WO1994020499A1

WO1994020499A1 - Benzylimidazopyridine derivatives as angiotensin ii receptor antagonists

Info

Publication number: WO1994020499A1
Application number: PCT/US1994/001207
Authority: WO
Inventors: Paul A. Da Silva Jardine; Ronald T. Wester; Philip A. Carpino
Original assignee: Pfizer Corp Belgium; Pfizer Corp SRL
Current assignee: Pfizer Corp Belgium; Pfizer Corp SRL
Priority date: 1993-03-10
Filing date: 1994-02-14
Publication date: 1994-09-15
Anticipated expiration: 1995-09-10
Also published as: AU6297494A; IL108842A0; FI941117A0; JPH08502757A; CA2157037A1; EP0690859A1; FI941117A7; FI941117L

Abstract

Compounds of formula (I) wherein A, together with the carbon to which it is attached, forms a C3 to C7 carbocylic or C7 to C11 carbobicyclic group, each of which can be saturated or unsaturated, optionally mono-, di- or trisubstituted with a substituent or substituents independently selected from C1 to C6 alkyl, C1 to C6 alkenyl and halo; M is a single bond or C1 to C5 alkyl; Q is phenyl or phenyl mono- or disubstituted with a substituent or substituents independently selected from halo, hydroxy, C1 to C4 alkyl and C1 to C4 hydroxyalkyl; R1 is -CO2H, -PO3H, -SO3H, -NHSO2CF3, -CONHSO2(C6H5), -CONHSO2CF3 or tetrazolyl; R2 is C2 to C8 alkyl, C3 to C8 cycloalkyl or -(CH2)n-S-(CH2)nCH3; each n is independently an integer from 0 to 4; one of W, X, Y and Z is N; three of W, X, Y and Z are CR3 and each R3 is independently hydrogen, halo, C¿1? to C5 alkyl or CO2H, inhibit angiotensin II in mammals and are useful in treating conditions such as hypertension, congestive heart failure and glaucoma and as the active ingredient in pharmaceutical compositions for treating such conditions.

Description

BENZYLIMIDAZOPYRIDINE DERIVATIVES

AS ANGIOTENSIN II RECEPTOR ANTAGONISTS

Background of the Invention This invention relates to a certain class of benzylimidazopyridines which have utility as regulators of the action of angiotensin II (All), mediated by the All receptor, in mammals, including humans, and accordingly, are useful in the treatment of hypertension, congestive heart failure, glaucoma and other conditions for which the action of All is implicated. This invention relates also to pharmaceutical compositions containing these compounds and to methods of inhibiting All in mammals by administration of such compounds.

The renin-angiotensin system (RAS) acts as a crucial regulatory mechanism in the control of homeostasis and fluid/electrolyte balance in mammals, including humans. Consequently, RAS activity has a direct influence on blood pressure and has been found to play an important role in congestive heart failure and in the development and maintenance of hypertension. Additionally, All activity has been implicated in the development of elevated intraocular pressure, for example, as caused by glaucoma. All, an octapeptide hormone produced via the cleavage of angiotensin I (Al) by angiotensin converting enzyme (ACE), is a potent and direct arterial vasoconstrictor, thereby effecting an increase in vascular resistance and blood pressure. All is also known to stimulate the release of aldosterone, resulting in vascular congestion and hypertension by promoting the retention of sodium and fluids. The present invention concerns regulation of the actions of All which are mediated by the All receptor.

Various benzylimidazole-derived compounds have been described as All antagonists. For example, see P.C. Wong et al., Hypertension. 15 (5), 459-468 (1990), US 4,207,324, EP 403158, EP 425211 A1 and WO 91/11999. Additionally, compounds of the same nature as those of the present invention are disclosed generically, but not specifically, in EP 513533 A2. Summarv of the Invention The present invention relates to a class of compounds having the formula

wherein A, together with the carbon to which it is attached, forms a C₃ to C₇ carbocyclic or C₇ to C→→ carbobicyclic group, each of which can be saturated or unsaturated, optionally mono-, di- or trisubstituted with a substituent or substituents independently selected from C, to C₆ alkyl, C, to C₆ alkenyl and halo; M is a single bond or C, to C₅ alkyl; Q is phenyl or phenyl mono- or disubstituted with a substituent or substituents independently selected from halo, hydroxy, C→ to C₄ alkyl and C→ to C₄ hydroxyalkyl; R¹ is -CO₂H, -PO₃H, -SO₃H, -NHSO₂CF₃, -CONHSO₂(C₆H₅), -CONHSO₂CF₃ or tetrazolyl; R² is C₂ to C₈ alkyl, C₃ to C₈ cycloalkyl or -(CH₂)_n-S- (CH₂)_nCH₃; each n is independently an integer from 0 to 4; one of W, X, Y and Z is N; three of W, X, Y and Z are CR³; and each R³ is independently hydrogen, halo, C→ to C₅ alkyl or CO₂H, and their pharmaceutically acceptable salts.

The preferred compounds are those wherein W is N; X and Z are each CR³; and Y is CH. Particularly preferred are those of the formula V, below:

wherein A, together with the carbon to which it is attached, forms cyclopentyl, substituted cyclopentyl, cyclopentenyl, cyclohexenyl, 2-vinyl-1 -cyclopropyl or 2-indanyl; and R¹ is CO₂H or 5-tetrazolyl, for example, 1-[4'-(2"-ethyl-5",7"-dimethylimidazo[4,5- b]pyridin-3-yl)methylphenyl]cyclohex-3-ene-1 -carboxylic acid; c/^'s-3,4-difluoro-1 -[4'-(2"- ethyl-5",7"-dimethylimidazo[4,5-b]pyridin-3-yi)methylphenyl]cyclopentane-1-carboxylic acid; 1-[4'-(2"-ethyl-5",7"-dimethylimidazo[4,5-b]pyridin-3-yl)methylphenyl]-2- vinylcyclopropane-1 -carboxylic acid; 2-[4'-(2"-ethyl-5",7"-dimethylimidazo[4,5-b]pyridin-3- yl)methylphenyl]indane-2-carboxylic acid; 1-[4'-(2"-ethyl-5",7"-dimethylimidazo[4,5- b]pyridin-3-yl)methylphenyl]cyclopentane-1 -carboxylic acid; and 1 -[4'-(2"-ethyl-5",7"- dimethylimidazo[4,5-b]pyridin-3-yl)methylphenyl]cyclopentane-1-(5"'-1"Η-tetrazole).

Also particularly preferred are those compounds of the formula VI, below:

wherein R² is ethyl, n-propyl, cyclopropyl or n-butyl; and R³ is hydrogen, bromo, methyl or CO₂H, for example, 1-[4'-(2"-ethyl-7"-methylimidazo[4,5-b]pyridin-3-yl)methylphenyl]- cyclopent-3-ene-1 -carboxylic acid; 1 -[4'-(5"-bromo-2"-ethyl-7"-methylimidazo[4,5-b]- pyridin-3-yl)methylphenyl]cyclopent-3-ene-1 -carboxylic acid; 1 -[4'-(5"-carboxy-2"-ethyl-7"- methylimidazo[4,5-b]pyridin-3-yl)methylphenyl]cyclopent-3-ene-1 -carboxylic acid; 1 -[4'- (5",7"-dimethyl-2"-propylimidazo[4,5-b]pyridin-3-yl)methylphenyl]cyclopent-3-ene-1- carboxylic acid; 1 -[4'-(2"-cyclopropyl-5",7"-dimethylimidazo[4,5-b]pyridin-3-yl)methyl- phenyl]cyclopent-3-ene-1 -carboxylic acid; and 1-[4'-(2"-butyl-5",7"-dimethylimidazo[4,5- b]pyridin-3-yl)methylphenyl]cyclopent-3-ene-1 -carboxylic acid.

This invention also concerns pharmaceutical compositions comprising said compounds, methods of making and using said compounds and intermediates in the preparation of said compounds. The novel intermediates of the invention include the C→ to C₄ alkyl and halosubstituted C₂ to C₄ alkyl esters of said compounds (see, for example, Example 1 , Steps 5 and 3A). This invention relates also to pharmaceutically acceptable compositions of these novel compounds in combination with other antihypertensive and cardiotonic agents, including beta blockers, diuretics, angiotensin converting enzyme inhibitors, calcium channel blockers, atrial natriuretic factor peptidase inhibitors, renin inhibitors and digitalis. This invention further relates to the use of these novel compounds in the treatment of central nervous system disorders such as, for example, cognitive dysfunction including Alzheimer's disease, amnesia and senile dementia, depression, anxiety and dysphoria. Furthermore, they may be used to treat glaucoma and diabetic complications such as diabetic renal disease.

Detailed Description of the Invention As used herein, the following definitions are used.

"Halo" means radicals derived from the elements fluorine, chlorine, bromine and iodine.

"Alkyl" means straight or branched saturated hydrocarbon radicals, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and -f-butyl.

"Alkenyl" means straight or branched unsaturated hydrocarbon radicals, for example, ethenyl, 1 - or 2-propenyl, 2-methyl-1 -propenyl and 1 - or 2-butenyl.

"Cycloalkyl" means a saturated carbocyclic radical, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The compounds of the present invention may be prepared by a number of routes, including the following.

R ¹ (Droiecled)

In the reaction scheme depicted above, the compounds of the present invention are prepared by alkylating an imidazopyridine (II, prepared, for example, by the methods described in EP 400974 A2) with a bromide (I, prepared by standard methods, as illustrated in the examples below) in the presence of a basic agent. Suitable bases include, for example, sodium hydride, potassium tert-butoxide and potassium carbonate. The reaction preferably takes place in a reaction-inert solvent such as, for example, dimethylformamide (DMF), tetrahydrofuran (THF) and/or acetone. The desired protected compound (III) is purified by standard methods, for example, chromatography and/or recrystallization. The R¹ functionality is then deprotected by standard methods, for example, with an aqueous base such as sodium or lithium hydroxide in methanol or THF, to afford the desired final product (IV), which can be further purified by standard methods such as chromatography and/or recrystallization.

The compounds of the present invention are readily adapted to clinical use as modulators of All action at the All receptor. The ability of the compounds to modulate All action was determined by an in vitro All rat liver binding assay which measures their ability to displace ¹²⁵i sarcosine-1 , isoleucine-8, angiotensin II (SARILE All, obtained from New England Nuclear) from rat liver All receptors. For this assay, the following materials are used.

Homogenation buffer (10 mM Tris, 0.2 M sucrose, 1.0 mM EDTA), prepared using 1.21 g Tris base, 6.84 g sucrose and 336 mg EDTA in 1000 ml water, adjusted to pH 7.4 using HCI.

Buffer A (50 mM Tris, 5 mM MgCI₂), prepared using 6.05 g Tris base and 1.02 g

MgCI₂- 6H₂O in 1000 ml water.

Assay buffer, prepared using 200 ml Buffer A and 0.5 g BSA.

Male Sprague-Dawley rats are sacrificed by decapitation and the livers are removed quickly and placed in ice cold homogenation buffer (all the following procedures are performed at 4°C). The liver is minced with scissors and homogenized in a chilled ground glass homogenizer at approximately 10 ml buffer/1 g liver (wet weight). The homogenate is centrifuged at 3000 g (5000 rpm, SM24 rotor) for 10 minutes, then the supernatant is centrifuged at 10,000 g for 13 minutes. The resulting supernatant is then centrifuged at 100,000 g for one hour. The pellet is resuspended in buffer A to an approximate concentration of 1 ml protein/ml. A BioRad protein assay using Coomassie blue dye is then run. The membrane preparation is aliquoted, frozen and stored at -20°C. On the day of the assay, the preparation is diluted with assay buffer to a final concentration of 600 μg/ml or with buffer A to a final concentration of 200 μg/ml. Due to the fact that some compounds of the invention bind to proteins, the use of BSA may interfere with some tests. Accordingly, the assay may be run with or without BSA; the differences are identified below.

The compound being tested is made up to an initial concentration of 2 mM in 100% DMSO. Dilutions are then made using 10% DMSO in assay buffer or buffer A. Radiolabelled (hot) SARILE All is made up at 0.5 nM concentration in assay buffer or 1.0 nM concentration in buffer A. Non-radiolabelled (cold) SARILE All is made up at 20 μM in 10% DMSO in assay buffer or buffer A for non-specific binding. Using microtitre plates, each incubate receives: 50 μl hot SARILE All; 50 μl membrane preparation; and 100 μl buffer (total), cold SARILE All (nonspecific binding) or compound to be tested. Each plate consists of the following in triplicate: total binding; nonspecific binding; and varying concentration of compound. Plates are incubated at room temperature for 40 minutes for assays containing BSA or for 120 minutes for assays without BSA, on a rocker plate at high speed. Plates are then aspirated using an inotech cell harvester. The filters are cut, placed in test tubes and counted on a Gamma Counter. The mean for all triplicate points are calculated and total specific binding is calculated by subtracting nonspecific counts from total counts. Binding in the presence of compound (COUNTS) is calculated by subtracting nonspecific counts from counts in the presence of compound. Percent binding of SARILE All in the presence of compound is calculated by dividing COUNTS by total specific counts. Percent inhibition is (1- percent binding) *100. IC^, values (concentration of compound which inhibits binding by 50%) is read from a plot of percent inhibition (linear scale) versus compound concentration (log scale). The compounds of the present invention were found to have IC_gg values at or less than 10^"5 M.

The ability of the compounds of the invention to lower blood pressure in mammals was determined by the following in vivo protocol. Sprague-Dawley rats are placed on a low sodium diet (Purina Labs, 0.07% sodium) for 15 days. On days 11 and 13 of this period, the rats are given furosemide (Lasix, 8 mg/kg, i.m.). On day 13, the animals are anesthetized with a pentobarbital-chloral hydrate mixture (30 mg/kg pentobarbital sodium and 10 mg/kg chloral hydrate, i.p.) and the carotid artery and jugular vein are cannulated using PE50 tubing (Clay-Adams). After a 24 hour recovery period, the animals are injected on day 14 with Lasix (10 mg/kg, i.m.) and are placed in plexiglass chambers for blood pressure recording. After dosing rats by either the oral or parenteral routes with the compound being tested, blood pressure is monitored for 5 hours and is displayed on a polygraph. When possible, blood pressure is also checked after 24 hours. According to this protocol, the compounds of the invention are effective in lowering mean arterial pressure at oral dosages from about 0.1 mg/kg to about 30 mg/kg, and at parenteral dosages from about 0.01 mg/kg to about 10 mg/kg, often with a duration of action of greater than 24 hours.

Also within the scope of this invention are the pharmaceutically acceptable salts of the compounds of this invention. The pharmaceutically acceptable acid salts are those formed from acids which form non-toxic acid salts, for example, hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, citrate, fumarate, gluconate, iactate, maleate, succinate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate and formate salts. Pharmaceutically acceptable cationic salts include those non-toxic salts based on alkali and alkaline earth metals, for example, sodium, lithium, potassium, calcium and magnesium, as well as non-toxic ammonium, quaternary ammonium and amine cations, for example, ammonium, tetramethyl- ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine and triethylamine.

Such salts are formed by methods well known to those skilled in the art. The pharmaceutically acceptable salts of the novel compounds of the present invention are readily prepared by contacting said compounds with a stoichiometric amount of, in the case of a non-toxic cation, an appropriate metal hydroxide, alkoxide or amine in either aqueous solution or a suitable organic solvent. In the case of non-toxic acid salt, an appropriate mineral or organic acid in either aqueous solution or a suitable organic solvent can be used. The salt may then be obtained by precipitation or by evaporation of the solvent. For treatment of the various conditions described above, the compounds of the invention and their pharmaceutically acceptable salts can be administered to the patient either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition, according to standard pharmaceutical practice. A compound can be administered via a variety of conventional routes of administration including orally, parenterally and by inhalation. When the compounds are administered orally, the dose range will generally be from about 0.1 to about 50 mg/kg/day, based on the body weight of the subject to be treated, preferably from about 1 to about 10 mg/kg/day in single or divided doses. If parenteral administration is desired, then an effective dose will generally be from about 0.01 to about 10 mg/kg/day. In some instances it may be necessary to use dosages outside these limits, since the dosage will necessarily vary according to the age, weight and response of the individual patient as well as the severity of the patient's symptoms and the potency of the particular compound being administered.

For oral administration, the compounds of the invention and their pharmaceutically acceptable salts can be administered, for example, in the form of tablets, powders, lozenges, syrups or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are commonly added. In the case of capsules, useful diluents are lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added.

For intramuscular, intraperitoneal, subcutaneous and intravenous use, a sterile injectable solution of the active ingredient is usually prepared, and the pH of the solution should be suitably adjusted and buffered. For intravenous use, the total concentration of solute should be controlled to make the preparation isotonic.

Examples The present invention is illustrated by the following examples. Proton nuclear magnetic resonance (¹H NMR) spectra were measured at 300 MHz unless otherwise indicated and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane. The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.

Example 1 1-[4'-(2"-ethyl-5",7"-dimethylimidazo[4,5-b]- pyridin-3-yl)methylphenyl1cvclopent-3-ene-1 -carboxylic acid

The compound having the formula V, wherein R¹ is CO₂H and A is

-CH₂CH=CHCH₂-.

Step 1. methyl 4-f-butyldimethylsilyloxymethylphenylacetate To a solution of methyl p-hydroxymethylphenylacetate (3.30 g, 18.3 mmol, prepared according to the method of G. Biagi et al., E. Ed. Farmaco.. 43, 597 (1988)) in 6.6 ml DMF was added TBDMS-CI (3.31 g, 22.0 mmol) and imidazole (3.12 g, 45.8 mmol), and the resulting solution was stirred at ambient temperature for 18 hours. The mixture was poured into 100 ml H₂O and extracted (EtOAc, 4 x 50 ml). The combined extracts were dried (MgSO₄), filtered and concentrated. The crude material was chromatographed (EtOA hexane, 5:95) to afford the title compound (5.0 g, 92% yield) as an oil.

¹H NMR (CDCI₃) δ 0.09 (s, 6H), 1.94 (s, 9H), 3.60 (s, 2H), 3.67 (s, 3H), 4.70 (s, 2H), 7.23 (m, 4H).

Step 2, methyl 1-(4'-f-butyldimethylsilyloxy- methylphenyl)cvclopent-3-ene-1-carboxylate

To a solution of the product of Step 1 , above, (1.0 g, 3.4 mmol) in 10 ml THF at -20°C was added a 1 M solution of potassium f-butoxide in THF (3.73 ml, 3.73 mmol) over 15 minutes. After 30 minutes at -20°C, c/s-1 ,4-dichlorobut-2-ene (0.393 ml, 3.73 mmol) was added dropwise and the reaction was warmed to room temperature. After

20 minutes the reaction was cooled to -20°C and treated with potassium f-butoxide in

THF (3.73 ml, 3.73 mmol). The reaction was allowed to warm to room temperature, then was heated at 50°C for 30 minutes and quenched with saturated ammonium chloride solution. The solvents were removed in vacuo and the residue was taken up in ethyl acetate and washed with water. The organic layer was washed with saturated sodium chloride solution and dried over magnesium sulfate. After filtration, evaporation and gravity silica gel chromatography (SGC) with 2% ethyl acetate in petroleum ether as eluant, a mixture of the title compound and methyl 1 -(4'-f-butyldimethylsilyloxymethyl- phenyl)-2-vinylcyclopropane-1 -carboxylate (7:1 ratio, total 708 mg) was obtained as an oil. Since the two compounds were inseparable, the mixture was taken on.

¹H NMR (CDCy δ 0.09 (s, 6H), 0.9 (s, 9H), 2.75 (d, 2H), 3.40 (d, 2H), 3.65 (s, 3H), 4.72 (s, 2H), 5.78 (s, 2H), 7.25 (m, 4H).

Step 3, methyl 1 -(4'-hvdroxymethylphenyl)cyclopent-3-ene-1 -carboxylate

To a solution of the title compound of Step 2, above, (1.8 g, 5.23 mmol) in 25 ml

THF was added n-Bu₄NF (1.5 g, 5.75 mmol), and the resulting solution was stirred at ambient temperature for 3 hours. The mixture was poured into 50 ml 1 N HCI and extracted (EtOAc, 4 x 30 ml). The combined extracts were dried over MgSO₄, filtered and concentrated to yield 1.51 g of the title compound as an oil which was used crude in the next step.

¹H NMR (CDCy δ 2.74 (d, 2H), 3.40 (d, 2H) 3.66 (s, 3H), 4.65 (s, 2H), 5.76 (s,

2H), 7.26 (m, 4H).

Step 4. methyl 1 -(4'-bromomethylphenvDcvclopent-3-ene-1 -carboxylate To a solution of triphenylphosphine (8.03 g, 30.6 mmol) in 100 ml CH₂CI₂ at 0°C was added dropwise bromine (1.45 ml, 28.1 mmol). After 15 minutes at 0°C a white precipitate formed and a solution of the product of Step 3, above, (5.93 g, 25.5 mmol) in 30 ml CH₂CI₂ was added dropwise. After 1 hour the solvent was removed in vacuo and the residue was taken up in ether to precipitate the triphenylphosphine oxide formed in the reaction. After filtration, evaporation and SGC (5% EtOAc-hexanes) the title compound (5 g) was obtained as a colorless oil which crystallized on standing.

¹H NMR (CDCI₃) δ 2.73 (d, 2H), 3.62 (s, 3H), 4.48 (s, 2H), 5.77 (s, 2H), 7.20 (m,

4H).

Step 5, methyl 1-[4 2"-ethyl-5^M,7"-dimethylimidazo[4,5-b]- pyridin-3-yl)methylphenyl1cvclopent-3-ene-1 -carboxylate

To a suspension of sodium hydride (0.885 g, 22.1 mmol) in 50 ml of DMF at 0°C was added a solution of 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (3.57 g, 20 mmol, prepared from 2-amino-4,6-dimethylpyridine by nitration, hydrogenolysis to the diamine and condensation with propionic acid and polyphosphoric acid, as described in EP 400974 A2) in 10 ml of DMF dropwise and the reaction mixture was warmed to room temperature. After 20 minutes the reaction was cooled to 0°C and a solution of the product of Step 4, above, (5 g, 17 mmol) in 10 ml of DMF was added dropwise. The reaction was then allowed to warm to room temperature and stirred overnight then the DMF was removed in vacuo. The residue was taken up in water and extracted three times with ethyl acetate. The combined organics were washed with saturated sodium chloride solution, dried with MgSO₄, filtered, evaporated and chromatographed on silica gel with a gradient elution from 5:1 hexanes:ethyl acetate to 1 :1 hexanes:ethyl acetate to yield 5.8 g of the title compound as a pale yellow oil.

¹H NMR (CDCI₃) δ 1.3 (t, 3H), 2.59 (s, 3H), 2.62 (s, 3H), 2.7 (d, 2H), 2.8 (q, 2H), 3.4 (d, 2H), 3.63 (s, 3H), 5.4 (s, 2H), 5.72 (s, 2H), 6.9 (s, 1 H), 7.1 (d, 2H), 7.28 (d, 2H).

Step 6, 1-[4^,-(2"-ethyl-5",7"-dimethylimidazo[4,5-b]pyridin- 3-vDmethylphenyl]cvclopent-3-ene-1 -carboxylic acid

A solution of the product of Step 5, above (5.76 g, 14.9 mmol) and lithium hydroxide monohydrate (6.23 g, 148 mmol) in 148 ml of methanol and 148 ml of water was heated at reflux for 2 hours. The reaction was then concentrated in vacuo, the residue was taken up in water and the pH was adjusted to 4 with concentrated HCI when the title compound precipitated as a colorless solid which was filtered off, dried in vacuo and recrystallized first from ethyl acetate/methanol, then from methanol to yield 1.9 g of title compound which was contaminated with 2.5% of 1-[4'-(2"-ethyl-5",7"- dimethylimidazo[4,5-b]pyridin-3-yl)methylphenyl]-2-vinylcyclopropane-1 -carboxylic acid. Another recrystallizaton from methanol yielded 1.5 g of title compound, mp 232-233°C, now about 98.3% pure, as determined by reverse-phase HPLC using a C-18 Beckman 25 cm long column and 30% pH 2.3 phosphate buffer in acetonitrile as eluant.

¹H NMR (DMSO-d₆) δ 1.24 (t, 3H), 2.5 (s, 6H), 2.6 (d, 2H), 2.8 (q, 2H), 3.3 (d, 2H), 5.4 (s, 2H), 5.75 (s, 2H), 6.95 (s, 1 H), 7.09 (d, 2H), 7.3 (d, 2H).

Alternatively, and preferably, the compound of Example 1 can be prepared via the following method. Step 1A, 4'-(2"-ethyl-5",7"-dimethylimidazo- r4.5-blpyridin-3-yl)methylphenylacetic acid

A solution of 4-(bromomethyl)phenylacetic acid (24.53 g, 107 mmol) in 60 ml

DMF was added slowly to a suspension of sodium hydride (4.29 g, 60% dispersion in oil, 107 mmol) in 240 ml of DMF at -25°C and the reaction mixture was stirred at -20°C for 30 minutes. Meanwhile, 2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine (15 g, 85.7 mmol) was added as a solid to a suspension of sodium hydride (3.43 g, 60% dispersion in oil,

85.7 mmol) in 180 ml of DMF at -10°C and the reaction was allowed to warm to room temperature over 30 minutes, then was cooled to -20°C and treated via cannula with the solution of the sodium salt of 4-(bromomethyl)phenylacetic acid in DMF prepared above. After the addition was complete, the reaction mixture was cooled in a ice bath at -10°C and was allowed to warm to room temperature overnight. The DMF was removed in vacuo and the residue was taken up in water and extracted with ethyl acetate. The aqueous layer was adjusted to pH 4 with concentrated hydrochloric acid an was extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium chloride and dried over magnesium sulfate. Concentration afforded the title compound (18 g) as a pale yellow solid which was used without further purification.

¹H NMR (CD₃OD) δ 1.25 (t, 3H), 2.55 (s, 3H), 2.6 (s, 3H), 2.8 (q, 2H), 3.6 (s, 2H),

5.5 (S, 2H), 6.9-7.3 (m, 5H).

Step 2A, methyl 4'-(2"-ethyl-5",7"-dimethyl- imidazor4.5-blpyridin-3-yl)methylphenylacetate The product of Step 1A, above (56 g), was dissolved in 1 t methanol at room temperature and was treated with 11 ml concentrated sulfuric acid and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate solution and concentrated. The residue was taken up in water and extracted three times with ethyl acetate. The combined organic layers were washed with saturated sodium chloride and dried over magnesium sulfate.

Concentration and silica gel chromatography (1 :1 ethyl acetate:hexanes) afforded the title compound (42 g) as a pale yellow oil.

¹H NMR (CDCI₃) δ 1.3 (t, 3H), 2.6 (s, 3H), 2.65 (s, 3H), 2.8 (q, 2H), 3.6 (s, 2H), 3.75 (s, 3H), 5.45 (s, 2H), 6.9 (s, 1H), 7.1 (d, 2H), 7.2 (d, 2H). Step 3A, methyl 1-[4'-(2"-ethyl-5^M,7"-dimethylimidazo[4,5- blpyridin-3-yl)methylphenyl cvclopent-3-ene-1 -carboxylate

The product of Step 2A, above (42 g, 126 mmol), was dissolved in 620 ml anhydrous THF and 124 ml of 1 ,3-dimethyl-3,4,5,6-tetrahydro-2-(1 H)-pyrimidinone (DMPU) and the solution was cooled to -78°C and treated with potassium tert-butoxide

(138.8 ml, 1 M in THF, 138.8 mmol). After 15 minutes, c/s-1 ,4-dichlorobut-2-ene (14.6 ml, 138.8 mmol) was added neat. The reaction mixture was then stirred at -78°C for one hour and at -50°C for another hour, then potassium tert-butoxide (138.8 ml, 1 M in

THF, 138.8 mmol) was added. After warming to room temperature the reaction mixture was heated to 50°C for 1 hour and was then quenched with water. The THF was removed in vacuo and the residue was taken up in water and extracted with ethyl acetate. The combined organic layers were washed four times with saturated lithium chloride solution and dried over magnesium sulfate. Concentration and silica gel chromatography (3:1 hexanes:ethyl acetate) yielded the title compound (29 g) as a yellow oil.

¹H NMR (CDCIg) δ 1.3 (t, 3H), 2.59 (s, 3H), 2.62 (s, 3H), 2.7 (d, 2H), 2.8 (q, 2H), 3.4 (d, 2H), 3.63 (s, 3H), 5.4 (s, 2H), 5.72 (s, 2H), 6.9 (s, 1 H), 7.1 (d, 2H), 7.28 (d, 2H).

Step 4A, l-μ'-f -ethyl-^.r-dimethylimidazotøδ-b]-

Pyridin-3-yl)methylphenvπcvclopent-3-ene-1 -carboxylic acid

A solution of the product of Step 3A, above (52 g, 134 mmol), and lithium hydroxide monohydrate (56.5 g) in 1350 ml of methanol and 1350 ml of water was heated to reflux for 3.5 hours. The reaction mixture was concentrated in vacuo to about one third of its original volume and the residue was washed with ether. The aqueous layer was adjusted to pH 4 with concentrated hydrochloric acid and acetic acid and was extracted three times with ethyl acetate-THF. The combined organic layers were washed with saturated sodium chloride solution and were dried over magnesium sulfate. Concentration afforded the title compound as a pale yellow solid which was purified as follows. The crude title compound (83 g) was suspended in 650 ml of ortΛo-dichlorobenzene and heated to reflux for 14 hours, then was allowed to cool slowly to room temperature over 6 hours. The precipitate that formed was filtered off and was washed with ethyl acetate. Two recrystallizations from ethyl acetate-THF afforded the purified title compound (45 g) as a colorless solid, mp 233-234°C. ¹H NMR (DMSO-d₆) δ 1.24 (t, 3H), 2.5 (s, 6H), 2.6 (d, 2H), 2.8 (q, 2H), 3.3 (d, 2H), 5.4 (s, 2H), 5.75 (s, 2H), 6.95 (s, 1 H), 7.09 (d, 2H), 7.3 (d, 2H).

Example 2 1 -[4'-(2"-ethyl-5",7"-dimethylimidazo[4,5-b]- pyridin-3-yl)methylphenyl1cvclohex-3-ene-1 -carboxylic acid

The compound having the formula V, wherein R¹ is CO₂H and A is

-CH₂CH=CHCH₂CH₂-.

Step 1 , methyl 1 -(4' -butyldimethylsilyloxy- methylphenyltovclohex-3-ene-1 -carboxylate

Sodium hydride (312 mg, 7.8 mmol, 60% in oil) was washed with hexane then was suspended in 5 ml of DMF at 50°C. A solution of c/s-1 ,5-dichloropent-2-ene (0.54 g, 3.9 mmol) and methyl 4-f-butyldimethylsilyloxymethylphenylacetate (1.04 g, 3.55 mmol, prepared as described in Example 1 , Step 1 , above) in 10 ml of DMF was added over 45 minutes and the heating continued for a further 2 hours. The DMF was then removed in vacuo and the residue taken up in water and extracted (3 times) with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over MgSO₄, filtered, concentrated and chromatographed on silica gel (gravity with a gradient elution of from 35:1 to 25:1 petroleum etheπethyl acetate) to give 0.59 g of the title compound as an oil.

H NMR (CDCI₃) δ 0.95 (s, 9H), 2-3 (m, 6H), 3.65 (s, 3H), 4.75 (s, 2H), 7.26 (m, 4H).

Step 2. methyl 1 -(4'-hvdroxymethylphenyl)cvclohex-3-ene-1 -carboxylate

The product of Step 1 , above (582 mg), was deprotected as in Example 1 , Step 3 to yield the title compound (350 mg).

¹H NMR (CDCI₃) δ 3.6 (s, 3H), 4.65 (s, 1 H), 7.3 (m, 4H).

Step 3. methyl 1 -(4'-bromomethylphenyl)cvclohex-3-ene-1 -carboxylate The product of Step 2, above (350 mg), was brominated as in Example 1 , Step 4 to yield the title compound (250 mg).

¹H NMR (CDCI₃) δ 3.65 (s, 3H), 4.47 (s, 2H), 7.35 (m, 4H). Step 4, methyl 1-[4'-(2"-ethyl-5",7"-dimethylimidazo[4,5- blpyridin-3-yl)methylphenyllcvclohex-3-ene-1 -carboxylate

Alkylation was carried out on the product of Step 3, above (237 mg), as in

Example 1 , Step 5 to yield the title compound (205 mg).

¹H NMR (CDCI₃) δ 1.3 (t, 3H), 2.60 (s, 3H), 2.63 (s, 3H), 2.77 (m, 2H), 2.4 (m,

2H), 3.6 (S, 3H), 5.4 (s, 2H), 6.88 (s, 1 H), 7.07 (d, 2H), 7.25 (d, 2H).

Step 5, 1-[4^,-(2"-ethyl-5",7"-dimethylimidazo[4,5- blpyridin-3-vhmethylphenyllcvclohex-3-ene-1 -carboxylic acid

Hydrolysis on 205 mg of the product of Step 4, above, was carried out as in

Example 1 , Step 6 to yield 48 mg of the title compound, mp 209-211°C, as a colorless solid after recrystallization from EtOAc/MeOH.

¹H NMR (MeOH-d₄) δ 1.3 (t, 3H), 1.9-2.5 (m, 5H), 2.6 (s, 3H), 2.7 (s, 3H), 2.8 (d,

1 H), 2.9 (q, 2H), 5.6 (s, 2H), 5.7 (dt, 1 H), 5.8 (dt, 1 H), 7.05 (s, 1 H), 7.1 (d, 2H), 7.4 (d, 2H).

Example 3 c/s-3,4-difluoro-1 -[4^,-(2"-ethyl-5",7"-dimethylimid- azor4.5-b1pyridin-3-yl)methylphenyl1cvclopentane-1 -carboxylic acid

The compound having the formula V, wherein R¹ is CO₂H and A is (cis)

-CH₂CHFCHFCH₂-.

Step 1. methyl 1 -to-tolyl)cvclopent-3-ene-1 -carboxylate Bisalkylation of methyl p-tolylacetate (10 g, 61 mmol) by c/s-1 ,4-dichlorobut-2- ene (7.05 ml, 66 mmol) was carried out as in Example 2, Step 1 to yield 5 g of the title compound (contaminated with about 30% of the vinyl cyclopropyl compound, see Example 1 , Step 2) after gravity silica gel chromatography with 2-4% ethyl acetate/hexanes.

¹H NMR (CDCI₃) δ 2.4 (s, 3H), 2.72 (d, 2H), 3.39 (d, 2H), 3.65 (s, 3H), 5.77 (s, 2H), 7.12 (d, 2H), 7.2 (d, 2H). Step 2. methyl c/s-3.4-dihvdroxy-1 -(p-tolvDcvclopentane-1 -carboxylate The product of Step 1 , above (2 g, 9.3 mmol), N-methylmorpholine-N-oxide (1.3 g, 11 mmol) and 2.5% osmium tetroxide solution in f-butanol (470 μl, 0.05 equivalents) were combined at room temperature in 21 ml of acetone and 2.6 ml of water and the mixture was stirred overnight. The reaction was quenched with saturated sodium bisulfite solution and extracted twice with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, concentrated and subjected to SGC with a gradient elution from 1 :6 to 2:3 ethyl acetate :hexanes to yield 970 mg of the title compound.

¹H NMR (CDCy δ 2.35 (s, 3H), 2.3 (dd, 2H), 2.85 (d, 2H), 3.64 (s, 3H), 4.2 (m, 2H), 7.11 (d, 2H), 7.16 (d, 2H).

Step 3. methyl c/s-3.4-difluoro-1 -(p-tolyl)cvclopentane-l -carboxylate To a solution of the product of Step 2, above (920 mg, 4.3 mmol), in anhydrous dimethoxyethane at -30°C was added dropwise DAST (3.4 ml, 6 equivalents). The solution was allowed to warm to room temperature, stirred overnight then quenched carefully with saturated sodium bicarbonate solution and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered, concentrated and subjected to SGC with a gradient elution from 1 :20 to 1 :12 ethyl acetate:hexanes to yield 250 mg of the title compound.

¹H NMR (CDCI₃) δ 2.32 (s, 3H), 2.5 (m, 2H), 3.1 (m, 2H), 3.65 (s, 3H), 4.9 (m, 1 H), 5.1 (m, 1 H), 7.12 (d, 2H), 7.2 (d, 2H).

Step 4, methyl 1 -(4'-bromomethylphenyl)- c/s-3.4-difluorocvclopentane-1 -carboxylate

A mixture of the product of Step 3, above (208 mg, 8 mmol), N-bromosuccini- mide (160 mg, 9.2 mmol) and 10 mg AIBN in 5 ml of CCI₄ was heated at reflux for 4 hours, cooled to 0°C and filtered through Celite. The residue was washed well with

CCI₄ and the filtrate was concentrated and subjected to SGC with 12:1 petroleum ether:ethyl acetate as eluant to yield 295 mg of the title compound. H NMR (CDCI₃) δ 2.5 (m, 2H), 3.1 (m, 2H), 3.65 (s, 3H), 4.47 (s, 2H), 4.85 (m, 1 H), 5.1 (m, 1 H), 7.3 (d, 2H), 7.39 (d, 2H).

Step 5, methyl c/s-3,4-difiuoro-1-[4'-(2"-ethyl-5",7"-dimethyl- imidazof4,5-b]pyridin-3-vDmethylphenyl]cvclopentane-1 -carboxylate

Alkylation of the product of Step 4, above (290 mg, 0.91 mmol), with 2-ethyl-5,7- dimethyl-3H-imidazo[4,5-b]pyridine (175 mg, 1 mmol), proceeded as described in Example 1 , Step 5 to afford the title compound (173 mg) as a gum after flash chromatography (hexane:ethyl acetate, 1 :1).

¹H NMR (CDCI₃) δ 1.31 (t, 3H), 2.4 (m, 2H), 2.58 (s, 3H), 2.62 (s, 3H), 2.77 (q, 2H), 3.1 (m, 2H), 3.6 (s, 3H), 4.82 (m, 1 H), 5.05 (m, 1 H), 5.4 (s, 2H), 6.87 (s, 1 H), 7.06 (d, 2H), 7.2 (d, 2H).

Step 6, c/s-3,4-difluoro-1 -[4'-(2"-ethyl-5",7"-dimethylimidazo- r4.5-blPyridin-3-yl)methylphenyl]cvclopentane-1 -carboxylic acid

Hydrolysis of the product of Step 5, above (167 mg, 0.39 mmol), proceeded as described in Example 1 , Step 6 to afford the title compound (71 mg) as a colorless solid, mp 216-218°C, after precipitation from the aqueous reaction mixture (adjusted to pH 4) and recrystallization with ethyl acetate/methanol.

¹H NMR (MeOH-d4) δ 1.28 (t, 3H), 2.4 (m, 2H), 2.6 (s, 3H), 2.7 (s, 3H), 2.9 (q, 2H), 3.15 (m, 2H), 4.9 (m, 1 H), 5.1 (m, 1 H), 5.6 (s, 2H), 7.05 (s, 1 H), 7.1 (d, 2H), 7.4 (d, 2H).

Example 4 1-[4 2"-ethyl-5",7"-dimethylimidazo[4,5-b]- pyridin-3-v methylphenyl1-2-vinylcvclopropane-1 -carboxylic acid

The compound having the formula V, wherein R¹ is CO₂H and A is

-CH₂CH(CH=CH₂)-.

Step 1 , methyl 1-(4'-f-butyldimethylsilyloxy- methylphenv0-2-vinylcvclopropane-1 -carboxylate

Dialkylation of methyl 4-f-butyldimethylsilyloxymethylphenylacetate (1.5 g, 5.1 mmol) as described in Example 1 , Step 2, with trans- ,4-dichlorobut-2-ene yielded a mixture of the title compound and methyl 1-(4'-f-butyldimethylsilyloxymethylphenyl)- cyclopent-3"-ene-1 -carboxylate (the title compound of Example 1 , Step 2, 4:1 ratio, total 360 mg) after gravity chromatography with a gradient elution of from 1 to 3% ethyl acetate in petroleum ether.

¹H NMR (CDCy δ 0.92 (s, 9H), 1.49 (dd, 1 H), 1.87 (dd, 1 H), 2.18 (dd, 1 H), 3.6 (s, 3H), 4.72 (s, 2H), 5.1 (d, 1 H), 5.3 (d, 1 H), 5.8 (dd, 1 H), 7.25 (m, 4H).

Step 2. methyl 1 -(4'-hvdroxymethylphenv0-2-vinylcvclopropane-1 -carboxylate Deprotection of the product of Step 1 , above (362 mg, 1 mmol), was carried out as described in Example 1 , Step 3 to yield, after flash chromatography (25% ethyl acetate in hexanes), the title compound (220 mg) as a colorless oil.

¹H NMR (CDCI₃) δ 1.5 (dd, 1 H), 1.9 (dd, 1 H), 2.2 (dd, 1 H), 3.6 (s, 3H), 4.7 (d, 2H), 5.15 (d, 1 H), 5.3 (d, 1 H), 5.8 (dd, 1 H), 7.3 (m, 4H).

Step 3. methyl 1 -(4'-bromomethylphenyl)-2-vinylcvclopropane-1 -carboxylate

Bromination of the product of Step 2, above (219 mg, 0.95 mmol), was carried out as described in Example 1 , Step 4, to yield, after flash chromatography (15% ethyl acetate in hexanes), the title compound (158 mg) as a colorless oil. TLC (15% EtOAc/hexanes) R,=0.31.

Step 4, methyl 1-[4'-(2"-ethyl-5",7"-dimethylimidazo[4,5-b]- pyridin-3-yl)methylphenyll-2-vinylcvclopropane-1 -carboxylate

Alkylation of the product of Step 3, above (155 mg, 0.53 mmol), with 2-ethyl-5,7- dimethylimidazo[4,5-b]pyridine (111 mg, 0.64 mmol) proceeded as described in Example 1 , Step 5 to afford the title compound (227 mg) as a gum which was taken on crude to the next step.

¹H NMR (CDCI₃) δ 2.58 (s, 3H), 2.61 (s, 3H), 2.8 (q, 2H), 3.6 (s, 3H), 5.1 (d, 1 H),

5.3 (d, 1 H), 5.45 (s, 2H), 5.8 (dd, 1 H), 6.89 (s, 1 H), 7.07 (d, 2H), 7.25 (d, 2H).

Step 5, 1-[4M2"-ethyl-5",7"-dimethylimidazo[4,5-b]pyridin- 3-vDmethylphenyl]-2-vinylcvclopropane-1 -carboxylic acid

Hydrolysis of the product of Step 4, above (225 mg, 0.58 mmol), proceeded as described in Example 1 , Step 6 to afford the title compound (50 mg, contaminated with about 16% of the cyclopentene analog 1-[4'-(2"-ethyl-5",7"-dimethylimidazo[4,5-b]- pyridin-3-yl)methylphenyl]cyclopent-3-ene-1 -carboxylic acid (the title compound of Example 1 ) as a colorless solid after precipitation from the aqueous reaction mixture (adjusted to pH 4) and recrystallization with ethyl acetate/methanol. A second recrystallization from methanol yielded 35 mg of the title compound, mp 199-200°C, contaminated with about 10% of the abovementioned cyclopentene analog.

¹H NMR (MeOH-d4) δ 1.3 (t, 3H), 1.5 (m, 1 H), 1.7 (m, 1 H), 2.2 (m, 1 H), 2.6 (s, 3H), 2.62 (s, 3H), 2.9 (q, 2H), 5.1 (d, 1 H), 5.3 (d, 1 H), 5.6 (s, 2H), 5.4 (dd, 1 H), 7.05 (s, 1 H), 7.1 (d, 2H), 7.35 (d, 2H).

Example 5 2-[4'-(2"-ethyl-5",7"-dimethylimidazo- f4.5-blpyridin-3-yllmethylphenyllindane-2-carboxylic acid

The compound having the formula V, wherein R¹ is CO₂H and A, together with the carbon to which it is attached, forms 2-indanyl.

Step 1. methyl 2-(4'-f-butyldimethylsilyloxymethylphenyl)indan-2-carboxylate Bisalkylation of methyl 4-f-butyldimethylphenylacetate (0.88 g, 2.9 mmol) with a, α-dichloro-o-xylene proceeded as described in Example 2, Step 1 to yield, after flash chromatography (EtOAc:hexane, 3:97), the title compound (0.57 g) as an oil.

¹H NMR (CDCI₃) δ 0.08 (s, 6H), 0.91 (s, 9H), 3.28 (d, J=16 Hz, 2H), 3.56 (s, 3H), 3.92 (d, J=16 Hz, 2H), 4.67 (s, 2H), 7.20 (m, 8H).

Step 2. methyl 2-(4'-hvdroxymethylphenyl)indan-2-carboxylate Deprotection of the product of Step 1 , above (570 mg, 2 mmol), proceeded as described in Example 1 , Step 3 to yield, after flash chromatography (methanol :CH₂CI₂, 3:97), the title compound (380 mg) as a colorless solid.

¹H NMR (CDCI₃) δ 3.29 (d, J=16 Hz, 2H), 3.56 (s, 3H), 3.93 (d, J=16 Hz, 2H), 4.64 (s, 2H), 7.22 (m, 8H).

Step 3, methyl 2-(4'-bromomethylphenyl)indan-2-carboxylate To a solution of the product of Step 2, above (370 mg, 1.31 mmol), and 2 drops pyridine in 1 ml ether at 0°C was added slowly a solution of PBr₃ (116 mg, 0.43 mmol) in 1 ml ether. After stirring at ambient temperature for 4 hours, the mixture was poured into 10 ml water and extracted (EtOAc, 4 x 25 ml). The combined extracts were dried over MgSO₄, filtered and concentrated. The crude material was chromatographed (EtOAc:hexane, 3:97) to afford the title compound (250 mg, 55% yield).

¹H NMR (CDCI₃) δ 3.26 (d, J=16 Hz, 2H), 3.55 (s, 3H), 3.89 (d, J=16 Hz, 2H),

4.42 (S, 2H), 7.13 (m, 4H), 7.30 (s, 4H).

Step 4, methyl 2-[4'-(2"-ethyl-5",7"-dimethylimidazo- f4,5-bjpyridin-3-vnmethylphenvnindane-2-carboxylate Alkylation of the product of Step 3, above with 2-ethyl-5,7-dimethyl-3H- imidazo[4,5-b]pyridine proceeded as described in Example 1 , Step 5 to afford the title compound.

Step 5, 2-[4'-(2"-ethyl-5",7"-dimethylimidazo[4,5-b]- pyridin-3-yl)methylphenvπindane-2-carboxylic acid

Hydrolysis of the product of Step 4, above (299 mg, 0.68 mmol), was carried out as described in Example 1 , Step 6 to afford the title compound (180 mg) as a colorless solid, mp 249-251 °C, after recrystallization with ethyl acetate/methanol.

¹H NMR (MeOH-d4) δ 1.2 (t, 3H), 2.5 (s, 6H) 2.8 (q, 2H), 3.1 (d, 2H), 3.8 (d, 2H),

5.4 (s, 2H), 6.9 (s, 1 H), 7.1 (m, 4H), 7.2 (m, 2H), 7.35 (d, 2H).

Example 6 1-[4'-(2"-ethyl-5",7^M-dimethylimidazo[4,5-b]- pyridin-3-yl)methylphenyllcvclopentane-1 -carboxylic acid The compound having the formula V, wherein R¹ is CO₂H and A is -(CH₂)₄-.

Step 1. methyl 1 -(4'-methylphenyl)cvclopentane-1 -carboxylate To a suspension of petroleum ether-washed 60% NaH (1.48 g, 37 mmol) in 5 ml DMF at 50°C was added over 30 minutes a solution of methyl 4-methylphenylacetate (2.50 g, 15 mmol) and 1 ,4-dibromobutane (3.24 g, 15 mmol) in 15 ml DMF. After heating for an additional hour, the reaction mixture was poured into 125 ml H₂O and extracted (EtOAc, 5 x 25 ml). The combined extracts were washed (H₂O, 5 x 25 ml), dried over MgSO₄ and concentrated. Flash chromatography (hexane: EtOAc, 19:1) afforded the title compound (1.58 g, 48% yield) as a white solid, mp 56-57°C, which was then recrystallized from hexane. Anal. (C₁₄H₁₈O₂). ¹H NMR (CDCI₃) δ 1.70 (m, 4H), 1.88 (m, 2H)^', 2.32 (s, 3H), 2.61 (m, 2H), 3.60 (s, 3H), 7.09 (d, J=9 Hz, 2H), 7.23 (d, J=9 Hz, 2H).

Step 2. methyl 1 -(4'-bromomethylphenyl)cvclopentane-1 -carboxylate A solution of the product of Step 1, above (2.82 g, 12.9 mmol), NBS (2.40 g,

13.5 mmol) and AIBN (151 mg) in 120 ml CCI₄ was refluxed for 17 hours. The cooled reaction mixture was filtered and the filtrate was concentrated. The residue was chromatographed (hexane: EtOAc, 19:1) to afford the title compound (3.17 g, 83% yield) as a pale yellow solid, mp 60-62°C, which was then recrystallized from hexane. Anal. (C₁₄H₁₇O₂Br).

¹H NMR (CDCI₃) δ 1.65 (m, 4H), 1.82 (m, 2H), 2.57 (m, 2H), 3.55 (s, 3H), 4.42 (s, 3H), 7.26 (s, 4H).

Step 3, methyl 1 -[4'-(2"-ethyl-5",7"-dimethylimidazo- f4.5-blPyridin-3-yl)methylphenyl)cvclopentane-1 -carboxylate

Alkylation of the product of Step 2, above (250 mg, 1.42 mmol), with 2-ethyl-5,7- dimethyl-3H-imidazo[4,5-b]pyridine (273 mg, 1.56 mmol) proceeded as described in

Example 1 , Step 5 to afford the title compound (360 mg) as a wax after flash chromatography (hexane:acetone, 4:1).

¹H NMR (CDCI₃) δ 1.30 (t, J=7 Hz, 3H), 1.68 (m, 4H), 1.82 (m, 2H), 2.57 (m, 2H),

2.58 (s, 3H), 2.62 (s, 3H), 2.78 (q, J=7 Hz, 2H), 3.57 (s, 3H), 5.42 (s, 2H), 6.89 (s, 1H),

7.05 (d, J=8 Hz, 2H), 7.26 (d, J=8 Hz, 2H).

Step 4, 1-[4M2"-ethyl-^7"-dimethylimidazo[4,5-b]- pyridin-3-yl)methylphenvπcvclopentan-1 -carboxylic acid

A mixture of the product of Step 3, above (360 mg, 0.92 mmol), in 5 ml 1N

NaOH and 6 ml CH₃OH was heated to reflux for 3 hours. The reaction mixture was concentrated and the residue was dissolved in 25 ml 1 N NaOH and washed (EtOAc, 3 x 7 ml). The aqueous phase was neutralized and the resulting precipitate was collected and washed with H₂O. Recrystallization from 2-propanol afforded the title compound (218 mg, 63% yield) as a white solid, mp 239-241 °C. Anal. (C₂₃H₂₇N₃O₂). ¹H NMR (DMS0-d6) δ 1.22 (t, J=7 Hz, 3H), 1.61 (m, 4H), 1.70 (m, 2H), 2.42 (m, 2H), 2.49 (s, 6H), 2.77 (q, J=7 Hz, 2H), 5.41 (s, 2H), 6.93 (s, 1 H), 7.04 (d, J=8 Hz, 2H), 7.27 (d, J=8 Hz, 2H).

Example 7 1 -[4 2"-ethyl-5",7"-dimethylimidazo[4,5-b]- pyridin-3-vnmethylphenyl1cvclopentane-1-(5'"-1 '"H-tetrazole)

The compound having the formula V, wherein R¹ is 5-tetrazolyl and A is -(CH₂)₄-.

Step 1. 1 -(4'-bromomethylphenyl)cvclopentane-1 -nitrile 1 -(4'-methylphenyl)cyclopentane-1 -nitrile (2.35 g, 12.7 mmol) was brominated as described in Example 6, Step 2 to afford the title compound which was used crude in the next step.

¹H NMR (CDCI₃) δ 1.9-2.2 (m, 6H), 2.5 (m, 2H), 4.47 (s, 2H), 7.4 (m, 4H).

Step 2, l- -^-ethyl-S'^'-dirnethylimidazo- f4.5-blpyridin-3-v methylphenyllcvclopentane-1 -nitrile

Alkylation of the product of Step 1 , above (450 mg, 1.7 mmol), with 2-ethyl-5,7- dimethyl-3H-imidazo[4,5-b]pyridine (298 mg, 1.7 mmol) proceeded as described in Example 1 , Step 5 to afford the title compound (358 mg) as a wax after flash chromatography (ethyl acetate).

¹H NMR (CDCy δ 1.8 (t, 3H), 1.9-2.2 (m, 6H), 2.45 (m, 2H), 2.6 (s, 3H), 2.65 (s,

3H), 2.78 (q, 2H), 5.45 (s, 2H), 6.88 (s, 1 H), 7.13 (d, 2H), 7.37 (d, 2H).

Step 3, 1 -[4^2"-ethyl-^7"-dimethylimidazo[4,5-b]pyri- din-3-vDmethylphenyllcvclopentane-1 -(5"'-1 '"H-tetrazole)

A solution of the product of Step 2, above (358 mg, 1.13 mmol), and trimethyltin azide (490 mg, 2.3 mmol) was heated at 155°C overnight. The reaction was then cooled and the xylene removed in vacuo. The residue was absorbed onto silica gel and flash chromatographed with gradient elution (2% to 5% methanol in methylene chloride) to afford the title compound as a foam which was taken up in chloroform and precipitated with hexane to give the title compound (217 mg) as a colorless solid. ¹H NMR (CDCy δ 1.08 (t, 3H), 1.78 (m, 4H), 2.2 (m, 2H), 2.45 (q, 2H), 2.46 (s, 3H), 2.52 (s, 3H), 2.66 (m, 2H), 5.3 (s, 2H), 6.78 (d, 2H), 6.87 (s, 1 H), 7.15 (d, 2H).

Example 8 1 -[4'-(2"-ethyl-7"-methylimidazo[4,5-b]- pyridin-3-yl)methylphenyl1cvclopent-3-ene-1 -carboxylic acid

The compound having the formula VI, wherein R² is ethyl and R³ is hydrogen.

Step 1. methyl 1 -(4'-chloromethylphenvhcvclopent-3-ene-1 -carboxylate To a solution of methyl 1 -(4'-hydroxymethylphenyl)cyclopent-3-ene-1 -carboxylate (232 mg, 1.0 mmol, prepared as described in Example 1 , Step 3) in 1 ml DMF was added POCI₃ (0.102 ml, 1.1 mmol) in 0.120 ml DMF over 5 minutes. The reaction mixture was stirred at ambient temperature for 16 hours and then the mixture was poured into 10 ml sodium acetate solution and extracted (EtOAc, 3 x 10 ml). The combined extracts were dried over MgSO₄, filtered and concentrated to obtain the title compound which was used crude in the next step.

¹H NMR (CDCI₃) δ 2.75 (d, 2H), 3.4 (d, 2H), 3.65 (s, 3H), 4.55 (s, 2H), 5.75 (s, 2H), 7.32 (d, 2H), 7.34 (d, 2H).

Step 2, methyl 1-[4 2"-ethyl-7"-methylimidazo[4,5-b]- pyridin-3-vDmethylphenvπcvclopent-3-ene-1 -carboxylate

To a suspension of petroleum-ether washed NaH (18 mg, 0.44 mmol) in 3 ml

DMF was added 2-ethyl-7-methyl-3H-imidazo[4,5-b] pyridine (70 mg, 0.44 mmol, prepared as described in EP 400974 A2, EP 420237 A and EP 399731 A). The system was stirred for 15 minutes at ambient temperature and then the product of Step 1 , above (100 mg, 0.40 mmol), dissolved in 2 ml DMF was cannulated into the anion. The reaction mixture was stirred at ambient temperature for 17 hours and then was poured into 10 ml saturated NaCI solution and extracted (EtOAc, 2 x 10 ml). The combined extracts were dried over MgSO₄, filtered and concentrated. The crude material was chromatographed on silica gel with a gradient elution from 50% EtOAc in hexanes to 60% EtOAc in hexanes to yield 100 mg of the title compound.

¹H NMR (CDCy δ 1.35 (t, 3H), 2.68 (d, 2H), 2.70 (s, 3H), 2.80 (q, 2H), 3.35 (d, 2H), 3.60 (s, 3H), 5.45 (s, 2H), 5.70 (s, 2H), 7.00 (d, 1 H), 7.05 (d, 2H), 7.20 (d, 2H), 8.20 (d, 1 H). Step 3, 1-[4'-(2"-ethyl-7"-methylimidazo[4,5-b]pyridin- 3-yl)methylphenyllcvclopent-3-ene-1 -carboxylic acid

To a solution of the product of Step 2, above, in 2.5 ml methanol was added 1 ml 2N NaOH and 1 crushed pellet of NaOH. The reaction mixture was heated to 80°C for 1 hour, cooled to ambient temperature, the solvent was evaporated and 10 ml water was added to the residue which was then extracted (EtOAc, 2 x 10 ml). The aqueous layer was acidified with 10% HCI and the resulting white suspension was extracted

(EtOAc, 2 x 10 ml). The organics were dried over MgSO₄, filtered and concentrated to a solid which was crystallized from EtOAc to yield 100 mg of the title compound.

¹H NMR (MeOH-d4) δ 1.30 (t, 3H), 2.62 (d, 2H), 2.65 (s, 3H), 2.90 (q, 2H), 3.35 (d, 2H), 5.50 (s, 2H), 5.75 (s, 2H), 7.05 (d, 2H), 7.15 (d, 1 H), 7.30 (d, 2H), 8.15 (d, 1 H).

Example 9 1-[4'-(5"-bromo-2"-ethyl-7"-methylimidazo[4,5-b]- pyridin-3-yl)methylphenyπcvclopent-3-ene-1 -carboxylic acid

The compound having the formula VI, wherein R² is ethyl and R³ is bromo.

Step 1 , methyl 1-[4'-(5"-bromo-2"-ethyl-7"-methylimidazo- f4.5-b]pyridin-3-yl)methylphenvncvclopent-3-ene-1 -carboxylate Alkylation was carried out on methyl 1-(4'-chloromethylphenyl)cyclopent-3-ene-1- carboxylate (prepared as described in Example 8, Step 1) as described in Example 8,

Step 2, using 5-bromo-2-ethyl-7-methyl-3H-imidazo[4,5-b] pyridine to yield the title compound.

H NMR (CDCI₃) δ 1.30 (t, 3H), 2.65 (s, 3H), 2.70 (d, 2H), 2.80 (q, 2H), 3.35 (d,

3H), 3.60 (s, 3H), 5.40 (s, 2H), 5.75 (s, 2H), 7.05 (d, 2H), 7.20 (s, 1H), 7.25 (d, 2H).

Step 2, 1-[4'-(5"-bromo-2"-ethyl-7"-methylimidazo[4,5-b]- pyridin-3-yl)methylphenyl1cvclopent-3-ene-1 -carboxylic acid Hydrolysis was carried out on the product of Step 1 , above, as described in

Example 8, Step 3 to yield the title compound.

¹H NMR (MeOD-d4) δ 1.30 (t, 3H), 2.65 (s, 3H), 2.70 (d, 2H), 2.90 (q, 2H), 3.40 (d, 2H), 5.50 (s, 2H), 5.75 (s, 2H), 7.15 (d, 2H), 7.33 (s, 1 H), 7.35 (d, 2H). Example 10 1-[4'-(5"-carboxy-2"-ethyl-7"-methylimidazo[4,5-b]- pyridin-3-vπmethylphenyllcvclόpent-3-ene-1 -carboxylic acid

The compound having the formula VI, wherein R² is ethyl and R³ is -CO₂H.

Step 1 , methyl l-^^&'-ethoxycarbonyl-Z'-ethyl-r-methylimidazo- f4.5-blpyridin-3-yl)methylphenyl1cvclopent-3-ene-1 -carboxylate

Alkylation was carried out on methyl 1 -(4'-chloromethylphenyl)cyclopent-3-ene-1 - carboxylate (prepared as described in Example 8, Step 1 ) as described in Example 8,

Step 2 using ethyl 2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (prepared as described in EP 400974 A2, EP 420237 A and EP 399731 A) to yield the title compound.

¹H NMR (CDCy δ 1.35 (t, 3H), 1.45 (t, 3H), 2.68 (d, 2H), 2.70 (s, 3H), 2.85 (q, 2H), 3.35 (d, 2H), 3.60 (s, 3H), 4.45 (q, 2H), 5.55 (s, 2H), 5.70 (s, 2H), 7.10 (d, 2H), 7.25 (d, 2H), 7.95 (s, 1H).

Step 2, 1-[4 5"-carboxy-2"-ethyl-7"-methylimidazo[4,5-b]- pyridin-3-vhmethylphenyl]cvclopent-3-ene-1 -carboxylic acid

Hydrolysis was carried out on the product of Step 1 , above, as described in Example 8, Step 3 to yield the title compound.

¹H NMR (MeOH-d4) δ 1.30 (t, 3H), 2.70 (s, 2H), 2.75 (s, 3H), 2.95 (q, 2H), 3.40 (d, 2H), 5.70 (s, 2H), 5.78 (s, 2H), 7.20 (d, 2H), 7.35 (d, 2H), 8.05 (s, 1 H).

Example 11 1-[4'-(5",7"-dimethyl-2"-propylimidazo[4,5-b]- pyridin-3-vhmethylphenyllcvclopent-3-ene-1 -carboxylic acid

The compound having the formula VI, wherein R² is propyl and R³ is methyl.

Step 1 , methyl 1-[4'-(5",7"-dimethyl-2"-propylimidazo[4,5- blpyridin-3-v0methylphenyl]cvclopent-3-ene-1 -carboxylate

Alkylation was carried out on methyl 1 -(4'-chloromethylphenyl)cyclopent-3-ene-1 - carboxylate (prepared as described in Example 8, Step 1) as described in Example 8,

Step 2 using 5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine (prepared as described in

EP 400974 A2, EP 420237 A and EP 399731 A) to yield the title compound. ¹H NMR (CDCy δ 0.95 (t, 3H), 1.75 (m, 2H), 2.58 (s, 3H), 2.62 (s, 3H), 2.68 (d, 2H), 2.72 (t, 2H), 3.35 (d, 2H), 3.60 (s, 3H), 5.40 (s, 2H), 5.75 (s, 2H), 6.90 (s, 1 H), 7.05 (d, 2H), 7.20 (d, 2H).

Step 2, 1-[4'-(5",7"-dimethyl-2"-propylimidazo[4,5-b]- pyridin-3-vOmethylphenyl]cvclopent-3-ene-1 -carboxylic acid

Hydrolysis was carried out on the product of Step 1 , above as described in

Example 8, Step 3 to obtain the title compound.

¹H NMR (MeOH-d4) δ 1.00 (t, 3H), 1.70 (m, 2H), 2.61 (s, 3H), 2.65 (s, 3H), 2.70

(d, 2H), 2.85 (t, 2H), 3.40 (d, 2H), 5.55 (s, 2H), 5.80 (s, 2H), 7.08 (s, 1 H), 7.10 (d, 2H), 7.35 (d, 2H).

Example 12 1-[4'-(2"-cyclopropyl-5",7"-dimethylimidazo[4,5- blpyridin-3-v0methylphenvπcvclopent-3-ene-1 -carboxylic acid

The compound having the formula VI, wherein R² is cyciopropyl and R³ is methyl.

Step 1 , methyl 1-[4'-(2"-cyclopropyl-5",7"-dimethylimidazo- f4.5-blpyridin-3-yl)methylphenvncvclopent-3-ene-1 -carboxylate

Alkylation was carried out on methyl 1-(4'-chloromethylphenyl)cyclopent-3-ene-1- carboxylate (prepared as described in Example 8, Step 1 ) as described in Example 8,

Step 2 using 2-cyclopropyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (prepared as described in EP 400974 A2, EP 420237 A and EP 399731 A) to yield the title compound.

¹H NMR (CDCI₃) δ 1.00 (m, 2H), 1.15 (m, 2H), 1.85 (m, 1 H), 2.55 (s, 6H), 2.70 (d,

2H), 3.35 (d, 2H), 3.60 (s, 3H), 5.55 (s, 2H), 5.75 (s, 2H), 6.85 (s, 1 H), 7.15 (d, 2H), 7.23

(d, 2H).

Step 2, 1-[4'-(2"-cyclopropyl-5",7"-dimethylimidazo[4,5-b]- pyridin-3-v0methylphenyl1cvclopent-3-ene-1 -carboxylic acid

Hydrolysis was performed on the product of Step 1 , above as described in

Example 8, Step 3 to obtain the title compound. ¹H NMR (MeOH-d4) δ 1.10 (m, 4H), 2.10 (m, 1 H), 2.60 (s, 6H), 2.70 (d, 2H), 3.40 (d, 2H), 5.15 (s, 2H), 5.78 (s, 2H), 7.00 (s, 1 H), 7.15 (d, 2H), 7.35 (d, 2H).

Example 13 1-[4'-(2"-butyl-5^,,,7"-dimethylimidazo[4,5-b]- pyridin-3-v methylphenyllcyclopent-3-ene-1 -carboxylic acid

The compound having the formula VI, wherein R² is butyl and R³ is methyl.

Step 1 , methyl 1-[4'-(2"-butyl-5\7"-dimethylimidazo[4,5- blpyridin-3-yl)methylphenvπcvclopent-3-ene-1 -carboxylate Alkylation was carried out on methyl 1-(4'-chloromethylphenyl)cyclopent-3-ene-1 - carboxylate (prepared as described in Example 8, Step 1) as described in Example 8,

Step 2 using 2-butyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (prepared as described in

EP 400974 A2, EP 420237 A and EP 399731 A) to obtain the title compound.

¹H NMR (CDCI₃) δ 0.85 (t, 3H), 1.35 (m, 2H), 1.65 (m, 2H), 2.58 (s, 3H), 2.60 (s,

3H), 2.70 (d, 2H), 2.75 (t, 2H), 3.35 (d, 2H), 3.60 (s, 3H), 5.40 (s, 2H), 5.70 (s, 2H), 6.90 (s, 1H), 7.05 (d, 2H), 7.20 (d, 2H).

Step 2, 1-[4'-(2"-butyl-5",7"-dimethylimidazo[4,5-b]- pyridin-3-yl)methylphenyl1cvclopent-3-ene-1 -carboxylic acid

Hydrolysis was performed on the product of Step 1 , above as described in

Example 8, Step 3 to yield the title compound.

¹H NMR (MeOD-d4) δ 0.85 (t, 3H), 1.35 (m, 2H), 1.60 (m, 2H), 2.60 (s, 3H), 2.63 (s, 3H), 2.68 (d, 2H), 2.85 (t, 2H), 3.40 (d, 2H), 5.55 (s, 2H), 5.75 (s, 2H), 7.05 (s, 1 H), 7.10 (d, 2H), 7.35 (d, 2H).

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, of the formula

wherein:

A, together with the carbon to which it is attached, forms a C₃ to C₇ carbocyclic or C₇ to C→→ carbobicyclic group, each of which can be saturated or unsaturated, optionally mono-, di- or trisubstituted with a substituent or substituents independently selected from the group consisting of C→ to C₆ alkyl, C→ to C₆ alkenyl and halo;

M is a single bond or C→ to C₅ alkyl;

Q is phenyl or phenyl mono- or disubstituted with a substituent or substituents independently selected from the group consisting of halo, hydroxy, C→ to C₄ alkyl and C₁ to C₄ hydroxyalkyl;

R¹ is -CO₂H, -PO₃H, -SO₃H, -NHSO₂CF₃, -CONHSO₂(C₆H₅), CONHSO₂CF₃ or tetrazolyl;

R² is C₂ to C₈ alkyl, C₃ to C₈ cycloalkyl or -(CH₂)_n-S-(CH₂)_nCH₃; each n is independently an integer from 0 to 4; one of W, X, Y and Z is N; three of W, X, Y and Z are CR³; and each R³ is independently hydrogen, halo, C, to C₅ alkyl or CO₂H.

2. A compound according to Claim 1 of the formula

wherein:

A, M, Q, R s1 , r R>2 and each R"³ are as defined previously.

3. A compound according to Claim 2 of the formula

wherein:

A, together with the carbon to which it is attached, forms cyclopentyl, substituted cyclopentyl, cyclopentenyl, cyclohexenyl, 2-vinyl-1 -cyclopropyl or 2-indanyl; and

R¹ is CO₂H or 5-tetrazolyl.

4. A compound according to Claim 2 of the formula

wherein: R² is ethyl, n-propyl, cyclopropyl or n-butyl; and

R³ is hydrogen, bromo, methyl or CO₂H.

5. A compound according to Claim 3 which is 1 -[4'-(2"-ethyl-5",7"- dimethylimidazo[4,5-b]pyridin-3-yl)methylphenyl]cyclohex-3-ene-1 -carboxylic acid.

6. A compound according to Claim 3 which is c/s-3,4-difluoro-1-[4'-(2"-ethyl- 5",7"-dimethylimidazo[4,5-b]pyridin-3-yl)methylphenyl]cyclopentane-1 -carboxylic acid.

7. A compound according to Claim 3 which is 1 -[4'-(2"-ethyl-5",7"- dimethylimidazo[4,5-b]pyridin-3-yl)methylphenyl]-2-vinylcyclopropane-1 -carboxylic acid.

8. A compound according to Claim 3 which is 2-[4'-(2"-ethyl-5",7"- dimethylimidazo[4,5-b]pyridin-3-yl)methylphenyl]indane-2-carboxylic acid.

9. A compound according to Claim 3 which is 1 -[4'-(2"-ethyl-5",7"- dimethylimidazo[4,5-b]pyridin-3-yl)methylphenyl]cyclopentane-1 -carboxylic acid.

10. A compound according to Claim 3 which is 1 -[4'-(2"-ethyl-5",7"-dimethyl- imidazo[4,5-b]pyridin-3-yl)methylphenyl]cyclopentane-1-(5'"-1 '"H-tetrazole).

11. A compound according to Claim 4 which is 1 -[4'-(2"-ethyl-7"- methylimidazo[4,5-b]pyridin-3-yl)methylphenyl]cyclopent-3-ene-1 -carboxylic acid.

12. A compound according to Claim 4 which is 1 -[4'-(5"-bromo-2"-ethyl-7"- methylimidazo[4,5-b]pyridin-3-yl)methylphenyl]cyclopent-3-ene-1 -carboxylic acid.

13. A compound according to Claim 4 which is 1 -[4'-(5"-carboxy-2"-ethyl-7"- methylimidazo[4,5-b]pyridin-3-yl)methylphenyl]cyclopent-3-ene-1 -carboxylic acid.

14. A compound according to Claim 4 which is 1 -[4'-(5",7"-dimethyl-2"- propylimidazo[4,5-b]pyridin-3-yl)methylphenyl]cyclopent-3-ene-1 -carboxylic acid.

15. A compound according to Claim 4 which is 1 -[4'-(2"-cyclopropyl-5",7"- dimethylimidazo[4,5-b]pyridin-3-yl)methylphenyl]cyclopent-3-ene-1 -carboxylic acid.

16. A compound according to Claim 4 which is 1 -[4'-(2"-butyl-5",7^M- dimethylimidazo[4,5-b]pyridin-3-yl)methylphenyl]cyclopent-3-ene-1 -carboxylic acid.

17. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition for the treatment of hypertension, congestive heart failure, glaucoma, renal disease or cognitive dysfunction in a mammal comprising a therapeutically effective amount of a compound according to Claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. A method of inhibiting the effects of angiotensin II in a mammal comprising administering to said mammal an angiotensin ll-inhibiting amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.

20. A method of treating hypertension in a mammal comprising administering to said mammal a blood pressure-lowering amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.

21. A method of treating glaucoma, renal disease or cognitive dysfunction in a mammal comprising administering to said mammal a therapeutically effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt thereof.

22. A compound of the formula

wherein:

A, together with the carbon to which it is attached, forms a C₃ to C₇ carbocyclic or C₇ to C→→ carbobicyclic group, each of which can be saturated or unsaturated, optionally mono-, di- or trisubstituted with a substituent or substituents independently selected from the group consisting of C, to C₆ alkyl, C→ to C₆ alkenyl and halo;

M is a single bond or C₁ to C₅ alkyl;

Q is phenyl or phenyl mono- or disubstituted with a substituent or substituents independently selected from the group consisting of halo, hydroxy, C→ to C₄ alkyl and C, to C₄ hydroxyalkyl;

R¹ is -CO₂R⁴;

R² is C₂ to C₈ alkyl, C₃ to C₈ cycloalkyl or -(CH₂)_n-S-(CH₂)_nCH₃;

R⁴ is C, to C₄ alkyl or halosubstituted C₂ to C₄ alkyl; each n is independently an integer from 0 to 4; one of W, X, Y and Z is N; three of W, X, Y and Z are CR³; and each R³ is independently hydrogen, halo, C→ to C₅ alkyl or CO₂H.

23. A compound according to Claim 22 wherein R ,4 is methyl