). The fastest eluting product (~ 1 g) was discarded. The desired material eluted next and was isolated as a white solid

(1 g). The positional isomer at positions 4,5(2-butyl-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5-(1-oxo-butyl)-4-methoxy carbonyl-1H-imidazole), was eluted next and isolated as a white solid

(2.63 g). Step 2; Preparation of 2-butyl-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl) [ 1 , 1 ' -biphenyl] -4-yl]methyl ] -4-propyl-7 -hydroxy-1H-imidazo[4,5-d]pyridazine.

The ketoester 2-butyl-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(1-oxo-butyl)- 5-methoxycarbonyl-1H-imidazole prepared in step 1 (1 g, 1.37 mmol) and hydrazine (1.5 mmol, 48 uL) were refluxed in 125 mL chloroforme overnight. Two more equivalents of hydrazine were added and the mixture refluxed for 24h. The reaction mixture was concentrated in vacuo to a white solid which was used in the following deprotection step without more purification.

Step 3: Preparation of 2-butyl-1-[2'-(1H-tetrazol-5- yl)[1,1'-hiphenyl]-4-yl]methyl]-4-propyl-5-hydroxy-1H- imidazo[4.5-d]pyridazine.

The protected pyridazine, 2-butyl-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]-4-propyl-5-hydroxy-1H-imidazo[4,5-d]pyridazine, obtained in step 2 was dissolved in a solution of acetic acid (90%) in H₂O (10%) and stirred for 4 days at room temperature. The solvent was removed and the residue was dried in vacuo. The residue was dissolved in water made basic with NaOH, filtered (difficult), the filtrate acidified, the precipitate collected and rinsed with hexane. The precipitate was then rinsed with ether which dissolved all of it but a gummy yellow oil. Hexane were added which caused the cooled filtrate to give a

precipitate which was collected and air dired. (mp 160170°C with decomp.): !H NMR (DMSO-d6) d 7.6 (m, 4H), 7.1 (m, 4H), 5.85(s, 2H), 2.81(t, 2H, J = 7H), 2.75(t, 2H, J =

7Hz), 1.8 (m, 2H), 1.6 (m, 2H), 1.3 (m, 3H), 0.95(t, 3H, J = 7Hz), 0.85(t, 3H, 7Hz): HRMS (Calcd. M+H⁺ for C₂₆H₂₈N₈O₁, observed): 469.2464, 469.2457.

EXAMPLE #7

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-7-propyl-4-hydroxy-1H-imidazo[4,5-d]pyridazine

A solution of 0.25 g of 2-butyl-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5-(1-oxo-butyl)-4-methoxy carbonyl-1H-imidazole obtained in Example 6, step 1, in toluene was refluxed overnight in the presence of an excess hydrazine. The reaction mixture was concentrated in vacuo and the

resulting intermediate imine (260 mg, 0.35 mmol) was refluxed for 16 h in methanol in which 8 mg of sodium (0.35 mmol) had been dissolved. The solvents were removed in vacuo and the residue was dissolved in water.

Hydrochloric acid was added to achieve a pH value of 3. The resultant off-white precipitate was collected by filtration and rinsed with 20 mL cold methanol. After drying, the off-white solid had an mp 259.2-259.3°C: ¹H NMR (DMSO-d6) ∂ 12.5 (s, 1H), 7.5-7.75 (m, 4H), 7.0 (m, 4H), 5.6(s, 2H), 2.8(t, 2H, J = 7Hz), 2.65(t, 2H, J = 7Hz);

1.7 (m, 2H); 1.55 (m, 2H); 1.35 (m, 2H, J = 7Hz); 0.9(t, 3H), 0.8(t, 3H, J = 7Hz): HRMS (Calcd. M+H⁺ for C₂₆H₂₈N₂O observed) 469.2464, 469.2425. EXAMPLE #8

2-butyl-1- [2 ' - (1H-tetrazol-5-yl) [1 , 1 ' -biphenyl ] -4- yl] methyl] -7-hydroxy-1H-imidazo [4 , 5-d]pyridazine

Step 1 : Preparation of 2-butyl-4-hydroxymethyl-5-methoxycarbonyl-imidazole.

The diester (24 g, 0.1 mol) was dissolved in 700 mL THF, cooled to -0°C, and superhydride (300 mL; 0.3 mol) was added over lh. After stirring for 2.5h a TLC showed no starting material. The reaction was quenched with 50 mL of 4M HCl and the mixture stirred for lh. The solvent was basified with 50% w/v NaOH and NaHCO₃. The reaction mixture was concentrated, silica gel (50 g) was added, the mixture taken up in EtOAc, concentrated, and left to mix and dry on the rotovap overnight. A bed of silica gel (200 g) was prepared on a large fritted filter, the free-flowing silica gel/product residue layered on top and the SiO₂ cake rinsed with 1000 mL EtOAc, and then 1000 mL MeOH. The EtOAc layer was condensed to give 4.55 g of an orange oil. The MeOH layer was condensed to give 37.2 g of an orange oil which was purified by silica gel chromatography (using a Waters Prep 500 system) with ethylacetate:hexane as solvent. The fractions containing the product were combined and concentrated to give ~ 14.0 g of a yellow glass.

Step 2: Preparation of 2-butyl-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl_[1,1'-biphenyl-4-yl]methyl]-4-hydroxymethyl-5-methoxycarbonyl-1H-imidazole.

The alcohol/ester (8.25 g, 0.039 mol) from step 1 was suspended in acetonitrile (300 mL) along with Cs₂CO₃ (12.7 g; 0.039 mol). After stirring 45 minutes, 39 mmol (27.2 g, 80%) N-triphenylmethyl-5-[2-(4'-bromomethylbiphen-2-yl)tetrazole were added and the reaction mixture stirred at room temperature overnight. TLC indicated that the

reaction was mostly complete. The mixture was filtered and the filtrate concentrated to give a quantitative yield of the alkylated imidazole as a 70:30 mixture of the desired 4-hydroxymethylimidazole and its positional isoner, the 7-hydroxymethylimidazole. This mixture was used as such in the subsequent oxidation step.

Step 3; Preparation of 2-butyl-1-[2'(N-triphenylmethyl-1H- tetrazol-5-yl)[1.1'-biphenyl]-4-yl]methyl]-4-carboxaldehyde-5-methoxycarbonyl-1H-imidazole.

The alcohol/ester 2-butyl-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)[1,1'-biphenyl-4-yl]methyl]-4-hydroxymethyl-5-methoxycarbonyl-1H-imidazole (52 g) was dissolved in AcCN, MNO₂ (52 g) was added and the reaction mixture stirred for 2h. Another portion (52 g) of MNO₂ was added and the reaction mixture was stirred for another 3h. The reaction mixture was then filtered through a bed of sand and celite. Four fractions were collected: the

acetonitrile from the reaction mixture, 800 mL EtOAc, and two times 800 mL of methanol. The fractions were spotted on a TLC plate and eluted with ethylacetate/hexane. The first two fractions contained mostly desired material, the last two fractions contained mostly starting material (combined gave 3 g of starting material). The first two fractions were combined and concentrated to give 50.3 g of an orange paste. A first fraction of the product was precipitated from which was collected by filtration (16.98 g, off-white powder). The filtrate was purified by chromatography using a Waters Prep 500 system (silica gel, 25% EtOAc in hexane). Further recrystallization from acetone/water gave about 5 g of the desired product as a peach colored product. The remaining material (~ 20 g) from the first chromatography was repurified by

chromatography on silca gel (eluant EtOAc:hexane/25: 75). The appropriate fractions were combined to give 10 g of an off white solid. The total recovery in the desired aldehyde was 32 g.

Step 4; Preparation of 2-butyl-1-[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-yl]methyl]-7-hydroxy-1H-imidazo[4,5- d]pyridazine.

The aldehyde-ester (17 g; 0.025 mol) was suspended in 500 mL isopropanol, hydrazine (0.076 mol, 2.4 mL) was added, and the reaction mixture stirred at 75°C overnight. The solvent was removed and the residue stirred in acetic acid/10% H₂O for 1 1/2 days. The acetic acid was removed, the residue triturated in ether to give ~ 11.9 g of a fluffy white to light yellow solid. Analytical HPLC showed it to be 85% desired material, so it was reprecipitated from a filtered, basic solvent of the material with HCl aq. Analytical HPLC showed it to be 88.5% pure. An attempt was made to crystallize the material from MeOH/ethylether at 0°C overnight. No crystals formed so the solvent was removed. The reaction was repeated on 7.15 g (11 mmol) of starting aldehyde and treated as above. All crude material was purified by reverse phase HPLC in 1-2 g batches (ACN: H₂O as solvent; Delta Pak Column; 15 m; lOOA) . The fractions were analyzed by analytical HPLC, the appropriate fractions combined and reprecipitated from basic medium (aqueous sodium hydroxyde) with HCl The precipitate was collected and dried to give ~ 6.8 g of a white solid (mp 169-171°C): ¹HNMR (DMSO-d6) ∂ 12.4(s, 1H) ; 8.35(s, 1H) ; 7.6 (m, 4H), 7.08(m, 4H) ; 5.73(s, 2H) , 2.71(t, 2H, J = 7Hz) , 1.58 (m, 2H), 1.3 (m, 2H) , 0.81 (t, 3H, J = 7Hz) ; HRMS

(C₂₃H₂₂N₈O₁) Calcd. 427.1995 Obs. 427,1949;

Elemental Analysis: Calcd: C, 64.77; H, 5.20; N, 26.27

Found: C, 64.55; H, 5.48; N, 25.65

EXAMPLE #9

2-butyl -1-[2 ' (1H-tetrazol-5-yl) [1 , 1 ' -biphenyl] -4 - yl] methyl ] -4-hydroxy-1H-imi dazo[4 , 5-d] pyridazine

Step 1: Preparation of 2-butyl-4(5)-carboxaldehyde-(5)4- carbomethoxy-imidazole.

The diester (20 g, 83 mmol) and the NaH (100 mmol, 2.4 g) were suspended in THF (600 mL) and heated to a gentle boil. The solution was then cooled to room

temperature and then to -78°C. Diisobutylaluminum hydride (DIBAL) (100 mL, IM in CH₂CI₂, 100 mmol) was added over 30 min. with stirring under N₂. TLC after 1.5 h showed the starting mixture still present so another 0.5 eq. of DIBAL was added over ~ 20 min. TLC after ~1h showed that some starting mixture was still present but the reaction was quenched by the addition of 40 mL propionic acid and 30 mL H₂O. The solvent was removed and the residue suspended in EtOAc but attempts to filter this solvent were unsuccessful (tried coarse fritted glass funnels and celite). So water was added, acidified to pH ~ 3, extracted with much difficulty (emulsions greatly slowed separation) with CHCI₃ (2X) and the combined CHCI₃ layers dried (MgSO₄) and concentrated to give 22.89 g of a yellowish solid (132%). The aqueous phase was basified to pH ~ 8 with NaHCO₃ and extracted with EtOAc. This EtOAc layer combined with EtOAc layer from extraction of pre-basified solvent, dried

(MgSO₄), and concentrated to give 3.15 g of a yellow oil. The combined solids were suspended in hot EtOAc and a white insoluble material collected via filtration (slow) to give 13.3 g of a granular white solid which was discarded. The filtrate was condensed to give 14.5 g of an oil which TLC showed to contain three major products. This sample was dissolved in EtOAc and run through the prep 500 (SiO2, hexane: EtOAc 12:1). The faster migrating product was collected and isolated as a white solid (6.17 g, 30% yield from diester). Step 2: Preparation of 2-butyl-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5-carboxaldehyde-4-methoxycarbonyl-1H-imidazole.

The aldehyde prepared in step 1 (2 g, 9.5 mmol) and K₂CO₃ (1.5 g, 14.3 mmol, 1.97 g) were heated at 70°C in

AcCN and N-triphenylmethyl-5-[2-(4'-bromomethyl)biphenyl-2-yl]tetrazole (6.5 g, 10.5 mmol, 90%) was added. The reaction mixture was refluxed at ~94°C overnight. TLC showed reaction complete. The solvent was removed and the residue extracted from water with EtOAc (5X), the organic layers dried (MgSO₄) and evaporated to give 7.56 g of a brown glass. The products were separated and purified on a gravity column using SiO₂ and 1 EtOAc/1 hexane as the eluent. The slower migrating product was the desired compound (isolated as a white solid after removal of the solvent; 1.32 g) while the faster migrating product was its positional isomer, (2-butyl-1-[2'(N-triphenylmethyl-1H- tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-carboxaldehyde-5-methoxycarbonyl-1H-imidazole, isolated as a white foam, 3.76 g. Step 3; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-hvdroxy-1H-imidazo14.5-d]pyridazine.

The aldehyde/ester 2-butyl-1-[2'-(N-triphenylmethyl- 1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5- carboxaldehyde-4-methoxycarbonyl-1H-imidazole (0.5 g, 0.74 mmol) obtained in step 2 was suspended in isopropanol (20 mL) and hydrazine (2.2 mmol, 71 mg) was added. The reaction mixture was heated to 75°C (went clear) and left overnight, under nitrogen. The reaction mixture was concentrated and the residue suspended in acidic acid (10% H₂O) and stirred over the weekend. The solvent was removed. A sample of 100 mg of the residue was

chromatographied on C₁₈ reverse phase silica gel (Delta Pak; 15m; 100A ; eluent 70% H₂O/30% AcCN) using a Waters

4000 pumping system. The product was isolated as a tan solid: ¹HNMR (DMSO) ∂ 12.3(s, 1H), 8.4(s, 1H), 7.65- 7.78 (m, 4H), 7.05 (s, 4H) , 5.55 (s, 2H) , 2.75 (t, 2H, J = 7Hz), 1.62 (m, 2H), 1.3 (m, 2H), 0.83 (t, 3H, J. = 7Hz), HRMS (calcd. for M+H⁺ C₂₃H₂₂N₈O₁; observed): 427.1995;

427.1974.

EXAMPLE #10

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-1H-imidazo[4,5-d]pyridazine

Step 1: Preparation of 2-butyl-1-[2'-(N-triphenylmethyl-1H-tetrasol-5-yl)[1,1'biphepyl]-4-yl]methyl]-4,7-bis-carboxaldehyde-1H-imidazole.

The 2-butyl-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis-hydroxymethyl-1H- imidazole (100 mg) was dissolved in AcCN and 150 mg MnO2 was added. After 2 1/2 h, another 150 mg was added, and after another 2h a TLC was run which showed that some desired material was propably present. The room

temperature was filtered through a filter using EtOAc and MeOH. TLC of the AcCN, EtOAc, MeOH fractions showed most of the material in the AcCN layer so it was concentrated and an NMR taken which showed a mixture of ~ 70%

monoaldehyde + 30% dialdehyde. The material was

redissolved in ~ 8 mL AcCN and 200 mg of MnO2 were added and the reaction mixture left overnight. TLC still showed some starting material so another 200 mg of MnO₂ were added and the reaction mixture stirred another day. TLC showed reaction complete so it was filtered using AcCN as eluent. TLC of the filtrate showed one compound. The filtrate was concentrated to 100 mg of a clear glass which was used as such in the next step. Step 2: Preparation of 2-butyl-1-[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo,4.5- d]pyridazine.

The 2-butyl-1-[2'-(N-triphenylmethyl-1H-tetrazol-5- yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis-carboxaldehyde-1H- imidazole (100 mg, 0.15 mmol) was refluxed in 3 mL

isopropanol with 14 uL (0.45 mmol) of hydrazine for one day. Reaction was stopped when TLC indicated disappearance of starting material. The solvent was removed in vacuo and the material was subjected to HPLC on SiO2 using 5% isopropanol in CH₂CI₂ + 3% AcOH TLC of fractions showed poor separation. The fractions, except for the first few which contained fast eluting material, were combined and concentrated. NMR showed that they contained mostly undesired materials. The column was further eluted with

~ 15% isopropanol in dichloromethane + 3% AcOH and one major compound eluted, the appropriate fractions were combined and concentrated to give 10 mg of white solid (mp 195.5-200°C): ¹HNMR (CHCI3) d 9.35(s, 1H), 9.14(s, 1H); 7.95 (m, 1H) 7.43 (m, 2H), 7.30 (d, 1H, J = 8Hz), 6.95(m, 4H), 5.4 (s, 2H), 2.95 (t, 2H, J = 7Hz) , 1.85 (m, 2H), 1.45 (m, 2H), 0.95(t, 3H, J = 7Hz): HRMS (M+H⁺ Calcd. for C₂₃H₂₂N₈, obs.) 411.2046; 411.2022. EXAMPLE #11

2-butyl-1-[2'-(1H-tetrazol-5-yl)[[1.1'-biphenyl]-4-yl]methyl]-4-pentanoyloxy-7-hydroxy-1H-imidazo[4,5-dipyridazine A solution of 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-4,7-bis-hydroxy-1H-imidazo[4,5-d]pyridazine (0.5 g, 1.1 mmol) and pyridine (1.0 mL, 11.3 equivalents) in 5 mL DMF was stirred at 25°C and valeroyl chloride (1.77 mL, 14.7 equivalents) was slowly added. The reaction was monitered by HPLC. The reaction mixture was diluted with water, then extracted with ethyl acetate. The ethyl acetate was dried over MgSO4 and concentrated in vacuo to yield a solid. This crude product was dissolved in 25 mL acetone and 25 mL water was added. It was purified by RPHPLC using water/acetonitrile as the eluant. The product was extracted from the acetonitrile/water mixture using ethyl acetate. It was concentrated to an oil in vacuo then dissolved in acetone and concentrated in vacuo to give 100 mg (17.8% yield) of a white solid: ¹H NMR (CDCI3) δ 7.95(d, 2H, J = 9Hz,), 7.58-7.45(m, 4H) , 7.35(d, 2H, J =

9Hz,), 5.85(s, 2H), 2.84 (t, 2H, J = 7Hz,), 2.68 (t, 2H, J = 7Hz,), 1.76-1.56 (m, 4H) , 1.48-1.27 (m, 4H), 0.99-0.78 (m, 6H); MS (Calc'd for C₂₈H₃₀N₈O₃ obs,.) M+H = 527, M+Na 549.

EXAMPLE #12

2-butyl-1- [2 '- (1H-tetrazol-5-yl) [1 , 1 ' -biphenyl1 -4-yl]methyl] -4- (2-methyl-propanoyloxy) -7-hydroxy-1H-imidazo[4,5-d]pyridazine

A solution of 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-4,7-bis-hydroxy-1H-imidazo[4,5-d]pyridazine (0.5 g, 1.1 mmol) and triethylamine (0.23 mL,

1.5 equivalents) in 5 mL DMF was stirred at 25°C and isobutyryl chloride (0.18 mL, 1.5 equivalents) was added. The reaction was monitored by TLC. The reaction mixture was poured into 50 mL of 0.5N HCl, then extracted with ethyl acetate. The ethyl acetate was dried over MgSO4 and concentrated in vacuo to a small volume. The residue precipitated using hexane to yield 150 mg of a white solid. This crude material was dissolved in 25 mL acetone, then diluted with 25 mL water and purified by RPHPLC using water/acetonitrile as the eluant. The product was

lyophilized to give 25 mg (4.4% yield) of a white solid.

(mp 131.5-133°C): ¹HNMR (DMSO-d6) 67.70-7.50 (m, 4H) , 7.20- 7.06 (m, 4H), 5.76 (s, 2H), 3.01-2.94 (m, 1H), 2.74 (m, 2H), 1.60-1.49 (m, 2H), 1.34-1.22 (m, 8H), 0.87-0.77 (m, 3H).

EXAMPLE #13

2-butyl-1- [2 ' - (1H-tet razol-5_-yl ) [1, 1 ' -biphenyl 1 -4-yl] methyl] -4-cyclohexanecarbonyloxy-7-hydroxy-1H-imidazo [4,5-d]pyridazine

A solution of 2-buty1-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-4,7-bis-hydroxy-1H-imidazo[4,5-d]pyridazine (0.5 g, 1.1 mmol) and triethylamine (0.23 mL, 1.5

equivalents) in 5 mL DMF was stirred at 25°C and

cyclohexanecarbonylchloride (0.23 mL, 1.5 equivalents) was added. The reaction was monitered by TLC. The reaction mixture was poured into 50 mL of 0.5 N HCl, then extracted with ethyl acetate. The ethyl acetate was dried over MgSO4 and concentrated in vacuo to a small volume. The residue was precipitated using hexane to give 320 mg (52.7% yield) of a white solid (mp 140-144°C): ¹H NMR (DMSO-d6) δ 7.70-7.44 (m, 4H), 7.18-7.03 (m, 4H) , 5.72 (s, 2H) , 2.80-2.66 (m,

3H), 1.87-1.49 (m, 8H), 1.47-1.15 (m, 6H), 0.88-O.75 (m, 3H). EXAMPLE #14

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-7-(2.2-dimethylpropanoyloxy)-4-hydroxy-1H- imidazo[4,5-d]pyridazine A solution of 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-4,7-bis-hydroxy-1H-imidazo[4,5-d]pyridazine (0.10 g, 0.23 mmol) and triethylamine (0.5 mL, 15.6 equivalents) in 2 mL DMF was stirred at 25°C and pivaloyl chloride (0.19 mL, 6.5 equivalents) was added. The reaction was monitored by TLC. The reaction mixture was poured into 50 mL of 0.5N HCl, then extracted with ethyl acetate. The ethyl acetate was dried over MgSO₄ and concentracted in vacuo to an oil. This crude material was dissolved in 10 mL acetone, then diluted with 10 mL water and purified by RPHPLC using water/acetonitrile as the eluant. The product was lyophilized to give 5.4 mg (4.5% yield) of a white solid: ¹H NMR (DMSO-d6) δ 87.72-7.53 (m, 3H), 7.49(m, Hz, 1H), 7.12 (m, 2H), 6.91(m, 2H), 5.46 (s, 2H), 2.73 (t, 2H, J = 7Hz), 1.68-1.55 (m, 2H) , 1.34-1.23 (m, 2H), 1.12(s, 9H), 0.93(t, 3H, J= 7Hz); MS. Calc'd for M+H: 527.3. M + Na: 549.2. EXAMPLE #15

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(2.2-dimethylpropanoyloxy)-7-hydroxv-1H-imidazo[4,5-d]pyridazine This product was obtained from the reaction mixture in example 13 using the same procedures. The fractions containing a product slower to elute were pooled and 6.8 mg (5.7% yield) of the product was recovered as a white powder: ¹HNMR (DMSO-d6) δ 7.71-7.53 (m, 4H), 7.16(m, 2H), 7.09 (m, 2H), 5.76 (s, 2H), 2.75-2.69 (m, 2H) , 1.64-1.53 (m, 2H), 1.38(s, 9H), 0.84(t, 3H, J= 7Hz,); MS. Calc'd for M+H: 527.3. M+Na: 549.3.

EXAMPLE #16

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis-(2,2-dimethylpropanpyloxy)-1H-imidazo[4.5-d]pyridazine This product was obtained from the reaction mixture in example 13 using the same procedures. The fractions containing the slowest product -to elute were pooled and 7.2 mg (5.1% yield) of the product was recovered as a white powder: ¹HNMR (DMSO-d6) δ 7.73-7.48 (m, 4H), 7.10(m, 2H), 6.92(m, 2H), 5.48(s, 2H) , 2.73(t, 2H, J = 7Hz), 1.68- 1.55 (m, 2H), 1.38-1.28 (m, 2H), 1.13 (s, 9H), 1.11 (s, 9H), 0.83 (t, 3H, J = 7Hz); MS. Calc'd for M+H: 611. EXAMPLE #17

2-butyl-1-[2 ' - (1H-tetrazol-5-yl ) [1, 1 ' -biphenyl] -4-yl]methyl] -4-phenylacetylchloride-7-hydroxy-1H-imidazo [4. 5- d]pyridazine A solution of 2-butyl-1-[2'(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]4,7-bis-hydroxy-1H-imidazo[4,5-d]pyridazine (0.5 g, 1.1 mmol) and triethylamine (0.31 mL, 2 equivalents) in 10 mL DMF was stirred at 25°C and 1.5 equivalent of phenylacetylchloride (0.25 g) were added. The reaction was stirred for lh at 25°C. The reaction mixture was quenched with HCl IN and extracted with ethyl acetate. The organic phase was dried on MgSO4 and

concentrated in vacuo. The crude reaction mixture was purified by reverse phase chromatography (using a Waters Delta Prep System) to obtain an homogeneous yellow oil which was recrystallized from hexane/ethyl acetate to obtain 200 mg of yellow crystaline solid (mp 145-47°C): ¹HNMR (CDCI₃): δ 11.0 (bs, 1H), 7.9 (m, 2H), 7.2-7.4 (bm, 8H), 7.0 (m, 3H), 5.6(s, 2H) , 4.0 (s, 2H) , 2.65 (m, 2H) , 1.65 (m, 2H), 1.25 (m, 2H), 0.8 (t, 3H, J = 7Hz); MS: (M+H⁺) 561; Elemental Analysis Calc'd: C, 66.4; H, 5.03; N, 19.98 Found: C, 66.0; H. 4.89; N, 19.80

EXAMPLE #18

2-butyl-1- [2 ' - (1H-tetrazol-5-yl) [1 , 1 ' -biphenyl 1 -4-yl]methyl]-4,7-diacetyl-1H-imidazo[4 ,5-d]pyridazine

A solution of 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-4,7-bis-hydroxy-1H-imidazo[4,5-d]pyridazine

(1.0 g, 2.2 mmol) in 50 mL acetyl chloride was achieved by refluxing the suspension overnight. The excess acetyl chloride was removed in vacuo, yielding an oil, which was triturated with ethyl ether. The resulting solid was filtered, dissolved in 10 mL acetone, then treated with 10 mL 0.25M sodium bicarbonate. After stirring overnight, the solution was adjusted to pH 4.0 with concentrated HCl. The mixture was extracted with ethyl acetate, the ethyl acetate dried over MgSO₄, then concentrated in vacuo to give 640 mg

(55.3% yield) of a white solid: ¹H NMR (DMSO-d6) δ 7.65 (d, 2H, J = 3HZ), 7.6-7.48 (m, 2H) , 7.2-7.05 (m, 4H), 5.74 (s, 2H), 2.78-2.64 (m, 2H) , 2.38 (s, 3H) , 2.35 (s, 3H), 1.62-1.46 (m, 2H), 1.34-1.21 (m, 2H) , 0.88-O.78(t, 3H, = 7Hz,); MS. Found for M+H: 559 BIOLOGICAL EVALUATION

Assay A: Angiotensin II Binding Activity

Compounds of the invention 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. 1²⁵I-angiotensin II (specific activity of 2200 Ci/mmol) was purchased from Du Pont-New England Nuclear. Other chemicals were obtained from Sigma Chemical Co. This assay was carried out according to the method of Douglas et al

[Endocrinology, 106, 120-124 (1980)]. Rat uterine membranes were prepared from fresh tissue. All procedures were carried out at 4°C. Uteri were stripped of fat and

homogenized in phosphate-buffered saline at pH 7.4

containing 5 mM EDTA. The homogenate was centrifuged at 1500 × g for 20 min., and the supernatant was recentrifuged at 100,000 × g for 60 min. The pellet was resuspended in buffer consisting of 2 mM EGTA 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 AII antagonist which gives 50% displacement of the total specifically bound ¹²⁵I-AII from the high affinity ("Type 1") AII receptor. Binding data were analyzed by a non-linear least-squares curve fitting program. Results are reported in Table I.

Assay B: In Vitro Vascular Smooth Muscle-Response for AII

The compounds of the invention 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 FTO3 Grass transducer coupled to a Model 8 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 AII Aorta rings were exposed to the test antagonist at 10^-5 M for 5 minutes before

challenging with AII. Adjacent segments of the same aorta ring were used for all concentration-response curves in the presence or absence of the test antagonist. The

effectiveness of the test compound was expressed in terms of pA₂ values and were calculated according to H.O. Schild [Br. J. Pharmacol. Chemother., 2,189-206 (1947)]. The pA₂ value is the concentration of the antagonist which increases the EC50 value for All by a factor of 2. Each test antagonist was evaluated in aorta rings from two rabbits. Results are reported in Table I. Assay C: In Vivo Intraduodenal Pressor Assay Response for All Antagonists

Male Sprague-Dawley rats weighing 225-300 grams were anesthetized with Inactin (100 mg/kg, i.p.) and catheters were implanted into the trachea, femoral artery, femoral vein and duodenum. Arterial pressure was recorded from the femoral artery catheter on a Gould chart recorder (Gould, Cleveland, OH). The femoral vein catheter was used for injections of angiotensin II, mecamylamine and

atropine. The tracheal catheter allow for airway patency, and the duodenal catheter was used for intraduodenal (i.d.) administration of test compounds. After surgery, the rats were allowed to equilibrate for 30 minutes. Mecamylamine (3 mg/kg, 0.3 ml/kg) and atropine (400 ug/kg, 0.3 ml/kg) were then given i.v. to produce ganglion blockade. These compounds were administered every 90 minutes throughout the test procedure. Angiotensin II was given in bolus does i.v. (30 ng/kg in saline with 0.5% bovine serum albumin, 0.1 ml/kg) every 10 minutes three times or until the increase in arterial pressure produced was within 3 mmHg for two consecutive AII injections. The last two AII injections were averaged and were taken as the control AII pressor response. Ten minutes after the final control AII injection, the test compound (dissolved in sodium

bicarbonate) was administered i.d. at a dose of 3, 10, 30 or 100 mg/kg in a volume of 0.2 ml. Angiotensin II

injections were then given 5, 10, 20, 30, 45, 60, 75, 90, and 120 minutes after administration of the test compound and response of arterial pressure was monitored. The response to All was calculated as percent of the control response and then the percent inhibition is calculated as 100 minus the percent control response. Duration of action of a test compound was defined as the time from peak percent inhibition to 50% of peak. One compound at one dose was tested in each rat. Each test compound was tested in two rats and the values for the two rats were averaged. Results are reported in Table I. Assay D: In Vivo Intragastric Pressor Assay Response for

All Antagonists

Male Sprague-Dawley rats weighing 225-300 grams were anesthetized with methohexital (30 mg/kg, i.p.) and catheters were implanted into the femoral artery and vein. The catheters were tunneled subcutaneously to exit

dorsally, posterior to the head and between the scapulae. The catheters were filled with heparin (1000 units/ml of saline). The rats were returned to their cage and allowed regular rat chow and water ad libitum. After full recovery from surgery (3-4 days), rats were placed in Lucite holders and the arterial line was connected to a pressure

transducer. Arterial pressure was recorded on a Gould polygraph (mmHg). After 1-2 hours of stable baseline recording, the intravenous infusion of angiotensin II (50 ng/kg/min) was given at a rate of 0.0096 ml/min. After allowing one hour for pressure to stabilize, the test compound (suspended in 0.5% methylcellulose in water) was administered by gavage. The volume administered was 2 ml/kg body weight. Arterial pressure was monitored for 5 hours post-dosing. The angiotensin II infusion was then discontinued and pressure was allowed to reach a stable recovery level. Percent inhibition (%I) of the angiotensin II pressor response was calculated from the difference in pressure at a given timepoint post-dosing with the test compound and the angiotensin Il-infused pressure, divided by the difference in pressure with and without the

angiotensin II infusion; this value was multiplied by 100. Duration of action of a test compound was defined as the time taken for pressure to return to angiotensin Il-infused baseline levels after compound administration. A compound at one dose was tested in two rats. Results are reported in Table I. TABLE I

In Vivo and In Vitro Angiotensin II Activity of Compounds of the Invention

Test ¹Assay A ²Assay B ³Assays C and D

Compound IC₅₀ PA₂ Dose Inhibition Duration

Example # (nM) (mg/kg) (%) (min.)

I 720 5.3 100* 45 90 2 250 7.3 30* 50 30

3 590 6.4 NT NT

4 45 9.0 30* 87 160

5 2000 5.2 NT NT

6 12 8.4 10 60 180 7 400 6.4 NT

8 11 8.2 3 40 >240

9 230 6.5 NT

10 170 6.5 NT

II 37 9.21/9.17 10* 70 120 12 16 9.21/9.00 3 20 60

13 25 9.05/8.77 10 80 240

14 46 NT NT

15 46 NT NT

16 50 NT NT

17 40 9.42/9.12 3 45 >180 18 40 9.25/8.80 3 35 >240

¹Assay A: Angiotensin II Binding Activity

2Assay B: In Vitro Vascular Smooth Muscle Response 3Assays C and D. In Vivo Pressor Response (all test

compounds administered intragastrically, except for compounds where dose is indicated by asterisk, which compounds were given

intraduodenally). Assay E: In Vivo Intravenous Pressor Assay Response for All Antagonists

In accordance generally with the procedures as set forth in Assay C, above, rats were anesthetized with Inactin (100 mg/kg i.p.) and ganglion blocked intravenously (i.v.) with mecamylamine (3 mg/kg) and atropine

(0.4 mg/kg). Angiotensin II was then infused (i.v.) at 50 ng/kg/min. After blood pressure stabilized, the test compound was administered i.v. in consecutively increasing doses to determine the dose-response relationship. An ED50 was then calculated from these data. The compound of Example #4 was administered i.v. at 0.01 mg/kg. When the blood pressure response to this dose had reached its maximum, a dose of 0.03 mg/kg was given i.v. Then doses at 0.10 and 0.30 mg/kg were given i.v. in a similar manner. Results are shown in Table II. From these data, an ED50 was calculated for each rat. A mean ED50 was calculated as 0.05 mg/kg.

Table II

In Vivo Inhibition of All Pressor Response in Anesthetized Rat by Compound Ex. #4

Dose All Pressor Inhibition

(mg/kg) % Mean SEM

0.01 20% 3%

0.04 49% 1%

0.14 71% 4%

0.44 94% 6% Also embraced within this invention is a class of pharmaceutical compositions comprising one or more compounds of Formula I in association with one or more non- toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as

"carrier" materials) and, if desired, other active

ingredients. The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.

Therapeutically effective doses of the compounds of the present invention required to prevent or arrest the progress of the medical condition are readily ascertained by one of ordinary skill in the art. The compounds and composition may, for example, be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical

composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules.

These may with advantage contain an amount of active ingredient from about 1 to 250 mg, preferably from about 25 to 150 mg. A suitable daily dose for a mammal may vary widely depending on the condition of the patient and other factors. However, a dose of from about 0.1 to 3000 mg/kg body weight, particularly from about 1 to 100 mg/kg body weight, may be appropriate.

The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable 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 os. 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 embodiments, 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 each of R¹ through R¹¹ and R³⁹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl,

cycloalkylalkoxy, alkoxyalkoxy, mercaptocarbonyl,

mercaptothiocarbonyl, alkoxycarbonyloxy, aroyloxy,

arylthiocarbonylthio, arylthiothiocarbonyl,

arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyi, aralkylcarbonylthio, aralkylthiocarbonyloxy,

aralkylthiocarbonylthio, alkylthiocarbonyl,

aralkylthiocarbonylthio, mercapto, alkylsulfinyl,

alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl,

wherein each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is

independently selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R¹² and R¹³ taken together, R¹⁴ and R¹⁵ taken together and Ri6 and R¹⁷ taken together may each form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein R¹² and R¹³ taken together and R¹⁴ and R¹⁵ 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 acidic moieties of the formula

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 Y is further selected from

alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl,

aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl,

wherein D is selected from oxygen atom, nitrogen atom and sulfur atom and R²⁴ is selected from-hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R²⁰, R²¹, R²², R²³, R²⁵ and R²⁶ is independently selected from hydrido, alkyl, cycloalkyl, cyano,

wherein each of R²⁷, R²⁸, R²⁹, R³⁰, R³¹ and R³² is

independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl,

haloalkylsulfonyl, aralkyl and aryl, and wherein R²⁰ and R²¹ taken together and R²² and R²³ taken together may each form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical, which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein R²⁰ and R²¹ taken together and R²⁵ and R²⁶ taken together may each form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

2. Compound of Claim 1 wherein m is one;

wherein each of R¹ through R¹¹ and R³⁹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, cycloalkoxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, formyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy,

alkylthiocarbonyloxy, alkylthiocarbonylthio,

alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl,

aralkylthiocarbonylthio, aralkylthiocarbonyl,

aralkylthiocarbonylthio, mercapto,

alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl,

wherein each of R¹², R¹³, R¹⁴, R15, R¹⁶ and R¹⁷ is

independently selected from acidic moieties of the formula wherein n is a number sele

cted 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; or wherein Y is one or more groups selected from

and -CH=CH-, wherein R¹⁸ is selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,

hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl,

3. Compound of Claim 2 wherein m is one;

wherein each of R¹ and R² is independently selected from hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkyloxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy,

alkoxyalkyl, alkylcarbonyl, formyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, alkylaminocarbonyloxy,

arylaminocarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, 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 each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is

independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein R³⁹ is selected from linear or branched alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, arylalkyl and

selected from hydrido, linear or branched alkyl (C₁-C₁₀), linear or branched alkenyl (C₂-C₁₀), linear or branched alkynyl (C₂-C₁₀), cycloalkyl (C₃-C₁₀). cycloalkenyl (C₃-C₁₀), cycloalkylalkyl (C4-C10)/ aryl, arylalkyl, alkylaryl, halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl, and wherein at least one of the R³ to R¹¹ substituents is a carboxylic acid radical of the formula

cycloalkenyl (C₃-C₁₀), cycloalkylalkyl (C₄-C₁₀) and

cycloalkenylalkyl (C₃-C₁₀) ; or wherein said R³ through R¹¹ substituent is a bioisostere of a free carboxylic acid having a pK_a in a range from about two to about ten, said bioisostere being selected from sulfenic acid, sulfinic acid, sulfonic acid, sulfonyl carboxamide, sulfonamides, hydroxamic acid, hydroxamate, aminotetrazole, phosphorus - containing and thiophosphorus-containing acids selected from

NH-R⁴⁶

fluoroalkylcarbonyl, fluoroarylcarbonyl and CO-R⁴¹ wherein R⁴¹ is selected from hydrido, linear or branched alkyl (C₁- C₁₀,), linear or branched alkenyl (C₂-C₁₀) , linear or branched alkynyl (C₂-C₁₀) , cycloalkyl (C₃-C₁₀), cycloalkenyl (C₃-C₁₀) , cycloalkylalkyl (C₄-C₁₀) and cycloalkenylalkyl (C₄-C₁₀) ; wherein any of the foregoing R³³ through R³⁸, R⁴⁰, R⁴¹ and R⁴⁶ substituents having a substitutable position may be substituted with one or more substituents selected from alkyl, haloalkyl, halo, nitro, cyano, aryl, arylalkyl, alkylaryl, hydroxyl, alkoxy, aryloxy, alkylthio,

alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl; or a tautomer thereof or a pharmaceuticallyacceptable salt thereof.

4. Compound of Claim 3 wherein said bioisostere of carboxylic acid is a heterocyclic group selected from

wherein each of R⁴², R⁴³ and R⁴⁴ is independently selected from H, Cl, CN, NO_2. CF₃, C₂F5, C₃F₇, CHF₂, CH₂F, CO₂CH₃, CO₂C₂H₅, SO₂CH₃ SO₂CF₃ and SO₂C₆F₅; wherein Z is selected from O, S, NR⁴⁵ and CH₂, wherein R⁴⁵ is selected from hydrido, CH₃ and CH₂C₆H₅.

5. Compound of Claim 3 wherein said bioisostere of carboxylic acid is a fused ring system including the phenyl rings of Formula I, said fused ring system selected from

6. Compound of Claim 3 wherein m is one;

wherein R¹ and R² is independently selected from hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl,

cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, mercapto,

alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl,

wherein each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is

consisting of CO₂H, CO₂CH₃, SH, CH₂SH, C₂H₄SH, PO₃H₂,

NHSO₂CF₃, NHSO₂C₆F_5, SO₃H, CONHNH₂, CONHNHSO₂CF₃, CONHOCH₃, CONHOC₂H₅, CONHCF₃, OH, CH₂OH, C₂H₄OH, OPO₃H₂, OSO₃H, NHCN₄H and

and wherein said acidic moiety may further be a

7. Compound of Claim 6 wherein m is one;

wherein each of R¹ and R² is independently selected from hydroxy, amino, aminomethyl, aminoethyl,

dimethylaminoethylamino, methyl, ethyl, n-propyl,

ethylcarbonyloxy, n-propylcarbonyloxy,

isopropylcarbonyloxy, n-butylcarbonyloxy, sec-butylcarbonyloxy, iso-butylcarbonyloxy, tert- butylcarbonyloxy, n-pentylcarbonyloxy,

cycloheptyloxy, isopropanoyloxy, benzoyloxy,

cycloalkenyl (C₃-C₁₀), cycloalkylalkyl (C₄-C₁₀) and cycloalkenylalkyl (C₃-C₁₀); wherein at least one of R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂H, SH, PO₃H₂, SO₃H, CONHNH₂,

CONHNHSO₂CF₃, OH, NHSO₂CH₃, NHSO₂CF₃, NHCOCF₃, CONHSO₂C₆,H₅, CONHOH, CONHOCH₃. CONHSO₂CH₃ ,

8. Compound of Claim 7 wherein m is one;

dimethylaminoethylamino, methyl, ethyl, n-propyl,

ethylcarbonyloxy, n-propylcarbonyloxy,

cycloheptyloxy, isopropanoyloxy, benzoyloxy,

methylaminocarbonyloxy, isopropylaminocarbonyloxy and phenylaminocarbonyloxy; wherein R³⁹ is selected from n-propyl, n-butyl, n-pentyl, propylthio and propoxy; wherein each of R³, R⁴, R⁶, R⁷, R⁸, R¹⁰ and R¹¹ is hydrido; wherein one R⁵ and R⁹ is an acidic group selected from CO₂H and tetrazole and the other of R⁵ and R⁹ is hydrido; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

9. Compound of Claim 8 selected from compounds, and their pharmaceutically-acceptable salts, of the group consisting of

4'-[(2-butyl-1H-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1'¬biphenyl]-2-carboxylic acid;

4'-[(2-methy1-1H-imidazo[4,5-d]pyridazin-1-yl-4,7-dioDmethyl][1,1'-biphenyl]-2-carboxylic acid;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diethoxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-diacetyloxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4,7-bis(methoxy-1-ethyloxy)-1H-imidazo[4,5- d]pyridazine;

2-buty1-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-pheny1-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-4-acetyloxy-7-hydroxy-1H-imidazo[4,5- d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-methyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4- . yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol;

2-neopentyl-1- [ [2 ' - (1H-tetrazol-5-yl) [1-, 1 ' -biphenyl] -4-yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-neopentyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis(methoxymethyloxy)-1H-imidazo[4,5- d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-7-propyl-4-hydroxy-1H-imidazo[4,5-d]pyridazine,

2-butyl-1-[2'(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-cyclohexanecarbonyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine;

2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(2,2-dimethylpropanoyloxy)-7-hydroxy-1H- imidazo[4,5-d]pyridazine;

10. Compound of Claim 9 which is 2-butyl-1-[2'- (1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically- acceptable salt thereof.

11. Compound of Claim 9 which is 2-butyl-1-[2'- (1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-7-hydroxy- 1H-imidazo [4, 5-d]pyridazine or a pharmaceutically- acceptable salt thereof.

12. Compound of Claim 9 which is 2-butyl-1-[2'- (1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4- pentanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.

13. Compound of Claim 9 which is 2-butyl-1-[2'- (1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(2-methylpropanoyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.

14. Compound of Claim 9 which is 2-butyl-1-[2'- (1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4- phenylacetylchloride-7-hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.

15. 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:

cycloalkylalkoxy, alkoxyalkoxy, mercaptocarbonyl,

mercaptothiocarbonyl, alkoxycarbonyloxy, aroyloxy,

alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy,.

arylthiocarbonylthio, arylthiothiocarbonyl,

aralkylthiocarbonylthio, alkylthiocarbonyl,

aralkylthiocarbonylthio, mercapto, alkylsulfinyl,

alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl,

wherein each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is

independently selected from 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;

and -CH=CH-, wherein R¹⁸ is selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbony1; and wherein any of the foregoing R¹ through R¹⁸, R³⁹, Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, halo, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy,

alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl,

aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl,

wherein X is selected from oxygen atom and sulfur atom;

wherein R¹⁹ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR²⁴ and

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

selected from hydrido, alkyl, cycloalkyl, cyano,

haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R²⁰, R²¹, R²², R²³, R²⁵ and R²⁶ is further independently selected from amino and amido radicals of the formula

wherein each of R²⁷, R²⁸, R²⁹, R³⁰, R³¹ and R³² is

16. The composition of Claim 15 wherein m is one; wherein each of R¹ through R¹¹ and R³⁹ is

independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, cycloalkoxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, formyl, alkoxycarbonyl, alkenyl,

cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro,

carboxyl, alkylcarbonyloxy, alkylaminocarbonyloxy,

arylaminocarbonyloxy, mercaptocarbonyl,

mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio,

alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl,

arylthiocarbonylthio, arylthiothiocarbonyl,

aralkylthiocarbonylthio, aralkylthiocarbonyl,

aralkylthiocarbonylthio, mercapto,

alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl,

wherein each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is

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,

wherein X is selected from oxygen atom and sulfur atom; wherein R¹⁹ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl; wherein each of R²⁰, R^21, R²² and R²³ is independently selected from hydrido, alkyl, cycloalkyl, cyano,

17. The composition of Claim 16 wherein m is one; wherein each of Ri and R² is independently selected from hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkyloxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, formyl,

alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,

alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl,

wherein each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is

independently selected from hydrido, alkyl, cycloalkyl,

aryl, monoalkylaminoalkyl, dialkylaminoalkyl,

monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl,

cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein R³⁹ is selected from linear or branched alkyl,

alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,

cycloalkenyl, cycloalkenylalkyl, arylalkyl and

alkylcycloalkylalkyl, and wherein any one of the foregoing

R³⁹ substituents having a substitutable position may be

substituted with one or more substituents selected from

alkyl, haloalkyl, halo, nitro, cyano, aryl, arylamino,

alkylamino, alkylarylamino, hydroxyl, alkoxy, aryloxy,

alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio,

selected from hydrido, linear or branched alkyl (C₁-C₁₀) ,

linear or branched alkenyl (C₂-C₁₀) , linear or branched

alkynyl (C₂-C₁₀) , cycloalkyl (C₃-C₁₀), cycloalkenyl (C₃- C₁₀), cycloalkylalkyl (C₄-C₁₀), aryl, arylalkyl, alkylaryl,

halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkylthio,

alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and

arylsulphonyl, and wherein at least one of the R³ to R¹¹

substituents is a carboxylic acid radical of the formula

wherein R³³ is selected from hydrido, linear or branched alkyl (C₁-C₁₀,), linear or branched alkenyl (C₂-C₁₀), linear or branched alkynyl (C₂-C₁₀) , cycloalkyl (C₃-C₁₀),

cycloalkenyl (C₃-C₁₀), cycloalkylalkyl (C₄-C₁₀) and

wherein W is selected from O, S and N-R⁴⁰; wherein each of R³⁴, R³⁵' R³⁶ and R⁴⁰ is independently selected from

hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyl and R³⁷-N-R³⁸, wherein R³⁷ and R³⁸ can be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl and alkanoyl; wherein said bioisostere of carboxylic acid may be further selected from heterocyclic groups containing 5 to 7 atoms of which one or more heterocyclic ring atoms are selected from oxygen and nitrogen, which heterocyclic group has an ionizable proton with a pk_a in a range from about two to about ten; 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

NH-R⁴⁶

fluoroalkylcarbonyl, fluoroarylcarbonyl and CO-R⁴¹ wherein R⁴¹ is selected from hydrido, linear or branched alkyl (C₁- C₁₀,), linear or branched alkenyl (C₂-C₁₀), linear or branched alkynyl (C₂-C₁₀) , cycloalkyl (C₃-C₁₀), cycloalkenyl (C₃-C₁₀), cycloalkylalkyl (C₄-C₁₀) and cycloalkenylalkyl

(C₃-C₁₀) / wherein any of the foregoing R³³ through R³⁸, R⁴⁰, R⁴¹ and R⁴⁶ substituents having a substitutable position may be substituted with one or more substituents selected from alkyl, haloalkyl, halo, nitro, cyano, aryl, arylalkyl, alkylaryl, hydroxyl, alkoxy, aryloxy, alkylthio,

alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl; or a tautomer thereof or a pharmaceutically- acceptable salt thereof.

18. The composition of Claim 17 wherein said bioisostere of carboxylic acid is a heterocyclic group selected from

wherein each of R⁴², R⁴³ and R⁴⁴ is independently selected from H, Cl, CN, NO₂, CF_3, C₂F₅, C₃F₇, CHF_2/ CH₂F, CO₂CH₃, CO₂C₂H₅, SO₂CH_3, SO₂CF₃ and SO₂C₆F₅; wherein Z is selected from O, S, NR⁴⁵ and CH₂, wherein R⁴⁵ is selected from hydrido, CH₃ and CH₂C₆H₅.

19. The composition of Claim 17 wherein said bioisostere of carboxylic acid is a fused ring system including the phenyl rings of Formula I, said fused ring system selected from

20. The composition of Claim 17 wherein m is one; wherein R¹ and R² is independently selected from hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl,

alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl,

wherein each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl,

consisting of CO₂H, CO₂CH₃, SH, CH₂SH, C₂H₄SH, PO₃H₂,

NHSO₂CF₃, NHSO₂C₆F_5, SO₃H, CONHNH₂, CONHNHSO₂CF₃, CONHOCH₃, CONHOC₂H_5, CONHCF₃, OH, CH₂OH, C₂H₄OH, OPO₃H₂, OSO₃H, NHCN₄H and

and wherein said acidic moiety may further be a

21. The composition of Claim 20 wherein m is one; wherein each of R¹ and R² is independently selected from hydroxy, amino, aminomethyl, aminoethyl,

dimethylaminoethyl-amino, methyl, ethyl, n-propyl,

isopropyl, n-butyl, secbutyl, isobutyl, tertbutyl, n- pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1- oxobutyl, 1-oxopentyl, hydroxyalkyl, halo, methylthio, propylthio, isopropylthio, cyclohexylthio, methoxy, ethoxy, isopropoxy, phenoxy, cyclohexyloxy, methoxymethoxy,

methoxy-1-ethyloxy, cyano, formyl, acetyloxy,

ethylcarbonyloxy, n-propylcarbonyloxy,

isopropylcarbonyloxy, n-butylcarbonyloxy, sec- butylcarbonyloxy, iso-butylcarbonyloxy, tert- butylcarbonyloxy, n-pentylcarbonyloxy,

cycloheptyloxy, isopropanoyloxy, benzoyloxy,

methylaminocarbonyloxy, isopropylaminocarbohyloxy and phenylaminocarbonyloxy; wherein R³⁹ is selected from hydrido, linear or branched alkyl (C₁-C₁₀), linear or branched alkenyl (C₂-C₁₀), linear or branched alkynyl (C₂-C₁₀), cycloalkyl (C₃-C₁₀),

cycloalkenyl (C₃-C₁₀), cycloalkylalkyl (C₄-C₁₀) and

cycloalkenylalkyl (C₄-C₁₀); wherein at least one of R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂H, SH, PO₃H₂, SO₃H, CONHNH₂,

CONHNHSO₂CF₃ , OH, NHSO₂CH₃, NHSO₂CF₃, NHCOCF₃, CONHSO₂C₆,H₅, CONHOH, CONHOCH₃, CONHSO₂CH₃,

22. The composition of Claim 21 wherein m is one; wherein each of R¹ and R² is independently selected from hydroxy, amino, aminomethyl, aminoethyl,

dimethylaminoethyl-amino, methyl, ethyl, n-propyl,

ethylcarbonyloxy, n-propylcarbonyloxy,

cycloheptyloxy, isopropanoyloxy, benzoyloxy,

23. The composition of Claim 22 wherein said antagonist compound is 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.

24. The composition of Claim 22 wherein said antagonist compound is 2-butyl-1-[2'-(-1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-7-hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.

25. The composition of Claim 22 wherein said antagonist compound is 2-butyl-1-[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-yl]methyl]-4-pentanoyloxy-7-hydroxy- 1H-imidazo[4,5-d]pyridazine or a pharmaceutically- acceptable salt thereof

26. The composition of Claim 22 wherein said antagonist compound is 2-butyl-1-[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-yl]methyl]-4-(2-methyl-propanoyloxy)- 7-hydroxy-1H-imidazo[4,5-d]pyridazine or a

pharmaceutically-acceptable salt thereof

27. The composition of Claim 22 wherein said antagonist compound is 2-butyl-1-[2'-(1H-tetrazol-5- yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenylacetylchloride-7- hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically- acceptable salt thereof

28. A therapeutic method for treating a circulatory disorder, said method comprising administering to a subject having such disorder a therapeutically- effective amount of a compound of Formula I:

cycloalkylalkoxy, alkoxyalkoxy, mercaptocarbonyl,

mercaptothiocarbonyl, alkoxycarbonyloxy, aroyloxy,

arylthiocarbonylthio, arylthiothiocarbonyl,

aralkylthiocarbonylthio, alkylthiocarbonyl,

aralkylthiocarbonylthio, mercapto, alkylsulfinyl,

alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl,

wherein each of R¹², Rⁱ³, R¹⁴, Rl⁵, R¹⁶ and R¹⁷ is

independently selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R¹² and R¹³ taken together, R¹⁴ and ^R15 taken together and R¹⁶ and R¹⁷ taken together may each form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical and which heterocyclic group may further contain one or more hetero atoms as ring members selected from oxygen, nitrogen and sulfur atoms and which heterocyclic group may be saturated or partially unsaturated; wherein R¹² and R¹³ taken

together and R¹⁴ and R¹⁵ 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 acidic moieties of the formula

and -CH=CH-, wherein R¹⁸ is selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbonyl; and wherein any of the foregoing R¹ through R¹⁸, R³⁹, Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, alkyl, halo, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy,

alkylthiocarbonyl, alkylsulfinyl, alkylsulfonyl,

aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl,

selected from hydrido, alkyl, cycloalkyl, cyano,

haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R²⁰, R²¹' R²², R²³, R²⁵ and R²⁶ is further independently selected from amino and amido radicals of the formula

wherein each of R²⁷, R²⁸, R²⁹, R³⁰, R³¹ and R³² is

29. The method of Claim 28 wherein m is one; wherein each of Ri through R¹¹ and R³⁹ is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, cycloalkoxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, formyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy,

alkylthiocarbonyloxy, alkylthiocarbonylthio,

aralkylthiocarbonylthio, aralkylthiocarbonyi,

aralkylthiocarbonylthio, mercapto,

alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl,

wherein each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is

independently selected from acidic moieties of the formula

-Y_nA

30. The method of Claim 29 wherein m is one; wherein each of R¹ and R² is independently selected from hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkyloxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy,

wherein each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is

cycloalkenyl (C₃-C₁₀), cycloalkylalkyl (C₄-C₁₀) and

cycloalkenylalkyl (C₄-C₁₀); or wherein said R³ through R¹¹ substituent is a bioisostere of a free carboxylic acid having a pK_a in a range from about two to about ten, said bioisostere being selected from sulfenic acid, sulfinic acid, sulfonic acid, sulfonyl carboxamide, sulfonamides, hydroxamic acid, hydroxamate, aminotetrazole, phosphorus-containing and thiophosphorus-containing acids selected from

NH-R⁴⁶

fluoroalkylcarbonyl, fluoroarylcarbonyl and CO-R⁴¹ wherein R⁴¹ is selected from hydrido, linear or branched alkyl (C₁-C₁₀,), linear or branched alkenyl (C₂-C₁₀), linear or branched alkynyl (C₂-C₁₀), cycloalkyl (C₃-C₁₀), cycloalkenyl (C₃-C₁₀), cycloalkylalkyl (C₄-C₁₀) and cycloalkenylalkyl (C₃-C₁₀); wherein any of the foregoing R³³ through R³⁸, R⁴⁰, R⁴¹ and R⁴⁶ substituents having a substitutable position may be substituted with one or more substituents selected from alkyl, haloalkyl, halo, nitro, cyano, aryl, arylalkyl, alkylaryl, hydroxyl, alkoxy, aryloxy, alkylthio,

31. The method of Claim 30 wherein said

bioisostere of carboxylic acid is a heterocyclic group selected from

wherein each of R⁴², R⁴³ and R⁴⁴ 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, NR₄₅ and CH₂, wherein R⁴⁵ is selected from hydrido, CH₃ and CH₂C₆H₅.

32. The method of Claim 30 wherein said bioisostere of carboxylic acid is a fused ring system including the phenyl rings of Formula I, said fused ring system selected from

33. The method of Claim 32 wherein m is one; wherein R¹ and R² is independently selected from hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl,

alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl,

wherein each of R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is

consisting of CO₂H, CO₂CH₃, SH, CH₂SH, C₂H₄SH, PO₃H₂,

NHSO₂CF₃, NHSO₂C₆F₅, SO₃H, CONHNH₂, CONHNHSO₂CF₃, CONHOCH₃, CONHOC₂H₅, CONHCF₃, OH, CH₂OH, C₂H₄OH, OPO₃H₂, OSO₃H, NHCN₄H and

and wherein said acidic moiety may further be a

34. The method of Claim 33 wherein m is one; wherein each of R¹ and R² is independently selected from hydroxy, amino, aminomethyl, aminoethyl,

dimethylaminoethyl-amino, methyl, ethyl, n-propyl,

isopropyl, n-butyl, secbutyl, isobutyl,. tertbutyl, n- pentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1- oxobutyl, 1-oxopentyl, hydroxyalkyl, halo, methylthio, propylthio, isopropylthio, cyclohexylthio, methoxy, ethoxy, isopropoxy, phenoxy, cyclohexyloxy, methoxymethoxy, methoxy-1-ethyloxy, cyano, formyl, acetyloxy,

ethylcarbonyloxy, n-propylcarbonyloxy,

isopropylcarbonyloxy, n-butylcarbonyloxy, secbutylcarbonyloxy, iso-butylcarbonyloxy, tertbutylcarbonyloxy, n-pentylcarbonyloxy,

cycloheptyloxy, isopropanoyloxy, benzoyloxy,

cycloalkenyl (C₃-C₁₀), cycloalkylalkyl (C₄-C₁₀) and

cycloalkenylalkyl (C₃-C₁₀); wherein at least one of R⁵, R⁶, R⁸ and R⁹ is an acidic group selected from CO₂H, SH, PO₃H₂, SO₃H, CONHNH₂,

35. The method of Claim 34 wherein m is one; wherein each of R¹ and R² is independently selected from hydroxy, amino, aminomethyl, aminoethyl,

dimethylaminoethyl-amino, methyl, ethyl, n-propyl,

ethylcarbonyloxy, n-propylcarbonyloxy,

cycloheptyloxy, isopropanoyloxy, benzoyloxy,

36. The method of Claim 35 wherein said compound is 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'- biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-1H-imidazo[4,5- d]pyridazine or a pharmaceutically-acceptable salt thereof

37. The method of Claim 35 wherein said compound is 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-7-hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.

38. The method of Claim 35 wherein said compound is 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-pentanoyloxy-7-hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.

39. The method of Claim 35 wherein said

compound is 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-(2-methyl-propanoyloxy)-7-hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.

40. The method of Claim 35 wherein said

compound is 2-butyl-1-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-phenylacetylchloride-7-hydroxy-1H-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.

41. The method of Claim 28 wherein said

circulatory disorder is a cardiovascular disorder.

42. The method of Claim 41 wherein said

cardiovascular disorder is hypertension.

43. The method of Claim 41 wherein said

cardiovascular disorder is congestive heart failure.