IE912042A1 - 1H-SUBSTITUTED-IMIDAZO[4,5-d]PYRIDAZINE COMPOUNDS FOR¹TREATMENT OF CARDIOVASCULAR DISORDERS - Google Patents

Abstract

The present invention relates to a process for the preparation of compounds of formula I: in which m is a number selected from one to four inclusive, and in which each of R1 to R11 and R39 is for example hydrogen. These compounds can be prepared for example by reacting a compound of formula 4 with NH2NH2, optionally followed by reaction with NOH or TFA, and are useful in the treatment of cardiovascular disorders, having particular interest as angiotensin II antagonists.

Description

Non-peptidic lH-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 10 interest are angiotensin II antagonist compounds provided by imidazo [4,5-d]pyridazine having a biphenylmethyl moiety attached to the N-l 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-l-(2-chlorobenzyl)imidazole-5 acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [P. C.

Wong et al, J, Pharmacol. Exp. Ther, . 247 (1) . 1-7 (1988) ] . Also, the sodium salt of 2-butyl-4-chloro-l- (2nitrobenzyl)imidazole-5-acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo tests [A. T. Chiu et al, European J. Pharmacol·., 157, 1321 (1988)]. A family of l-benzylimidazole-5-acetate derivatives has been shown to have competitive angiotensin II antagonist properties [A. T. Chiu et al, J, Pharmacol.

Exp, Ther., 250(3), 867-874 ¢1989)]. U.S. Patent No. 4,816,463 to Blankey et al describes a family of 4,5,6,7tetrahydro-lH-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-l, 2, 4-triazoles, including the compound 3,5-dibutyl-4-[(2'-carboxybiphenyl-4yl)methyl]-4H-1,2,4-triazole. U.S. Patent No. 4,880,804 to Carini et al describes a family of biphenylmethylbenzimidazole compounds as angiotensin II receptor blockers for use in treatment of hypertension and congestive heart failure.

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 4,7dichloro[4,5-d]pyridazine derivatives [I. Sekikawa, J, Heterocyclic Chem. . 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-Dribofuranosyl)imidazo[4,5-d]pyridazine-4,7-dione [C.

Tapiero et al, J, of Carbohydrates Nucleosides Nucleotides . 2(3), 191-195 (1976)]. In a study of chemical modification of antibiotic nucleosides, the compound 1-(2,3,5-tri-Obenzoyl-p-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-vIE 912042 triazolo[d]pyrimidine, several 4,7-disubstituted imidazo[4,5-d]pyridazines were synthesized including the compound 4,7-bisethylmercapto-l-ethylimidazo[4,5djpyridazine [R. N. Castle et al, J, Org, Chem,, 23, 1534 5 1538 (1958)]. Based on the antimalarial activity of certain quinoline derivatives, a family of ωdialkylaminoalkylaminoimidazo[4,5-d]pyridazines was synthesized including, typically, the compound 4- (3dimethylaminopropylamino)-7-chloro-l-(tetrahydro-2'10 pyranyl)imidazo[4,5-d]pyridazine [N. R. Patel et al, J, Heterocyclic Chem., fr, 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 fo use as cardiotonics, including a benzyloxy-substituted 2phenyl-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[4,5d]pyridazin-3-yl)methyl]biphenyl-2-carboxylate and 2-butyl· 4-hydroxy-3[(2'(lH-tetrazol-5-yl)biphenyl-4-yl)methyl]-3Himidazo[4,5-d]pyridazine. EP #400,974 published 5 Decembe: 1990 describes several families of imidazo-fused sixmembered heterocyclics as angiotensin II antagonists including, in particular 7-methyl-2-propyl-3-(21- (tetrazol -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. β DESCRIPTION OF THE INVENTION A class of ΙΗ-substituted-imidazo[4,5djpyridazine 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 through R11 and R^9 j_s 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, aralkylthiocarbonyi, araikylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, alkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula -N /R R -CN and "R IS -NC-R R17 wherein each of /21 r13, r14, r15, r16 and r17 £s independently selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein r!2 and r13 taken together, r!4 and r!5 taken together and r!6 and R^7 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 r!2 and r13 taken together and R14 and R1^ 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 through may be further independently selected from acidic moieties of the formula -¥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, wherein said YnA 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 0 0 II II II - C- CN—,—NC—,—O — S —,—N — R18 R18 Rl8 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, R89, 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 x ,20 ,21 and -NC-R22 wherein X is selected from oxygen atom and sulfur atom; wherein R·'-^ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR^4 and ,25 -N ,26 wherein D is selected from oxygen atom, nitrogen atom and sulfur atom and R3^ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R^O, r21, r22, r23z r25 and r26 fs 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, r22z r23z r25 anc; r26 fs further independently selected from amino and amido radicals of the formula ,27 -N 'R· II .

-CN R29 II / -NC and I ^r3° r3: , R30, R31 and ,31 independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalky 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 R2 and R2 positions of the imidazopyridazine ring. Such substituents are selected from the aforementioned R2 and R2 groups. Compounds having alkyl groups, especially lower alkyl groups at the R29 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 -YnA moiety, is intended to embrace chemical groups which, when attached to any of the R2 through R22 positions of Formula I, confers acidic character to the compound of Formula I.

Acidic character means proton-donor capability, that is, the capacity of the compound of Formula I to be a proton donor in the presence of a proton-receiving substance such as water. Typically, the acidic group should be selected to have proton-donor capability such that the product compound of Formula I has a pKa in a range from about one to about twelve. More typically, the Formula I compound would have a pKa in a range from about two to about seven. An example of an acidic group containing at least one acidic hydrogen atom is carboxyl group (-COOH). Where n is zero and A is -COOH, in the -YnA moiety, such carboxyl group would be attached directly to one of the R2 through R22 positions. The Formula I compound may have one -YnA moiety attached at one of the R2 through R22 positions, or may have a plurality of such -YnA moieties attached at more than one of the R2 through R22 positions, up to a maximum of nine such -YnA moieties. There are many examples of acidic groups other than carboxyl group, selectable to contain at least one acidic hydrogen atom. Such other acidic groups may be collectively referred to as bioisosteres of carboxylic acid or referred to as acidic bioisosteres. Specific examples of such acidic bioisosteres are described hereinafter. Compounds of Formula I having the -YnA moiety attached at one of positions R5, R6, R8 and R8 would be expected to have preferred properties, while attachment at R3 or R3 would be more preferred. Compounds of Formula I may have one or more acidic protons and, therefore, may have one or more pKa values. It is preferred, however, that at least one of these pKa values of the Formula I compound as conferred by the -YnA moiety be in a range from about two to about seven. The -YnA moiety may be attached to one of the R3 through R11 positions through any portion of the -YnA moiety which results in a Formula I compound being relatively stable and also having a labile or acidic proton to meet the foregoing pKa criteria. For example, where the -YnA acid moiety is tetrazole, the tetrazole is attached at the ring carbon atom.

A preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein each of R3 through and R3^ is independently selected from hydride, 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, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, 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 .14 -N -CN and -NC-R ,17 wherein each of R1^, r13, r!^, r!5z r16 and r17 j_s independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of r3 through R^ may be further independently selected from acidic moieties of the formula -Y„A wherein n is a number selected from zero through three, inclusive; wherein A is an acidic group selected from acids containing one or more atoms selected from oxygen, sulfur, phosphorus and nitrogen atoms, and wherein said acidic group is selected to contain at least one acidic hydrogen atom, wherein said YnA group is further characterized m 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 0 0 II II II - C- CN —NC—O — ,-S—N — R18 R18 Rl8 and -CH=CH-, wherein R1^ 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 through r!8, 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 ,20 -C-R -N ,21 > and -NC-R ,23 wherein X is selected from oxygen atom and sulfur atom; 25 wherein R29 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl; wherein each of R29, R21, R22 and R23 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylakyl, alkoxyalkyl, c· alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt 5 thereof.

A more preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein each of R1 and R3 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 -N and li NC-R16 wherein each of R13, r!3, r!4, rI-3, R1^ 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 through R11 is independently selected from hydrido, linear or branched alkyl (Ci-Cio), linear or branched alkenyl (C2~Cio) z linear or branched alkynyl (C2-C10), cycloalkyl (C3-C10), cycloalkenyl (C3C10), 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 R13 substituents is a carboxylic acid radical of the formula 11 33 -CO-R33 wherein R33 is selected from hydrido, linear or branched alkyl (Ci-Cioz)z linear or branched alkenyl (C2_Cio)z linear or branched alkynyl (C2-C10), cycloalkyl (C3-C10), cycloalkenyl (C3-C10), cycloalkylalkyl {C4-C10) and cycloalkenylalkyl (C4-C10) ; or wherein said R3 through R1substituent is a bioisostere of a free carboxylic acid having a pKa 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 -P-WH I W II -P-WH R34 L W II and -P-WH I 35 W-R35 wherein W is selected from 0, S and N-R4^; 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 R33 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 pka 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 or may be attached at any two positions selected from R3 through so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein 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 (Ci~ CiOz), linear or branched alkenyl (C2_Cio) , linear or branched alkynyl (C2-C10) , cycloalkyl (C3-C10), cycloalkenyl (C3-C10) z cycloalkylalkyl (C4-C10) and cycloalkenylalkyl (C4-C10); wherein any of the foregoing R22 through R28, R40, R41 and R48 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 10 arylsulphonyl; or a tautomer thereof or a pharmaceuticallyacceptable salt thereof.

Examples of heterocyclic groups which can be used as bioisosteres of carboxylic acid include: wherein each of R^2, r43 and r44 £S independently selected from H, Cl, CN, N02, CF3f C2F5, C3F7, CHF2, CH2F, CO2CH3, CO2C2H5, SO2CH3, SO2CF3 and SO2CgF5; wherein Z is selected from 0, S, NRand CH2, wherein R^5 is selected from hydrido, CH3 and CH2CgH5.

Examples of fused ring systems which include the phenyl rings of Formula I are as follows: OH An even more highly preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein R1 and R3 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, 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 II NC-R16 /R -N and -CN R R ,15 wherein each of R^, r!3, r!4, r15, r16 r17 ys independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein each of r3 through R^ 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 R8 through R^ is an acidic moiety independently selected from acidic moieties consisting of CO2H, CO2CH3, SH, CH2SH, C2H4SH, PO3H2/ NHSO2CF3, NHSO2CgF5, SO3H, CONHNH2, CONHNHSO2CF3, CONHOCH3, CONHOC2H5/ CONHCF3, OH, CH2OH, Ο2Η4ΟΗ, OPO3H2/ OSO3H, NHCN4H and and wherein said acidic moiety may further be a heterocyclic acidic group attached at any two adjacent positions of R^ through R^· 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 R2 and R^ is independently selected from hydroxy, amino, aminomethyl, aminoethyl, dimethylaminoethylamino, methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl, isobutyl, tertbutyl, npentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 115 oxobutyl, 1-oxopentyl, hydroxyalkyl, halo, methylthio, propylthio, isopropylthio, cyclohexylthio, methoxy, ethoxy, isopropoxy, phenoxy, cyclohexyloxy, methoxymethoxy, methoxy-l-ethyloxy, cyano, formyl, acetyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, secbutylcarbonyloxy, iso-butylcarbonyloxy, tertbutylcarbonyloxy, 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 (Cj-Cio), linear or branched alkenyl (C2~Cio) , linear or branched alkynyl (C2-Cio), cycloalkyl (C3-C10), cycloalkenyl (C3-C10) , cycloalkylalkyl (C4-C10) and cycloalkenylalkyi (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, Η Η H wherein each of R43 and R^3 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 R3 and R3 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-l-ethyloxy, acetyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, secbutylcarbonyloxy, iso-butylcarbonyloxy, tertbutylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy, n-hexylcarbonyloxy, benzyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cycloheptyloxy, isopropanoyloxy, benzoyloxy, methylaminocarbonyloxy, isopropylaminocarbonyloxy and phenylaminocarbonyloxy; wherein R39 3s selected from n30 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). 5 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 -CH210 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-difluoroerhyl, 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 cf 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 pharmaceutically5 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, ethane sulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic, β-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base additioxn 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 (Nmethylglucamine) 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-lH-imidazo[4,5-d]pyridazin-l-yl)methyl][1,1'biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dichloro-ΙΗ-imidazo[4,5-d]pyridazin-1yl)methyl][1,1’-biphenyl]-2-carboxylic acid; '- [(2-butyl-4,7-difluoro-lH-imidazo[4,5-d]pyridazin-110 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dibromo-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 41 -[(2-butyl-lH-imidazo[4,5-d]pyridazin-l-yl-4,7 diol)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dithio-lH-imidazo[4, 5-d]pyridazin-1yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diethoxy-lH-imidazo[4, 5-d]pyridazin-120 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 41-[(2-butyl-4,7-diisopropyloxy-lH-imidazo[4,5-d]pyridazin l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dicyclohexyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dibenzy1oxy-IH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dimethyl-IH-imidazo[4,5-d]pyridazin-130 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diethyl-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dicyclohehyl-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diphenyl-lH-imidazo[4, 5-d]pyridazin-lyl)methyl][1,1’-biphenyl]-2-carboxylic acid; 41 -[(2-butyl-4,7-di(phenylethyl)-IH-imidazo[4,5 — d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'—[(2-butyl-4,7-diamino-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; '- [ (2-butyl-4,7-bis(2-dimethylaminoethylamino)-1Himidazo[4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-butyl-4, 7-bis(3-dimethylaminopropylamino)-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-butyl-4,7-dimethylthio-lH-imidazo[4,5-d]pyridazin-l yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'—[(2-butyl-4,7-diethylthio-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diisopropylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'—[(2-butyl-4,7-dicyclohexylthio-lH-imidazo[4,520 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4,7-diphenylthio-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 41-[(2-butyl-4,7-dibenzylthio-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazin-lyl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diisopropanoyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4,7-dibenzoyloxy-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dicyclohexanoyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acia; 4' - [ (2-butyl-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5 — d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4' - [(2-butyl-4,7-dicyano-lH-imidazo[4,5-d]pyridazin-1 yUmethyl] [1,1'-biphenyl]-2-carboxylic acid; 4[(2-butyl-4,7-di-(formyl)-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'- [(2-butyl-4,7-di-(1,1-dimethoxy-isopropyl)-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4’—[(2-butyl-4, 7-di-(1-oxo-butyl)-ΙΗ-imidazo[4,5d]pyridazin-l-yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-di-(1-oxo-cyclohexyl)-ΙΗ-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4-chloro-7-hydroxy-lH-imidazo[4,5-d]pyridazin 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-methyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-ethyl-7-hydroxy-lH-imidazo[4,5-d]pyridazinl-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'—[(2-butyl-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4-isopropyl-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4-cyclohexyl-7-hydroxy-lH-imidazo[4,525 d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-methoxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl] [1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-fluoro-7-hydroxy-lH-imidazo[4,5-d]pyridazin l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-bromo-7-hydroxy-lH-imidazo[4,5-d]pyridazinl-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4-isopropyloxy-7-hydroxy-lH-imidazo[4,535 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4-cyclohexyloxy-7-hydroxy-ΙΗ-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4' - [(2-butyl-4-phenoxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'—[(2-butyl-4-benzyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin 1-yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-(phenylethyl)-7-hydroxy-IH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-(2-dimethylaminoethylamino)-7-hydroxy-lH10 imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[ (2-butyl-4- (3-dimethylaminopropylamino)-7-hydroxy-1Himidazo[4,5-d]pyridazin-1-yl) methyl] [1,1'-biphenyl] -2 carboxylic acid; 4' — [(2-butyl-4-methylthio-7-hydroxy-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[(2-butyl-4-ethylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-isopropylthio-7-hydroxy-lH-imidazo[4,520 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-cyclohexylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl] [1,1’-biphenyl]-2-carboxylic acid; 4' - [ (2-butyl-4-phenylthio-7-hydroxy-lH-imidazo[4,5 — d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-benzylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-acetyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,530 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-cyclohexanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’—[(2-butyl-4-(methoxymethyloxy)-7-hydroxy-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4’—[ (2-butyl-4-(methoxy-l-ethyloxy)-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-butyl-4-cyano-7-hydroxy-lH-imidazo[4,5-d]pyridazin5 l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-formyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 10 carboxylic acid; 4'-[ (2-butyl-4-(1-oxo-butyl)-7-hydroxy-ΙΗ-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-(1-oxo-cyclohexyl)-7-hydroxy-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-ΙΗ-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1' biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dichloro-lH-imidazo[4,5-d]pyridazin-l20 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-difluoro-lH-imidazo[4,5-d]pyridazin-lyl) methyl] [1,11-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dibromo-lH-imidazo[4, 5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-lH-imidazo[4,5-d]pyridazin-1-yl-4,7diol)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-methyl-4,7-dithio-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methy1-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazin-1 30 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-diethoxy-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,11-biphenyl]-2-carboxylic acid; 41-[(2-methyl-4,7-diisopropyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic ac:a; 41-[(2-methyl-4,7-dicyclohexyloxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; ' - [(2-methyl-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4[(2-methyl-4,7-dibenzyloxy-lH-imidazo[4,5-d]pyridazin-l yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dimethyl-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4' - [(2-methyl-4,7-diethyl-lH-imidazo[4, 5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methy1-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dicyclohehyl-lH-imidazo[4,5-d]pyridazinl-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 41-[(2-methyl-4,7-diphenyl-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-di(phenylethyl)-1H-imidazo[4,5d]pyridazin-l-yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4,7-diamino-lH-imidazo(4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-bis(2-dimethylaminoethylamino)-1H20 imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2carboxylic acid; 41 -[(2-methyl-4,7-bis(3-dimethylaminopropylamino)-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl] -2 carboxylic acid; 4' - [(2-methyl-4,7-dimethylthio-lH-imidazo[4,5-d]pyridazinl-yl) methyl] [1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-methy1-4,7-diethylthio-lH-imidazo[4, 5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-diisopropylthio-lH-imidazo[4,530 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dicyclohexylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-diphenylthio-lH-imidazo[4,5-d]pyridazir1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dibenzylthio-lH-imidazo[4,5-d]pyridazinl-yl) methyl] [ 1,1’-biphenyl]-2-carboxylic acid; 4'- [(2-methyl-4,7-diacetyloxy-lH-imidazo[4, 5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-diisopropanoyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4’—[(2-methyl-4,7-dibenzoyloxy-lH-imidazo[4,5-d]pyridazin1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dicyclohexanoyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-bis(methoxymethyloxy)-ΙΗ-imidazo[4,510 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-methyl-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dicyano-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'—[(2-methyl-4,7-di-(formyl)-IH-imidazo[4,5-d]pyridazin-1 yl)methyl] [ 1, 1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-di-(1,1-dimethoxy-isopropyl)-1Himidazo[4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-methyl-4,7-di-(1-oxo-butyl)-IH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-di-(1-oxo-cyclohexyl)-ΙΗ-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin-125 yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-chloro-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-methyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-methy1-4-ethyl-7-hydroxy-IH-imidazo[4,5-d]pyridazin 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methy1-4-propy1-7-hydroxy-IH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-isopropyl-7-hydroxy-lH-imidazo[4,535 d]pyridazin-l-yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-cyclohexyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; ' - [ (2-methyl-4-methoxy-7-hydroxy-lH-imidazo [4,5d]pyridazin-l-yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4[(2-methyl-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[(2-methyl-4-fluoro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[(2-methyl-4-bromo-7-hydroxy-lH-imidazo[4,5-d]pyridazin l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[(2-methyl-4-isopropyloxy-7-hydroxy-lH-imidazo[4,510 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[ (2-methyl-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[(2-methyl-4-phenoxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4’-[(2-methyl-4-benzyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[(2-methyl-4-phenyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[(2-methyl-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,520 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[ (2-methyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1’-biphenyl]-2 carboxylic acid; 4’-[(2-methyl-4-(3-dimethylaminopropylamino)-7-hydroxy-lH25 imidazo[4,5-d]pyridazin-l-yl)methyl][1,11-biphenyl]-2carboxylic acid; 4’-[(2-methyl-4-methylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-ethylthio-7-hydroxy-lH-imidazo[4,530 d]pyridazin-l-yl) methyl][1,11-biphenyl]-2-carboxylic acid; 4’-[(2-methyl-4-isopropylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[(2-methyl-4-cyclohexylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl) methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[(2-methyl-4-phenylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-benzylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4[(2-methyl-4-acetyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4’ — [(2-methyl-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-cyclohexanoyloxy-7-hydroxy-lH-imidazo[4,510 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’—[(2-methyl-4-(methoxymethyloxy)-7-hydroxy-lHimidazo[4,5-d]pyridazin-1-yl)methyl] [1,1'-biphenyl] - 2 carboxylic acid; 4'—[(2-methyl-4-(methoxy-l-ethyloxy)-7-hydroxy-lH15 imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1’-biphenyl]-2 carboxylic acid; 4'-[ (2-methyl-4-cyano-7-hydroxy-lH-imidazo[4,5-d]pyridazin l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-formyl-7-hydroxy-lH-imidazo[4,520 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-methyl-4-(1-oxo-butyl)-7-hydroxy-lH-imidazo[4,525 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4’-[(2-methyl-4-(1-oxo-cyclohexyl)-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl) methyl] [1,1'-biphenyl] -2 carboxylic acid; 4'-[(2-methyl-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,530 d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-lH-imidazo[4,5-d]pyridazin-l yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dichloro-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'—[(2-isopropyl-4,7-difluoro-ΙΗ-imidazo[4,5-d]pyridazin-1 yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4[(2-isopropyl-4,7-dibromo-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'- [ (2-isopropyl-ΙΗ-imidazo[4, 5-d]pyridazin-l-yl-4,7diol)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dithio-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 41 -[(2-isopropyl-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazin1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4' - [ (2-isopropyl-4,7-diethoxy-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diisopropyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dicyclohexyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazin1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dibenzyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl}-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dimethyl-ΙΗ-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diethyl-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diisopropyl-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4,7-dicyclohehyl-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4,7-diphenyl-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-di(phenylethyl) -ΙΗ-imidazo[4,530 d]pyridazin-l-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)-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 35 carboxylic acid; ’ — [(2-isopropyl-4,7-bis(3-dimethylaminopropylamino)-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-isopropyl-4,7-dimethylthio-lH-imidazo[4,55 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diethylthio-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropy1-4,7-diisopropylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dicyclohexylthio-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diphenylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dibenzylthio-lH-imidazo[4,515 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diacetyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 41-[(2-isopropyl-4,7-diisopropanoyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dibenzoyloxy-lH-imidazo[4,5 — d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dicyclohexanoyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-bis(methoxymethyloxy)-ΙΗ-imidazo[4,525 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-bis(methoxy-l-ethyloxy)-1Himidazo[4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2carboxylic acid; 4'-[(2-isopropyl-4,7-dicyano-lH-imidazo[4,5-d]pyridazin-130 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4' — [(2-isopropyl-4,7-di-(formyl)-ΙΗ-imidazo[4,5 d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4’—[(2-isopropyl-4, 7-di-(1,1-dimethoxy-isopropyl)-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 35 carboxylic acid; 4'-[(2-isopropyl-4,7-di-(1-oxo-butyl)-ΙΗ-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[(2-isopropyl-4,7-di-(1-oxo-cyclohexyl)-ΙΗ-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4’ — [ (2-isopropyl-4-chloro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-methyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4-ethyl-7-hydroxy-lH-imidazo[4,510 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-propyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4-isopropyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4 *—[(2-isopropyl-4-cyclohexyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4’-[(2-isopropyl-4-methoxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,520 d]pyridazin-l-yl) methyl] [1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4-fluoro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4-bromo-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4 '- [ (2-isopropyl-4-isopropyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl) methyl] [1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4-phenoxy-7-hydroxy-lH-imidazo[4,530 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4-benzyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl) methyl] [1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-phenyl-7-hydroxy-ΙΗ-imidazo[4,5d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4[ (2-isopropyl-4-(2-dimethylaminoethylamino)-7-hydroxyIH-imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl] -2 carboxylic acid; 4'-[ (2-isopropyl-4-(3-dimethylaminopropylamino)-7-hydroxy5 lH-imidazo[4,5-d]pyridazin-l-yl)methyl] [1,11-biphenyl]-2 carboxylic acid; 4'-[(2-isopropyl-4-methylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-ethylthio-7-hydroxy-IH-imidazo[4,510 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4' - [ (2-isopropyl-4-isopropylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4-cyclohexylthio-7-hydroxy-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-phenylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-benzylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-acetyloxy-7-hydroxy-lH-imidazo[4,520 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 41 -[(2-isopropyl-4-isopropanoyloxy-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; ' - [(2-isopropyl-4-benzoyloxy-7-hydroxy-IH-imidazo[4,525 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-cyclohexanoyloxy-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[ (2-isopropyl-4-(methoxymethyloxy)-7-hydroxy-lH30 imidazo[4,5-d]pyridazin-l-yl)methylj [1,1'-biphenylj-2 carboxylic acid; 4'-[(2-isopropyl-4-(methoxy-l-ethyloxy)-7-hydroxy-iHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-isopropyl-4-cyano-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-formyl-7-hydroxy-lH-imidazo[4,5 — d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 5 carboxylic acid; 4'-[(2-isopropyl-4-(1-oxo-butyl)-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'—[(2-isopropyl-4-(1-oxo-cyclohexyl)-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 10 carboxylic acid; 4'-[(2-isopropyl-4-cyclohexyloxy-7-hydroxy-ΙΗ-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'—[(2-neopentyl-4,7-dichloro-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-4,7-difluoro-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-4,7-dibromo-lH-imidazo[4,5-d]pyridazin-120 yl)methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-ΙΗ-imidazo[4,5-d]pyridazin-1-yl-4,7diol)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-4,7-dithio-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazinl-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diethoxy-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-4,7-diisopropyloxy-lH-imidazo[4,530 d]pyridazin-l-yl) methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dicyclohexyloxy-lH-imidazo[4,5d]pyridazin-l-yi)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazinl-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dibenzyloxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dimethyl-lH-imidazo[4, 5-d]pyridazin-l yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4' - [(2-neopentyl-4,7-diethyl-lH-imidazo[4,5-d]pyridazin-lyl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4’—[(2-neopentyl-4,7-diisopropyl-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dicyclohehyl-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diphenyl-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4’—[(2-neopentyl-4,7-di(phenylethyl)-ΙΗ-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-buty1-4,7-diamino-IH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-bis(2-dimethylaminoethylamino)-1Himidazo[4,5-d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-neopentyl-4,7-bis(3-dimethylaminopropylamino)-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 20 carboxylic acid; 4'-[ (2-neopentyl-4,7-dimethylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diethylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diisopropylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dicyclohexylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-4,7-diphenylthio-lH-imidazo[4,530 d]pyridazin-l-yi)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'—[(2-neopentyl-4,7-dibenzylthio-IH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diacetyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-4,7-diisopropanoyloxy-IH-imidazo[4,5 — d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dibenzoyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4 ' - [ (2-neopentyl-4,7-dicyclohexanoyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyi-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-4,7-bis(methoxy-l-ethyloxy) -1Himidazo[4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2carboxylic acid; 4 ’ — [(2-neopentyl-4,7-dicyano-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-di-(formyl)-ΙΗ-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-di-(1,1-dimethoxy-isopropyl)-1H15 imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2carboxylic acid; 4'-[(2-neopentyl-4,7-di-(1-oxo-butyl)-ΙΗ-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-di-(1-oxo-cyclohexyl)-IH-imidazo[4,520 d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4’-[(2-neopentyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin-lyl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-4-chloro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[ (2-neopentyl-4-methyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[(2-neopentyl-4-ethyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-propyl-7-hydroxy-lH-imidazo[4,530 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[(2-neopentyl-4-isopropyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-cyclohexyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4’-[(2-neopentyl-4-methoxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl) methyl] [1,1’-biphenyl]-2-carboxylic acid; ' - [ (2-neopentyl-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-fluoro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'—[(2-neopentyl-4-bromo-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'—[ (2-neopentyl-4-isopropyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,510 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-phenoxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyi-4-benzyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-phenyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-4-(2-dimethylaminoethylamino)-7-hydroxy20 ΙΗ-imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2carboxylic acid; 4'-[(2-neopentyl-4-(3-dimethylaminopropylamino)-7-hydroxyΙΗ-imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4’—[(2-neopentyl~4-methylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-4-ethylthio-7-hydroxy-lH-imidazo[4,5 — d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-isopropylthio-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4'—[(2-neopentyl-4-cyclohexylthio-7-hydroxy-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-phenylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-4-benzylthio-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-acetyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-isopropanoyloxy-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 5 carboxylic acid; 4'-[(2-neopentyl-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-cyclohexanoyloxy-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 10 carboxylic acid; 4'-[(2-neopentyl-4-(methoxymethyloxy)-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-neopentyl-4-(methoxy-l-ethyloxy)-7-hydroxy-1H15 imidazo[4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-neopentyl-4-cyano-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 41 -[(2-neopentyl-4-formyl-7-hydroxy-lH-imidazo[4,520 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-neopentyl-4-(1-oxo-butyl)-7-hydroxy-lH-imidazo[4,525 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-(1-oxo-cyclohexyl)-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-neopentyl-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,530 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-IH-imidazo[4,5-d]pyridazin-lyl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-dichloro-lH-imidazo[4,5-d]pyridazinl-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-difluoro-IH-imidazo[4,5-d]pyridazinl-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4, 7-dibromo-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-lH-imidazo[4,5-d]pyridazin-l-yl-4,7 diol)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dithio-lH-imidazo[4,5-d]pyridazin-lyl) 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-lH-imidazo[4,5-d]pyridazin10 1-yl)methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diisopropyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dicyclohexyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazin 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-dibenzyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-dimethyl-lH-imidazo[4,5-d]pyridazin20 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-diethyl-1H-imidazo[4,5-d]pyridazin-1 yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4[ (2-cyclohexyl-4,7-diisopropyl-lH-imidazo[4,5d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dicyclohehyl-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-diphenyl-ΙΗ-imidazo[4,5-d]pyridazinl-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-di(phenylethyl)-ΙΗ-imidazo[4,530 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-bis(2-dimethylaminoethylamino)-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl] - 2 carboxylic acid; 4'-[ (2-cyclohexyl-4,7-bis(3-dimethylaminopropylamino)-1H35 imidazo[4,5-d]pyridazin-l-yl)methyl] [1, 1'-biphenyl]-2carboxylic acid; 4'-[(2-cyclohexyl-4,7-dimethylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-diethylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4' — [ (2-cyclohexyl-4,7-diisopropylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dicyclohexylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diphenylthio-lH-imidazo[4,510 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dibenzylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-diacetyloxy-lH-imidazo[4,5 — d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diisopropanoyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-dibenzoyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl] [1,1'-biphenyl 1-2-carboxylie acid; 4'-[ (2-cyclohexyl-4,7-dicyclohexanoyloxy-lH-imidazo[4,520 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-bis(methoxy-l-ethyloxy)-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 25 carboxylic acid; 4'-[ (2-cyclohexyl-4,7-dicyano-lH-imidazo[4, 5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-di-(formyl)-IH-imidazo[4,5— d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4’ — [(2-cyclohexyl-4,7-di-(1,1-dimethoxy-isopropyl)-1Himidazo[4,5-d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2carboxylic acid; 4’-[ (2-cyclohexyl-4,7-di-(1-oxo-butyl)-IH-imidazo[4,5d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-di-(1-oxo-cyclohexyl)-IH-imidazo[4,5 d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; ’ — [(2-cyclohexyl-7-hydroxy-1H-imidazο[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-chloro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-methyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-ethyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-propyl-7-hydroxy-lH-imidazo[4,510 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-isopropyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-cyclohexyl-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’—[(2-cyclohexyl-4-methoxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 41-[(2-cyclohexyl-4-fluoro-7-hydroxy-ΙΗ-imidazo[4,520 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-bromo-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4-isopropyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4’-[(2-cyclohexyl-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-phenoxy-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4’—[ (2-cyclohexyl-4-benzyloxy-7-hydroxy-lH-imidazo[4,530 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-phenyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4’—[(2-cyclohexyl-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acio; 4’—[(2-cyclohexyl-4-(2-dimethylaminoethylamino)-7-hydroxyΙΗ-imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4[(2-cyclohexyl-4-(3-dimethylaminopropylamino)-7-hydroxy IH-imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1’-biphenyl]-2 carboxylic acid; 4'-[(2-cyclohexyl-4-methylthio-7-hydroxy-lH-imidazo[4,55 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-ethylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-isopropylthio-7-hydroxy-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-cyclohexylthio-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1’-biphenyl]-2 carboxylic acid; 4'-[(2-cyclohexyl-4-phenylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4-benzylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-acetyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4-isopropanoyloxy-7-hydroxy-lH20 imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[ (2-cyclohexyl-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4-cyclohexanoyloxy-7-hydroxy-lH25 imidazo[4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2carboxylic acid; 4'-[(2-cyclohexyl-4-(methoxymethyloxy) -7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 3D 4'-[(2-cyclohexyl-4-(methoxy-l-ethyloxy)-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-cyclohexyl-4-cyano-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-formyl-7-hydroxy-lH-imidazo[4,5djpyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-lH imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-cyclohexyl-4-(1-oxo-butyl)-7-hydroxy-lH-imidazo[4,5 5 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'- [ (2-cyclohexyl-4-(1-oxo-cyclohexyl)-7-hydroxy-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-cyclohexyl-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yljmethyl]-IH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-difluoro-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dibromo-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-420 yljmethyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-butyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yljmethyl]-4,7-dithio-IH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[21 -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yl]methyl]-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'—(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yljmethyl]-4,7-diisopropyloxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 30 yljmethyl]-4,7-dicyclohexyloxy-lH-imidazo[4,5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-diphenoxy-ΙΗ-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-dibenzyloxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dimethyi-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl] -4 yl]methyl]-4,7-diethyl-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2’—(lH-tetrazol-5-yl)[1,1*-biphenyl]-4yl]methyl]-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-dicyclohehyl-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'—(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-diphenyl-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-410 yl]methyl]-4,7-di(phenylethyl)-IH-imidazo[4,5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,11-biphenyl]-4yljmethyl]-4,7-diamino-lH-imidazo[4, 5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1H15 imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-bis(3-dimethylaminopropylamino)-1Himidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 20 yl]methyl]-4,7-dimethylthio-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-diethylthio-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-diisopropylthio-lH-imidazo[4,5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yl]methyl]-4,7-dicyclohexylthio-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yl]methyl]-4,7-diphenylthio-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dibenzylthio-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[21 - (lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-435 yl]methyl]-4,7-diisopropanoyloxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-dibenzoyloxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohexanoyloxy-lH-imidazo[4,55 d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 10 yljmethyl]-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,5 d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-dicyano-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 15 yl]methyl]-4,7-di-(formyl)-IH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-di-(1,1-dimethoxy-isopropyl)-IH-imidazo[4,5 d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 20 yl]methyl]-4,7-di-(1-oxo-butyl)-IH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-7-hydroxy-IH-imidazo[4, 5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 25 yl]methyl]-4-chloro-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-ethyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-isopropyl-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-cyclohexyl-7-hydroxy-IH-imidazo[4,535 d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-methoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yljmethyl]-4-fluoro-7-hydroxy-lH-imidazo[4, 5-d]pyridazine; 2-butyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-bromo-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-isopropyloxy-7-hydroxy-lH-imidazo[4,510 d]pyridazine; 2-butyl-l-[[2'- (lH-tetrazol-5-yl) [1,1’-biphenyl]-4yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 15 yljmethyl]-4-phenoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-benzyloxy-7-hydroxy-lH-imidazo[4,5— djpyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 20 yljmethyl]-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[21 - (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[21 - (lH-tetrazol-5-yl) [1,1'-biphenyl]-4 25 yljmethyl]-4-(2-dimethylaminoethylamino)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-butyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4- (3-dimethylaminoethylamino)-7-hydroxy-1Himidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-methylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-ethylthio-7-hydroxy-lH-imidazo[4,535 d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-isopropylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 5 yl]methyl]-4-cyclohexylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-phenylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yl]methyl]-4-benzylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'- (lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,515 d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 20 yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[21-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-(methoxymethyloxy)-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-(methoxy-l-ethyloxy)-7-hydroxy-lH-imidazo[4,5 d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yllmethyl]-4-cyano-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-formyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-butyl-l-[ [2' -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yljmethyl]-4-(1-oxo-butyl)-7-hydroxy-lH-imidazo[4,5d] pyridazine; 2-butyl-l-[[21 -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 5 yl]methyl]-4-(1-oxo-cyclohexyl)-7-hydroxy-IH-imidazo[4,5 d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-IH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yl]methyl]-4,7-difluoro-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yllmethyl]-4,7-dibromo-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dithio-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-425 yl]methyl]-4,7-diethoxy-IH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-diisopropyloxy-lH-imidazo[4, 5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dicyclohexyloxy-lH-imidazo[4,5-d]pyridazine 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-dibenzyloxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-435 yl]methyl]-4,7-dimethyl-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-diethyl-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohehyl-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diphenyl-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-di(phenylethyl)-ΙΗ-imidazo[4,5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 10 yl]methyl]-4,7-diamino-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1Himidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yl]methyl]-4,7-bis(3-dimethylaminopropylamino)-1Himidazo[4,5-d]pyridazine; 2-methyl-l-[[21 - (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-dimethylthio-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-420 yl]methyl]-4,7-diethylthio-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-diisopropylthio-lH-imidazo[4,5-d]pyridazine 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohexylthio-lH-imidazo[4,525 d]pyridazine; 2-methyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-diphenylthio-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1*-biphenyl]-4yl]methyl]-4,7-dibenzylthio-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yljmethyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[21 -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-diisopropanoyloxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[21 -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-dibenzoyloxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohexanoyloxy-lH-imidazo[4,5— d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yljmethyl]-4,7-bis(methoxymethyloxy)-ΙΗ-imidazo[4,5d]pyridazine,· 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dicyano-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-di-(formyl)-IH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yljmethyl]-4,7-di-(1,1-dimethoxy-isopropyl)-IH-imidazo[4,5 d]pyridazine; 2-methyl-l-[[2'—(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-di-(1-oxo-butyl)-lH-imidazo[4,5— d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl J-4yl]methyl]-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethylj-4-chloro-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-425 yljmethyl]-4-ethyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropyl-7-hydroxy-lH-imidazo[4,530 d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-cyclohexyl-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-435 yljmethyl]-4-methoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-methyl-1-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1*-biphenyl]-45 yl]methyl]-4-fluoro-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[ [2 (lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-bromo-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-isopropyloxy-7-hydroxy-lH-imidazo[4,510 d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yljmethyl]-4-phenoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-methyl-l-[ [2' -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-benzyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-420 yljmethyl]-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-425 yl]methyl]-4-(2-dimethylaminoethylamino)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-methyl-l-[[2’—(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-methylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-ethylthio-7-hydroxy-lH-imidazo[4,5 35 d]pyridazine; 2-methyl-1-[[21 -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-isopropylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-45 yl]methyl]-4-cyclohexylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-phenylthio-7-hydroxy-IH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-benzylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,515 d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-420 yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(methoxymethyloxy) - 7-hydroxy-IH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(methoxy-l-ethyloxy)-7-hydroxy-lH-imidazo[4,5 d]pyridazine; 2-methyl-l-[ [2' -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyano-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl] -4yl]methyl]-4-formyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yljmethyl]-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-1Himidazo[4,5-d]pyridazine; 2-methyl-1-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-(1-oxo-butyl)-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-1-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yl]methyl]-4-(1-oxo-cyclohexyl)-7-hydroxy-IH-imidazo[4,5— d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1*-biphenyl]-4yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d] pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yljmethyl]-4,7-difluoro-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2’-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-dibromo-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-ΙΗ-imidazo[4,5-d]pyridazine-4,7-diol; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dithio-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-425 yl]methyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diisopropyloxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohexyloxy-lH-imidazo[4,5-d]pyridazine 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dibenzyloxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-435 yl]methyl]-4,7-dimethyl-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diethyl-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2' —(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dieyelohehyl-IH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-diphenyl-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-di(phenylethyl)-IH-imidazo[4,5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4 10 yl]methyl]-4,7-diamino-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-IHimidazo [4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yl] methyl]-4,7-bis(3-dimethylaminopropylamino)-1Himidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dimethylthio-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-420 yl]methyl]-4,7-diethylthio-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diisopropylthio-lH-imidazo[4,5-d]pyridazine 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohexylthio-lH-imidazo[4,525 d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diphenylthio-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dibenzylthio-lH-imidazo[4,5-d]pyridazine; 3D 2-isopropyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yljmethyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diisopropanoyloxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dibenzoyloxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2 * —(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohexanoyloxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-45 yljmethyl]-4,7-bis(methoxymethyloxy)-ΙΗ-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(methoxy-l-ethyloxy)-ΙΗ-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyano-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-di-(formyl)-IH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yljmethyl]-4,7-di-(1,1-dimethoxy-isopropyl)-IH-imidazo [4,5 d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-di-(1-oxo-butyl)-IH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2’-(lH-tetrazol-5-yl) [1,1’-biphenyl]-4yl]methyl]-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-chloro-7-hydroxy-lH-imidazo[4, 5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-425 yljmethyl]-4-ethyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropyl-7-hydroxy-lH-imidazo[4,530 d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-cyclohexyl-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-435 yl]methyl]-4-methoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-45 yl]methyl]-4-fluoro-7-hydroxy-lH-imidazo[4, 5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-bromo-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropyloxy-7-hydroxy-lH-imidazo[4,510 d]pyridazine; 2-isopropyl-l-[[2’—(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yl]methyl]-4-phenoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-isopropyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-benzyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[21 -(lH-tetrazol-5-yl) [1,1'-biphenyl]-420 yl]methyl]-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-425 yl]methyl]-4-(2-dimethylaminoethylamino)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-methylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-ethylthio-7-hydroxy-lH-imidazo[4,535 d]pyridazine; 2-isopropyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-isopropylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yljmethyl]-4-cyclohexylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-phenylthio-7-hydroxy-1H-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-benzylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,515 d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-420 yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-(methoxymethyloxy)-7-hydroxy-1H-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(methoxy-l-ethyloxy)-7-hydroxy-lH-imidazo[4,5 d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyano-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-formy1-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(1-oxo-butyl)-7-hydroxy-lH-imidazo[4,5— d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-45 yljmethyl]-4-(1-oxo-cyclohexyl)-7-hydroxy-IH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yl]methyl]-4,7-difluoro-ΙΗ-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dibromo-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dithio-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-425 yl]methyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-diisopropyloxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dicyclohexyloxy-lH-imidazo[4,5-d]pyridazine 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-diphenoxy-IH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dibenzyloxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-435 yljmethyl]-4,7-dimethyl-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-diethyl-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[ [ 2 ' —(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazine,· 2-neopentyl-l-[ [2' -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohehyl-IH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diphenyl-lH-imidazo[4,5-d]pyridazine,· 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-di(phenylethyl)-IH-imidazo[4,5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 10 yl]methyl]-4,7-diamino-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1Himidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yl]methyl]-4,7-bis(3-dimethylaminopropylamino)-1Himidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dimethylthio-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-420 yl]methyl]-4,7-diethylthio-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diisopropylthio-lH-imidazo[4,5-d]pyridazine 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohexylthio-lH-imidazo[4,525 d]pyridazine; 2-neopentyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-diphenylthio-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dibenzylthio-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl] -4yllmethyl]-4, 7-diisopropanoyloxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dibenzoyloxy-IH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohexanoyloxy-lH-imidazo[4,5d] pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yl]methyl]-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5d] pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,5 d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dicyano-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-di-(formyl)-IH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yl]methyl]-4,7-di-(1,1-dimethoxy-isopropyl)-IH-imidazo[4,5 d]pyridazine; 2-neopentyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-di-(1-oxo-butyl)-IH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-chloro-7-hydroxy-lH-imidazo[4, 5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-425 yl]methyl]-4-ethyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropyl-7-hydroxy-lH-imidazo[4,530 d]pyridazine; 2-neopentyl-l-[[2’—(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-cyclohexyl-7-hydroxy-lH-imidazo[4,5— d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-435 yl]methyl]-4-methoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine; c 2-neopentyl-l-[ [2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine, 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yl]methyl]-4-fluoro-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-bromo-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropyloxy-7-hydroxy-lH-imidazo[4,510 d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yl]methyl]-4-phenoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-benzyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-420 yl] methyl]-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yllmethyl]-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-425 yl]methyl]-4-(2-dimethylaminoethylamino)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2 * -(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-methylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-ethylthio-7-hydroxy-lH-imidazo[4,535 d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-isopropylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-45 yljmethyl]-4-cyclohexylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-phenylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4yl]methyl]-4-benzylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,515 d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl] -420 yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-ΙΗ-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2(lH-tetrazol-5-yl)[1,11-biphenyl]-4yl]methyl]-4-(methoxymethyloxy)-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(methoxy-l-ethyloxy)-7-hydroxy-lH-imidazo[4,5 d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyano-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-formyl-7-hydroxy-lH-imidazo[4, 5-d]pyridazine; 2-neopentyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-1Himidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(1-oxo-butyl)-7-hydroxy-lH-imidazo[4,5d] pyridazine ; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yl]methyl]-4-(1-oxo-cyclohexyl)-7-hydroxy-ΙΗ-imidazo[4,5 d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d] pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-ΙΗ-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-415 yl]methyl]-4,7-difluoro-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dibromo-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-ΙΗ-imidazo[4,5-d]pyridazine-4,7-diol; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-dithio-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-425 yl]methyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'- (ΙΗ-tetrazol-5-yl) [1,1’-biphenyl] - 4yl]methyl]-4,7-diisopropyloxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohexyloxy-lH-imidazo[4,5-d]pyridazine 2-cyclohexyl-l-[[21 -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dibenzyloxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-435 yl]methyl]-4,7-dimethyl-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[ [2' —(lH-tetrazol-5-yl)[1,11-biphenyl]-4yl]methyl]-4,7-diethyl-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[21-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohehyl-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[21-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diphenyl-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-di(phenylethyl)-1H-imidazo[4, 5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 10 yljmethyl]-4,7-diamino-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1Himidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yljmethyl]-4,7-bis(3-dimethylaminopropylamino)-1Himidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dimethylthio-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-420 yl]methyl]-4,7-diethylthio-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diisopropylthio-lH-imidazo[4,5-d]pyridazine 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohexylthio-1H-imidazo[4,525 d]pyridazine; 2-cyclohexyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-diphenylthio-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dibenzylthio-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diisopropanoyloxy-lH-imidazo[4,5 d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dibenzoyloxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohexanoyloxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yl]methyl]-4,7-bis(methoxymethyloxy)-ΙΗ-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yllmethyl]-4,7-bis(methoxy-l-ethyloxy)-ΙΗ-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyano-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-di-(formyl)-IH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yl]methyl]-4,7-di-(1,1-dimethoxy-isopropyl)-IH-imidazo[4,5 d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-di-(1-oxo-butyl)-IH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-chloro-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-425 yl]methyl]-4-ethyl-7-hydroxy-ΙΗ-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropyl-7-hydroxy-lH-imidazo[4,530 d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyl-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[21 -(lH-tetrazol-5-yl)[1,1'-biphenyl]-435 yl]methyl]-4-methoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine , IE 912042 2-cyclohexyl-l-[[2’—(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yl]methyl]-4-fluoro-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-bromo-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropyloxy-7-hydroxy-lH-imidazo[4,510 d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yl]methyl]-4-phenoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-benzyloxy-7-hydroxy-lH-imidazo[4,5 d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-420 yljmethyl]-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5— d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-425 yl]methyl]-4-(2-dimethylaminoethylamino)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-methylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-ethylthio-7-hydroxy-lH-imidazo[4,535 d]pyridazine; 2-cyclohexyl-l-[[2(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yl]methyl]-4-cyclohexylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-phenylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-benzylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,515 d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-420 yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,11-biphenyl]-4yl]methyl]-4-(methoxymethyloxy)-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(methoxy-l-ethyloxy)-7-hydroxy-lH-imidazo[4,5 d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyano-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-formyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(1,1-dimethoxy-isopropyl)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(1-oxo-butyl)-7-hydroxy-ΙΗ-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-45 yljmethyl]-4-(1-oxo-cyclohexyl)-7-hydroxy-1H-imidazo[4,5 d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-7-propyl-4-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[2’(lH-tetrazol-5-yl) [1,1’-biphenyl]-4yl]methyl]-4-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[2(lH-tetrazol-5-yl)[1,1’-biphenyl]-415 yljmethyl]-1H-imidazo[4,5-d]pyridazine; 2-butyl-l-[21- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-pentanoyloxy-7-hydroxy-lH-imidazo[4,5— d]pyridazine; 2-butyl-l-[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-420 yljmethyl]-4-cyclohexanecarbonyloxy-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-butyl-l-[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yljmethyl]-7-(2,2-dimethylpropanoyloxy)-4-hydroxy-lHimidazo[4,5-d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-(2,2-dimethylpropanoyloxy)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-butyl-l-[2'- (lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-bis-(2,2-dimethylpropanoyloxy)-1H30 imidazo[4,5-d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-phenylacetylchloride-7-hydroxy-lH-imidazo[4,5 d]pyridazine; and 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-435 yljmethyl]-4,7-diacetyl-lH-imidazo[4,5-d]pyridazine. c I * 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-lH-imidazo[4,5-d]pyridazin-l-yl)methyl][1,1'biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dichloro-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-lH-imidazo[4,5-d]pyridazin-l-yl-4, 710 diol)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4,7-dithio-lH-imidazo[4, 5-d]pyridazin-lyl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazin-lyl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4,7-diisopropyloxy-lH-imidazo[4,5-d]pyridazin1-yljmethyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-dimethyl-lH-imidazo[4,5-d]pyridazin-l2 0 yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazin-lyl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diphenyl-lH-imidazo[4,5-d]pyridazin-lyl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4 ' - [ (2-butyl-4,7-di (phenylethyl) -IH-imidazo [4,5d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-bis(3-dimethylaminopropylamino)-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 0 4 ' - [ (2-butyl-4,7-diisopropylthio-ΙΗ-imidazo [4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diphenylthio-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-diacetyloxy-ΙΗ-imidazo[4,5-d]pyridazin-135 yl) methyl] [ 1, 1'-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4,7-dibenzoyloxy-lH-imidazo[4,5-d]pyridazin-1yljmethyl][1,1'-biphenyl]-2-carboxylic acid; 4’-[ (2-butyl-4,7-bis(methoxymethyloxy)-lH-imidazo[4,5 — d]pyridazin-l-yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4,7-di-(formyl)-ΙΗ-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4[(2-butyl-7-hydroxy-1H-imidazo[4, 5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-chloro-7-hydroxy-lH-imidazo[4,5-d]pyridazin l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 41-[(2-butyl-4-methyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4' - [ (2-butyl-4-fluoro-7-hydroxy-lH-imidazo[4,5-d]pyridazin l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4-benzyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4-(phenylethyl)-7-hydroxy-lH-imidazo[4, 5 20 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-butyl-4-(2-dimethylaminoethylamino)-7-hydroxy-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[ (2-butyl-4-isopropylthio-7-hydroxy-lH-imidazo[4,525 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4' - [ (2-butyl-4-phenylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 0 4 '-[ (2-methyl-lH-imidazo [4,5-d]pyridazin-l-yl) methyl] [1,1' biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dichloro-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-methyl-lH-imidazo[4,5-d]pyridazin-l-yl-4,735 diol)methyl] [1,1 '-biphenyl]-2-carboxylic acid; 4'-[ (2-methyl-4,7-dithio-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4' - [(2-methyl-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-diisopropyloxy-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazin-l yDmethyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dimethyl-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-methyl-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazin-1 yDmethyl] [1,1'-biphenyl]-2-carboxylic acid; 4[(2-methyl-4,7-diphenyl-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-methy1-4,7-di(phenylethyl)-IH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4 '- [ (2-methyl-4,7-bis(3-dimethylaminopropylamino)-IHimidazo [4,5-d] pyridazin-l-yl) methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[ (2-methyl-4,7-diisopropylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-diphenylthio-lH-imidazo[4,5-d]pyridazinl-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-dibenzoyloxy-lH-imidazo[4,5-d]pyridazin25 l-yl)methyl)[1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5d]pyridazin-l-yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4,7-di-(formyl)-IH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin-lyl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-chloro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4 ' - [(2-methyl-4-methyl-7-hydroxy-lH-imidazo[4,5 35 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-propyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-fluoro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-benzyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-phenyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-methyl-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4 ' - [ (2-methyl-4-(2-dimethylaminoethylamino)-7-hydroxy-lH10 imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-methyl-4-isopropylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4 '-[ (2-methyl-4-phenylthio-7-hydroxy-lH-imidazo[4,515 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-methyl-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-lH-imidazo[4,5-d]pyridazin-l yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dichloro-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-ΙΗ-imidazo[4,5-d]pyridazin-1-y1-4,7diol)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4,7-dithio-lH-imidazo[4,5-d]pyridazin-125 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazinl-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4’-[ (2-isopropyl-4,7-diisopropyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 0 4'- [ (2-isopropyl-4,7-diphenoxy-ΙΗ-imidazo[4,5-d]pyridazinl-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dimethyl-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diisopropyl-lH-imidazo[4,5 35 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-diphenyl-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-di(phenylethyl)-IH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-bis(3-dimethylaminopropylamino)-IHimidazo [4,5-d] pyridazin-l-yl) methyl] [1,1'-biphenyl]-2 5 carboxylic acid; 4'-[ (2-isopropyl-4,7-diisopropylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4[(2-isopropyl-4,7-diphenylthio-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4 ' - [ (2-isopropyl-4,7-diacetyloxy-lH-imidazo [4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-dibenzoyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-bis(methoxymethyloxy)-1H-imidazo[4,515 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4,7-di-(formyl)-IH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1’-biphenyl]-2-carboxylic acid; 0 4’-[ (2-isopropyl-4-chloro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-methyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-propyl-7-hydroxy-lH-imidazo[4,525 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[ (2-isopropyl-4-fluoro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'- [ (2-isopropyl-4-benzyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-phenyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[ (2-isopropyl-4-(2-dimethylaminoethylamino)-7-hydroxy3 5 1H-imidazo[4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2 carboxylic acid; 4' - [(2-isopropyl-4-isopropylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4 ' - [(2-isopropyl-4-phenylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'- [(2-isopropyl-4-isopropanoyloxy-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2 carboxylic acid; 4' - [(2-neopentyl-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4’-[ (2-neopentyl-4,7-dichloro-lH-imidazo[4,5-d]pyridazin-l yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-lH-imidazo[4,5-d]pyridazin-l-yl-4,7diol)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-4,7-dithio-lH-imidazo[4,5-d]pyridazin-115 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazinl-yl) methyl] [1,1’-biphenyl]-2-carboxylic acid; ' - [(2-neopentyl-4,7-diisopropyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazinl-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dimethyl-IH-imidazo[4,5-d]pyridazin-1 yljmethyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diisopropyl-lH-imidazo[4,525 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-neopenty1-4,7-diphenyl-IH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4[(2-neopentyl-4,7-di(phenylethyl)-IH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 0 4'-[ (2-neopentyl-4,7-bis(3-dimethylaminopropylamino)-IHimidazo [4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-neopentyl-4,7-diisopropylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4 ' - [ (2-neopentyl-4,7-diphenylthio-lH-imidazo [4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-diacetyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,11-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-dibenzoyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-bis(methoxymethyloxy)-ΙΗ-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4,7-di-(formyl)-IH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin-110 yl) methyl] [ 1,1'-biphenyl]-2-carboxylic acid; ' - [(2-neopentyl-4-chloro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-methyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-4-propyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-fluoro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl}-2-carboxylic acid; 4'-[(2-neopentyl-4-benzyloxy-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-phenyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'—[(2-neopentyl-4-(2-dimethylaminoethylamino)-7-hydroxy IH-imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[ (2-neopentyl-4-isopropylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-phenylthio-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-isopropanoyloxy-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl] -2 carboxylic acid; 4'-[<2-cyclohexyl-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4[(2-cyclohexyl-4,7-dichloro-lH-imidazo[4,5-d]pyridazinl-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-lH-imidazo[4,5-d]pyridazin-l-yl-4,7 diol)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-dithio-lH-imidazo[4,5-d]pyridazin-lyl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-dimethoxy-lH-imidazo[4,5-d]pyridazin l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diisopropyloxy-lH-imidazo[4,510 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazin 1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-dimethyl-lH-imidazo[4,5-d]pyridazinl-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-diisopropyl-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl)-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diphenyl-lH-imidazo[4,5-d]pyridazinl-yl) methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-di(phenylethyl)-ΙΗ-imidazo[4,520 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-bis(3-dimethylaminopropylamino)-1Himidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4’-[ (2-cyclohexyl-4,7-diisopropylthio-lH-imidazo[4,525 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diphenylthio-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4,7-diacetyloxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 0 4'-[ (2-cyclohexyl-4,7-dibenzoyloxy-lH-imidazo[4,5d]pyridazin-l-yl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4 '-[ (2-cyclohexyl-4,7-bis(methoxymethyloxy)-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4,7-di-(formyl)-ΙΗ-imidazo[4,535 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; ’ - [(2-cyclohexyl-4-chloro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-methyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-propyl-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-fluoro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-benzyloxy-7-hydroxy-lH-imidazo[4,510 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-phenyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-(2-dimethylaminoethylamino)-7-hydroxy1H-imidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-cyclohexyl-4-isopropylthio-7-hydroxy-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-phenylthio-7-hydroxy-lH-imidazo[4,5— d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4-isopropanoyloxy-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yljmethyl]-IH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 3 0 yljmethyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-butyl-l-[[2'—(lH-tetrazol-5-yl)[1,l'-biphenyl]-4yl]methyl J-4,7-dithio-IH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridaz ine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yl]methyl]-4,7-diisopropyloxy-lH-imidazo[4, 5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-dicyclohexyloxy-lH-imidazo[4,5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1’-biphenyl]-4 yl]methyl]-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dimethyl-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 10 yl]methyl]-4,7-diphenyl-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1Himidazo[4,5-d]pyridazine ; 2-butyl-l-[[2'—(lH-tetrazol-5-yl)[1,1'-biphenyl]-41 5 yl]methyl]-4,7-diisopropylthio-lH-imidazo[4,5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-dibenzylthio-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 0 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yl]methyl]-4,7-dibenzoyloxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-bis(methoxymethyloxy)-ΙΗ-imidazo[4,5d]pyridazine; 2-butyl-l-[ [2'-(lH-tetrazol-5-yl) [1,1’-biphenyl]-4yl]methyl]-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,5— d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-dicyano-lH-imidazo[4,5-d]pyridazine; 0 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yl]methyl]-4-chloro-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 3 5 yljmethyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-isopropyl-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yljmethyl]-4-cyclohexyl-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1’-biphenyl]-4 yl]methyl]-4-methoxy-7-hydroxy-lH-imidazo[4,5-d]pyridaz ine 2-butyl-l-[[2’—(lH-tetrazol-5-yl)[1,l'-biphenyl]-41 0 yljmethyl]-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 1 5 yl]methyl]-4-ethylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2’-(lH-tetrazol-5-yl)[1,l'-biphenyl]-4 yljmethyl]-4-benzylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 0 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,5— d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,52 5 d] pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 3 0 yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-lH-imidazo[4,5— d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1’-biphenyl]-4 yljmethyl]-4-(methoxy-l-ethyloxy)-7-hydroxy-lH-imidazo[4,5 d]pyridazine; 2-butyl-l- [ [2 '- (lH-tetrazol-5-yl) [1,1 ’ -biphenyl]-4 yljmethyl]-4-cyano-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-ΙΗ-imidazo[4,5-d]pyridazine-4,7-diol; 2-methyl-l-[ [2' —(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-dithio-lH-imidazo[4, 5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,11-biphenyl]-41 0 yljmethyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diisopropyloxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dicyclohexyloxy-lH-imidazo[4,5-d]pyridazine 2-methyl-l-[ [2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-dimethyl-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-42 0 yljmethyl]-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-diphenyl-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1H2 5 imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diisopropylthio-lH-imidazo[4,5-d]pyridazine 2-methyl-l-[[21 - (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yljmethyl]-4,7-dibenzylthio-lH-imidazo[4,5-d]pyridazine; 0 2-methyl-l-[ [2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yljmethyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-dibenzoyloxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 5 yl]methyl]-4,7-bis(methoxymethyloxy)-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[ [2' -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yl]methyl]-4,7-dicyano-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[21 -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-chloro-7-hydroxy-lH-imidazo[4, 5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropyl-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyl-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-methoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-phenyl-7-hydroxy-IH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-IH imidazo[4,5-d]pyridazine; 2-methyl-l-[[2(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-ethylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-benzylthio-7-hydroxy-lH-imidazo[4,53 0 d] pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 5 yl]methyl]-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(methoxy-l-ethyloxy)-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l- [ [2 (lH-tetrazol-5-yl) [1,1' -biphenyl] -4yl]methyl]-4-cyano-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-ΙΗ-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-41 5 yl]methyl]-4, 7-dichloro-lH-imidazo[4, 5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-1H-imidazo[4,5-d]pyridazine-4,7-diol; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dithio-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diisopropyloxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl] - 42 5 yl]methyl]-4,7-dicyclohexyloxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diphenoxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dimethyl-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'—(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diphenyl-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 5 yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1Himidazo[4,5-d]pyridazine; 2-isopropyl-l-[ [2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yljmethyl]-4,7-diisopropylthio-lH-imidazo[4,5-d]pyridazine 2-isopropyl-l-[ [2' -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dibenzylthio-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dibenzoyloxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-41 0 yljmethyl]-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,5 d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yljmethyl]-4,7-dicyano-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'—(lH-tetrazol-5-yl)[1,1'-biphenyl]-42 0 yljmethyl]-4-chloro~7-hydroxy-lH-imidazo[4, 5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-propyl-7-hydroxy-IH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropyl-7-hydroxy-lH-imidazo[4,52 5 d] pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-cyclohexyl-7-hydroxy-lH-imidazo[4,5— djpyridazine; 2-isopropyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 0 yl]methyl]-4-methoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-isopropyl-l-[[21 -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-phenyl-7-hydroxy-IH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-lH3 5 imidazo [4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-ethylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yl]methyl]-4-benzylthio-7-hydroxy-lH-imidazo[4,5— d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[ [2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yljmethyl]-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5 d]pyridazine; 2-isopropyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,515 d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yllmethyl]-4-cyclohexanoyloxy-7-hydroxy-lH-imidazo[4,5d] pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-42 0 yl]methyl]-4-(methoxy-l-ethyloxy)-7-hydroxy-lH-imidazo[4,5 d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyano-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-42 5 yl]methyl]-ΙΗ-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-ΙΗ-imidazo[4,5-d]pyridazine-4,7-diol; 0 2-neopentyl-l-[ [2 (lH-tetrazol-5-yl) [1,1' -biphenyl] -4yl]methyl]-4,7-dithio-ΙΗ-imidazo[4, 5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'—(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 5 yl]methyl]-4,7-diisopropyloxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dicyclohexyloxy-lH-imidazo[4,5-d]pyridazine 2-neopentyl-l-[[2(lH-tetrazol-5-yl) [1,l'-biphenyl]-4yl]methyl] - 4,7-diphenoxy-ΙΗ-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dimethyl-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[21 - (lH-tetrazol-5-yl) [1,11-biphenyl]-4yljmethyl]-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[ [2' -(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-diphenyl-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[ [2' -(lH-tetrazol-5-yl)[1,1'-biphenyl]-410 yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1Himidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-diisopropylthio-ΙΗ-imidazo[4,5-d]pyridazine 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-41 5 yljmethyl]-4,7-dibenzylthio-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l- [ [2 '- (lH-tetrazol-5-yl) [1-, 1' -biphenyl] -4yl]methyl]-4,7-dibenzoyloxy-1H-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,52 5 d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,11-biphenyl]-4yljmethyl]-4,7-dicyano-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-chloro-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-435 yl]methyl]-4-isopropyl-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexyl-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,l'-biphenyl]-45 yljmethyl]-4-methoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-lH10 imidazo [4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-ethylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-415 yljmethyl]-4-benzylthio-7-hydroxy-lH-imidazo[4,5 d]pyridazine; 2-neopentyl-l-[[2'—(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yljmethyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,52 5 d] pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-cyclohexanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 0 yljmethyl]-4-(methoxy-l-ethyloxy)-7-hydroxy-IH-imidazo[4,5 d]pyridazine; 2-neopentyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-cyano-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 5 yljmethyl]-IH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dithio-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4yl]methyl]-4,7-diisopropyloxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-410 yljmethyl]-4,7-dicyclohexyloxy-lH-imidazo[4,5-d]pyridazine 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-diphenoxy-ΙΗ-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dimethyl-lH-imidazo[4,5-d]pyridazine,· 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diisopropyl-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diphenyl-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-42 0 yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-IHimidazo [4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yljmethyl]-4,7-diisopropylthio-lH-imidazo[4,5-d]pyridazine 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-42 5 yljmethyl]-4,7-dibenzylthio-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dibenzoyloxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,53 5 d] pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-dicyano-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[ [2' -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-7-hydroxy-lH-imidazo[4, 5-d]pyridazine; 2-cyclohexyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-chloro-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-propyl-7-hydroxy-lH-imidazo[4, 5-d]pyridazine; 2-cyclohexyl-l-[[2(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-isopropyl-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-cyclohexyl-7-hydroxy-lH-imidazo[4,5— d] pyridazine; 2-cyclohexyl-l-[[2' -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-methoxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(3-dimethylaminoethylamino)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-ethylthio-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl] - 4yl]methyl]-4-benzyIthio-7-hydroxy-ΙΗ-imidazo[4,52 5 d] pyridazine; 2-cyclohexyl-l-[[2'- (lH-tetrazol-5-yl)[1,1'-biphenyl]-4y1]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 0 yl]methyl]-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5 — d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[ [2' -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(methoxy-l-ethyloxy)-7-hydroxy-IH-imidazo[4,5 d]pyridazine; and 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yl]methyl]-4-cyano-7-hydroxy-lH-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-butyl-lH-imidazo[4,5-d]pyridazin-l-yl)methyl][1,1'biphenyl]-2-carboxylic acid; 4'-[(2-butyl-lH-imidazo[4,5-d]pyridazin-1-y1-4,7 dioDmethyl] [1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-chloro-7-hydroxy-lH-imidazo[4,5-d]pyridazin 1-yDmethyl] [ 1,1'-biphenyl]-2-carboxylic acid; 4’-[(2-butyl-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-butyl-4-(2-dimethylaminoethylamino)-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl] - 2 2 5 carboxylic acid; 4'-[(2-butyl-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-lH-imidazo[4,5-d]pyridazin-1-yl)methyl][1,1' biphenyl]-2-carboxylic acid; 0 4 ’ - [ (2-methyl-lH-imidazo [4, 5-d]pyridazin-l-yl-4,7diol)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-methyl-4-chloro-7-hydroxy-lH-imidazo[4,535 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'- [ (2-methyl-4-propyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4' - [(2-methyl-4-(phenylethyl)-7-hydroxy-IH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4' - [(2-methyl-4-(2-dimethylaminoethylamino)-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 5 carboxylic acid; 4'- [ (2-methyl-4-isopropanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-lH-imidazo[4,5-d]pyridazin-1yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-lH-imidazo[4,5-d]pyridazin-l-yl-4,7diol)methyl][1,1’-biphenyl]-2-carboxylic acid; 4’-[(2-isopropyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-4-chloro-7-hydroxy-lH-imidazo[4,515 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4-propyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-isopropyl-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 0 4'-[ (2-isopropyl-4-(2-dimethylaminoethylamino)-7-hydroxy1H-imidazo[4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2 carboxylic acid; 41-[(2-isopropyl-4-isopropanoyloxy-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl] -2 2 5 carboxylic acid; 4'-[(2-neopentyl-lH-imidazo[4,5-d]pyridazin-1 yljmethyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[ (2-neopentyl-lH-imidazo[4,5-d]pyridazin-l-yl-4,7diol)methyl][1,1'-biphenyl]-2-carboxylic acid; 0 4'-[ (2-neopentyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin-lyl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-chloro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl] [1,1’-biphenyl]-2-carboxylic acid; 4’-[ (2-neopentyl-4-propyl-7-hydroxy-lH-imidazo[4,535 d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-neopentyl-4-(phenylethyl)-7-hydroxy-1H-imidazo[4,5d]pyridazin-l-yl)methyl][1,1’-biphenyl]-2-carboxylic acid; 100 4'-[ (2-neopentyl-4-(2-dimethylaminoethylamino)-7-hydroxylH-imidazo[4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2carboxylic acid; 4'-[(2-neopentyl-4-isopropanoyloxy-7-hydroxy-lH5 imidazo[4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-cyclohexyl-lH-imidazo[4,5-d]pyridazin-lyl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 4' - [(2-cyclohexyl-lH-imidazo[4,5-d]pyridazin-l-yl-4,7 10 diol)methyl][1,1’-biphenyl]-2-carboxylic acid; ' - [(2-cyclohexyl-7-hydroxy-lH-imidazo[4,5-d]pyridazin-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4' - [(2-cyclohexyl-4-chloro-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'—[(2-cyclohexyl-4-propyl-7-hydroxy-lH-imidazo[4,5d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[ (2-cyclohexyl-4-(phenylethyl)-7-hydroxy-lH-imidazo[4,5 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-4-(2-dimethylaminoethylamino)-7-hydroxy20 IH-imidazo[4,5-d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2 carboxylic acid; 4'-[(2-cyclohexyl-4-isopropanoyloxy-7-hydroxy-lHimidazo[4,5-d]pyridazin-l-yl)methyl] [1,1'-biphenyl]-2 carboxylic acid; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yljmethyl]-IH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yljmethyl]-4,7-dichiorο-IH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 0 yljmethyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yljmethyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yljmethyl]-4,7-bis(2-dimethylaminoethylamino)-1H3 5 imidazo [4, 5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yljmethyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 101 2-butyl-l-[[2(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-bis(methoxymethyloxy)-ΙΗ-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-45 y1]methyl]-4,7-bis(methoxy-l-ethyloxy)-ΙΗ-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl)-4 1 0 yl]methyl]-4-chloro-7-hydroxy-lH-imidazo[4, 5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1’-biphenyl]-4yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,52 0 d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-ΙΗ-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-ΙΗ-imidazo[4,5-d]pyridazine-4,7-diol; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 0 yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1Himidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 5 yl]methyl]-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5— d]pyridazine; 102 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-bis(methoxy-l-ethyloxy)-1H-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-45 yl]methyl]-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2’-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-chloro-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-methyl-l-[[2 * -(lH-tetrazol-5-yl) [1,1’-biphenyl]-4yljmethyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-methyl-l-[ [2'-(lH-tetrazol-5-yl) [l,l'-biphenyl]-4yl]methyl]-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,5 d]pyridazine; 2-methyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'—(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-1H-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-lH-imidazo[4,5-d]pyridazine-4,7-diol; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-42 5 yljmethyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2’—(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-IHimidazo [4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 0 yljmethyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'—(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 5 yljmethyl]-4,7-bis(methoxy-l-ethyloxy)-1H-imidazo[4,5d]pyridazine; 103 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-chloro-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4yl]methyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,l'-biphenyl]-4yl]methyl]-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-410 yljmethyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-42 0 yljmethyl]-lH-imidazo[4,5-d]pyridazine-4,7-diol; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2’- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4,7-bis(2-dimethylaminoethylamino)-1H2 5 imidazo [4,5-d]pyridazine,· 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4, 7-bis(methoxymethyloxy)-lH-imidazo[4,53 0 d] pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,5 d]pyridazine; 2-neopentyl-l-[[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 5 yl]methyl]-7-hydroxy-lH-imidazo[4, 5-d]pyridazine; 2-neopentyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-chloro-7-hydroxy-lH-imidazo[4,5-d]pyridazine 104 2-neopentyl-l-[[21 -(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-neopentyl-l- [ [2'- (lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,5 d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,510 d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-IH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yllmethyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-42 0 yljmethyl]-4,7-bis(2-dimethylaminoethylamino)-1Himidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-42 5 yljmethyl]-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-7-hydroxy-lH-imidazo[4, 5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-chloro-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-43 5 yl]methyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-pheny1-7-hydroxy-IH-imidazo[4,5-d]pyridazine 105 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[2'- (lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-7-propyl-4-hydroxy-lH-imidazo[4,5-d]pyridazine 2-butyl-l-[2'(lH-tetrazol-5-yl)[1,1’-biphenyl]-41 0 yl]methyl]-4-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[2’-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-pentanoyloxy-7-hydroxy-lH-imidazo[4,51 5 d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexanecarbonyloxy-7-hydroxy-1Himidazo[4,5-d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-42 0 yljmethyl]-7-(2,2-dimethylpropanoyloxy)-4-hydroxy-lHimidazo[4,5-d]pyridazine; 2-butyl-l-[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(2,2-dimethylpropanoyloxy)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4y1]methyl]-4,7-bis-(2,2-dimethylpropanoy1oxy) -1Himidazo[4,5-d]pyridazine; 2-butyl-l-[2'- (lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-phenylacetylchloride-7-hydroxy-lH-imidazo[4, 0 d]pyridazine; and 2-butyl-l-[2(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diacetyl-lH-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: 106 41 — [(2-butyl-lH-imidazo[4,5-d]pyridazin-l-yl)methyl][1,1'biphenyl]-2-carboxylic acid; 4'-[(2-butyl-lH-imidazo[4,5-d]pyridazin-l-yl-4,7diol)methyl][1,1’-biphenyl]-2-carboxylic acid; 4[(2-methyl-lH-imidazo[4,5-d]pyridazin-l-yl-4,7diol)methyl][1,1’-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-lH-imidazo[4,5-d]pyridazin-l-yl-4,7diol) methyl][1,1'-biphenyl]-2-carboxylic acid; ’-[ (2-neopentyl-4-propyl-7-hydroxy-lH-imidazo[4,510 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-lH-imidazo[4,5-d]pyridazin-lyl) methyl] [1,1'-biphenyl]-2-carboxylic acid; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yljmethyl]-4,7-dichloro-ΙΗ-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-IH-imidazo[4,5-d]pyridazine-4, 7-diol; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yljmethyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 2 0 yl]methyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yljmethyl]-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-42 5 yl]methyl]-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yljmethyl]-4-phenyl-7-hydroxy-lH-imidazo[4, 5-d]pyridazine; 0 2-butyl-l-[ [2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,5— d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,53 5 d] pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine; 107 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4ylJmethyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-IH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-41 0 yljmethyl]-IH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenylJ-4yljmethyl]-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yljmethyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-42 5 yljmethyl]-7-propyl-4-hydroxy-lH-imidazo[4,5-d]pyridazine 2-butyl-l-[2'(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-hydroxy-lH-imidazo[4, 5-d]pyridazine; 2-butyl-l-[2'- (lH-tetrazol-5-yl) [1,1’-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine; 0 2-butyl-l-[2 '- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yljmethyl]-4-pentanoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-butyl-l-[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-cyclohexanecarbonyloxy-7-hydroxy-1H3 5 imidazo [4,5-d]pyridazine; 108 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-7-(2,2-dimethylpropanoyloxy)-4-hydroxy-1Himidazo[4,5-d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-45 yl]methyl]-4-(2,2-dimethylpropanoyloxy)-7-hydroxy-1Himidazo[4,5-d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis-(2,2-dimethylpropanoyloxy)-1Himidazo[4,5-d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4-phenylacetylchloride-7-hydroxy-lH-imidazo[4,5 d]pyridazine; and 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1’-biphenyl]-4yl]methyl]-4,7-diacetyl-lH-imidazo[4,5-d]pyridazine. 109 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: CHCI 3 = chloroform DMF dimethy1formamide 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'-azobisisobutyronitri. 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 Nbromosuccinimide in the presence of AIBN in a suitable 110 solvent such as carbon tetrachloride. The resulting benzyl bromide 2 is used to alkylate a 4,5-dicarboxyimidazole 2A 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 0 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 2 are obtained by a cyclocondensation reaction between the imidazole 4 and hydrazine. Depending on the reactivity of the imidazole 2, 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 2 is obtained from the corresponding ester 2 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. 111 SCHEME 1 R1CO tl R2CO R39 3.

KtBuO or NaH in DMF wherein R = CH3 or C(CH3)3; and R39 is as defined above. 112 In Scheme 2, a biphenylcarboxylic acid ester 7 is converted to the cyanoderivative £ by a method described by J. A. Krynitsky et al fOrg. Synth. Coll., 2, 698 (1955) ] and J. Cason fOrg. 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 £. The cyano derivative £. is reacted by a 1,3dipolar cycloaddition with trialkyltin azide to produce the corresponding tetrazole 2 as described by K. Sisido et al fJ. Qrganometal. Chem.. £2, 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 2 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. 113 SCHEME 2 ILL 114 In Scheme 3, the bromomethylbiphenyl tetrazole 11 is used to alkylate a 4,5-dicarboxyimidazole 13. 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 15 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. 115 SCHEME 3 wherein R1, R2 and R39 are as defined above. 116 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 17 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 19 is formed which can be subsequently converted into a dialkoxy compound 20 by treatment with a halide, alkyltosylate 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. 117 SCHEME 4 OH wherein R1, R2 and R39 are as defined before 118 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-dimethoxycarbonylimidazole. 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 0 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 23. The adehyde-ester 23 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, 119 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 0 aqueous acetic acid. 120 SCHEME 5.

COOMe n-Bu CHO , COOMe CH2-BT2 j CHO CH2BT2 22. 1. n2h4 CHC^reflux; 16hr 2. MeOH/MeONa NB: BT2 = biphenyl trityl tetrazole 121 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 t25 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 29 122 which can be easily separated by a chromatographic procedure or by crystallization. The pyridazine 27 is obtained by a cyclocondensation reaction between the imidazole 24 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 0 derivative 27 is obtained directly from the reaction mixture. 123 SCHEME 6 1· H2SO4,HNO3 HO. .COOH ?· NH3 3. Valeraldehyde 4. MeOH,H2SO4H0 COOH n-Bu-^ j ,COOMe j Li(C2H5)3BH,THI 2. HCI H COOMe XCH2OH H COOMe 2£ XCH2OH CsCO3,AcCN 16h; 25°C 90% n-Bu—jf Ν*χ, ,COOMe I COOMe CH2 bt2 ch2oh ch2bt2 MnO2 AcCN, (80%) CHO n-Bu —(' Ύ ___ I ‘COOMe CH2-BT2 N ι NH NB Bt2 = biphenyl trityl tetrazole. 124 Scheme 7 describes a general procedure for preparation of ester derivatives.

A solution of 2-butyl-l-[2'-(lH-tetrazol-5-yl) [1,1'5 biphenyl]-4-yl]methyl]-4,7-bis-hydroxy-1H-imidazo[4,5d]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). 125 SCHEME 7 R = alkyl, aryl, aralkyl 126 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. 127 4’-Γ[2-butyl-lH-imidazo f4.5-d1pyridazin-l-ylImethvll-fl,11 biphenyl1- 2- carboxylic acid: The target compound was prepared through the intermediates described in steps below: 0 Step 1: 2-n-butyl-lH-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 (S1O2, MeOH-CHCl3/l-5).

IH NMR (CDCl 3, 6 ppm) : 9.9 (bs, IH) ; 3.8 (s, 6H) ; 2.65 (m, 2H) ,· 1.6 (m, 2H) ; 1.25 (m, 2H); 0.8 (m, 3H) . 128 Step 2 :_1-f2-(trimethylsilyl)ethoxy1methyl-2-n-butyl-lHimidazole-4.5-dicarboxylic acid, dimethyl ester: The diester (23g, mw = 240, 96 mmol) was dissolved in 300 5 mL DMF. Potassium t-butoxide (100 mL of a 1M 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 (SiC>2, MeOH-CHCl3/l-10) a single major spot was observed. This crude product (38g,) was used in subsequent steps without further purification.

-H 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, CH3C); 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)ethoxy1methyl-2-n-butyl-4,5di-(hydroxymethyl)-1H-imidazole: The protected diester prepared above (lOg, 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 1M 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 129 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. !h NMR (CDCI3, δ ppm) : 5.3(s, 2H, N-CH2-O) ; 4.65 (s, 2H, CCH2-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-S1); 0.0 (s, 9H, CH3-S1) .

Step 4: 2-n-butyl-4.5-di-(hydroxymethyl)-ΙΗ-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.

Ih NMR (DMSO-dg, δ ppm): 11.5 (bs, IH); 4.2 (bs, 4H); 2.45 (t, 2H); 1.6 (m, 2H); 1.3 (m, 2H); 1.85 (t, 3H).

Step 5: 4'-rf2-butyl-4,5-bis(hvdroxymethvl)-lH-imidazol-lyllmethymifllrbirphenyn-2-carboxylic. acid, methyl ester: 0 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 130 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.ΧΗ NMR (CDC13 , δ ppm): 7.85 (d, IH); 7.5 (t, IH); 7.4 (t IH); 7.35 (d, IH) ; 7.3 (d, 2H) ; 7.1 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. 0 Step 6:_4 1-Γf2-butyl-4,5-bis(carboxaldehyde)-lH-imidazol1-vllmethyl]-il,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 (CDC13, δ ppm) : 10.35 (s, IH) ; 10.1 (s, IH); 7.85 (d, IH) ; 7.6 (t, IH) ; 7.5 (t, IH) ; 7.4 7.1 (d, 2H) ; 5.7 (s, 2H) ; 3.60 (s, 3H) ; 2.7 (t, 2H, C-CH2C); 1.65 (m, 2H, C-CH2-C); 1.30 ( m, 2H); 0.95 (t, 3H). 0 step 7;_4’-ff2-butyl-lH-imidazor4,5-d1pyridazin-1 vl1methvll-ί1.1'-biphenvll-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 131 S1O2 with 5% ethanol in chloroform. The fractions containing a product with Rf = 0.1 (S1O2, 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). 0 Step 8: 4'-ίi2-butyl-lH-imidazoΓ4.5-dl pyridazin-1yl)methyl)-f1.11-biphenyl1-2- carboxylic acid: The product isolated from the previous step was hydrolyzed 15 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). 3HNMR (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) ; .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. 132 Example 2 4'-Γr2-butyl-lH-imidazoi4.5-dlpyridazin-l-yl-4,7diol1 methyl!-(1.1'-biphenyl!- 2- carboxylic acid: Step 1:_4 '-Γ Γ2-butyl-4.5-bis(methoxycarbonyl)-lH-imidazoll-yl]methyll-fl«1biphenyl!- 2-carboxylic acid, t-butyl ester: The imidazole (1.2g, 5 mmol) was dissolved in 20 mL dry DMF, and 5 mL of a 1M 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 1 - {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 0 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 (Rf = 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 IH NMR. 1H NMR ( CDC13 , δ ppm): 7.8 (d, IH) ; 7.65 (t, IH); 7.6 (t, IH); 7.25 (d, IH); 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) ; 0 1.35 (m, 2H); 1.25 (s, 9H); 0.9 (t, 3H) . 133 Step-2:_4'— Γr2-butyl-lH-imidazor4,5-dlpyridazin-l-yl-4,7diollmethyll-Fl.1'- biphenyll- 2- carboxylic acid, t-butyl 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 0 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 recrystaliized from acetone/ethyl acetate (150 mg, m.p. - 206.5-206.8°C). 2H NMR (CD3OD , δ ppm) : 7.6 (d, IH) ; 7.4 (t, IH) ; 7.3 (t, IH) ; 7.2 (d, IH); 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 ’- Γ r2-butyl-lH-imidazor4.5-dlpyridazin-l-yl-4.7diollmethyl!-fl,1'-biphenyll- 2- carboxylic acid: The t-butyl ester prepared above was dissolved in a mixture of 5 mL TFA and 5 mL di chloromethane 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) 2H NMR ( CD3OD , δ ppm) : 8.1 (d, IH) ; 7.64 (t, IH); 7.5 (t, IH) ; 7.35 (d, IH) ; 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. 134 Example 3 2-butyl-4,7-dichloro-l-Γ2(lH-tetrazol-5-yl) Π, 1' biphenyl1-4-yl1 methyl1-ΙΗ-imidazo ί 4.5-dlpyridazine: Step 1:_2-Butyl-4. 7-dihydroxyimidazo f 4,5-dlpyridazine: 0 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-dg & 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-dichloroimidazof4.5-dipyridazine: 2-Butyl-4,7-dihydroxyimidazo[4,5-d]pyridazine (320 mg, 1.5 mmol), 320 uL Ν,Ν-dimethylaniline and 8 mL phosphorus oxychloride were mixed together and stirred under an argon atmosphere for lh. 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. 0 This solution was extracted with chloroform and the residue 135 (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, 0 44.14; H, 4.11, 4.12; N, 22.58, 22.78.

Step 3:_N-triphenylmethyl-5-f2-(41-bromomethylbiphen-2yl 1 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 0 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) 8 2.40 (S, 3H), 7.17-7.28 (m, 4H), 7.35-7.45 (m, 2H), 7.51-7.59 (m, IH) , 7.90-7.97 (m, IH). The crude acid was suspended in 1 L of toluene and slowly treated with 400 g (3.15 mol) 0 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: 136 mp 128-130°C; NMR (CDCI3) 52.40 (s, 3H) , 5.28 (br s, IH), 5.77 (br s, IH), 7.21-7.53 (m, 7H), 7.76-7.83 (m, IH). The crude amide was treated with 1420 mL (19.5 mol) of thionyl chloride at reflux for 3.5 h. The reaction was filtered and 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) 52.42 (s, 3H), 7.22-7.34 (m, 2H) , 7.37-7.52 (m, 3H), 7.58-7.66 (m, IH), 7.72-7.78 (m, IH). 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 600g of crude N-trimethylstannyl-5[2-(4'-methylbiphen-2-yl]tetrazole: mp 271-272°C (dec.); NMR (DMSO-dg) 50.36 (br t, J=34 Hz, 9H), 2.24 (s, 3H), 6.89-7.06 (m, 4H), 7.35-7.55 (m, 4H). The crude Ntrimethylstannyl tetrazole was suspended in 4270 mL of toluene and 287 mL of anhydrous tetrahydrofuran (THF) and treated with 63.4g (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) 52.28 (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 (MgSO^), 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) 52.27 (s, 3H), 6.86-6.96 (m, 8H), 6.98-7.04 (m, 2H), 7.09-7.52 (m, 12H), 7.86-7.94 (m, IH). The N-triphenylmethy1 tetrazole 137 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-2yl)]tetrazole as a colorless solid: mp 140-142°C; NMR (CDC13) 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, 0 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-l-(21 -fN-triphenylmethyl-lH-tetrazol-5yl)-Π.1'-biphenyl1-4-yllmethyl)-IH-imidazof 4.5dlpyridazine-4,7-dichloro: Tin aliquot of 200 mg of the 2-butyl-4,7dichloroimidazo[4,5-d]pyridazine (mw 245; 0.8 mmol) was dissolved in 5 mL dry dimethyl formamide. Potassium tbutoxide (0.8mL; 1M solution) was added and the solution stirred at 25°C for 15 minutes. An equimolar amount of (Ntriphenylmethyl-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 (Rf = 0.5 in hexane/ethyl acetate 2/1) and identified by NMR.

FABMS (calcd C42H34N8C12, found M + Li+) : 720.7, 727 (dichloro isotopic pattern). 138 Step 5:—2-butyl-l-(2flH-tetrazol-5-yl)- fl,1'-biphenyl!4-yl1 methyl)-1H-imidazo Γ4.5-dlpyridazine-4.7-dichloro: The product (100 mg) obtained above is stirred in 25 ml of 5 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 C23H20N8C12Z found M + H + ) : 479.3, 479 (dichloro isotopic pattern). 139 Example 4 OH N N NH 2-butyl-l-(2' - ΓlH-tetrazol-5-yl) - Γ1,1'-biphenyl1-4 yl1 methyl)-IH-imidazo ί4.5-d1pyridazine-4.7-diol: Step 1;_2-butyl-l-(21-rN-triphenylmethyl-lH-tetrazol-5yl)-fl,1'-biphenyl1-4-yllmethyl)-lH-imidazo-4.5dicarboxylic acid methyl ester: Tin 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; o 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.

^HNMR (CDCl 3, δ ppm) : 7.95-6.75 (unresolved signals; 23 H); .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). 140 Step 2 ;_2-butyl-l-121-ΓlH-tetrazol-5-yl) -Γ1.1'-biphenyl1 4-yl)methvl)-IH-imidazo-4,5-dicarboxylie acid methyl ester: The compound isolated above (2g, 2.7 mmol) was dissolved in 5 100 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. J:_2-butyl-l-f2'-[lH-tetrazoltS-yD-Γ1,l'-biphenylJ4-yllmethyl)-lH-imidazol4,5-d)pyridazine-4,7-diol: 2-butyl-l-{2’ — [lH-tetrazol-5-yl)-[1,1'-biphenyl]-4 25 yl]methyl}-lH-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. 0 ^HNMR (CDCI3, δ ppm) : 7.65 (m; IH); 7.4 (m, 2H) ; 7.25 (m, IH); 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. 141 Example 5 OC2H5 N N.

NH 2-butvl-4.7-diethoxv-l-{21-flH-tetrazol-5-yl) -ί1,1'bipheny11-4-yllmethylΪ-1Η-imidazo f 4,5-dlpyridazine: Step,1;_l-Benzyl-2-butyl-4,7-diethoxyimidazo (4,5dlpyridazine: An aliquot of 210 mg of the 2-butyl-4,7dichloroimidazo[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, o 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 .

Sb.eP-2;_2-butyl-4,7-diethoxyimidazo f 4,5-dl pyridazine: The l-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 142 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-l-(2'-ΓlH-tetrazol-5-yl)-f1.1'-biphenyl1 4-yl1methyl)-ΙΗ-imidazo f 4.5-dlpyridazine-4.7-diethoxy: An aliquot of 250 mg of the 2-butyl-4,710 diethoxyimidazo[4,5-d]pyridazine (mw 264; 0.9 mmol) was dissolved in 5 mL dry dimethylformamide. Potassium tbutoxide (0.8 mL; 1M solution) was added and the solution 0 stirred at 25 C for 15 minutes. An equimolar amount of (Ntriphenylmethyl-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) 0 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. 143 EXAMPLE #6 N-N H n-butyl—^ N N OH 2-butyl-l-[21 -(lH-tetrazol-5-yl) Γ1.1'-biphenyl1-4vl1methvl1-4-propyl-7-hydroxv-lH-imidazo[4,5-dipyridazine Step 1: Preparation of 2-butyl-l-Γ2'-(N-triphenylmethyllH-tetrazol-5-yl) fl,1'biphenyl1-4-yllmethvl1-4- (1oxobutyl)-5-methoxy carbonyl-ΙΗ-imidazole.

The diester 2-butyl-l-[21-(N-triphenylmethyl-1Htetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]4,5-bis methoxycarbonyl-lH-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 l/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 144 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-l5 [2’-(N-triphenylmethyl-lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-5-(1-oxo-butyl)-4-methoxy carbonyl-lHimidazole), was eluted next and isolated as a white solid (2.63 g). 0 Step 2.1_Preparation of 2-butyl-l- ί21 - (N-triphenylmethyl lH-tetrazol-5-yl) fl.1'-biphenyl1-4-yllmethy11-4-propvl-7hydroxy-lH-imidazo f 4.5-dlpyridazine.

The ketoester 2-butyl-l-[2'-(N-triphenylmethyl-lH15 tetrazol-5-yl)[1,1’-biphenyl]-4-yl]methyl]-4-(1-oxo-butyl)5-methoxycarbonyl-lH-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. 145 Step 3:_Preparation of 2-butyl-l-Γ21-(lH-tetrazol-5yl) ί1,1'-biphenyl1-4-yllmethyl!-4-propyl-5-hydroxy-lHimidazo ί4 , 5-dlpyridazine.

The protected pyridazine, 2-butyl-l-[2'-(Ntriphenylmethyl-lH-tetrazol-5-yl)[1,1'biphenyl]-4yl]methyl]-4-propyl-5-hydroxy-lH-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.): 3H 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 C26H28N80i, observed): 469.2464, 469.2457. 146 EXAMPLE #7 OH I N 2-butvl-l-f21 -(lH-tetrazol-5-yl) il.l,-biphenyl1-4vllmethyl1-7-propyl-4-hvdroxy-lH-imidazo[4,5-dipyridazine A solution of 0.25 g of 2-butyl-l-[2(N10 triphenylmethyl-lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-5-(1-oxo-butyl)-4-methoxy carbonyl-ΙΗ-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: ^H NMR (DMSO-d6) d 12.5 (s, IH), 7.5-7.75(m, 4H), 7.0(m, 4H), .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 C26H28N20 observed) 469.2464, 469.2425. 147 EXAMPLE #8 H 2-butyl-l-(21 -(lH-tetrazol-5-yl) Γ1,1'-biphenyll-4yllmethyl1-7-hydroxy-lH-imidazo f 4,5-dlpyridazine Step 1:_Preparation of 2-butyl-4-hydroxymethyl~5methoxycarbonyl-imidazole. 0 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 0 (200 g) was prepared on a large fritted filter, the freeflowing 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 148 combined and concentrated to give ~ 14.0 g of a yellow glass.

Step 2:_Preparation of 2-butyl-l-Γ2(N-triphenylmethyl 5 lH-tetrazol-5-yl) Γ1,1'-biphenyl-4-yllmethyl1-4hydroxymethyl-5-methoxycarbonyl-lH-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-2yl)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 7hydroxymethylimidazole. This mixture was used as such in the subsequent oxidation step.

Step 3:_Preparation of 2-butyl-l-f2'(N-triphenyImethyl-1Htetrazol-5-yl) il,1'-biphenyll-4-yllmethyl1-4 carboxaldehyde-5-methoxycarbonyl-lH-imidazole.

The alcohol/ester 2-butyl-l-[2'-(N-triphenylmethyl-lHtetrazol-5-yl)[1,1'-biphenyl-4-yllmethyl]-4-hydroxymethyl5- methoxycarbonyl-lH-imidazole (52 g) was dissolved in AcCN, MNO2 (52 g) was added and the reaction mixture 0 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 c149 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-l-f2'-(lH-tetrazol-5yl) il,1’-biphenyl!-4-yllmsthyl]-Inhydroxy-lH-imidazof4,5r dlpyridazine.

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; IOOA). The fractions were analyzed by analytical HPLC, the appropriate 150 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) : 2H NMR (DMSO-d6) 3l2.4(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, 25.65 151 EXAMPLE #9 2-butyl-l-Γ2' (lH-tetrazol-5-yl) ri,l'-biphenyn-4yl1 methyl1-4-hydroxy-lH-imidazo14,5-dlpyridazine Step 1:_Preparation of 2-butyl-4(5)-carboxaldehyde-(5)4 carbomethoxv-imidazole. 0 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, 1M in CH2CI2, 100 mmol) was added over 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 ~lh 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%) . 152 The aqueous phase was basified to pH ~ 8 with NaHCC>3 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 (S1O2, 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-l-Γ2'-(N-triphenylmethyllH-tetrazol-5-yl) ί 1,11-biphenyl1-4-yl1 methyl1-5 carboxaldehyde-4-methoxycarbonyl-lH-imidazole.

The aldehyde prepared in step 1 (2 g, 9.5 mmol) and 0 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-2yljtetrazole (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 (MgSO^) 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 0 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-l-[2'(N-triphenylmethyl-lHtetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-4 carboxaldehyde-5-methoxycarbonyl-lH-imidazole, isolated as a white foam, 3.7 6 g. 153 Step 3:_2-butyl-l-f2(lH-tetrazpl-5-yl)..I.l,,±l-biphenyl 1 ~4~ yllmethyl)-4-hydroxy-lH-imidazo f 4.5-d)pyridazine.

The aldehyde/ester 2-butyl-l-[2(N-triphenylmethyl5 lH-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-5 carboxaldehyde-4-methoxycarbonyl-lH-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 0 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 Ci8 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: 1H NMR (DMSO) d 12.3(S, IH) , 8.4(s, IH) , 7.657.78(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+ 023Η22Ν8θΐ; observed): 427.1995; 427.1974. 154 EXAMPLE #10 2-butyl-l-i2(lH-tetrazol-5-yl) ri,l'-biphenyll-4yllmethyl1-1H-imidazoΓ4,5-dlpyridazine Step 1:_Preparation of 2-butvl-1-f2'-(N-triphenylmethyl10 lH-tetrazol-5-yl) fl,1'biphenyl!-4-yllmethyl]-4,7-biscarboxaldehvde-lH-imidazole.

The 2-butyl-l-[2'-(N-triphenylmethyl-lH-tetrazol-5yl) [1,1'-biphenyl]-4-yl]methyl]-4,7-bis-hydroxymethyl-1H 1 5 imidazole (100 mg) was dissolved in AcCN and 150 mg Mn02 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 Mn0 2 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. 155 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-l-f2'-(lH-tetrazol-5yl) f 1,l'-biphenyl1-4-yninethyn-lH-imidazo[4,5dlpyridazine.

The 2-butyl-l-[2'-(N-triphenylmethyl-lH-tetrazol-510 yl)[1,1'-biphenyl]-4-yl]methyl]-4,7-bis-carboxaldehyde-lHimidazole (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 SiC>2 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) : 1H NMR (CHCI3) d 9.35(s, IH) , 9.14(s, IH) ; 7.95(m, IH) 7.43(m, 2H), 7.30(d, IH, J= 8Hz), 6.95(m, 4H) , 5.4 (s, 2H), 2.95 (t, 2H, jl = 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. 156 EXAMPLE #11 H 2-butyl-l-Γ2(lH-tetrazol-5-vl) il, I.'-biphenyl]-4r yl]methyl!-4-pentanoyloxy-7-hydroxy-lH-imidazo(4.5dlpyridazine A solution of 2-butyl-l-[2(lH-tetrazol-5-yl)[1,1'biphenyl]-4-yl]-4,7-bis-hydroxy-lH-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: ^-H 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 C28H30N8°3 obs.) M+H = 527, M+Na 549. 158 EXAMPLE #12 O H 2-butyl-l-F2'-(lH-tetrazol-5-yl) Π,1'-biphenyl!-4yl!methyl!-4-(2-methyl-propanoyloxy)-7-hydroxy-lH1 0 imidazo ί4,5-dlpyridazine A solution of 2-butyl-l-[2'-(lH-tetrazol-5-yl) [1,1' biphenyl]-4-yl]-4,7-bis-hydroxy-lH-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 HCI, then extracted with ethyl acetate. The ethyl acetate was dried over MgSC>4 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) : 3H NMR (DMSO-d6) δ7.70-7.50(m, 4H), 7.20IE 912042 159 7.06(m, 4H), 5.76(s, 2H), 3.01-2.94(m, IH) , 2.74(m, 2H) 1.60-1.49(m, 2H), 1.34-1.22(m, 8H), 0.87-0.77(m, 3H). 160 EXAMPLE #13 2-butyl-l-[2’-(lH-tetrazol-5-yl)[1.l'-biphenyll-4yllmethyl1-4-cyclohexanecarbonyloxy-7-hydroxy-lHimidazo f4.5-dipyridazine A solution of 2-butyl-l-[2(lH-tetrazol-5-yl)[1,1'10 biphenyl]-4-yl]-4,7-bis-hydroxy-lH-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) : XH NMR (DMSO-d6) δ 7.7020 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), 0.88-0.75(m, 3H). 161 EXAMPLE #14 nC4H9 OH N N O-CC(CH3)3 N-N H II 2-butyl-l-f2'-(lH-tetrazol-5-yl) fl,1'-biphenyl1-4yllmethyll-7-(2,2-dimethvlpropanoyloxy)-4-hvdroxy-lHimidazof4,5-dlpyridazine A solution of 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1'biphenyl]-4-yl]-4,7-bis-hydroxy-lH-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 MgSC>4 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: 2H 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. 162 EXAMPLE #15 O H 2-butyl-l-i2(lH-tetrazol-5-yl) Γ1,11-biphenyl1-4ynmethyn-4- (2, 2-dimethylpropanoyloxy) -7-hydroxy-lHimidazof4.5-dipyridazine 0 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: ^H NMR (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. 163 EXAMPLE #16 O H 2-butyl-l-r2-'-U.H-tetrazol-5-yl) il, 1'-biphenyl!-4vl!methyl!-4.7-bis-(2,2-dimethylpropanoyloxy)-IHimidazo f4.5-d!pyridazine 0 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: 3H NMR (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), 1.681.55(m, 2H) , 1.38-1.28 (m, 2H) , 1.13(s, 9H) , l.ll(s, 9H) , 0.83 (t, 3H, 2 = 7Hz); MS. Calc'd for M+H: 611. 164 EXAMPLE #17 O H 2-butyl-l-Γ2(lH-tetrazol-5-yl) flfl’-biphenyn-4yl1 methyl1-4-phenylacetylchloride-7-hydroxy-lH-imidazoΓ 4,5dl pyridazine A solution of 2-butyl-l-[2'(lH-tetrazol-5-yl) [1,1'biphenyl]-4-yl]methyl]4,7-bis-hydroxy-lH-imidazo[4,5djpyridazine (0.5 g, 1.1 mmol) and triethylamine (0.31 mL, 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 MgSC>4 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) : 1H NMR (CDCI3): δ 11.0 (bs, IH) , 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 + ) 165 561; Elemental Analysis Calc'd: C, 66.4; H, 5.03; N, 19.98 Found: C, 66.0; H. 4.89; N, 19.80 166 EXAMPLE #18 O H 2-butyl-l-Γ2'-(lH-tetrazol-5-yl) Ii.11-biphenyl)-4yl) methyl1-4.7-diacetyl-lH-imidazo ί 4.5-d)pyridazine A solution of 2-butyl-l-[2'-(lH-tetrazol-5-yl) [1,1'10 biphenyl]-4-yl]-4,7-bis-hydroxy-lH-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 MgSC>4, then concentrated in vacuo to give 640 mg 0 (55.3% yield) of a white solid: 3H 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) , 1.621.46(m, 2H) , 1.34-1.21(m, 2H), 0.88-0.78(t, 3H, J = 7Hz,); MS. Found for M+H: 559 167 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. 122I-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 fEndocrinology. 106. 120-124 (1980)]. Rat uterine membranes were prepared from fresh tissue. All procedures were carried out at 4°C. Uteri were stripped of fat and homogenized in phosphate-buffered saline at pH 7.4 containing 5 mM EDTA. The homogenate was centrifuged at 1500 x g for 20 min., and the supernatant was recentrifuged at 100,000 x g for 60 min. The pellet was resuspended in buffer consisting of 2 mM 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 Tris25 HCl, pH 7.5 and 222I-AII (approximately 102 cpm) in the absence or in the presence of unlabelled ligand. The reaction was initiated by the addition of membrane protein and the mixture was incubated at 25°C for 60 min. The incubation was terminated with ice-cold 50 mM Tris-HCl (pH 7.5) and the mixture was filtered to separate membranebound labelled peptide from the free ligand. The incubation tube and filter were washed with ice-cold buffer. Filters were assayed for radioactivity in a Micromedic gamma counter. Nonspecific binding was defined as binding in the presence of 10 μΜ of unlabelled All. Specific binding was calculated as total binding minus nonspecific binding. The receptor binding affinity of an All antagonist compound was indicated by the concentration (IC50) of the tested All antagonist which gives 50% displacement of the total 168 specifically bound 335i-aii from the high affinity (Type 1) All receptor. Binding data were analyzed by a nonlinear least-squares curve fitting program. Results are reported in Table I.

Assay B; In vitro Vascular Smooth Muscle-Response for All 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 FT03 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 NaHCOg, 15 KCl, 1.2 NaH2P04, 1.2 MgS04, 2.5 CaCl2, and 11.4 glucose. The preparations were equilibrated for one hour before approximately one gram of passive tension was placed on the rings. Angiotensin II concentration-response curves were then recorded (3 X 10_1θ to 1 X 10-3 M). Each concentration of All was allowed to elicit its maximal contraction, and then All was washed out repeatedly for 30 minutes before rechallenging with a higher concentration of All. Aorta rings were exposed to the test antagonist at 10-5 M for 5 minutes before challenging with All. Adjacent segments of the same aorta ring were used for all concentration-response curves in the presence or absence of the test antagonist. The effectiveness of the test compound was expressed in terms of pA2 values and were calculated according to H.O. Schild (Br. J. Pharmacol. Chemother,, 2,189-206 (1947)]. The pA2 value is the concentration of the antagonist which 169 increases the EC5Q 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 All injections. The last two All injections were averaged and were taken as the control All pressor response. Ten minutes after the final control All injection, the test compound (dissolved in sodium bicarbonate) was administered i.d. at a dose of 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 170 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. 171 TABLE I In Vivo and In Vitro Angiotensin II Activity of Compounds of the Invention Test -'-Assay A 2 Assay b 3Assays q ancj □ Compound IC5Q pA2 Dose Inhibition Duration Example # (nM) (mg/kg) . . .(%) . (min.) 1 720 5.3 100* 45 90 10 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 15 7 400 6.4 NT 8 11 8.2 3 40 >240 9 230 6.5 NT 10 170 6.5 NT 11 37 9.21/9.17 10* 70 120 20 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 25 17 40 9.42/9.12 3 45 >180 18 40 9.25/8.80 3 35 >240 1 Assay A: Angiotensin II Binding Activity2 Assay B: in Vitro Vascular Smooth Muscle Response 303 As says 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). 172 Assay E: In Vivo Intravenous Pressor Assay Response for All Antagonists In accordance generally with the procedures as 5 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 U In Vivo Inhibition of All Pressor Response in Anesthetized Rat by Compound Ex. #4 Dose All Pressor Inhibition (mcj/kcr) % Mean se: 0.01 20% 3% 0.04 49% 1% 0.14 71% 4% 0.44 94% 6% 173 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 nontoxic, 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 174 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 subdoses 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 hydroxypropylmethy1 cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile 175 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 (47)

1. A compound of Formula I: wherein m is a number selected from one to four, inclusive; wherein each of R 1 through R 11 and R 3 9 is independently 10 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, 15 nitro, carboxyl, formyl, alkylcarbonyloxy, cycloalkylalkoxy, alkoxyalkoxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, aroyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, 20 alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyi, 25 araikylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, alkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more 3D ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula -Ν 177 R 12 -NC-R 16 wherein each of R 22 , R 22 , R 2 ^, R 22 , R 2 6 and R 27 is 5 independently selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R 22 and R 22 taken together, R 2 ^ and R 22 taken together and R 22 and R 27 taken together may each form a heterocyclic 10 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 15 or partially unsaturated, wherein R 22 and R 22 taken together and R 2 ^ and R 22 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 20 one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and wherein each of R 2 through R 22 may be further independently selected from acidic moieties of the formula -Y n A wherein n is a number selected from zero through three, inclusive, and wherein A is an acidic group selected to 30 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 178 ring atoms selected from oxygen, sulfur and nitrogen atoms and wherein Y is further selected from II - c0 0 II II ,-CN-,-NC-,-Ol· 8 U R»» and -CH=CH-, wherein R 18 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 R 3 through R 38 , R 39 , 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 ,20 -C-R -N ,21 • and -NC-R ,23 wherein X is selected from oxygen atom and sulfur atom; wherein R 39 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR 34 and -N ,25 X ,26 179 wherein D is selected from oxygen atom, nitrogen atom and sulfur atom and R 24 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each 5 of R 2( \ R 21 , R 22 , R 23 , R 2 ^ and R 26 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, 10 haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R 2 ^' R 22 ' R 22 , R 23 , R 23 and R 26 is further independently selected from amino and amido radicals of the formula ,27 ,29 -N ,28 -CN ,30 and -NC-R L wherein each of R 27 , R 2 ^, r29, r30, r31- and r32 as independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, 20 cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein r20 and r21 taken together and R 22 and R 23 taken together may each form a heterocyclic group having five to seven ring members including the nitrogen atom of said amino or amido radical, 25 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 R 20 and R 2 taken together and R 23 and R 26 taken together may each form 30 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 35 a pharmaceutically-acceptable salt thereof. 180

2. Compound of Claim 1 wherein m is one; wherein each of R x through R xx and R 39 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, 5 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, 10 alkylaminocarbonyloxy, arylaminocarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, 15 arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, 20 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 25 formula ,12 -N 13 -CN and •NC-R wherein each of R-Z r!3, r!4, rZ r16 and r17 j_ s 30 independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R 3 through R xx may be further 35 independently selected from acidic moieties of the formula 181 -YnA wherein n is a number selected from zero through three, inclusive; wherein A is an acidic group selected from acids containing one or more atoms selected from oxygen, sulfur, 5 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, 10 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 0 0 0 II II II - C- , — CN —NC—O — -s —N — 15 R 18 R 18 R and -CH=CH~, wherein R 18 is selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl, 20 alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbonyl; and wherein any of the foregoing R 2 through R 28 , R 2 ^, γ and a groups having a substitutable position may be substituted by one or more groups selected from alkyl, halo, alkenyl, aralkyl, hydroxyalkyl, trifluoromethyl, difluoroalkyl, 25 alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercaptocarbonyl, alkylthio, alkylthiocarbonyl, and amino and amido radicals of the formula -C-R 19 , -N and -NC-R 1,3 R X ,20 X ,21 182 wherein X is selected from oxygen atom and sulfur atom; wherein R 33 i s selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl; 5 wherein each of R 20 , R 23 , R 22 and R 23 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.

3. Compound of Claim 2 wherein m is one; 15 wherein each of R 3 and R 2 is independently selected from hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkyloxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, formyl, alkoxycarbonyl, 20 alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, 25 aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula -N 13 -CN θ r 14 II / R and II NC-R 16 wherein each of R 32 , R 33 , R 34 , R 33 , R 33 and R 37 is independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, 183 monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein R 39 is selected from linear or branched alkyl, 5 alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyi, arylalkyl and alkylcycloalkylalkyl, and wherein any one of the foregoing R 39 substituents having a substitutable position may be substituted with one or more substituents selected from 10 alkyl, haloalkyl, halo, nitro, cyano, aryl, arylamino, alkylamino, alkylarylamino, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl and arylsulfonyl; 15 and wherein each of R 3 through R 11 is independently selected from hydrido, linear or branched alkyl (Ci-Cio), linear or branched alkenyl (C2-C10), linear or branched alkynyl (C 2 _ Cio) , cycloalkyl (C3-C10), cycloalkenyl (C3— C10), cycloalkylalkyl (C4-C10), aryl, arylalkyl, alkylaryl, 20 halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl, and wherein at least one of the R 3 to R 11 substituents is a carboxylic acid radical of the formula II 33 25 -co-R 3 wherein R 33 is selected from hydrido, linear or branched alkyl (Ci-Cio, ) , linear or branched alkenyl (C 2 -Cio), linear or branched alkynyl (C 2 -Cio), cycloalkyl (C3-C10) , cycloalkenyl (C3-C10), cycloalkylalkyl (C4-C10) and 30 cycloalkenylalkyi (C4-C10); or wherein said R 3 through R 11 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, 35 hydroxamic acid, hydroxamate, aminotetrazole, phosphoruscontaining and thiophosphorus-containing acids selected from 184 W II w || -P-WH 1 II -P-WH and II -P-WH R 34 R 35 W-R 35 wherein W is selected from 0, S and N-R 49 ; wherein each of 5 R 34 , R 35 ' R 36 and R 40 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyl and R 37 -N-R 38 , wherein R 37 and R 38 can be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, 10 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 15 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 20 hetero atom selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R 33 or may be attached at any two 25 positions selected from R 3 through R 33 so as to form a fused-ring system with one of the phenyl rings of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups; wherein said bioisostere of carboxylic acid may be further selected from substituted 33 amino groups of the formula NH-R 46 wherein R 48 is selected from alkylsulfonyl, arylsulfonyl, fluoroalkylsulfonyl, fluoroarylsulfonyl, fluoroalkylcarbonyl, fluoroarylcarbonyl and CO-R 41 wherein 35 R 43 is selected from hydrido, linear or branched alkyl (Ci~ 185 CiOz)/ linear or branched alkenyl (C2 _ Cio), linear or branched alkynyl (C2-C10) , cycloalkyl (C3-C10)/ cycloalkenyl (C3-C10) , cycloalkylalkyl (C4-C10) and cycloalkenylalkyl (C4-C10) ; wherein any of the foregoing R 33 through R 38 , R 40 , 5 R 41 and R 48 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 10 arylsulphonyl; or a tautomer thereof or a pharmaceuticallyacceptable salt thereof.

4. of carboxylic Compound of Claim 3 wherein said bioisostere acid is a heterocyclic group selected from o CH2CH3 ch 2 c 6 h 5 186 wherein each of R^2 r r43 r44 as independently selected from H, Cl, CN, NO2, CF 3, C2F5, C3F7, CHF 2/ CH 2 F, CO2CH3, CO2C2H5, SO 2^3, SO2CF3 and SO2C6F5; wherein Z is selected from 0, S, NR 43 and CH2, wherein R^ 3 is selected from 5. 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 10 from OH

6. Compound of Claim 3 wherein m is one; 15 wherein R 3 and R 2 is independently selected from hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, 20 cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl 25 having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula -N Z R 13 -CN 187 an d -NC-R wherein each of R 22 , R 23 , R^, R^, r16 and r17 y s independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein each of R 3 through is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, 15 acetyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein at least one of R 3 through R 1 * is an acidic moiety independently selected from acidic moieties 20 consisting of CO 2 H, CO2CH3, SH, CH 2 SH, C 2 H 4 SH, PO 3 H 2/ NHSO 2 CF 3 , NHSO 2 CgF 5i SO 3 H, CONHNH 2/ CONHNHSO 2 CF 3 , CONHOCH3, CONHOC 2 H 5/ CONHCF 3 , OH, CH 2 OH, C 2 H 4 OH, OPO 3 H 2/ OSO 3 H, NHCN4H and and wherein said acidic moiety may further be a heterocyclic acidic group attached at any two adjacent 188 positions of R 2 through R 22 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. Ί. Compound of Claim 6 wherein m is one; wherein each of R 2 and R 2 is independently selected from hydroxy, amino, aminomethyl, aminoethyl, dimethylaminoethylamino, methyl, ethyl, n-propyl, 15 isopropyl, n-butyl, secbutyl, isobutyl, tertbutyl, npentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1oxobutyl, 1-oxopentyl, hydroxyalkyl, halo, methylthio, propylthio, isopropylthio, cyclohexylthio, methoxy, ethoxy, 20 isopropoxy, phenoxy, cyclohexyloxy, methoxymethoxy, methoxy-l-ethyloxy, cyano, formyl, acetyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, secbutylcarbonyloxy, iso-butylcarbonyloxy, tert25 butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy, n-hexylcarbonyloxy, benzyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cycloheptyloxy, isopropanoyloxy, benzoyloxy, methylaminocarbonyloxy, isopropylaminocarbonyloxy and 30 phenylaminocarbonyloxy; wherein R 29 is selected from hydrido, linear or branched alkyl (Ci-Cio) > linear or branched alkenyl (C2-C10) , linear or branched alkynyl (C2-C10), cycloalkyl (C3-C10), 35 cycloalkenyl (C3-C10), cycloalkylalkyl (C4-C10) and cycloalkenylalkyl (C4-C10); 189 wherein at least one of R 5 , R 8 , R 8 and R 9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, NHSO2CH3, NHSO2CF3, NHCOCF3, CONHSO2Cβ,H5, 5 CONHOH, CONHOCH3, CONHSO2CH3, Η Η H 10 wherein each of R 42 and R 43 is independently selected from Cl, CN, NO2/ CF3, CO2CH3 and SO2CF3; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

7. 8. Compound of Claim 7 wherein m is one; 15 wherein each of R 3 and R 2 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, 20 methoxymethoxy, methoxy-l-ethyloxy, acetyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, secbutylcarbonyloxy, iso-butylcarbonyloxy, tertbutylcarbonyloxy, n-pentylcarbonyloxy, 25 isopentylcarbonyloxy, n-hexylcarbonyloxy, benzyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cycloheptyloxy, isopropanoyloxy, benzoyloxy, methylaminocarbonyloxy, isopropylaminocarbonyloxy and phenylaminocarbonyloxy; wherein R 39 3s selected from n-propyl, n-butyl, n-pentyl, propylthio and propoxy; wherein each of R 3 , R 4 , R 6 , R 7 , R 8 , R 30 and R 33 is hydrido; 190 wherein one R 5 and R 9 is an acidic group selected from CO 2H and tetrazole and the other of R 5 and R 9 is hydrido; 5 or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

8. 9. Compound of Claim 8 selected from compounds, and their pharmaceutically-acceptable salts, of the group

9. 10 consisting of 4' - [(2-butyl-IH-imidazo[4,5-d]pyridazin-1-yl)methyl][1,l’biphenyl ] —2—carboxylic acid; 4'-[(2-butyl-lH-imidazo[4,5-d]pyridazin-l-yl-4,7diol)methyl][1,1'-biphenyl]-2-carboxylic acid; 15 4'-[(2-methyl-lH-imidazo[4,5-d]pyridazin-l-yl-4,7diol)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-isopropyl-lH-imidazo[4, 5-d]pyridazin-l-yl-4,7diol)methyl][1,1'-biphenyl]-2-carboxylic acid; 4' - [ (2-neopentyl-4-propyl-7-hydroxy-lH-imidazo[4,520 d]pyridazin-l-yl)methyl][1,1'-biphenyl]-2-carboxylic acid; 4'-[(2-cyclohexyl-lH-imidazo[4,5-d]pyridazin-lyl) methyl] [ 1,1'-biphenyl]-2-carboxylic acid; 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yljmethyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 25 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yljmethyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-butyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yljmethyl]-4,7-diethoxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4 30 yljmethyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2’-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4,7-bis(methoxy-l-ethyloxy)-IH-imidazo[4,5d]pyridazine; 2-butyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyli-4 35 yl]methyl]-7-hydroxy-1H-imidazo[4,5-d]pyridazine; 2-butyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yljmethyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine; 191 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-phenyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-butyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4 yl]methyl]-4-acetyloxy-7-hydroxy-lH-imidazo[4,55 d]pyridazine; 2-butyl-l-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-benzoyloxy-7-hydroxy-lH-imidazo[4,5d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-410 yl]methyl]-IH-imidazo[4,5-d]pyridazine; 2-methyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine; 15 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1 1 -biphenyl]-4yl]methyl]-4,7-dichloro-lH-imidazo[4,5-d]pyridazine; 2-isopropyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-420 yl]methyl]-IH-imidazo[4,5-d]pyridazine; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-diethoxy-ΙΗ-imidazo[4,5-d]pyridazine; 25 2-neopentyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4,7-bis(methoxymethyloxy)-IH-imidazo[4,5d]pyridazine; 2-cyclohexyl-l-[[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-IH-imidazo[4,5-d]pyridazine-4,7-diol; 30 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1 1 -biphenyl]-4yl]methyl]-4,7-diacetyloxy-lH-imidazo[4,5-d]pyridazine; 2-cyclohexyl-l-[[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-propyl-7-hydroxy-lH-imidazo[4,5-d]pyridazine 2-butyl-l-[2 1 - (lH-tetrazol-5-yl) [1,1'-biphenyl]-435 yl]methyl]-7-propyl-4-hydroxy-lH-imidazo[4,5-d]pyridazine, 2-butyl-l-[2' (lH-tetrazol-5-yl) [1,1'-biphenyl]-4 yl]methyl]-4-hydroxy-lH-imidazo[4, 5-d]pyridazine; 192 2-butyl-l-[2’-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-IH-imidazo[4,5-d]pyridazine; 2-butyl-l-[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yl]methyl]-4-pentanoyloxy-7-hydroxy-lH-imidazo[4,55 d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-cyclohexanecarbonyloxy-7-hydroxy-lHimidazo[4,5-d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-410 yljmethyl]-7-(2,2-dimethylpropanoyloxy)-4-hydroxy-lHimidazo[4,5-d]pyridazine; 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-(2,2-dimethylpropanoyloxy)-7-hydroxy-lHimidazo[4,5-d]pyridazine; 15 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1'-biphenyl]-4yljmethyl]-4,7-bis-(2,2-dimethylpropanoyloxy)-IHimidazo [4, 5-d]pyridazine; 2-butyl-l-[2'- (lH-tetrazol-5-yl)[1,1'-biphenyl]-4yl]methyl]-4-phenylacetylchloride-7-hydroxy-lH-imidazo[4,5 20 d]pyridazine; and 2-butyl-l-[2'- (lH-tetrazol-5-yl) [1,1'-biphenyl]-4yljmethyl]-4,7-diacetyl-lH-imidazo[4,5-d]pyridazine. 10. Compound of Claim 9 which is 2-butyl-l-[2' 25 (lH-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7hydroxy-lH-imidazo[4,5-d]pyridazine or a pharmaceuticallyacceptable salt thereof.

10. 11. Compound of Claim 9 which is 2-butyl-l-[2' 30 (lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-7-hydroxyΙΗ-imidazo[4,5-d]pyridazine or a pharmaceuticallyacceptable salt thereof.

11. 12. Compound of Claim 9 which is 2-butyl-l-[2' 35 (lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-4 pentanoyloxy-7-hydroxy-lH-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof. 193

12. 13. Compound of Claim 9 which is 2-butyl-l-[2' (lH-tetrazol-5-yl)[1,1'-biphenyl]-4-yllmethyl]-4-(2-methyl propanoyloxy)-7-hydroxy-lH-imidazo[4, 5-d]pyridazine or a pharmaceutically-acceptable salt thereof.

13. 14. Compound of Claim 9 which is 2-butyl-l-[2' (lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yllmethyl] -4 phenylacetylchloride-7-hydroxy-lH-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.

14. 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 15 a family of compounds of Formula I: wherein m is a number selected from one to four, inclusive; wherein each of R 2 through R 20 * 22 * * 25 * * * and R 29 30 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, 25 alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, formyl, alkylcarbonyloxy, cycloalkylalkoxy, alkoxyalkoxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, aroyloxy, 30 alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, 194 alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, 5 arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, alkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, 10 arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula -N 13 -CN and ,15 • NCR R 15 * 17 * * 4 * * * * at wherein each of R 42 , R 43 , R 44 , R 43 , R 46 and R 47 is independently selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R 42 and R 43 taken together, R 44 and R 43 taken together and R 46 and R 47 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 R 42 and R 43 taken together and R 44 and R 43 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which aromatic heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and wherein each of R 2 through R 22 may be further independently selected from acidic moieties of the formula -Y n A wherein n is a number selected from zero through three, inclusive, 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; 10 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 0 0 0 II II II - C- ,-CN-,-NC-,-O- ,-S -,- N — R 18 R 18 Rli< and -CH=CH-, wherein R 22 is selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and 20 aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbonyl; and wherein any of the foregoing R 2 through R 23 , R 39 , Y and A groups having a substitutable position may be substituted by one or more groups selected from hydroxy, halo, alkyl, 25 alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloalkyl, oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, nitro, alkylcarbonyloxy, alkoxycarbonyloxy, alkylcarbonyl, alkoxycarbonyl, carboxyl, 30 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 35 and amido radicals of the formula ,20 196 -C-R -N ,21 > and -NC-R ,23 wherein X is selected from oxygen atom and sulfur atom; 5 wherein R 29 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR 2 ^ and R' -N ,26 10 wherein D is selected from oxygen atom, nitrogen atom and sulfur atom and R 24 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R 2i2 , R 22 , R 22 , R 22 , R 25 * and R 28 * 30 is independently selected from hydrido, alkyl, cycloalkyl, cyano, 15 hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R 28 ' R 22 ' R 22 , R 22 , R 25 and R 28 is further 20 independently selected from amino and amido radicals of the formula .27 ,29 ,28 -CN ,30 and -NC-R ,32 25 wherein each of R 27 , R 22 , R 2 ^, r30, r31 r32 j_ s independently selected from hydrido, alkyl, cycloalkyl, cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein R 20 ana 30 R 22 taken together and R 22 and R 22 taken together may each form a heterocyclic group having five to seven ring members 197 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 5 saturated or partially unsaturated; wherein R 39 and r21 taken together and R 33 and R 38 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 10 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.

15. 16. The composition of Claim 15 wherein m is 15 one; wherein each of R 3 through R 33 and R 39 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, cycloalkoxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, 20 alkylcarbonyl, formyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, 25 alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, 30 arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, 35 aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms and amino and amido radicals of the formula -N 198 ,14 , II / „ 13 -CN ’NCR ^\ n 15 ' wherein each of R 25 * * * * 30 * 32 , R 33 , R 34 , R 33 , R 38 and R 37 is 5 independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; and wherein each of R 3 through R 33 may be further 10 independently selected from acidic moieties of the formula -Y„A wherein n is a number selected from zero through three, inclusive; wherein A is an acidic group selected from acids containing one or more atoms selected from oxygen, sulfur, 15 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, 20 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 0 0 0 II II II - C- CN —NC—O — S —N — 25 R 18 R 18 Rl8 and -CH=CH-, wherein R 38 is selected from hydrido, alkyl, cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl, 30 alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbonyl; and wherein any of the foregoing R 3 through R 38 , R 39 , Y and A groups having a substitutable position may be substituted by one or more groups selected from alkyl, halo, alkenyl, 199 aralkyl, hydroxyalkyl, trifluoromethyl, difluoroalkyl, alkoxy, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, mercaptocarbonyl, alkylthio, alkylthiocarbonyl, and amino and amido radicals of the formula II R‘ -C-R R‘ and II -NC-R' R' wherein X is selected from oxygen atom and sulfur atom; 10 wherein R 3 ^ is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl; wherein each of R 20 , R 21 , R 22 and R 23 is independently selected from hydrido, alkyl, cycloalkyl, cyano, 15 hydroxyalkyl, haloalkyl, cycloalkylakyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt 20 thereof.

16. 17. The composition of Claim 16 wherein m is one; wherein each of R 3 and R 2 is independently selected from hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, 25 cycloalkyl, cycloalkylalkyl, alkoxy, cycloalkyloxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, formyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, 30 alkylaminocarbonyloxy, arylaminocarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl 35 having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula -N 13 -CN 200 and ,15 -NC-R il, wherein each of R 33 , R 33 , R 3 ^, R 33 , r16 and r17 as independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein R 3 ^ is selected from linear or branched alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl cycloalkenyl, cycloalkenylalkyl, arylalkyl and 15 alkylcycloalkylalkyl, and wherein any one of the foregoing R 3 ^ 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, 20 alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl and arylsulfonyl; and wherein each of R 3 through R 33 is independently selected from hydrido, linear or branched alkyl (Ci-Cio), 25 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 30 arylsulphonyl, and wherein at least one of the R 3 to R 33 substituents is a carboxylic acid radical of the formula 11 „ -CO-R 33 201 wherein R 15 * * * * 20 * * * * 25 * * * * * * * 33 is selected from hydrido, linear or branched alkyl (Ci-CiOz)z linear or branched alkenyl (C2 - Cio), linear or branched alkynyl (C2-C10), cycloalkyl (C3-C10)/ cycloalkenyl (C3-C10)/ cycloalkylalkyl (C4-C10) and 5 cycloalkenylalkyl (C4-C10) ; or wherein said R 3 through R 11 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, 10 hydroxamic acid, hydroxamate, aminotetrazole, phosphorus containing and thiophosphorus-containing acids selected from w II W II II -P-WH and •P-WH | R 35 ' 35 W-R J wherein W is selected from 0, S and N-R 40 ; wherein each of r 34, r 35, R 36 and r 40 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyl and 20 R 37 -N-R 38 , wherein R 37 and R 38 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 25 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 33 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 35 heterocyclic ring may be attached at a single position 202 selected from R 3 through R 22 or may be attached at any two positions selected from R 3 through R 22 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 5 heterocyclic acidic groups; wherein said bioisostere of carboxylic acid may be further selected from substituted amino groups of the formula NH-R 46 wherein R 42 is selected from alkylsulfonyl, arylsulfonyl, 10 fluoroalkylsulfonyl, fluoroarylsulfonyl, fluoroalkylcarbonyl, fluoroarylcarbonyl and CO-R 42 wherein R 4l is selected from hydrido, linear or branched alkyl (Ci~ CiOz)/ linear or branched alkenyl (C2 _ Cio), linear or branched alkynyl (C 2 -Cio) / cycloalkyl (C3-C10), cycloalkenyl 15 (C3-C10) z cycloalkylalkyl (C4-C10) and cycloalkenylalkyi (C4-C10) : wherein any of the foregoing R 33 through R 33 , R 43 , R 41 and R 42 substituents having a substitutable position may be substituted with one or more substituents selected from alkyl, haloalkyl, halo, nitro, cyano, aryl, arylalkyl, 20 alkylaryl, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and arylsulphonyl; or a tautomer thereof or a pharmaceuticallyacceptable salt thereof. 203

17. 18. The composition of Claim 17 wherein said bioisostere of carboxylic acid is a heterocyclic group selected from wherein each of R 42 , r43 and r44 y s independently selected from H, Cl, CN, NO 2 , CF 3/ C 2 F 5 , C 3 F 7 , CHF 2 , CH 2 F, CO 2 CH 3 , 10 CO 2 C 2 H5, SO 2 CH 3 , SO 2 CF 3 and SO 2 CgF5,· wherein Z is selected from 0, S, NR 43 and CH2, wherein R 43 is selected from hydrido, CH3 and CH 2 CgH5·

18. 19. The composition of Claim 17 wherein said 15 bioisostere of carboxylic acid is a fused ring system including the phenyl rings of Formula I, said fused ring system selected from 204 OH

19. 20. The composition of Claim 17 wherein m is one; wherein R 2 and R 2 is independently selected from 5 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, 10 mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur 15 and nitrogen atoms, and amino and amido radicals of the formula ,14 -N 13 -CN and NC-R R 17 20 wherein each of R 20 * 22 * , R 22 , R 24 , R 22 , R 28 and R 27 is independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; 205 wherein each of R 3 through R 33 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, 5 acetyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein at least one of R 3 through R 33 is an acidic moiety independently selected from acidic moieties 10 consisting of CO2H, CO2CH3, SH, CH2SH, C2H4SH, PO3H2, NHSO2CF3, NHSO2CgF 5i SO3H, CONHNH2, CONHNHSO2CF3, CONHOCH3, CONHOC2H5, CONHCF3, OH, CH2OH, C2H4OH, OPO3H2, OSO3H, NHCN4H and OH and wherein said acidic moiety may further be a heterocyclic acidic group attached at any two adjacent positions of R 3 through R 33 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 25 and the esters, amides and salts of said acidic moieties; or a tautomer thereof or a pharmaceutically-acceptable salt thereof. 206

20. 21. The composition of Claim 20 wherein m is one; wherein each of R 3 and R 2 is independently selected from hydroxy, amino, aminomethyl, aminoethyl, dimethylaminoethyl-amino, methyl, ethyl, n-propyl, 5 isopropyl, n-butyl, secbutyl, isobutyl, tertbutyl, npentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1oxobutyl, 1-oxopentyl, hydroxyalkyl, halo, methylthio, propylthio, isopropylthio, cyclohexylthio, methoxy, ethoxy, 10 isopropoxy, phenoxy, cyclohexyloxy, methoxymethoxy, methoxy-l-ethyloxy, cyano, formyl, acetyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, secbutylcarbonyloxy, iso-butylcarbonyloxy, tert15 butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy, n-hexylcarbonyloxy, benzyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cycloheptyloxy, isopropanoyloxy, benzoyloxy, methylaminocarbonyloxy, isopropylaminocarbonyloxy and 20 phenylaminocarbonyloxy; wherein R 39 is selected from hydrido, linear or branched alkyl (Ci-Cio) > linear or branched alkenyl (C2-C10) , linear or branched alkynyl (C2-C10), cycloalkyl (C3-C10), 25 cycloalkenyl (C3-C10), cycloalkylalkyl (C4-C10) and cycloalkenylalkyl (C4-C10); wherein at least one of R 3 , R 8 , R 8 and R 9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, 30 CONHNHSO2CF3, OH, NHSO2CH3, NHSO2CF3, NHCOCF3, CONHSO2C6,H 5 , CONHOH, CONHOCH3, CONHSO2CH3, Η Η H 207 wherein each of R 42 and R 43 is independently selected from Cl, CN, N0 2 , CF3, CO 2 CH3 and SO 2 CF3; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

21. 22. The composition of Claim 21 wherein m is one; wherein each of R 1 and R 2 is independently selected from hydroxy, amino, aminomethyl, aminoethyl, dimethylaminoethyl-amino, methyl, ethyl, n-propyl, 10 isopropyl, n-butyl, secbutyl, isobutyl, n-pentyl, phenyl, benzyl, 1-hydroxyalkyl, halo, methylthio, propylthio, methoxymethoxy, methoxy-l-ethyloxy, acetyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, sec15 butylcarbonyloxy, iso-butylcarbonyloxy, tertbutylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy, n-hexylcarbonyloxy, benzyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cycloheptyloxy, isopropanoyloxy, benzoyloxy, 20 methylaminocarbonyloxy, isopropylaminocarbonyloxy and phenylaminocarbonyloxy; wherein R 39 is selected from n-propyl, n-butyl, n-pentyl, propylthio and propoxy; wherein each of R 3 , R 4 , R 2 , R 7 , R 8 , R 10 and R 11 is hydrido; wherein one R 5 and R 9 is an acidic group selected from CO2H and tetrazole and the other of R 2 and R 9 is hydrido; or a tautomer thereof or a pharmaceutically-acceptable salt thereof. 23

22. 23. The composition of Claim 22 wherein said 35 antagonist compound is 2-butyl-l-[2'-(lH-tetrazol-5yl)[1,1'-biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-lHimidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof. 208

23. 24. The composition of Claim 22 wherein said antagonist compound is 2-butyl-l-[2’-(lH-tetrazol-5yl)[1,1'-biphenyl]-4-yljmethyl]-7-hydroxy-IH-imidazo[4,55 djpyridazine or a pharmaceutically-acceptable salt thereof

24. 25. The composition of Claim 22 wherein said antagonist compound is 2-butyl-l-[2' -(lH-tetrazol-5yl)[1,1'-biphenyl]-4-yl]methyl]-4-pentanoyloxy-7-hydroxy10 IH-imidazo[4,5-d]pyridazine or a pharmaceuticallyacceptable salt thereof

25. 26. The composition of Claim 22 wherein said antagonist compound is 2-butyl-l-[2'-(lH-tetrazol-515 yl)[l,l'-biphenyl]-4-yl]methyl]-4-(2-methyl-propanoyloxy)7-hydroxy-lH-imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof

26. 27. The composition of Claim 22 wherein said 20 antagonist compound is 2-butyl-l-[2'-(lH-tetrazol-5yl) [1,1'-biphenyl]-4-yl]methyl]-4-phenylacetylchloride-7 hydroxy-lH-imidazo[4,5-d]pyridazine or a pharmaceuticallyacceptable salt thereof 25

27. 28. A therapeutic method for treating a circulatory disorder, said method comprising administering to a subject having such disorder a therapeuticallyeffective amount of a compound of Formula I: 209 wherein m is a number selected from one to four, inclusive; wherein each of R 3 through R 13 and R 39 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, 5 haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, formyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cyano, nitro, carboxyl, formyl, alkylcarbonyloxy, 10 cycloalkylalkoxy, alkoxyalkoxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, aroyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, 15 alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, 20 aralkylthiocarbonylthio, alkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, 25 and amino and amido radicals of the formula -N 13 -CN and NC-R “R is wherein each of R 33 , R 33 , R 34 , R 33 , R 38 and R 37 is 30 independently selected from hydrido, alkyl, oyoloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R 33 and R 33 taken together, R 34 and R 33 taken together and R 3 ^ and R 37 taken together may each form a heterocyclic 35 group having five to seven ring members including the 210 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 5 or partially unsaturated; wherein R x ^ and r 13 taken together and R X4 and R X3 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 10 one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms; and wherein each of R 3 through R xx may be further independently selected from acidic moieties of the formula -YnA wherein n is a number selected from zero through three, inclusive, and wherein A is an acidic group selected to 20 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 25 ring atoms selected from oxygen, sulfur and nitrogen atoms; and wherein Y is further selected from 0 0 0 II II II - C- ,- CN-,-NC-,-O- ,-S -,-NR 18 R 18 Rl8 and -CH=CH-, wherein R 18 is selected from hydrido, alkyl, 30 cycloalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, formyl, alkylcarbonyl, arylcarbonyl, carboxyl, alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbonyl; and wherein any of the foregoing R 1 through R 18 , R 39 , Y and A 35 groups having a substitutable position may be substituted 211 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, 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, and amido radicals of x sulfur and nitrogen atoms, and ammo the formula ,20 -N ,21 • and -NC-R ,23 wherein X is selected from oxygen atom and sulfur atom; wherein R 29 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, DR 24 and ,25 -N R· wherein D is selected from oxygen atom, nitrogen atom and sulfur atom and R 24 is selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each 25 of R 22 , R 22 , R 22 , R 22 , R 22 and R 28 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, 30 haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each of R 28 ' R 22 ' R 22 , R 22 , R 25 and R 28 is further independently selected from amino and amido radicals of the formula ,27 -N ,28 -CN 212 ,29 ,30 and -NC-R ,32 wherein each of R 23 , R 23 , R 2 ^, r30 z r31 r32 y s independently selected from hydrido, alkyl, cycloalkyl, 5 cyano, amino, monoalkylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein R 2 * 3 and R 23 taken together and R 22 and R 23 taken together may each form a heterocyclic group having five to seven ring members 10 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 R 23 and R 23 15 taken together and R 23 and R 23 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 20 oxygen, nitrogen and sulfur atoms; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

28. 29. The method of Claim 28 wherein m is one; wherein each of R 3 through R 29 * * * 33 and R 3 ^ is independently 25 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,

29. 30 cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, 35 alkylthiothiocarbonyl, alkylthiothiocarbonylthio, arylthio, 213 arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, aralkylthiocarbonyloxy, 5 aralkylthiocarbonylthio, aralkylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur 10 and nitrogen atoms and amino and amido radicals of the formula ,12 and -NC-R 16 15 wherein each of R 20 * 22 , R 23 , R 24 , R 22 , R 22 * and R 27 * * 30 is independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; 20 and wherein each of R 3 through R 22 may be further independently selected from acidic moieties of the formula •YnA wherein n is a number selected from zero through three, inclusive; wherein A is an acidic group selected from acids 25 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 30 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 214 0 0 0 II II II - C- CN —NC—O— ,-S - ,-NR 18 R 18 Rl8 and -CH=CH-, wherein R 38 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 R 3 through R 38 , R 39 , γ 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 ,20 -C-R -N >21 ’ and -NC-R ,23 wherein X is selected from oxygen atom and sulfur atom; wherein R 39 is selected from hydrido, alkyl, cycloalkyl, 20 cycloalkylalkyl, aralkyl, aryl; wherein each of R 20 , R 23 , R 22 and R 23 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylakyl, alkoxyalkyl, 25 alkanoyl, alkoxycarbonyl, carboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl; or a tautomer thereof or a pharmaceutically-acceptable salt thereof. 30 30. The method of Claim 29 wherein m is one; wherein each of R 3 and R 3 is independently selected from hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, 215 cycloalkylalkyl, alkoxy, cycloalkyloxy, alkoxyalkoxy, aralkyl, aryl, aroyl, aryloxy, aroyloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, formyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro 5 carboxyl, alkylcarbonyloxy, alkylaminocarbonyloxy, arylaminocarbonyloxy, mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl 10 having one or more ring atoms selected from oxygen, sulfur and nitrogen atoms, and amino and amido radicals of the formula -N 13 -CN and -NC-R wherein each of R 42 , R 43 , R 44 , R 43 , R 46 and R 47 is independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; wherein R 39 is selected from linear or branched alkyl, alkenyl, alkynyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, arylalkyl and 25 alkylcycloalkylalkyl, and wherein any one of the foregoing R 39 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, 30 alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfinyl and arylsulfonyl; and wherein each of R 3 through R 44 is independently selected from hydrido, linear or branched alkyl (Ci-Cio), 35 linear or branched alkenyl (C2-C10) , linear or branched 216 alkynyl (C2-C10)/ cycloalkyl (C3-C10), cycloalkenyl (C 3C10)/ cycloalkylalkyl (C4-C10), aryl, arylalkyl, alkylaryl, halo, nitro, cyano, hydroxyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulphonyl, arylthio, arylsulfinyl and 5 arylsulphonyl, and wherein at least one of the R 3 to R 11 substituents is a carboxylic acid radical of the formula II 33 -CO-R 33 wherein R 33 is selected from hydrido, linear or branched 10 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 R 3 through R 11 substituent is a bioisostere of a free carboxylic acid 15 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, phosphoruscontaining and thiophosphorus-containing acids selected 20 from -P-WH R 34 w II w II II -P-WH and -P-WH I l 35 1 35 W-R 3S wherein W is selected from 0, S and N-R 49 ; wherein each of 25 R 34 , R 35 ' R 36 and R 40 is independently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, arylalkyl, hydroxyalkyl, alkoxyalkyl, alkanoyl and r37_n- R 38, wherein R 37 and R 38 can be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, 30 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 35 ionizable proton with a pk a in a range from about two to 217 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 5 hetero atom selected from oxygen, sulfur and nitrogen atoms, which heterocyclic ring may be saturated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position selected from R 3 through R xx or may be attached at any two 10 positions selected from R 3 through R xx 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 15 amino groups of the formula NH-R 46 wherein R 48 is selected from alkylsulfonyl, arylsulfonyl, fluoroalkylsulfonyl, fluoroarylsulfonyl, fluoroalkylcarbonyl, fluoroarylcarbonyl and CO-R 41 wherein 20 R 41 is selected from hydrido, linear or branched alkyl (Ci~ CiO/), linear or branched alkenyl (C2-C10)< linear or branched alkynyl (C2-C10) , cycloalkyl (C3~Cio)z cycloalkenyl (C3-C10) / cycloalkylalkyl (C4-C10) and cycloalkenylalkyl (C4-C10) ! wherein any of the foregoing R 33 through R 38 , R 48 , 25 R 41 and R 48 substituents having a substitutable position maybe 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 30 arylsulphonyl; or a tautomer thereof or a pharmaceuticallyacceptable salt thereof. 31 * *

30. 31. The method of Claim 30 wherein said bioisostere of carboxylic acid is a heterocyclic group 35 selected from 218 wherein each of R 42 , R 42 and R 44 is independently selected from H, Cl, CN, NO 2 , CF 3/ C 2 F 5 , C3F7, CHF 2/ CH 2 F, CO 2 CH 3 , 5 CO 2 C 2 H5, SO 2 CH 3/ SO 2 CF 3 and SO 2 CgF5,· wherein Z is selected from 0, S, NR 42 and CH2, wherein R 42 is selected from hydrido, CH3 and CH 2 CgH5·

31. 32. The method of Claim 30 wherein said 10 bioisostere of carboxylic acid is a fused ring system including the phenyl rings of Formula I, said fused ring system selected from 219 OH

32. 33. The method of Claim 32 wherein m is one; wherein R 3 and R 2 is independently selected from hydroxy, 5 alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, 10 mercaptocarbonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, mercapto, alkylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur 15 and nitrogen atoms, and amino and amido radicals of the formula -N 13 -CN and -NC-R IS 20 wherein each of R 32 , R 33 , R 3 ^, R 33 , R 33 and R 33 is independently selected from hydrido, alkyl, cycloalkyl, aryl, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; 220 wherein each of R 2 through R 22 is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, 5 acetyl, alkoxycarbonyl, alkenyl, cyano, nitro, carboxyl, alkylthio and mercapto; and wherein at least one of R 2 through R 22 is an acidic moiety independently selected from acidic moieties 10 consisting of CO 2 H, CO2CH3, SH, CH 2 SH, C 2 H 4 SH, PO 3 H 2/ NHSO 2 CF 3 , NHSO 2 CgF 5z SO 3 H, CONHNH 2/ CONHNHSO 2 CF 3 , CONHOCH3, conhoc 2 h 5/ conhcf 3 , OH, ch 2 oh, c 2 h 4 oh, opo 3 h 2; oso 3 h, NHCN4H and and wherein said acidic moiety may further be a heterocyclic acidic group attached at any two adjacent positions of R 2 through R 22 so as to form a fused ring 20 system to include one of the phenyl rings of the biphenyl moiety of Formula I, said fused ring system selected from 25 and the esters, amides and salts of said acidic moieties; or a tautomer thereof or a pharmaceutically-acceptable salt thereof. 221

33. 34. The method of Claim 33 wherein m is one; wherein each of R 2 and R 2 is independently selected from hydroxy, amino, aminomethyl, aminoethyl, dimethylaminoethyl-amino, methyl, ethyl, n-propyl, 5 isopropyl, n-butyl, secbutyl, isobutyl, tertbutyl, npentyl, isopentyl, neopentyl, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, 1-oxoethyl, 1-oxopropyl, 1oxobutyl, 1-oxopentyl, hydroxyalkyl, halo, methylthio, propylthio, isopropylthio, cyclohexylthio, methoxy, ethoxy, 10 isopropoxy, phenoxy, cyclohexyloxy, methoxymethoxy, methoxy-l-ethyloxy, cyano, formyl, acetyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, secbutylcarbonyloxy, iso-butylcarbonyloxy, tert15 butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy, n-hexylcarbonyloxy, benzyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cycloheptyloxy,isopropanoyloxy, benzoyloxy, methylaminocarbonyloxy, isopropylaminocarbonyloxy and 20 phenylaminocarbonyloxy; wherein R 39 is selected from hydrido, linear or branched alkyl (Ci-Cio), linear or branched alkenyl (C2-C10) , linear or branched alkynyl (C2-C10) < cycloalkyl (C3-C10), 25 cycloalkenyl (C3-C10) , cycloalkylalkyl (C4-C10) and cycloalkenylalkyi (C4-C10) i wherein at least one of R 2 , R 2 , R 8 and R 9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, 3D CONHNHSO2CF3, OH, NHSO2CH3, NHSO2CF3, NHCOCF3, CONHSO2Cg,H5, CONHOH, CONHOCH 3/ CONHSO2CH3, c 222 wherein each of R 43 and R 43 is independently selected from Cl, CN, NC>2' CF3, CO2CH3 and SO2CF3; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

34. 35. The method of Claim 34 wherein m is one; wherein each of R 3 and R 3 is independently selected from hydroxy, amino, aminomethyl, aminoethyl, dimethylaminoethyl-amino, methyl, ethyl, n-propyl, 10 isopropyl, n-butyl, secbutyl, isobutyl, n-pentyl, phenyl, benzyl, 1-hydroxyalkyl, halo, methylthio, propylthio, methoxymethoxy, methoxy-l-ethyloxy, acetyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, sec15 butylcarbonyloxy, iso-butylcarbonyloxy, tertbutyl carbony loxy, n-pent y1c arbony1oxy, isopentylcarbonyloxy, n-hexylcarbonyloxy, benzyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cycloheptyloxy, isopropanoyloxy, benzoyloxy, 20 methylaminocarbonyloxy, isopropylaminocarbonyloxy and phenylaminocarbonyloxy; wherein R 39 3s selected from n-propyl, n-butyl, n-pentyl, propylthio and propoxy; wherein each of R 3 , R 4 , R 8 , R 7 , R 8 , R 381 and R 33 is hydrido; wherein one R 5 and R 9 is an acidic group selected from CO2H and tetrazoie and the other of R 5 and R 9 is hydrido; or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

35. 36. The method of Claim 35 wherein said 35 compound is 2-butyl-l-[2(lH-tetrazol-5-yl) [1,1'biphenyl]-4-yl]methyl]-4-propyl-7-hydroxy-lH-imidazo[4,5d]pyridazine or a pharmaceutically-acceptable salt thereof cIE 912042 223

36. 37. The method of Claim 35 wherein said compound is 2-butyl-l-[2'-(lH-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]-7-hydroxy-lH-imidazo[4,5 d]pyridazine or a pharmaceutically-acceptable salt thereof 5

37. 38. The method of Claim 35 wherein said compound is 2-butyl-l-[2(lH-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]-4-pentanoyloxy-7-hydroxy-1Himidazo[4,5-d]pyridazine or a pharmaceutically-acceptable 10 salt thereof.

38. 39. The method of Claim 35 wherein said compound is 2-butyl-l-[2’-(lH-tetrazol-5-yl) [1,1'biphenyl]-4-yl]methyl]-4-(2-methyl-propanoyloxy)-7-hydroxy 15 IH-imidazo[4,5-d]pyridazine or a pharmaceuticallyacceptable salt thereof.

39. 40. The method of Claim 35 wherein said compound is 2-butyl-l-[2'-(lH-tetrazol-5-yl) [1,1'20 biphenyl]-4-yl]methyl]-4-phenylacetylchloride-7-hydroxy-lH imidazo[4,5-d]pyridazine or a pharmaceutically-acceptable salt thereof.

40. 41. The method of Claim 28 wherein said 25 circulatory disorder is a cardiovascular disorder.

41. 42. The method of Claim 41 wherein said cardiovascular disorder is hypertension. 30

42. 43. The method of Claim 41 wherein said cardiovascular disorder is congestive heart failure. 224

43. 44. A compound of Formula I given and defined in Claim 1 or a tautomer thereof or a pharmaceutically-acceptable salt thereof, substantially as hereinbefore described and exemplified.

44. 45. A process for the preparation of a compound of Formula I given and defined in Claim 1 or a tautomer thereof or a pharmaceutically-acceptable salt thereof, substantially as hereinbefore described and exemplified.

45.

46. A compound of Formula I given and defined in Claim 1 or a tautomer thereof or a pharmaceutically-acceptable salt thereof, whenever prepared by a process claimed in Claim 45.

47. A pharmaceutical composition according to Claim 15, substantially as hereinbefore described.