ANGIOTENSIN II ANTAGONISTS INCORPORATING A SUBSTITUTED BENZYL ELEMENT

Abstract: Substituted heterocycles attached through a methylene bridge to novel substituted phenyl derivatives of Formula (I) are useful as angiotensin II antagonists.

Description: 0 TITLE OF THE INVENTION ANGIOTENSIN II ANTAGONISTS INCORPORATING A SUBSTITUTED BENZYL ELEMENT 5 BACKGROUND OF THE INVENTION The present application is a continuation-in-part of copending application Serial No. 479,786 filed on February 13, 1990. The Renin-angiotensin system (RAS) plays a o central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance as well as congestive heart failure. Angiotensin II (A II), is an octapeptide hormone produced mainly in the blood 5 during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs. It is the eηd product of the renin- angiotensin system (RAS) and is a powerful arterial Q vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes. One of the possible modes of controlling the RAS is angiotensin II receptor antagonism. Several peptide analogs of A II are known to inhibit the effect of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by partial agonist activity and lack of oral absorption [M. Antonaccio. Clin. Exp. Hvpertens. A4, 27-46 (1982); D. H. P. Streeten and G. H. Anderson, Jr. - Handbook of Hypertension. Clinical Pharmacology of Antihvpertensive Drugs, ed. A. E. Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984]. Recently, several non-peptide compounds have been described as A II antagonists. Illustrative of such compounds are those disclosed in U.S. Patents 4,207,324; 4,340,598; 4,576,958; 4,582,847; and 4,880,804 and in European Patent Applications 028,834; 245,637; 253,310; and 291,969; and in articles by A.T. Chiu, et al. rEur. J. Pharm. Exp. Therap. 151, 13-21 (1988)] and by P.C. Wong, fit &!• ΓJ. Pharm. Exυ. Therap. 247_, 1-7(1988)]. All of the U.S. Patents, European Patent Applications 028,834 and 253,310 and the two articles disclose substituted imidazole compounds which are generally bonded through a lower alkyl bridge to a substituted phenyl. European Patent Application 245,637 discloses derivatives of 4,5,6,7-tetrahydro-2H- imidazo[4,5-£.]-pyridine-6-carboxylic acid and analogs thereof as antihypertensive agents. None of the compounds disclosed within this application or in any US Patent, European Applications or literature publication are of the type containing substituted heterocycles bonded through an alkyl bridge to a novel substituted phenyl of the type disclosed herein. The imidazole-5-,6-, and 7-fused heterocycles have been disclosed in earlier U.S. Patent applications focusing on the heterocyclic fragment of the antagonist design. The serial numbers of these applications are 351,508; 358,971; 375,655; 360,673; 375,217; and 386,328 and are hereby incorporated by reference. BRIEF DESCRIPTION OF THE INVENTION This invention is directed to substituted heterocycles attached through a methylene bridge to novel substituted phenyl derivatives to give ^ compounds of the Formula I, which are angiotensin II antagonists and are useful in the treatment of hypertension and congestive heart failure. Specifically, the compounds of this invention contain a heterocyclic moiety which is substituted at the specified positions and to which a methylene bridge connecting a novel substituted phenyl group as defined by the lower portion of Formula I, is attached. Additionally, pharmaceutically acceptable compositions of these novel compounds, as the sole therapeutically active ingredient and in combination with diuretics and other antihypertensive agents, including beta blockerε, angiotensin converting enzyme inhibitors, calcium channel blockers or a combination thereof are disclosed and claimed. Further, methods of treating hypertension and congestive heart failure are described and claimed. The compounds of this invention have central nervous system (CNS) activity. They are useful in the treatment of cognitive dysfunctions including Alzheimer's disease, amnesia and senile dementia. These compounds also have anxiolytic and antidepressant properties and are therefore, useful in the relief of symptoms of anxiety and tension and in the treatment of patients with depressed or dysphoric mental states. DETAILED DESCRIPTION OF THE INVENTION This invention relates to compounds of the general Formula I: R 1 is: (a) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: i) aryl as defined below in R- * -*(b), ii) (C 3 -C 7 )-cycloalkyl, iii) Cl, Br, I, F, iv> OH, v) NH 2 , vi) NH(C 1 -C 4 )-alkyl, vii) N[(C 1 -C 4 )-alkyl)] 2 , viii) NHSΘ 2 R 2 , i χ > C 3 , x) COOR 2 ,, or xi) S0 2 NHR 2a ; and (b) aryl, wherein aryl is defined as phenyl or naphthyl and is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of: i) Cl, Br, I, F, ii) (C 1 -C )-alkyl, iii) (CX-C4)-alkoxy, iv) N0 2 v) CF 3 vi) S0 2 NR 2a R 2a , vii) (C 1 -C 4 )-alkylthio, viii) hydroxy, ix) amino, x) (C3-Cy)-cycloalkyl, xi) (C 3 -C- * L Q )-alkenyl; and (c) heteroaryl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety, which can contain one or two members selected from the group consisting of N, 0, S and wherein the heteroaryl is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of: i) Cl, Br, I, F, ϋ) OH, iii) SH, iv) N0 2 , v) (C 1 -C 4 )-alkyl, vi) (C 2 -C 4 )-alkenyl, vii) (C 2 -C 4 )-alkynyl, viii) (Cι~C )-alkoxy, or ix) CF 3 , or (d) perfluoro-(C 1 -C )-alkyl; and - 7 - -A 1 -A 2 -A 3 -A 4 -A 5 - is: when A 4 and A*** are absent, then -A- ** --A 2 -A3- is: ,22 (b) -N-G-O (e) =N-G-N= wherein . represents a single bond in these definitions of A in structure I but, hereafter will represent a double bond. R' 22 I (1) -S-C=CH-, , 2 (O) -G-C=N-, R22 (p) -N=C-G-, R22 (q) -C=N-G-, (r) -G-N=C-, R 22 I (v) -G-C=C-, ^22 15 i 2^ R 24 o (bd) _C—N-C-, 23 when A 4 is present and A * ^ is absent, then -A 1 -A2-A3-A 4 - represents: R 4 (bf) -C=C—C=N-, A* (bg) -N=C—C=C-, R 4 (bh) -C=C—N=C-, R* R (bj) -C=C— N=N- , R* R* (bk) -N=N— C-C-, R* (bl) _C=N— =C-, R* (bm) -N=C— C=N-, (bn) -N=N-N=C- , R* (bo) -C=N-N=N-, (bp) -N=N-C=N-, R* (bq) -N=C-N=N-, R* R (br) -N=C— N=C-, R* (bs -C=N— C=N-, 0 0 II ti (bt) -C-N— C-N- , p5 p5 R *3 R- 5 (bu) -N-C— N-C- , II u 0 0 R 0 I II (bv) -C=C— C-N-, I Ε 4 - R (bw) -N-C-C=N~, II 0 (bx) -N=C-C-N-, II 0 R 4 0 (by) -C=C-C-N-, ■ A* * (bz) -C=C-N-C-, ■ A « R 4 0 (ca) -ά-c-έ=c-, 8 A* (ce) _C-N-N=N-, II 0 0 R 5 30 (ch) -C-N-N-C- , I c II R 5 0 0 0 II II (Ci) _d-N=N-C-, R 3 0 I u (cj) -N-C-C-N- , II I c 0 R 5 R 6a R 6a R 5 (cm) -C — C — C-N-, A 6a R 6a 0 R 6a R 6a R 5 (en) -C -—C — N-C-, A 6a R 6a 0 0 R 6a R 6a R 5a n i l I (cq) -C—C —C —N-, A 6a A 6a when A 4 and A 5 are present, then -A 1 -A 2 -A 3 -A 4 -A 5 - are R 6 R 7 R 8 (CS) -N-C—C— -C-, II II 0 0 0 R 7 R 8 R 6 M N / I (ct) -C-D—C—C-N-, u 0 0 R 7 R 8 II \ / (cu) -C-N—C—C=N-, A 6 A 2a R 6 R 7 R 8 (cv) -N-C—C—C=N-, or II ι 7 . 0 R 2a • 0 R 7 R 8 n \ / (cw) -C-N—C—CH 2 -T-; and A* B is: (a) a single bond, (b) -S(0) n (CH 2 ) s -, or (c) -0-; and n is 0 to 2; and s is 0 to 5; and D is (a) -0-, or (b) -N(R 6 )-; and G is: (a) -0-, or (b) -S(0) n ; and T is -S-, -0- or -N(R 20 )-; and R 2 is: (a) H, or (b) (C 1 -C 6 )-alkyl; and R 2a is: < a > R2 ' (b) CH 2 -aryl, or (c) aryl; and R 4 groups are independently: (a) H, 10 15 25 30 (p) -S0 2 NR 2a R 2a , (q) -N0 2 , (r) -NHS0 2 -(Ci-C 4 )-alkyl, or (s) when R 4 groups are on adjacent carbon atoms they may join to form a phenyl ring; and R 5 is: (a) H, or (b) (C^Cg)-alkyl or (C 2 -C 6 )-alkenyl, optionally substituted with: i) hydroxy, or ii) (C^-C 4 )-alkoxy; and (a) H, (b) (C 1 -C 6 )-alkyl, or (c) (C-^-C^-alkyl substituted with hydroxy; and R 6a is: (a) R 6 , or (b) (C 1 -C 6 )-alkyl substituted with: i) C0 2 R 2 , ii) CONHR 2 , iii) C0N(R 2 ) 2 ; .and R 7 and R 8 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -Cg)-alkynyl unsubstituted or substituted 5 with a substituent selected from the group consisting of: i) hydroxy, ii) (Cι-C 4 )-alkoxy, iii) (Cι-C 4 )-alkylthio, 10 iv) amino, v) (Cι~C 4 )-alkylamino, vi) di(Cι-C )-alkylamino, vii) carboxy, viii) carboxamido, 15 x C0 2 R 2a , x) OC(0)R 2a , or xi) gυanidino, (c) phenyl or phenyl-(Cι~C )-alkyl, wherein the phenyl group is unsubstituted or substituted 20 with a member selected from the group consisting of: i) hydroxy, ii) Cl, Br, I, F, iii) (C 1 -C )-alkyl, 25 iv) (C!-C 4 )-alkoxy, ( ) imidazolyl-(Cι-C 4 )-alkyl, or (e) indolyl-(C 1 -C )-alkyl; and 30 R 9 and R10 are independently: (a H, (b (Cι-Cg)-alkyl, unsubstituted or substituted with (C 3 -C7)-cycloalkyl, (c (C 2 -C 6 )-alkenyl, (d (C 2 -C 6 )-alkynyl, (e Cl, Br, F, I, (f (C 1 -C 6 )-alkoxy, ( g when R.9 and R 1 ^ are on adjacent carbons, they can be joined to form a phenyl ring, (h perfluoro-(Cι-C6)-alkyl, (i (C 3 -Cy)-cycloalkyl, unsubstituted or substituted with (C 1 -C 6 )-alkyl, (j aryl; and X is: (a -0-, (b -S(0) n -, (c -NR 13 - (d -CH 2 0-, (e -CH 2 S(0) n , (f -CH 2 NR 13 -, ( -0CH 2 -, (h -NR 13 CH 2 -, (i -S(0) n CH 2 -, (j -CH 2 -, (k -(CH 2 ) 2 -, (1 single bond, or (m -CH=, wherein Y and R 12 are absent forming a -C=C- bridge to the carbon bearing Z and R 11 ; and Y is : (a) single bond, (b) -0-, (c) -S(0) n -, (d) -NR 13 -, or (e) -CH 2 -; and Except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (0, N, S, SO, S0 2 ). R***** ** * and R * - **2 are independently: (a) H, (b) (C ** L-C 6 )-alkyl, unsubstituted or substituted with a substituent selected from the group consisting of: (i) aryl, or (ii) (C 3 -C7)-cycloalkyl, (c) aryl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of: i) Cl, Br, I, F, ii) (C 1 -C )-alkyl, iii) [(C 1 -C 5 )-alkenyl]CH 2 -, iv) [(C 1 -C 5 )-alkynyl]CH 2 -, v) (C 1 -C )-alkoxy, vi) (C 1 -C 4 )-alkylthio, vii) -N0 2 , viii) -CF 3 , ix) -C0 2 R 2a , or x) -OH, 113/VJC45 - 22 - (d) aryl-(Cι-C 2 )-alkyl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of i) Cl, Br, I, F, ii) (C 1 -C 4 )-alkyl, iii) [(C 1 -C 5 )-alkenyl]CH 2 -, iv) [(C 1 -C 5 )-alkynyl]CH 2 -, v) (C!-C 4 )-alkoxy, vi) (Cι-C 4 )-alkylthio, vii) -N0 2 , viii) -CF 3 , ix) -C0 2 R 2a , or x) -OH, or (e) (C 3 -C 7 )-cycloalkyl; and ,13 is: (a) H, (f) -C0NH-S0 2 -(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: -OH, -SH, -0(Ci-C )-alkyl, -S-(C 1 -C 4 )-alkyl, -CF 3 , Cl, Br, F, I, -N0 2 , -C0 2 H, -C0 2 -(Ci-C 4 )-alkyl, -NH 2 , -NH[(C 1 -C 4 )-alkyl], or -N[(C 1 -C 4 )-alkyl] 2 , (g) -CONH-S0 -perfluoro-(Cι~C 4 )-alkyl, , (j) -S0 2 NHC0-aryl, (k) -S0 2 NHC0-(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: -OH, -SH, -0(C 1 -C 4 )-alkyl, -S-(C 1 -C 4 )-alkyl, -CF 3 , Cl, Br, F, I, -N0 2 , -C0 H, -C0 2 -(C 1 -C 4 )-alkyl, -NH 2 , -NH[(C 1 -C 4 )-alkyl], or -N[(C 1 -C 4 )-alkyl] 2 , (1) -S0 2 NHC0-(Cι-C )-perfluoroalkyl, (m) -S0 2 NHCO-heteroaryl, (n) -S0 2 C0NR 2a R 2a , (o) -P0(0H) 2 , (p) -P0(0R 2 ) 2 , or (q) -P0(0H)(0R 2 ); and (a) H, (b) (C 1 -C 6 )-alkyl, (c) allyl, (d) (C 3 -C 6 )-cycloalkyl, (e) (C 1 -C 4 )-acyl, (f) benzyl, or (g) phenyl; and R22 groups are independently: ( a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or C 2 -C5)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C 3 -Cy)-cycloalkyl, Cl, Br, I, F, -OH, -NH 2 , -NH[(C 1 -C 4 )-alkyl], -N[(C 1 -C 4 )-alkyl] 2 , -NHS0 2 R 25 , -C0 2 R 25 , (C 1 -C 4 )-alkoxyl, (Cι-C 4 )-alkylthio, (C 1 -C 4 )-acyl, or C(=0)NH 2 , (c) aryl, (d) substituted aryl in which the substituents are V or W, as defined below, (e) aryl-(C 1 -C )-alkyl, which can be substituted with .V or W as defined below, (f) Cl ' , Br, I, F, (g) hydroxyl, (h) amino, - 25 - (i) NH[(C 1 -C )-alkyl], (j) N[(C 1 -C )-alkyl] 2 , (k) (C 1 -C 6 )-alkoxy, (1) CF 3 , (m) C0 2 R 25 , (n) C(«0)N(R 25 ) 2 , (0) N(R 25 )-C(*0)R 25 , (P) (C 1 -C )-alkylsulfonyl, (q) (C 1 -C 4 )-alkylsulfinyl, or (r) (Cι~C )-alkylthio; and (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -Cfc)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C 3 -C7)-cycloalkyl, Cl, Br, I, F, -OH, -NH 2 , -NH[(C 1 -C 4 )-alkyl], -N[(C 1 -C )-alkyl] 2 , -NHS0 2 R 25 , -C0 2 R 25 , (C 1 -C 4 )-alkoxyl, (Cι-C 4 )-alkylthio, (C 1 -C 4 )-acyl, or C(=0)NH 2 , (c) -C(=0)R 25 , (d) -C0 2 R 25 , (e) aryl, which is unsubstituted or substituted with substituents V or W, (f) aryl-(C!-C 4 )-alkyl, which is unsubstituted or substituted with V or W; and R 24 groups are independently: (a) H, (b) (C χ -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C6)-alkynyl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C 3 -C7)-cycloalkyl, Cl, Br, I, F, -OH, -NH 2 , -NH[(C 1 -C 4 )-alkyl], -N[(C 1 -C 4 )-alkyl] 2 , -NHS0 2 R 25 , -C0 2 R 25 , (C!-C 4 -alkoxy1, (Cι-C 4 )-alkylthio, (C) aryl or aryl-(Ci~C 4 )-alkyl which is unsubstituted or substituted with V or W the pharmaceutically acceptable salts thereof Wherein a preferred embodiment is when: R 1 is: (a) (C 1 -C 6 )-alkyl or (C 2 -C 6 )-alkenyl or (C 2 -C )-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: i) (C 1 -C 4 )-alkylthio, ii) (Cι-C )-alkoxy, iii) CF 3 , iv) CF 2 -CF 3 , or v) (C 3 -C5)-cycloalkyl, (b) perfluoro-(Cι-C 4 )-alkyl, or (c) (C 3 -C5)-cycloalkyl; and _A * 1-A 2 -A 3 -A -A 5 - is: when A 4 and A-- are absent, then -A----A 2 -A3- is (c) =N-S-N=, wherein a. represents a single bond in these definitions of -A 1 -A 2 -A 3 - in structure la but, hereafter will represent a double bond. R 22 R ,2'2 (h) -G-C=N- R 22 (i) -N=C-G- R 22 (j) -i=N-G- R 22 10 (m) -G-C=C- 22 R 24 R 24 \ / (n) _c—0-C- II 15 0 R 24 R 24 (o) -C-O-C- II 0 20 4 30 when A 4 is present and A-^ is absent, then -A-----A2-A -A 4 - represents: (s) _C=C—C=N-, R 4 R 4 (t) -C=C—N=C-, A 4 (u) -C=N-C=C-, R 4 (x) -N=N—C=C-, A 4 113/VJC45 - 31 - ( y ) -N=C-N * C-, R 4 (aa) -N=C—C=N-, A 4 5 (ae) -N-C-C-N-, 8 11 R 6a R 6a R 5 t I (ah) - -Cc — -Cc —— Cc--N-, R 6a R 6a J! R 6a R 6a R 5 (ai) -C — C — N-C-, R 6a R 6a Q R 6 R 8 (aj) -N-C-CH-D-C- , II H 0 0 R I 8 R I 6 (al) -C-D-CH-C-N- ; and Ii II 0 0 B is: (a) single bond, (b) -S-, or (c) -0-; and 113/VJC45 - 33 - n is 0, 1, or 2; and D is (a) -0-, or (b) -N(R 6 )-; and G is: (a) -0-, or (b) -S(0) n , is (a) H, or (b) (C 1 -C 6 )-alkyl; and R 2a is: (a) R 2 , (b) benzyl, or (c) phenyl; and R 4 groups are independently: (a) H, (b) which is unsubstituted or substituted with: i) OH, 113/VJC45 - 34 - (f) C(*0)NR 2a R 2a , (g) -C(=0)-aryl, (h) -OR 24 , (i) -S-(C 1 -C 4 )-alkyl, (j) -HC(C 1 -C 4 )-alkyl]2. (k) -NHC(=0)(C 1 -C 4 )-alkyl, (1) -NHC00(C 1 -C 4 )-alkyl, (m) -S0 2 NH(C 1 -C 4 )-alkyl, (n) -N0 2 , (0) -NHS0 2 CH 3 , (p) (C -C7)-cycloalkyl, or (q) when R 4 groups are on adjacent carbon atoms they may join to form a phenyl ring; and R 5 is: (a) H, or (b) (C^-C^-alkyl, which is unsubstituted or substituted with: hydroxyl, or C0 2 R 2 ; and > 5a (a) H, (b) (C 1 -C 4 )-alkyl, or (c) (C 1 -C )-acyl; and R6 is: (a) H, or (b) (C 1 -C 6 )-alkyl; and R 6a is: (a) H ' , or (b) (C 1 -C )-alkyl; and R 8 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) which is unsubstituted or substituted with a ' substituent selected from the group consisting of: i) hydroxy, iii) (C 1 -C 4 )-alkylthio, iv) amino, vii) carboxyl, viii) carboxamido, ix) C0 2 R 2a , x) 0C(0)R 2a , or xi) guanidino, (d) phenyl, (e) benzyl, (f) 4-hydroxybenzyl, (g) 4-imidazolylmethyl, or (h) 3-indolylmethyl; and R9 and R- * - * *- * are independently: (a) H, (b) unsubstituted or substituted with (C 3 -C7)cycloalkyl, (c) (C 2 -C 6 )-alkenyl, (d) (C 2 -C 6 )-alkynyl, (e) Cl, Br, F, I, (f) (C 1 -C 6 )-alkoxy, or (g) when R^ and 1 ^ are on adjacent carbons, they can be joined to form a phenyl ring, (h) perfluoro-(C 1 -C 6 )-alkyl, (i) (C 3 -C 7 ) cycloalkyl, which is unsubstituted or substituted with (C 1 -C 6 )-alkyl, or (j) aryl; and X is Except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (0, N, S, SO, S0 2 ) R 11 and R 12 are independently: (a) H, (b) (Cι-C )-al yl, unsubstituted or substituted with: i) aryl, or ii (C -C )-cycloalkyl, " (c) aryl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of: i) Cl, Br, I, F, ii) (C 1 -C )-alkyl, iv) [(Ci-Cs -alky yllCHz-, v) (Cι-C 4 )-alkoxy, or vi) (C 1 -C )-alkylthio, and (d) aryl-(Cι-C )-alkyl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of: i) Cl, Br, I, F, ii) (C 1 -C 4 )-alkyl, iii) [(C 1 -C 5 )-alkenyl]CH 2 -, iv) [(C 1 -C 5 )-alkynyl]CH 2 -, v) (C^-C 4 )-alkoxy, or vi) (Cι~C )-alkylthio, and (e) (C 3 -C7)-cycloalkyl; and ,13 is (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, (d) aryl-(C 1 -C 6 )-alkyl-(C=0)-, or (e) (C 1 -C 6 )-alkyl-(C=0)-; and Z is: (a) -C0 2 H, (b) -C0 2 -(C 1 -C 6 )-alkyl, (c) -tetrazol-5-yl, (d) -C0-NH(tetrazol-5-yl), (e) -CONH-S0 -aryl, (f ) -C0NH-S0 2 -(C 1 -C 4 )-alkyl , (g) -CONH-S0 2 -perf luoro-(Cι-C )-alkyl , (h) -C0NH-S0 2 -heteroaryl, wherein heteroaryl is defined as a 5 or 6 membered aromatic ring containing one or two heteroatoms selected from the group consisting of 0, N, or S; (i) -C0NHS0 2 NR 2a R 2a , (j) -S0 2 NHCO-aryl, (k) -S0 2 NHCO-(C 1 -C 6 )-alkyl, (1) -S0 2 NHC0-(Cι-C 4 )-perfluoroalkyl, (m) -S0 2 NHCO-heteroaryl, wherein heteroaryl is defined as a 5 or 6 membered aromatic ring containing one or two heteroatoms selected from the group consisting of 0, N, or S, (n) -S0 2 NHC0NR 2a R 2a , (o) -P0(0H) 2 , (p) -P0(0R 2 ) 2 , or (q) -P0(0H)(0R 2 ); and groups are independently: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -Cg)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C 3 -C7)-cycloalkyl, Cl, Br, I, F, -OH, -NH[(C 1 -C 4 )-alkyl], -N[(C 1 -C 4 )-alkyl] 2 , -C0 2 R 25 , or C(=0)NH[(C 1 -C 4 )-alkyl)], (c) aryl or aryl-(C 1 -C 4 )-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: H, Br, Cl, I, F, (C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, (C!-C 4 )-alkoxy, or C0 2 R 25 , 113/VJC45 - 39 - (d) Cl, Br, I, F, (e) amino, (f) NH[(C 1 -C 4 )-alkyl], (g) N[(C 1 -C 4 )-alkyl] 2 , (h) (C 1 -C 6 )-alkoxy, (i) C0 2 R 25 , (j) C(=0)N(R 25 ) 2 , or (k) (C 1 -C )-alkylthio; and R 23 is: (a) H, (b) (C^-C^-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: -OH, -NH , -N[(C 1 -C 4 )-alkyl] 2 , or -C0 2 R 25 , (c) aryl or aryl-(C* * L-C 4 )-alkyl, which is unsubstituted or substituted with: Br, Cl, F, I, (C 1 -C 4 )-alkyl, hydroxy-(C 1 -C 4 )-alkyl, C0 2 R 25 , C0 25, or S0 2 R 2 5, R24 ro ps are independently: (a) H, (b) (C^-C^-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: Cl, Br, I, F, -C0 2 R 25 , hydroxy-(C 1 -C 4 )-alkyl, or (C 1 -C 4 )-acyl, or (c) aryl or aryl-(Cι-C 4 )-alkyl; and >25 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, or (d) aryl-(C 1 -C 5 )-alkyl; and the pharmaceutically acceptable salt thereof Wherein a more preferred embodiment of the invention is when: R 1 is: (a) (Cι-Cg)-alkyl (C 2 -Cg)-alkenyl or (C 2 -C6)-alkynyl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of: i) (C 1 -C 4 )-alkylthio, ii) (C^-C 4 )-alkoxy, iii) CF 3 , iv) CF 2 CF 3 , or v) (C 3 -C5)-cycloalkyl, or (b) perfluoro-(C*^-C 4 )-alkyl; and _A1-A 2 -A 3 -A 4 -A 5 - is: when A 4 and A*- 5 are absent, then -A 1 -A 2 -A3- is: (C) -G-C=N- R 22 (d) -N=C-G- when A 4 is present and A 5 is absent, then -A- * - * -A 2 -A3-A 4 - represents: R R I I ( g ) -C=C—C=C-, I R (i) -C=N-C=N-, A 4 When A 1 -A 2 -A 3 -A 4 -A 5 are all present: B is a single bond; and G is -0-, or -S-; and (b) benzyl, or (c) phenyl; and R 4 groups are independently: (a) H, (b) (Cι-Cg)-alkyl, which is unsubstituted or substituted with: i) OH, ii) C0 2 R 2a , ϋ ) m 2 > iv) (Cι-C 4 )-alkylamino, v) di[(C 1 -C 4 )-alkyl]amino, R 8 is: (a) H, (b) (C^-C^-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: i) hydroxy, ii) (Cι-C 4 )-alkoxyl, iii) amino, iv) carboxyl, v) carboxamido, vi) C0 2 R 2a , vii) OC(0)R 2a , or viii) guanidino, (c) phenyl, (d) benzyl, (e) 4-hydroxybenzyl, (f) 4-imidazolylmethyl, or (g) 3-indolylmethyl; and R9 and R- * -^ are independently: (a) H, (b) (C*ι-C*5)-alkyl, unsubstituted or substituted with (C 3 -C 7 )cycloalkyl, (c) (C 2 -C 6 )-alkenyl, (d) (C 2 -C 6 )-alkynyl, (e) Cl, Br, F, I, (f) (C 1 -C 6 )-alkoxy, or (g) when R 9 and R 10 are on adjacent carbons, they can be joined to form an aryl ring, (h) perfluoro-(Cι-C )-alkyl, (i) (C 3 -C7)-cycloalkyl, unsubstituted or substituted with (C 1 -C 6 )-alkyl, or (j) aryl; and < ■ ? X ii 25 Except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (0, N, S, SO, S0 2 ). 3 0 R 11 and R 12 are independently: (a) H, (b) (C j -C^-alkyl, unsubstituted or substituted with: i) aryl, or ii) (C 3 -C 7 )-cycloalkyl, (c) aryl, (d) aryl-(Cι-C 2 )-alkyl, or (e) (C 3 -C 7 )-cycloalkyl; and ,13 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, (d) aryl-(C -C 6 )-alkyl-(C=0)-, or (e) (C 1 -C 6 )-alkyl-(C=0)-; and Z is: (a) -C0 2 H, (b) -C0 2 -(C 1 -C 6 )-alkyl, (c) -tetrazol-5-yl, (d) -C0-NH(tetrazol-5-yl), (e) -C0NH-S0 2 -aryl, (f) -C0NH-S0 2 -(C 1 -C )-alkyl, (g) -C0NH-S0 2 -perfluoro-(Cχ-C 4 )-alkyl, (h) -C0NH-S02-heteroaryl, where in heteroaryl is a 5 or 6 membered aromatic ring containing one or two heteroatoms selected from the group consisting of 0, N, or S, (i) -C0NHS0 2 NR 2a R 2a , (j) -S0 2 NHC0-aryl, (k) -S0 2 NHC0-(C 1 -C 4 )-alkyl, (1) -S0 2 NHC0-(C 1 -C 4 )-perfluoroalkyl, (m) -S0 2 NHC0-heteroaryl, where in heteroaryl is a 5 or 6 membered aromatic ring containing one or two heteroatoms selected from the group consisting of 0, N, or S, (n) -S0 2 NHC0NR 2a R 2a , (o) -P0(0H) 2 , (p) -P0(0R 2 ) 2 , or R groups are independently: (a) H, (b) (C-L-C )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C$)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C 3 -C7)-cycloalkyl, C1-, Br, I, F, -OH, -NH[(C 1 -C )-alkyl], -N[(C 1 -C 4 )-alkyl] 2 , -C0 2 R 25 , or C(=0)NH[(C 1 -C 4 )-alkyl)], (c) aryl or aryl-(Ci~C 4 )-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: Br, Cl, I, F, (C 1 -C 4 )-alkyl, hydroxy-(Cι-C )-alkyl, (C 1 -C 4 )-alkoxy, or (d) Cl, Br, I, F, (e) amino, (f) NH[(C 1 -C 4 )-alkyl], g) N[(C 1 -C 4 )-alkyl] 2 , (h) (C-L-Ce)-alkoxy, (i) C0 2 R 25 , (j) C(=0)N(R 25 ) 2 , or (k) (C; j _-C 4 )-alkylthio; and (a) H, (b) (C^-C^)-alkyl, which is unsubstituted or substituted with a substituent selected from the .group consisting of: -OH, -NH 2 , -N[(C 1 -C )-alkyl] 2 , or -C0 2 R 25 , - 48 - (c) aryl or aryl-(Cι-C 4 )-alkyl, which is unsubstituted or substituted with: Br, Cl, F, I, Cι-C 4 )-alkyl, hydroxy-(Cι-C 4 )-alkyl, C0 2 R 25 , COR 25 , or S0 2 R 25 , 2 ^ groups are independently: (a) H, (b) which is unsubstituted or substituted with a substituent selected from the group consisting of: Cl, Br, I, F, -C0 2 R 25 , hydroxy-(Cι-C 4 )-alkyl, or (C 1 -C 4 )-acyl, or (c) aryl or aryl-(C^-C 4 )-alkyl; and R 25 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, or (d) aryl-(C 1 -C 5 )-alkyl; or a pharmaceutically acceptable salt thereof. The alkyl substitutents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, iεobutyl, neopentyl, isopentyl, etc. The alkenyl and alkynyl substituents denote alkyl groups as described above which are modified so that each contains a carbon to carbon double bond or triple bond, respectively, such as vinyl, allyl and 2-butenyl. Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each which may be substituted or unsubstituted with other hydrocarbon substituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl. The alkoxy substituent represents an alkyl group as described above attached through an oxygen bridge. The aryl substituent recited above represents phenyl or naphthyl. The heteroaryl substituent recited above represents any 5- or 6-membered aromatic ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, for example, pyridyl, thienyl, furyl, i idazolyl, and thiazolyl. Compounds of the present invention illustrative of subclasses of Formula I are: • 5.5-FUSED I IDAZO ES: 2-εutyl-l-[4-(l-carboxy-l-phenyl)methoxyphenyl3methyl- 1,4-dihydro-4-methylimidazo[4,5-d]imidazole 1-C4-(1-Carboxy-l-phenyl)methoxyphenyl]methyl-l,4- dihydro-2-ethyl-4-methylimidazo[4,5-d]imidazole 1-[4-(1-Carboxy-1-(2-chloropheny1))methoxyphenyl]- methyl-l,4-dihydro-2-ethyl-4-methylimidazo[4,5-d]- imidazole 1_[ 4 _((l-Carboxy-l-(2-chlorophenyl))methoxy)-3-propyl- phenyl]methyl-l,4-dihydro-2-ethyl-4-methylimidazo- [4,5-d]imidazole l-[4-(l-Carboxy-l-(2-isopropylphenyl))methoxyphenyl]- methyl-l,4-dihydro-2-ethyl-4-methylimidazo[4,5-d]- imidazole l-[4-(l-Carboxy-l-(2-trifluromethylphenyl))methoxy- phenyl]methyl-l,4-dihydro-2-ethyl-4-methylimidazo- [4,5-d]imidazole 1_[ 4 _((l-Carboxy-1-phenyl)methoxy)-3-propylpheny1]- methyl-1,4-dihydro-2-ethyl-4-methylimidazo[4,5-d]- imidazole 1-[4-(1-Carboxy-1-(1-naphthyl))methoxyphenyl]methy1- l,4-dihydro-2-ethyl-4-methylimidazo[4,5-d]imidazole l-[4-N-(l-Carboxy-l-(2-chlorophenyl))methylamino- phenyl]methyl-l,4-dihydro-2-ethyl-4-methylimidazo- [4,5-d]imidazole l-[4-N-(l-Carboxy-l-(2-chlorophenyl))methyl-N-ethyl- aminophenyl]methyl-l,4-dihydro-2-ethyl-4-methyl- imidazo[4,5-d]imidazole 1-[4-(1-Carboxy-l-(2-chlorophenyl))methylthiophenyl]- methyl-l,4-dihydro-2-ethyl-4-methylimidazo[4,5-d]- imidazole 1-[4-(1-Carboxy-1-phenyl)methoxyphenyl]methyl-l,4- dihydro-5-hydroxymethyl-4-methyl-2-propyl-imidazo- [4,5-d]imidazole 2-εutyl-l-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl- l,4-dihydro-4-ethyl-5-methylimidazo[4,5-d]imidazole 2-εutyl-l-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl- l,6-dihydro-6-methylimidazo[4,5-d]imidazole 2-buty1-1-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl- lH-thieno[3,4-d]imidazole l-[4-(l-Carboxy-l-phenyl)methoxyphenyl]methyl-2- propyl-lH-furo[3,4-d]imidazole 2-Hutyl-l-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl- 4-methyl-lH-thieno[3,4-d]imidazole l-[4-(l-Carboxy-l-phenyl)methoxyphenyl]methyl-4-ethyl- 2-propyl-lH-thieno[3,4-d]imidazole-5,5-dioxide 2-Butyl-l-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl- 1,5-dihydro-5-methylpyrrolo[3, -d]imidazole 2-Butyl-l-[4-(l-carboxy-l-ρhenyl)methoxyphenyl]methyl- 1,5-dihydro-4,5-dimethylpyrrolo[3, -d]imidazole 2-Butyl-l-[4-(l-carboxy-l-phenyl)methoxyphenyl]methyl- l,5-dihydro-4-ethyl-5-methylεulfonylpyrrolo[3,4-d]- imidazole 3-[4-(l-Carboxy-l-phenyl)methoxyphenyl]methyl-6-methyl -5-hydroxymethyl-2-propyl-3H-thieno[2,3-d]imidazole 2-εutyl-5-carboxy-3-[4-(1-carboxy-l-phenyl)methoxy- phenyl]methyl-6-methyl-3H-thieno[2,3-d]imidazole 2-Butyl-5-carbomethoxy-3-[4-(1-carboxy-l-phenyl)- methoxypheny1]methy1-6-methyl-3H-thieno[2,3-d]- imidazole 5-Carbomethoxy-3-[4-(1-carboxy-l-phenyl)methoxyphenyl] methyl-2-ethyl-6-methyl-3H-thieno[2,3-d]imidazole 5-Carbomethoxy-3-[4-(l-carboxy-l-(2-chlorophenyl))- methoxyphenyl]methyl-2-ethyl-6-methyl-3H-thieno- [2,3-d]imidazole 5-Carbomethoxy-3-[4-(l-carboxy-l-(2-isopropylphenyl))- methoxyphenyl]methy1-2-ethy1-6-methyl-3H-thieno- [2,3-d]imidazole 5-Carbomethoxy-3-[4-(l-carboxy-l-(l-naphthyl))- methoxyphenyl]methyl-2-ethyl-6-methyl-3H-thieno- [2,3-d]imidazole ' 5 5-Carbomethoxy-3-[4-(l-carboxy-l-(2-methoxyphenyl))- methoxyphenyl]methyl-2-ethyl-6-methyl-3H-thieno- [2,3-d]imidazole 5-Carbomethoxy-3-[4-(l-carboxy-l-(2-methoxyphenyl))- 10 methylthiophenyl]methyl-2-ethyl-6-methyl-3H-thieno- [2,3-d]imidazole 5-Carbomethoxy-3-[4-N-(l-carboxy-l-(2-methoxyphenyl))- methylaminophenyl]"methyl-2-ethyl-6-methyl-3H-thieno- 15 [2,3-d]imidazole 6-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl-l,6- dihydro-l,3-dimethyl-5-propylimidazo[4,5-c]pyrazole 2o 5-Butyl-6-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl- 2-hydroxymethyl-6H-imidazo[4,5-d]thiazole 5-Butyl-6-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl- 2-phenyl-6H-imidazo[4,5-d]thiazole 25 5-Buty1-6-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl- 2-(2-chloro)phenyl-6H-imidazo[4,5-d]thiazole *-. 6-[4-(l-Carboxy-l-phenyl)methoxyphenyl]methyl-5-ethyl- 30 2-phenyl-6H-imidazo[4,5-d]thiazole 114/VJC46 -54- 6-[4-(l-Carboxy-l-phenyl)methoxyphenyl]methyl-2-(2- chloro)phenyl-5-ethyl-6H-imidazo[4,5-d]thiazole 6-[4-(1-Carboxy-l-phenyl)methoxyphenyl]methyl-2-(2- chloro)phenyl-5-ethyl-6H-imidazo[4,5-d]oxazole 6-[4-(l-Carboxy-l-phenyl)methoxyphenyl]methyl-3-methyl -5-butyl-6H ^ imidazo[4,5-d]isothiazole 6_[ 4 _(l-Carboxy-1-phenyl)methoxyphenyl]methyl-5-ethy1- 3-methyl-6H-imidazo[4,5-d]isothiazole 6-[4-(1-Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-5-ethyl-3-methyl-6H-imidazo[4,5-d]isothiazole 6-[4-(1-Carboxy-l-(2-ethylphenyl))methoxyphenyl]methy1 -5-ethyl-3-methyl-6H-imidazo[4,5-d]isothiazole 6-[4-(1-Carboxy-l-(2-trifluromethylphenyl))methoxyphen yl]methyl-5-ethyl-3-methyl-6H-imidazo[4,5-d]- isothiazole 6-[4-(l-Carboxy-l-(2-nitrophenyl))methoxyphenyl]methyl -5-ethyl-3-methyl-6H-imidazo[4,5-d]isothiazole 6-[4-N-(l-Carboxy-l-(2-chlorophenyl))methylaminoρhenyl ]methyl-5-ethyl-3-methyl-6H-imidazo[4,5-d]isothiazole 6_[ 4 _.(i-Carboxy-1-(2-chlorophenyl))methylthiophenyl]- methyl-5-ethyl-3-methyl-6H-imidazo[4,5-d]isothiazole 6-[4-(l-Carboxy-l-(2-chlorophenyl))methylsulfonyl- phenyl]methyl-5-ethyl-3-methyl-6H-imidazo[4,5-d]- isothiazole 6-[4-(1-Carboxy-l-(1-naphthyl))methoxyphenyl]methyl- 5-ethyl-3-methyl-6H-imidazo[4,5-d]isothiazole 6-[4-(1-Carboxy-1-phenyl)methoxyphenyl]methyl-3,5- diethyl-6H-imidazo[4,5-d]isothiazole 2-εutyl-l,4-dihydro-4-methyl-l-[4-(l-(tetrazol-5-yl)- l-phenyl)methoxyphenyl]methylimidazo[4,5-d]imidazole l,4-Dihydro-2-ethyl-4-methyl-l-[4-(l-(tetrazol-5-yl)- l-phenyl)methoxyphenyl]methylimidazo[4,5-d]imidazole l,4-Dihydro-2-ethyl-4-methyl-l-[4-(l-(tetrazol-5-yl)- 1-(2-chloro)phenyl)methoxyphenyl]methylimidazo[4, -d]- imidazole l,4-Dihydro-2-ethyl-4-methyl-l-[4-(l-(tetrazol-5-yl)- l-(2-isopropyl)phenyl)methoxyphenyl]methylimidazo- [4,5-d]imidazole l,4-Dihydro-2-ethyl-4-methyl-l-[4-(l-(tetrazol-5-yl)- l-(2-trifluromethyl)phenyl)methoxyphenyl]methyl- imidazo[4,5-d]imidazole l,4-Dihydro-2-ethyl-4-methyl-l-[4-(l-(tetrazol-5-yl)- l-(l-naphthyl))methoxyphenyl]methylimidazo[4,5-d]- imidazole l,4-Dihydro-2-ethyl-4-methyl-l-[4-N-(l-(tetrazol-5- yl)-l-(2-chlorophenyl))methylaminophenyl]methyl- imidazo[4,5-d]imidazole l,4-Dihydro-2-ethyl-4-methyl-l-[4-N-(l-(tetrazol-5- yl)-l-(2-chloro)phenyl)methyl-N-ethylaminophenyl]- methylimidazo[4,5-d]imidazole l,4-Dihydro-2-ethyl-4-methyl-l-[4-(l-(tetrazol-5-yl)- l-(2-chlorophenyl))methylthiophenyl]methylimidazo- [4,5-d]imidazole 1,4-Dihydro-5-hydroxymethyl-4-methyl-2-propyl-l-[4-(l- (tetrazol-5-yl)-l-phenyl)methoxyρhenyl]methylimidazo- [4,5-d]imidazole 2-εutyl-l,4-dihydro-4-ethyl-5-methyl-l-[4-(1- (tetrazol-5-yl)-l-phenyl)methoxyphenyl]methylimidazo- [4,5-d]imidazole 2-εutyl-l,6-dihydro-6-methyl-l-[4-(l-(tetrazol-5-yl)- 1-phenyl)methoxyphenyl]methylimidazo[4,5-d]imidazole 2-εutyl-l-[4-(l-(tetrazol-5-yl)-l-phenyl)methoxy- phenyl]methyl-lH-thieno[3,4-d]imidazole 2-Propyl-l-[4-(l-(tetrazol-5-yl)-l-phenyl)methoxy- phenyl]methyl-lH-furo[3,4-d]imidazole 2-Hutyl-4-methyl-l-[4-(l-(tetrazol-5-yl)-l-phenyl)- methoxyphenyl]methyl-lH-thieno[3,4-d]imidazole 114/VJC46 -57- 4-Ethy1-2-propyl-1-[ -(1-(tetrazol-5-yl)-l-phenyl)- methoxyphenyl]methyl-lH-thieno[3, -d]imidazole-5,5- dioxide 2-Butyl-l,5-dihydro-5-methyl-l-[4-(l-(tetrazol-5-yl)- l-phenyl)methoxyphen^l]methylpyrrolo[3, -d]imidazole 2-Hutyl-l,5-dihydro-4,5-dimethyl-l-[4-(l-(tetrazol-5- yl)-l-phenyl)methoxyphenyl]methylpyrrolo[3,4-d]- imidazole 2-εutyl-l,5-dihydro-4-ethyl-5-methylsulfonyl-l-[4-(l- (tetrazol-5-yl)-l-phenyl)methoxyphenyl]methylpyrrolo- [3,4-d]imidazole 5-Hydroxymethyl-6-methyl-2-propyl-3-[4-(l-(tetrazol-5- yl)-l-phenyl)methoxyphenyl]methyl-3H-thieno[2,3-d]- imidazole 2-εutyl-5-carboxy-6-methyl-3-[4-(1-(tetrazol-5-yl)-l- phenyl)methoxyphenyl]methyl-3H-thieno[2,3-d]imidazole 2-Hutyl-5-carbomethoxy-6-methyl-3-[4-(l-(tetrazol-5- yl)-l-phenyl)methoxyphenyl]methyl-3H-thieno[2,3-d]- imidazole 5-Carbomethoxy-2-ethyl-6-methyl-3-[4-(l-(tetrazol-5- y1)-1-phenyl)methoxyρheny1]methyl-3H-thieno[2,3-d]- imidazole 5-Carbomethoxy-2-ethyl-6-methyl-3-[4-(l-(tetrazol-5- yl)-l-(2-chloro)phenyl)methoxyphenyl]methyl-3H- thieno[2,3-d]imidazole 5-Carbomethoxy-2-ethyl-6-methyl-3-[4-(l-(tetrazol-5- yl)-l-(2-isopropylphenyl))methoxyphenyl]methyl-3H- thieno[2,3-d]imidazole 5-Carbomethoxy-2-ethyl-6-methyl-3-[4-(l-(tetrazol-5- yl)-l-(l-naphthyl))methoxyphenyl]methyl-3H-thieno- [2,3-d]imidazole 5-Carbomethoxy-2-ethyl-6-methyl-3-[4-(1-(tetrazol-5- y 1 )-l-(2-methoxyphenyl))methoxyphenyl]methyl-3H- thieno[2,3-d]imidazole 5-Carbomethoxy-2-ethyl-6-methyl-3-[4-(l-(tetrazol-5- yl)-l-(2-methoxyphenyl))methylthiophenyl]methyl-3H- thieno[2,3-d]imidazole 5-Carbomethoxy-2-ethyl-6-methyl-3-[4-N-(l-(tetrazol-5- yl)-l-(2-methoxyphenyl))methylaminophenyl]methyl-3H- thieno[2,3-d]imidazole 1,6-dihydro-l,3-dimethyl-5-propyl-6-[4-(l-(tetrazol-5- yl)-l-phenyl)methoxyphenyl]methyl-imidazo[4,5-c]- pyrazole 5-Hutyl-2-hydroxymethyl-6-[4-(l-(tetrazol-5-yl)-l- phenyl)methoxyphenyl]methyl-6H-imidazo[4,5-d]thiazole 5-Hutyl-2-phenyl-6-[4-(l-(tetrazol-5-yl)-l-phenyl)- methoxyphenyl]methyl-6H-imidazo[4,5-d]thiazole 5-Hutyl-2-(2-chloro)phenyl-6-[4-(l-(tetrazol-5-yl)-l- phenyl)methoxyphenyl]methyl-6H-imidazo[4,5-d]thiazole 5-Ethyl-2-phenyl-6-[4-(l-(tetrazol-5-yl)-l-phenyl)- methoxyphenyl]methyl-6H-imidazo[4,5-d]thiazole 2-(2-Chloro)phenyl-5-ethyl-6-[4-(l-(tetrazol-5-yl)-l- phenyl)methoxyphenyl]methyl-6H-imidazo[4,5-d]thiazole 2-(2-Chloro)phenyl-5-ethyl-6-[4-(l-(tetrazol-5-yl)-l- phenyl)methoxyphenyl]methyl-6H-imidazo[4,5-d]oxazole 3-Methyl-5-butyl-6-[4-(l-(tetrazol-5-yl)-l-phenyl)- methoxyphenyl]methyl-6H-imidazo[4,5-d]isothiazole 5-Ethyl-3-methyl-6-[4-(l-(tetrazol-5-yl)-l-phenyl)- methoxyphenyl]methyl-6H-imidazo[4,5-d]isothiazole 5-Ethyl-3-methyl-6-[4-(l-(tetrazol-5-yl)-l-(2-chloro- phenyl))methoxyphenyl]methyl-6H-imidazo[4,5-d]- isothiazole 5-Ethyl-3-methyl-6-[4-(l-(tetrazol-5-yl)-l-(2-ethyl- phenyl))methoxyphenyl]methyl-6H-imidazo[4,5-d]- isothiazole 5-Ethyl-3-methyl-6-[4-(l-(tetrazol-5-yl)-l- (2-trifluoromethylphenyl))methoxyphenyl]methyl-6H- imidazo[4,5-d]isothiazole 5-£thyl-3-methyl-6-[4-(l-(tetrazol-5-yl)-l- (2-nitrophenyl))methoxyphenyl]methyl-6H-imidazo- [4, -d]isothiazole 5-Ethyl-3-methyl-6-[4-N-(l-(tetrazol-5-yl)-l-(2- chlorophenyl))methylaminophenyl]methyl-6H-imidazo- [4,5-d]isothiazole 5-Ethyl-3-methyl-6-[4-(l-(tetrazol-5-yl)-l-(2-chloro- phenyl))methylthiophenyl]methyl-6H-imidazo[4,5-d]- isothiazole 5-£thyl-3-methyl-6-[4-(l-(tetrazol-5-yl)-l-(2-chloro- phenyl))methylsulfonylphenyl]methyl-6H-imidazo[4,5-d]- isothiazole 5-Ethyl-3-methyl-6-[4-(l-(tetrazol-5-yl)-l-(l- naphthyl)methoxyphenyl]methyl-6H-imidazo[4,5-d]- isothiazole 3,5-Diethyl-6-[4-(1-(tetrazol-5-yl)-l-phenyl)methoxy- phenyl]methyl-6H-imidazo[4,5-d]isothiazole 2-Hutyl-l-[4-(l-((N-phenylsulfonyl)carboxamido)-l- phenyl)methoxyphenyl]methyl-l,4-dihydro-4-methyl- imidazo[4,5-d]imidazole 2-εutyl-l-[4-(l-((N-methylsulfonyl)carboxamido)-l- phenyl)methoxyphenyl]methyl-l,4-dihydro-4-methyl- imidazo[4,5-d]imidazole 2-εutyl-l-[4-(l-((N-trifluoromethylsulfonyl)- carboxamido)-l-phenyl)methoxyphenyl]methyl-l,4- dihydro-4-methylimidazo[4,5-d]imidazole 2-Butyl-l-[4-(l-((N-phenylsulfonyl)carboxamido)-l- phenyl)methoxyρhenyl]methyl-l,5-dihydro-5-methyl- pyrrolo[3, -d]imidazole 2-Butyl-l-[4-(l-((N-trifluoromethylsulfonyl)- carboxamido)-l-phenyl)methoxyphenyl]methyl-l,5- dihydro-5-methylpyrrolo[3,4-d]imidazole 2-(2-Chloro)phenyl-5-ethyl-6-[4-(l-((N-iεopropyl- εulfonyl)carboxamido)-l-phenyl)methoxyphenyl]methyl- 6H-imidazo[4,5-d]oxazole BENZIMIDAZOLES: 2-εutyl-l-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl- benzimidazole 2-εutyl-l-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl- 7-methylbenzimidazole l-[4-(l-Carboxy-l-phenyl)methoxyphenyl]methyl-7-methyl -2-propylbenzimidazole l-[4-(l-Carboxy-l-phenyl)methoxyphenyl]methyl-5,7- dimethyl-2-ethylbenzimidazole l-[4-(1-Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-5,7-dimethyl-2-ethylbenzimidazole l-[4-(l-Carboxy-l- ( 2-methylρhenyl))methoxyphenyl]- methyl-5,7-dimethyl-2-ethylbenzimidazole l-[4-(1-Carboxy-l-(2,6-dichlorophenyl))methoxyphenyl]- methyl-5,7-dimethyl-2-ethylbenzimidazole l-[4-(1-Carboxy-l-(2-nitrophenyl))methoxyphenyl]- methyl-5,7-dimethyl-2-ethylbenzimidazole 1-[4-(1-Carboxy-l-(2-trifluromethylphenyl))methoxy- phenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole 0 1-[4-(1-Carboxy-l-(2-ethoxyphenyl))methoxyphenyl]- methyl-5,7-dimethyl-2-ethylbenzimidazole 1-[4-(1-Carboxy-l-(1-naphthyl))methoxyphenyl]methyl- 5,7-dimethyl-2-ethylbenzimidazole 5 1-[4-(1-Carboxy-l-(2,6-dimethylpheny1))methoxyphenyl]- methyl-5,7-dimethyl-2-ethylbenzimidazole l-[4-(N-(l-Carboxy-l-(2-chlorophenyl))methyl)amino- o phenyl]methy1-5,7-dimethyl-2-ethylbenzimidazole l-[4-(N-(l-Carboxy-l-(2-chlorophenyl))methyl-N- methyl)aminophenyl]methyl-5,7-dimethyl-2- ethylbenzimidazole 5 1_[ 4 -(N-(1-Carboxy-l-(2-chlorophenyl))methyl-N-acetyl) . aminophenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole l-[4-(l-Carboxy-l-(2-chlorophenyl))methylthiophenyl]- methyl-5,7-dimethyl-2-ethylbenzimidazole l-[4-(l-Carboxy-l-(2-chlorophenyl))methylsulfinyl- phenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole l-[4-(1-Carboxy-l-(2-chlorophenyl))methylsulfony1- phenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole 1-[4-(1-Carboxy-l-(2-chlorophenyl))methoxy-3-methyl- phenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole 1-[4-(1-Carboxy-1-(2-chlorophenyl))methoxy-3-ethyl- phenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole 1-[4-(1-Carboxy-l-(2-chlorophenyl))methoxy-3-propyl- phenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole 1-[4-(1-Carboxy-1-(2-chlorophenyl))methoxy-3-chloro- phenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole 1-[4-(1-Carboxy-1-(2-chlorophenyl))methoxy-3,5- dichlorophenyl]methyl-5,7-dimethyl-2-ethyl- benzimidazole 1-[4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl]- methyl-2-ethyl-5-hydroxymethyl-7-methylbenzimidazole 5-Carboxy-l-[4-(l-carboxy-l-(2-chlorophenyl))methoxy- phenyl]methyl-2-ethyl-7-methylbenzimidazole 5-Carbomethoxy-l-[4-(l-carboxy-l-(2-chlorophenyl))- methoxyphenyl]methyl-2-ethyl-7-methylbenzimidazole 1-[4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl]- methyl-2,5-diethyl-7-methylbenzimidazole 1-[4-(1-Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-2,5;7-triethylbenzimidazole l-[4-(1-Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-2-ethyl-4,5,7-trimethylbenzimidazole l-[4-(l-Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-5,7-dimethyl-2-ethyl-4-hydroxybenzimidazole 5,7-Dimethyl-2-ethyl-l-[4-(l-(tetrazol-5-yl)-l- (2-chlorophenyl))methoxyphenyl]methylbenzimidazole 5,7-Dimethyl-2-ethyl-l-[4-(l-(tetrazol-5-yl)-l- (2-methylphenyl))methoxyphenyl]methylbenzimidazole 5,7-Dimethyl-2-ethyl-l-[4-(l-(tetrazol-5-yl)-l- (2-ethoxyphenyl))methoxyphenyl]methylbenzimidazole 5,7-Dimethyl-2-ethyl-l-[4-(l-(tetrazol-5-yl)-l- (2-trifluoromethylphenyl))methoxy-3-methoxyphenyl]- methylbenzimidazole 5,7-Dimethyl-2-ethyl-l-[4-N-(l-(tetrazol-5-yl)-l- (2-chlorophenyl))methylaminophenyl]methylbenzimidazole 5,7-Dimethyl-2-ethyl-l-[4-N-(1-(tetrazol-5-yl)-l- (2-chlorophenyl))methyl-N-methylaminophenyl]methyl- benzimidazole 5,7-Dimethyl-2-ethyl-l-[4-(l-(tetrazol-5-yl)-l-(2- chlorophenyl))methylthiophen l]methylbenzimidazole 5,7-Dimethyl-2-ethyl-l-[4-(l-(tetrazol-5-yl)-l- (2-chlorophenyl))methylsulfinylρhenyl]methyl- benzimidazole 5,7-Dimethyl-2-ethyl-l-[4-(l-(tetrazol-5-yl)-l- (2-chlorophenyl))methylsulfonylphenyl]methyl- benzimidazole 2-Ethyl-5-hydroxymethyl-7-methyl-l-[4-(l-(tetrazol-5- yl )-l-(2-chlorophenyl) )methoxyphenyl]methyl- benzimidazole 5-Carboxy-7-methyl-2-ethyl-l-[4-(l-(tetrazol-5-yl)-l- (2-chlorophenyl))methoxyphenyl]methylbenzimidazole 5-Carbomethoxy-2-ethyl-7-methyl-l-[4-(1-(tetrazol-5- yl)-l-(2-chlorophenyl))methoxyphenyl]methyl- benzimidazole 2,5-Diethyl-7-methyl-l-[4-(l-(tetrazol-5-yl)-l-(2- chlorophenyl))methoxyphenyl]m " ethylbenzimidazole 1-[4-(1-(Tetrazol-5-yl)-l-(2-chlorophenyl))methoxy- phenyl]methyl-2,5,7-triethylbenzimidazole 2-Ethyl-l-[4-(l-(tetrazol-5-yl)-l-(2-chlorophenyl))- methoxyphenyl]methyl-4,5,7-trimethylbenzimidazole 5,7-Dimethyl-2-ethyl-4-hydroxy-l-[4-(l-(tetrazol-5-yl) -l-(2-chlorophenyl))methoxyphenyl]methylbenzimidazole 5,7-Dimethyl-2-ethyl-l-[4-(l-(N-Phenylsulfonyl)- carboxamido-l-(2-chlorophenyl))methoxyphenyl]methyl- benzimidazole 5,7-Dimethyl-2-ethyl-l-[4-(l-(N-trifluoromethyl- εulfonyl)carboxamido-l-(2-chlorophenyl))methoxyphenyl] methylbenzimidazole 5,7-Dimethyl-2-ethyl-l-[4-(1-(N-methylsulfonyl)- carboxamido-l-(2-chlorophenyl))methoxyphenyl]methyl- benzimidazole IMIDAZOPYRIDINES: 2-εutyl-l-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl- 7-methyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-1-phenyl)methoxyphenyl]methyl-7-methyl -2-propyl-3H-imidazo[4,5-b]pyridine 3-[4-(l-Carboxy-l-phenyl)methoxyphenyl]methyl-5,7- dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3_[ 4 _(l_Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-7-methyl-2-ρropyl-3H-imidazo[4,5-b]pyridine 3-[4-(l-Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-l-(3-chlorophenyl))methoxyphenyl]- methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-l-(2,6-dichlorophenyl))methoxyphenyl]- methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-1-(4-chlorophenyl))methoxyphenyl]- methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3 ~[4-(1-Carboxy-1-(2-br ' omophenyl))methoxyphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-l-(2-methylphenyl))methoxyphenyl]- methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-1-(2-methylphenyl))methoxyphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-l-(2-methoxyphenyl))methoxyphenyl]- methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-1-(2-methoxyphenyl))methoxypheny1]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-1-(2-ethoxyphenyl))methoxyphenyl]- methyl-7-methyl-2-propyl-3H-imidazo[ ,5-b]pyridine 3-[4-(1-Carboxy-l-(2-ethoxyphenyl))methoxyphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3_[ 4 _(l_Carboxy-l-(2-(1-hexylox )phenyl))methoxy- phenyl]methyl-7-methyl-2-ρropyl-3H-imidazo- [4,5-b]pyridine 3-[4-(l-Carboxy-l-(2-(l-hexyloxy)phenyl))methoxy- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo- [4,5-b]pyridine 3-[4-(l-Carboxy-l-(2,6-dichlorophenyl))methoxy- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo- [4,5-b]pyridine 3-[4-(1-Carboxy-l-(2-nitrophenyl))methoxyphenyl]- methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-[4-(l-Carboxy-l-(2-nitrophenyl))methoxyphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-(l-Carboxy)-l-(2-carboxyphenyl)methoxyphenyl]- methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy)-1-(2-carboxyphenyl)methoxyphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-(l-Carboxy-l-(2-trifluoromethylphenyl))methoxy- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]- pyridine 3 _[ 4 _(l-Carboxy-1-phenyl)methoxy-3-chloropheny1]methy1 -7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3_[ 4 _(l-Carboxy-1-phenyl)methoxy-3-chlorophenyl]methyl -5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-((l-Carboxy-l-phenyl)methoxy)-2-chloroρhenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3_[ _(1-Carboxy-l-(2-chlorophenyl))methoxy-3-chloro- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo- [4,5-b]pyridine 3-[3-Henzoyl-4-((1-carboxy-l-phenyl)methoxy)phenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3_[3-Acetyl-4-((1-carboxy-l-phenyl)methoxy)phenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-((1-Carboxy-1-phenyl)methoxy)-3-methoxyphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-((l-Carboxy-l-phenyl)methoxy)-3-ethoxyphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[3-tert-εutyl-4-((1-carboxy-l-phenyl)methoxy)phenyl] methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-((l-Carboxy-l-phenyl)methoxy)-3-methylphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-((l-Carboxy-l-(2-methylphenyl))methoxy)-3-chloro- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo- [4,5-b]pyridine 3-[4-((1-Carboxy-l-phenyl)methoxy)-3,5-dichlorophenyl] methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-l-(2-chlorophenyl))methoxy-3,5- dichlorophenyl]methyl-5,7-dimethyl-2-ethyl-3H- imidazo[4,5-b]pyridine 3-[4-((l-Carboxy-l-phenyl)methoxy)-3-chloro-5-methoxy- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]- pyridine 3-[4-((l-Carboxy-l-phenyl)methoxy)-3-(prop-2-enyl)- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]- pyridine 3-[4-((1-Carboxy-1-phenyl)methoxy)-3-propylphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-((l-Carboxy-l-(2-methylphenyl))methoxy)-3-propyl- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]- pyridine 3-[4-((l-Carboxy-l-(2-chlorophenyl))methoxy)-3-proρyl- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]- pyridine 3-[4-((l-Carboxy-l-(4-chlorophenyl))methoxy)-3-propyl- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]- pyridine 3-[4-((1-Carboxy-l-(2-methoxyphenyl))methoxy)-3-propyl phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]- pyridine 3-[4-((l-Carboxy-l-(2,5-dibromo-3,4-dimethoxyphenyl))- methoxy)-3-propylphenyl]methyl-5,7-dimethyl-2-ethyl- 3H-imidazo[4,5-b]pyridine -71- 3-[4-((l-Carboxy-l-(3,4-dimethoxyρhenyl))methoxy)-3- propylphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo- [4,5-b]ρyridine 3-[4-(1-Carboxy-1-phenyl)methoxy-3-propylphenyl]- methyl-5-carbomethoxy-2-ethyl-7-methyl-3H-imidazo- [4,5-b]pyridine 3-[4-(1-Carboxy-l-phenyl)methoxy-3-propylphenyl]- methyl-5-carboxy-2-ethyl-7-methyl-3H-imidazo[4,5-b]- pyridine 3-[4-(1-Carboxy-l-phenyl)methoxy-3-propylphenyl]- methyl-5-carbobenzyloxy-2-ethyl-7-methyl-3H-imidazo- [4,5-b]pyridine 3-[4-((1-Carboxy-1-phenyl)methoxy)-3-(1-methyl- cyclohex-l-yl)phenyl]methyl-5,7-dimethyl-2-ethyl- 3H-imidazo[4,5-b]pyridine 3-[ -((1-Carboxy-l-phenyl)methoxy)-3,5-dipropylphenyl] methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3_[4_((1-Carboxy-l-(2-methoxyphenyl))methoxy)-3,5- dipropylphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[ 4,5-b]pyridine 3_[4_((l-Carboxy-l-(2,5-dibromo-3,4-dimethoxyphenyl))- methox )-3,5-dipropylphenyl]methyl-5,7-dimethyl- 2-ethyl-3H-imidazo[4,5-b]pyridine 3_[ _(l-Carboxy-1-(2-chlorophenyl))methoxyphenyl]- methyl-2-ethyl-5-hydroxymethyl-7-methyl-3H-imidazo- [4,5-b]pyridine 5-Carboxy-3-[ -(1-carboxy-l-(2-chlorophenyl))methoxy- phenyl]methyl-2-ethyl-7-methyl-3H-imidazo[4,5-b]- pyridine 5-Carbomethoxy-3-[4-(1-carboxy-l-(2-chlorophenyl))- methoxyphenyl]methyl-2-ethyl-7-methyl-3H-imidazo- [4,5-b]pyridine 5-Carbomethoxy-3-[4-(1-carboxy-l-(2-chlorophenyl))- methoxyphenyl]methyl-2-ethyl-7-trifluromethyl-3H-imida zo[4,5-b]pyridine 3-[4-(l-Carboxy-l-cyclohexyl)methoxyphenyl]methyl-7- methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-[4-(l-Carboxy-l-propyl)methoxyphenyl]methyl-7- methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-[4-((1-Carboxy-l-(3-phenyl)propyloxy)phenyl]methyl- 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-((l-Carboxy-l-(2-phenyl)ethoxy)phenyl]methyl-5,7- dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3_[4_(l_carboxy-l-phenoxy)methylphenyl]methyl-7- methyl-2-propyl-3H-imidazo[4,5-b]pyridine (Z)-3-[(4-((2-Carboxy-2-phenyl)ethylenyl)phenyl)- methyl]-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-[(4-((2-Carboxy-2-phenyl)ethyl)phenyl)methyl]-7- methyl-2-propyl'-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-1-methyl-l-phenyl)methoxyphenylj- methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-l-(naphth-1-yl))methoxyphenyl]methyl- 7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-l-(3-methylnaphth-2-yl))methoxy- phenyl]methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]- pyridine 3-[4-N-(1-Carboxy-1-phenyl)methyl)-N-methylamino- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo- [4,5-b]pyridine 3-[4-N-(1-Carboxy-l-phenyl)methyl)-N-ethylaminophenyl] methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3_[ -N-(1-Carboxy-l-phenyl)methyl)-N-propylamino- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo- [4,5-b]pyridine 3-[ -N-(1-Carboxy-l-phenyl)methy1)a inopheny1]methy1- 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3_[4-N-(1-Carboxy-l-phenyl)methyl)-N-allylaminophenyl] methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine 3-[4-N-(l-Carboxy-l-phenyl)methyl)-N-iso-butylamino- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo- [4,5-b]pyridine 3-[4-N-(1-Carboxy-l-phenyl)methyl)-N-cyclopropyl- methylaminophenyl]methyl-5,7-dimethyl-2-ethyl-3H- imidazo[4,5-b]pyridine 3-[4-N-(1-Carboxy-l-phenyl)methyl)-N-sec-butylamino- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo- [4,5-b]pyridine 3-[4-N-(1-Carboxy-l-phenyl)methyl)-N-iso-propylamino- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]- pyridine 3-[4-N-(l-(Tetrazol-5-yl)-l-phenyl)methyl)-N-methyl- aminophenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo- [ ,5-b]pyridine 2-εutyl-7-methyl-l-[4-(l-(tetrazol-5-yl)-l-phenyl)- methoxyphenyl]methyl-3H-imidazo[4,5-b]pyridine 7-Methyl-2-propyl-3-[4-(1-(tetrazol-5-yl)-l-phenyl)- methoxyphenyl]methyl-3H-imidazo[4,5-b]pyridine 7-Methyl-2-propyl-3-[4-(l-(tetrazol-5-yl)-l-(2-chloro- phenyl)methoxyphenyl]methyl-3H-imidazo[4,5-b]pyridine 7-Methyl-2-propyl-3-[4-(2-phenyl-2-(tetrazol-5-yl)- ethyl)phenyl]methyl-3H-imidazo[4,5-b]ρyridine 5,7-Dimethyl-2-ethyl-3-[4-(l-(tetrazol-5-yl)-l- phenyl)methoxyphenyl]methyl-3H-imidazo[4,5-b]pyridine 5,7-Dimethyl-2-ethyl-3-[4-(l-(tetrazol-5-yl)-l-(2- chlorophenyl))methoxyphenyl]methyl-3H-imidazo[4,5-b]- pyridine 5,7-Dimethyl-2-ethyl-3-[4-(l-(tetrazol-5-yl)-l-(2- methylphenyl))methoxyphenyl]methyl-3H-imidazo[4,5-b]- pyridine 5,7-Dimethyl-2-ethyl-3-[4-(l-(tetrazol-5-yl)-l-(2- ethoxyphenyl))methoxyphenyl]methyl-3H-imidazo- [4,5-b]pyridine 5,7-Dimethyl-2-ethyl-3-[4-(l-(tetrazol-5-yl)-l-(2,6- dichlorophenyl))methoxyphenyl]methyl-3H-imidazo- [4,5-b]pyridine 5,7-Dimethyl-2-ethyl-3-[4-(l-(tetrazol-5-yl)-l- (2-nitrophenyl))methoxyphenyl]methyl-3H-imidazo- [4,5-b]pyridine 5,7-Dimethyl-2-ethyl-3-[4-(l-(tetrazol-5-yl)-l-(2- trifluoromethylphenyl))methoxyphenyl]methyl-3H- imidazo[4,5-b]pyridine 5,7-Dimethyl-2-ethyl-3 r [4-(l-(tetrazol-5-yl)-l- (2-chlorophenyl))methoxy-3-chlorophenyl]methyl-3H- imidazo[4,5-b]pyridine 5,7-Dimethyl-2-ethyl-3-[4-(1-(tetrazol-5-yl)-l- (2-chlorophenyl))methoxy-3,5-dichlorophenyl]methyl-3H- imidazo[4,5-b]pyridine 2-Ethyl-5-hydroxymethyl-7-methyl-3-[4-(l-(tetrazol-5- yl)-l-(2-chlorophenyl))methoxyphenyl]methyl-3H- imidazo[4,5-b]pyridine 5-Carboxy-2-ethyl-7-methyl-3-[4-(l-(tetrazol-5-yl)-l- (2-chlorophenyl))methoxyphenyl]methyl-3H-imidazo- [4,5-b]pyridine 5-Carbmethoxy-2-ethyl-7-methyl-3-[4-(l-(tetrazol-5-yl) -1-(2-chlorophenyl))methoxyphenyl]methyl-3H-imidazo- [4,5-b]pyridine 5-Carbmethoxy-2-ethyl-3-[4-(1-(tetrazol-5-yl)-l-(2- chlorophenyl))methoxyphenyl]methyl-7-trifluromethyl- 3H-imidazo[4,5-b]pyridine ' 5,7-Dimethyl-2-ethyl-3-[4-(l-((N-phenylεulfonyl)- carboxamido)-l-(2-chloro)ρhenyl)methoxyphenyl]methyl- 3H-imidazo[4,5-b]pyridine 5,7-Dimethyl-2-ethyl-3-[4-(l-((N-methylsulfonyl)- carboxamido)-l-(2-chloro)ρhenyl)methoxyphenyl]methyl- 3H-imidazo[4,5-b]pyridine 5,7-Dimethyl-2-ethyl-3-[4-(l-((N-trifluoromethyl- sulfonyl)carboxamido)-l-(2-chloro)phenyl)methoxy- phenyl]methyl-3H-imidazo[4,5-b]pyridine 3_[4-(ι_(Hydroxymethøxyphosphoryl)-l-(2-methylphenyl)) methoxyphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo- [4,5-b]pyridine SΠ I S . 9-[4-(1-Carboxy-1-phenyl)methoxyphenyl]methyl-6- methyl-8-propylpurine 9-[4-(l-Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-6-methyl-8-propylpurine 4,6-Dimethyl-8-ethyl-9-[4-(1-carboxy-l-(2-chloro¬ phenyl))methoxyphenyl]methylpurine 9-[4-(1-Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-8-ethyl-6-methylpurine 9_[4-(1-Carboxy-l-(2-chlorophenyl))methoxy-3-propyl- phenyl]methyl-8-ethyl-6-methylpurine 9-[ -(1-Carboxy-l-phenyl)methoxy-3-propylphenyl]- methyl-8-ethyl-6-methylpurine 9-[4-(l-Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-4-dimethylamino-8-ethyl-6-methylpurine 9-[4-(l-Carboxy-l-(2-chlorophenyl))methoxyρhenyl]- methyl-8-ethyl-6-methyl-4-(morpholin-4-yl)purine 9_[4_(l-Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-8-ethyl-6-methyl-4-methylaminopurine 9_[4_(l_Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-4,8-diethyl-6-methylpurine 9-[4-(l-Carboethoxy-l-(2-chlorophenyl) )methoaηrphenyl]- methyl-4 , 8-diethyl-6-methylpurine 9-[4-(1-Carboxy-l-(2-chlorophenyl))methoxyphenyϊ]- methyl-4,8-diethyl-6-trifluoromethylpurine 9-[4-(1-Carboxy-l-(2-trifluoromethylphenyl))methoxy- phenyl]methyl-8-ethyl-6-methyl-4-methylaminopurine 6-Methyl-8-ρroρyl-9-[4-(l-(tetrazol-5-yl)-l-phenyl)- methoxyphenyl]methylpurine 6-Methyl-8-propyl-9-[4-(l-(tetrazol-5-yl)-l-(2-chloro- phenyl))methoxyphenyl]methylpurine 4,6-Dimethyl-8-ethyl-9-[4-(l-(tetrazol-5-yl)-l-(2- chlorophenyl))methoxyphenyl]methylpurine 8-Ethyl-6-methyl-9-[4-(l-(tetrazol-5-yl)-l-(2-chloro- phenyl))methoxyphenyl]methylpurine 4-Dimethylamino-8-ethyl-6-methyl-9-[4-(l-(tetrazol-5- yl)-l-(2-chlorophenyl))methoxyphenyl]methylpurine 8-Ethyl-6-methyl-4-(morpholin-4-yl)-9-[4-(l-(tetrazol- 5-yl)-ϊ-(2-chlorophenyl))methoxyphenyl]methylpurine 8-Ethyl-6-methyl-4-methylamino-9-[4-(l-(tetrazol-5- yl)-l-(2-chlorophenyl))methoxyphenyl]methylpurine 4,8-Diethyl-6-methyl-9-[4-(l-(tetrazol-5-yl)-l-(2- chlorophenyl))methoxyphenyl]methylρurine 4,8-Diethyl-6-methyl-9-[4-(l-(tetrazol-5-yl)-l-(2- chlorophenyl))methoxyphenyl]methylpurine 4,8-Diethyl-9-[4-(l-(tetrazol-5-yl)-l-(2-chloro- phenyl))methoxyphenyl]methyl-6-trifluoromethylpurine 8-Ethyl-6-methyl-4-methylamino-9-[4-(1-(tetrazol-5- yl)-l-(2-trifluoromethylphenyl))methoxyphenyl]methyl- purine 4,6-Dimethyl-8-ethyl-9-[4-(l-(N-phenylεulfonyl)- carboxamido-1-(2-chlorophenyl))methoxyphenyl]- methylpurine 4,6-Dimethyl-8-ethyl-9-[4-(l-(N-methylεulfonyl)- carboxamido-1-(2-chlorophenyl))methoxyphenyl]methyl- purine 4,6-Dimethyl-8-ethyl-9-[4-(l-(N-trifluoromethyl- εulfonyl)carboxamido-l-(2-chlorophenyl))methoxy- phenyl]methylpurine 4,6-Dimethyl-8-ethyl-9-[4-(l-(N-acetyl)εulfonamido-l- (2-chlorophenyl))methoxyphenyl]methylpurine 4,6-Dimethyl-8-ethyl-9-[4- ( l- ( N-benzoyl)εulfonamido-l- (2-chlorophenyl))methoxyphenyl]methylpurine 4,6-Dimethyl-8-ethyl-9-[4-(l-(N-pyrimidin-2-yl)- εulfonamido-1-(2-chlorophenyl))methoxyphenyl]methyl- purine 5.7-FϋSED IMIDAZO ES: 2-εutyl-l-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl- 1,4,6,7-tetrahydroimidazo[4,5-e][1,4]diazepine-5,8- dione 0 2-εutyl-l-[4-(1-carboxy-l-(2-chlorophenyl))methoxy- phenyl]methyl-l,4,6,7-tetrahydroimidazo[4,5-e][1,4]- diazepine-5,8-dione 5 2-εutyl-l-[4-((1-carboxy-l-phenyl)methoxy)-3-propyl- phenyl]methyl-l,4,6,7-tetrahydroimidazo[4,5-e][1,4]- diazepine-5,8-dione 2-εutyl-l-[4-((l-carboxy-l-(2-chlorophenyl))methox)- o 3-propylyphenyl]methyl-l,4,6,7-tetrahydroimidazo[4,5-e ][1,4]diazepine-5,8-dione 5 10DS FOR PREPARATION OF CQMPO TOS OF GKNKKAL FORMULA I : The methods described in PART I AND PART II below illustrate the preparation of angiotensin II antagonists of Formula I. There are several general approaches to the synthesis of antagonists of Formula I, and it is taken as a general principle that one or another method may be more readily applicable for the preparation of a given antagonist; some of the approaches illustrated below may not be readily applicable for the preparation of certain antagonists of Formula I. It should be recognized that antagonists of Formula I consiεt of a heterocyclic component designated above by formula I and a substituted benzyl substitutent which is attached to the heterocyclic component at a nitrogen atom. Thus, two generally applicable approaches to antagonists of formula I are these: 1. A heterocycle, designated above with Formula I is prepared as described in PART I below. Then the heterocycle is alkylated at a nitrogen atom with a substituted benzyl halide or pseudohalide giving an alkylated heterocycle. In the Schemes below, this alkylating agent is often designated as "Ar-CH 2 Q where Q is a halide (-Cl.Br.I) or pseudohalide (-OMs, OTs, 0Tf).r In some cases, alkylation may take place at more than one nitrogen atom of the heterocycle, and in these cases, separation by fractional crystallization or by chromotographic methods may be necessary for isolation of the deεired product. In some caseε, the alkylation εtep produceε a fully-assembled antagonist of Formula I, except that functional groups in the alkylating agent or in the heterocycle may be present in protected form and require deprotection steps to be carried out to complete the synthesis. In other cases, the alkylation is carried out with a substituted benzylic halide or pseudohalide ("Ar-CH 2 Q"), but here the alkylation step is followed by subεequent steps which are required to assemble the substituted benzyl element of the antagonist of Formula I. The alkylation εteps and subsequent steps used to prepare antagonistε of Formula I, are described in PART II below. 2. In another approach to antagonistε of Formula I, a εubεtituted benzyl element iε introduced at the beginning of, or during the preparation of the heterocyclic element. Routeε of thiε type are illuεtrated in Part II below. In moεt caεeε where thiε general approach iε uεed, the substituted benzyl component which is introduced during the syntheεis of the heterocycle must be subjected to further synthetic transformations in order to complete the synthesis of the antagonist of Formula I. In the Schemes shown below in PART II. this εubεtituted benzyl component iε deεignated aε ,f -CH 2 Ar," and iε usually introduced by an alkylation step with a substituted benzyl halide or pseudohalide designated ArCH 2 -Q (where Q is, for example, Cl, Br, I, F, OTs, or OMε). Subεtituted benzyl halides or pseudohalides which are useful in the preparation of alkylated heterocycles described in PART I are illustrated by those listed below in Table 1. In cases where these benzylic halides, or pseudohalides are not commercially available, they are prepared as described in Part II below or by standard methods of organic synthesis. Subsequent steps which may be required to complete the synthesis of antagonistε of Formula I are desribed in PART II below. The compoundε of thiε invention maybe reεolved uεing techniqueε known in the art. The diaεtereomeric εaltε or eεterε of the enantiomers are separated and the desired compound is the more active stereoisomer. The compoundε of thiε invention, their pharmaceutically acceptable εaltε and their prodrug forms are included within the εcope of thiε invention. Table 1 10 15 3 h 30 Abbreviations used in the εchemes and examples are listed in Table 3. Reagents NBS N-bromosuccinimide AiεN Azo(bis) isobutyronitrile DDQ Dichlorodicyanoquinone Ac 2 0 acetic anhydride TEA triethylamine DMAP 4-dimethylaminopyridine PPh 3 triphenylphosphine TFA trifluroacetic acid TMS-C1 trimethylεilyl chloride Im imidazole AcS potaεsium thioacetate p-TsOH p-toluenesulfonic acid FMOC-C1 9-Fluorenylmethyloxycarbonyl chloride Solvents: DMF dimethylformamide HOAC (AcOH) acetic acid EtOAc (EtAc) ethyl acetate Hex hexane THF tetrahydrofuran DMSO dimethylsulfoxide MeOH methanol iPrOH isopropanol PART I: Preparation of the heterocycles shown in Formula A. Preparation of the imidazo-5,6-and 7-membered fused heterocycles The preparations of the imidazo-5-, 6-, 7-membered heterocycles are deεcribed in the Schemeε below. There are several routeε which have been uεed to prepare theεe systemε. The first route involves, in the final steps, the closure of the imidazole ring. In other caseε it haε been advantageouε to do the imidazole ring closure early in the synthesis and generate the fused 5-, 6-, or 7- membered ring in the final stepε. IMIPAZQ-5-MSMBEREP FPSEP BETERPCYC ES 10 The compounds of Formula I, wherein -A *** --A 2 -A 3 - represents a 3 atom sequence defined by (a) - (dd) in the Detailed Description of the Invention to generate Jthe imidazo-5-fused system, can 15 be synthesized using the reactions and techniques described herein below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by 20 those skilled in the art of organic synthesiε that the functionality present on the heterocycle and other parts of the structure should be consistent with the chemical transformationε proposed. Depending upon the reactions and techniques employed, 25 this may involve, changing the order of synthetic I steps, the use of required protecting groups followed by deprotection, and, .depending upon the particular imidazo-fused 5-membered heterocycle being formed, the use of different strategies may be employed 30 regarding the cyclization steps and the particular starting material utilized. The starting materials for preparing the compounds of this invention are dependent upon the nature of the heterocycle being formed. In many cases the heterocycles can be prepared either from a suitably functionalized 5-membered heterocycle by a ring closure step which gives an i idazo fused bicyclic ring system (see Reaction Schemes 1-1 to 1-4) or by starting with a suitably functionalized substituted imidazole and ring closing to give an imidazo-fυsed 5-membered ring heterocycle (see Reaction Schemes 5-7). The particular route chosen depends upon the nature of the bicyclic ring system being formed and the availability of starting materials. One approach (Reaction Scheme 1-1) starts with monocyclic derivatives bearing vicinal carbon- bound nitro and amino functions, such as 2 which are often readily available, or can be prepared from the mono nitro derivatives 5. by reaction with hydroxylamine. Compounds 2 may be reduced by any one of several methods, including catalytic hydrogenation or reaction with SnCl 2 to give the diamino derivative 2. Such derivatives are often unstable and can be ring-closed to the imidazo fused heterocycle 4_ (E= single bond) by reaction with an appropriate carboxylic acid, nitrile, imidate ester, thioimidate ester, amidine, or orthoformate, either neat, or in a solvent appropriate and compatible with the starting materials and reagents, such as polyphoεphoric acid, ethanol, methanol, hydrocarbon solvents and with a catalytic amount of acid if required. Another possible approach, not shown in Reaction Scheme 1-1, to compounds having the general structure 4 (B= single bond) from 2 involves the reaction of 2 with an appropriate aldehyde in the presence of an oxidizing agent such as Cu 11 , nitrobenzene, or dicyanodichloroquinone (DDQ) to give heterocycles such as it- Ring closure of the vicinal diamino heterocycles 2, to give derivatives such as 5_ can be effected by treatment with reagents such as CS , CSC1 2 , C0C1 2 , NH 2 C0NH 2 , alkyl chloroformateε, dialkyl carbonates, or potassium cyanate in the presence of baseε εuch aε KOH or C0 3 . Another potential route to 5_ (B= 0) involves the uεe of a vicinal amino carboxylate εuch as £a. or £b_ which can be converted to 5_ via a Curtius or Hofmann rearrangement on suitable derivatives of ϋaAfeJa εuch as acyl azides, hydroxyamides or N-haloamideε. The bicyclic derivatives 5_ can be alkylated under the appropriate conditions with alkyl halides, alkyl mesylateε, alkyl toεylates, trialkyloxonium salts or with diazomethane to afford compounds of type 4 (B= 0 or S). Another approach to 4 (B= single bond) which has been used for example when A- * ---A 2 -A 3 - together are -N=C(CH 3 )-N(CH 3 )- starts from 2 and utilizes acylation of the amino function with an acyl chloride or anhydride to give the nitro amido compound ∑. SEACTION SCHEME 1-1 H - -A S 10 11 0 = a suitable leaving group such as Cl, Br, I, O-πesyl or O-to -91- Reduction of the nitro group leads to 8_ and thiε can be ring closed to 4 via cyclodehydration, by heating and/or acid catalysis. The imidazo fused heterocycle 4_ can then be alkylated with ArCH 2 -Q (where Q is a suitable leaving group such as Cl, Br, I, 0-mesyl, or 0-tosyl) in one of several ways. One way is initially to form the alkali metal salt of 4_ by using MH (where M is Li, Na or K) in anhydrous dimethylformamide (DMF) or by treating 4 with a ' metal alkoxide such as sodium, or potassium methoxide, ethoxide or t-butoxide in an appropriate alcohol such as methanol, ethanol or t-butanol as solvent. The alkylation is then carried out by dissolving the above-mentioned salt of A. in an anhydrous aprotic solvent such as DMF, dimethylsul- foxide (DMSO) or tetrahydrofuran (THF) and reacting it with the alkylating agent ArCH 2 -Q (preparation of ArCH 2 -Q is described ,hereinbelow) at 20 » C to reflux temperature of the solvent for 1 to 24 hours. If the substituentε on the heterocyclic ring system result in an unsymmetrical heterocycle, then the alkylation may produce a mixture of regioiεomerε. These regioiεomers possess distinct physico-chemical and biological properties and in most cases can be separated and purified using conventional separation techniques such as chromatography and/or crystallization. In those cases where the separation of regiosomers is difficult by conventional methods, the mixture can be transformed into suitable derivatives that are more amenable to the usual separation methods. The identification of the individual regioisomers can be made using Nuclear Overhauεer Effect (NOE) NMR methods, 13 C NMR methods (e.g. vicinal 13 C- 1 H coupling constantε) or by single crystal X-ray crystallography. It should be noted that the relative amounts of the regioisomerε formed in the alkylation reaction can be influenced by several factors including the nature of the base used (while the alkali metal salt of the heterocycle is generally used, the regioisomeric ratio can be altered in some inεtanceε 0 by using the heterocycle in the presence of a weaker base such as triethylamine, diisopropylethylamine,. potaεsium carbonate or sodium bicarbonate) and the nature of the solvent used in the reaction. An alternative approach, also shown in 5 Reaction Scheme 1-1, startε with the mono nitro derivative 2.. Thiε can be reacted with a substituted hydroxylamine bearing the ArCH 2 side chain, to give 10. Reduction of the nitro function gives the vicinal substituted diamine 11 which can be ring o closed in the usual fashion. Thiε allowε for regioselective introduction of the Ar-CH 2 side chain into the bicyclic system. Another approach to the compounds of this invention is shown in Reaction Scheme 1-2. In this 5 instance, a monoamino heterocycle such as 12 can be acylated under standard conditions to give the amido derivative 12.. This amido compound can be reduced with LiAlH^ in a anhydrous solvent such as THF or Et 2 0 to the alkylamino derivative 14 which can then be nitroεated with isoamyl nitrite to give 15_. Such alkylamino nitroso derivatives particularly, for example, when A * ^-A -A 3 - together are -C(CH3)«N-N(CH3)-, undergo cyclodehydration when heated in pyridine to give the imidazo fused bicyclic heterocycle 4. The conversion of A to 1 can be carried out as described in Reaction Scheme 1-1. Alternatively, it should be posεible to alkylate 15_ prior to ring closure to give the bis-N-alkylated derivative li which can then be subjected to cyclodehydration in hot pyridine to give the blocked 1. Separation of any regioisomers that may be formed can be effected by using conventional chromatographic methods. An alternative approach to the synthesis of 16 might utilize alkylation of the monoalkylated side-chain 1A with ArCH 2 -Q. This would provide the bis-N-alkylated derivative U which can be nitrosated with isoamyl nitrite to give li. An additional approach to the compounds of this invention is shown in Reaction Scheme 1-3. In this approach the starting material is a vicinal bromo nitro heterocycle lfi which is reacted with an appropriate mono alkylamine to give 19_. Ring closure can be effected using MeOH/NaOH with heating to give the N-oxide derivative 20. which can be reduced with either triethylphosphine, TiCl 2 or Si 2 Cl.£ to give the imidazo-fused bicyclic heterocycle 4. This can be converted to 1 in the usual fashion as described above in Reaction Scheme 1-1. Alternatively, IS. can be reacted with the appropriate dialkylamine to give 21 (which can also be prepared by alkylation of 12. with ArCH 2 -Q under the appropriate conditions). Ring closure of 21 in a faεhion εimilar to that described above in the converεion of 12 to 2Q is followed by reduction and εeparation of the products to give 1. Another approach to compounds of the Formula 1 (particularly where -A * ^-A -A 3 - together are -C(R 7a )=C(R 7b )-S-) is shown in Reaction Scheme 1-4. In these instances, the starting material is the substituted heterocycle 21 which can be alkylated with ArCH 2 -Q to give 2A- Treatment with hydrazine/nitrous acid and a refluxing alcohol (HOR 1 ) giveε rise to 25. via a Curtius rearrangement of the intermediate acyl azide. The cyclization of 25. can be accompliεhed with polyphosphoric acid or other acidic catalyst to provide 1. REACTION SCHEME 1-2 30 REACTION SCHEME ϊ-3 -97- Reaction Scheme 1-4 23 24 CH 2 Ar CH 2 Ar 25 1 The required heterocyclic precursors for these transformations which are shown in Reaction Schemes 1-4 may be prepared by adaptations of literature procedures. A listing of representative precursors to these imidazo fused bicyclic heterocycles, along with literature references to their preparations is shown below in Table 4. TABLE 4 Structure Narre Reference. {v 5-aπino-1- - hen > Soc* • || H πethyl- 2028 (1948) H,N^N imidazole *** I CH 3 5-ami no- Can. J. Res. 10 „ M M imidazole 19B 296 1941) I H 5-amLno-1,2- J- Chem Soc, dirrethyl- 164B (1954) imLdazole CH 3 15 Hzl W , 4-amLno-5- J - Hθt " chθrτ > J ^ nitro-1.2- 6. 53 (1969) NO, -N diiTB hyl- CH 3 Imidazole -N N0 2Υι s \^ 5-amino-4- ibid. 20 J ^ CH 3 4-nitro-1,2- H ~ 2,N l ? dirrethyl- imidazole CH 3 5-arτino-1 , 3- US. Patent diπethyl- 3,646, 059 pyrazole H 9 Ha X^ 5-arτino-3- Ibid. fl rrethyl- H 2 N -* pyrazole H h J. Gen. Chem 30 H 2 Nγ-^ 4, 5-diarτino- (USSR) 32, F 1-rrethyl- 1898 (1962) H 2 N I 3 -phenyl - CH, pyrazole , TABLE 4 (cont). Structure Naπe Reference 4-aπ±noiso- J. Chem Soc. thiazole 306 (1959) CHg 4-arτino- Ibid. 3-πe hyl- isothiazole H 5-arrino- Ibid. 3-rrethyl- isσthiazole 5-aπ±no- Ibid. 4-nitro- 3-πethyl- isothiazole 4, 5-diaπ±no- Izv. Akad. Nauk 1H-1-benzyl- SSRR, Ser Khim 1, " 2,3-triazole 11 * 2633 0985) 314, SUBSTI -100A- TABLE 4 (cont). Structure Narre Reference 4, 5-diarrino-3- Japanese Patent [ (phenylnethyl- 53/109527 ene)arτino] -2H- pyτrol-2-one Ber. 591 3, 4-diarτino- Bull Soc. thiophene Chem Fr. , 5-6, pt.2, 153 (1983) 3, 4-diaπino- J. Het. Chem , 1,2, 5-thia- 13, 13 (1976) diazole SUBSTITUTE SHEET -101- In certain cases due to the nature of the heterocycle being prepared and to the availability of starting materials, it may be advantageous to prepare some of the compounds of this invention from a suitably functionalized imidazole ring by ring closing to give compounds of Formula 1. Some specific examples are shown in Reaction Schemes 1-5 to 1-7. Thus, Reaction Scheme 6 shows an approach to the preparation of the substituted regioisomers of 0 IS- a 3E- thieno[2,3-i]imidazoles. The substituted imidazole 2& can be readily alkylated in the fashion described earlier by using NaΞ in DMF, followed by treatment of the anion so formed with the alkylating agent ArCH2~Q to give a separable mixture of the 5 regioisomers £7a and 27b. These can be independently converted to ketones 28a and 2£fc, respectively, via oxidation with a suitable oxidizing agent such as Mnθ2 to the aldehyde, followed by reaction with an appropriate Grignard reagent to give the secondary o alcohol which iε further oxidized with Mnθ£ to 28a. b_. These isomers can then be independently converted to the corresponding thieno[2,3-i.]imidazoleε 23. by treatment with a thioglycolic acid ester and the appropriate alkoxide in the appropriate refluxing 5 alcohol (i.e., 2S___ gives the 3fi-thieno- [2,3-d.]imidazole 2& and 2Sfc gives the lH-thieno- [2,3-d.]imidazole regioiεomer 2£b.). Saponification of 29a. gives the carboxylic acid 33a.. Other conversions possible with the 2__l___ . regioisomerε include -102- reduction with iAlH to the alcohol ^fia^, saponification followed by decarboxylation to give 31a.b. and conversion of the alkyl carbozylate to a ketone with an alkyl lithium reagent to give 22____ - 5 In addition, the intermediate 2δ& can be utilized as a precursor to the 1,6-dihydro-imidazo- [4,5-£.]pyrazole, series by cyclization with a subεtituted hydrazine derivative, to give 3t&- Similarly, 28b can be converted to the 10 imidazo[4,5-c pyrazole 1,4-dihydro series 34b. 15 20 25 * 30 -103- REACTION SCHEME 1-5 27b 27a 26 1 . ItaOs 20 28a 25 30 -104- KEACTIQW SCHEME 1-5 CON'T 32a Sirniarly. 26 b can be convert ad Into he rβgioiβonarlc 29b. 30b. 31 b. 32b. 33b. and 34b. -f halogen (Cl. Br. F. 1) p" * *" s H, all y I. aubatlεutad alkyl, aryl or •ubβ itutβd aryl R 31 = alkyl or aubitltutad alkyl. R" x alkyl or βubβtltutβd alkyl. -105- Similarly, 28b can be converted into the regioisomeric 2k. 2S_ , lit, 22h, 22 , and Mb.- R a =.halogen (Cl, Br, F, I) R 22a B H, alkyl, substituted alkyl, aryl or εubεtituted aryl R 23 B alkyl or substituted alkyl. R 25 ■ = alkyl or substituted alkyl. A similar cyclization using hydroxylamine can be used to give the 6S-imidazo[4,5-d]isoxazole εeries (starting from 2δ&) or the 42-imidazo[4,5-d]- isoxazole series (starting from 2£t). Preparation of the lactone derivatives 36a.b can probably be accomplished from the regioisomers 35a.b as shown in Reaction Scheme 1-6. These tertiary alcohol starting materials can be obtained from respective ketones εuch as δ&j-h (εee Reaction Scheme 1-5) by reaction with an appropriate Grignard reagent, followed by protection of the alcohol with t-butyldimethylεilylchloride. Thus, lithiation of 35a.b can be carried out with t-Bu i and the lithio derivative reacted with methyl chloroformate. The intermediate so formed can be treated with acid to remove the t-butyldimethylsilyl protecting group and to effect cyclization to the lactone. Deblocking can be effected as described earlier in Reaction Scheme 1. A possible route to the substituted l,5-dihydropy rolo[3,4-£]imidazole iε shown in Reaction Scheme 1-7. Thus, the functionalized -106- ■ * imidazole 21 (or its regioisomer) prepared as described in European Patent Application 253,310 can be treated with tosyl chloride in pyridine to give the O-tosylate which can then be converted to the 5 aminomethyl derivative via a Gabriel synthesis (displacement of tosylate with potassium phthalimide, followed by de-phthaloylation with hydrazine). This intermediate can be blocked by treatment with l,2-bis(chlorodimethylsilyl)ethane to give the 10 intermediate 3_£. Lithiation and subsequent formylation is accpmplished by treatment with butyllithium and DMF to give the intermediate . 3_£ which can cyclize under acid catalyεiε to the pyrroloC3,4-d.]imidazole derivative _0_. Compound 4J) 15 is then treated with an alkyl, acyl or εulphonyl halide to block the pyrrole ring nitrogen. Deblocking with acid under the conditions described earlier gives rise to the required Al. With regard to the preparation of 20 derivatives containing the furo[2,3-d]imidazole heterocycle (i.e., compounds of Formula 1. where A 1-A 2 -A 3 - together are -C(R 22 )«C(R 22 )-0- and -0-C(R 22 )=C(R 22 )-) these can be prepared by alkylation of the appropriate 25 furo[2,3-d.]imidazole [prepared as described in Chem. Pap., 4Q. 675(1986)] using the general procedures shown in Reaction Scheme I-l for the conversion of 4 - x to 1. 30 -107- REACTION SCHEME 1-6 3 35a 10 36a 20 35b 25 SUBSTITUTESHEET -107A- R 2 ^ a = aryl, substituted aryl, alkyl or substituted * alkyl Ar = subs:., pphheeinyl Ar* = deprotected Ar TBDMS = t-butyldimethylsilyl. 5 10 15 20 25 * * 30 SUBSTITUTE SHEET - 108 - REACTION SCHEME 1-7 1. Tosyl chloride/ N 2 H* 37 38 Si'~ Si 10 / ! I v /Et, ,N Cl Cl 25 41 40 R 23 = alkyl, acyl, or alkyls ulphonyl. 30 -109- BENZIMIPAZQ ES (Formula I, wherein A * - 5 iε a single bond and -A **** -A 2 -A 3 -A^- is as defined by (r) above) The compounds of Formula I wherein (-A****-A 2 -A 3 -A*-) is a 4-atom sequence as defined in the General Description of the invention can be synthesized using the reactions and techniques described herein below. The reactions are performed in a εolvent appropriate to the reagentε and materials employed and εuitable for the transformation being effected. It is understood by those skilled in the art of organic syntheses that the functionality present on the benzimidazole and other parts of the structure should be consistent with the chemical transformations proposed. Depending upon the reactions and techniques employed, this may involve changing the order of synthetic steps, use of required -110- protecting groups followed by deprotection, and activation of the benzylic position of the alkylating agents used to enable alkylation at the nitrogen on the imidazole part of benzimidazoleε. REACTION SCHEME 1-8 (Q = I , Br , OMs , OTs ) -111- As shown in Reaction Scheme 1-8, compounds of Formula (2) can be prepared by carrying out direct alkylation of alkali-metal salt of benzimidazole (1) (preparation of benzimidazoles are described in 5 Reaction Schemes 1-9 to 1-12) using appropriately protected benzyl halide, tosylate (OTs) or mesylate (OMs) derivatives (2). The salt is prepared preferably using MH (where M is lithium, sodium or potaεεium) in anhydrouε dimethylformamide (DMF), or 10 by treating it with metal alkoxide such as sodium or potassium methoxide, ethoxide or t-butoxide in an appropriate alcohol such as methanol, ethanol or t-butanol as the solvent. The alkylation is generally carried-out by dissolving the metal salt of 15 benzimidazole in a dipolar aprotic solvent such as DMF or dimethylεulfoxide (DMSO) and reacting it with the alkylating agent at 20°C to reflux temperature of the solvent for 1-24 hours. If substituents on the benzene ring result 20 in an unsymmetrical benzimidazole, the alkylation may produce a mixture of two regioisomers as products, which may be represented by formulas ___%. and __h. These regioisomers posεesε distinct phyεico-chemical and biological properties and in most caseε can be 25 separated and purified by using conventional separation techniques such as chromatography (flash column chromatography, medium-pressure liquid > chromatography, high pressure liquid chromatography (HPLC) and/or crystallization. In thoεe caεeε where 30 εeparation of regioiεomerε iε difficult by conventional techniques, the mixture can be transformed into suitable derivatives that can be -112- separated by usual separation methods. The structural assignments of the isomers can be made using proton NMR, Nuclear Overhauser Effect (NOE) experiments or X-ray crystallography. -113- » The starting benzimidazoles can be readily prepared by any of the standard procedures described in the literature [P. N. Preston, Chemis rv of Heterocyclic Compounds. Vol. 40, part I, pp. 1-286 5 (1981) and references cited therein]. Several alternative routes to obtain benzimidazoles are outlined in Reaction Scheme 1-9. The most widely used starting material, o-phenylenedi mines (11), can be readily prepared from the correεponding o-nitro- 10 aniline (1Q) υεing εtandard reductive procedures such as metal-acid reduction or catalytic reduction. The substituted or unsubstituted H can then be treated with an appropriate imidate hydrochloride (12) to form corresponding benzimidazoles (13). 15 Alternatively, the reaction of carboxylic acids (1£) with o-phenylenediamines in the presence of polyphosphoric acid (PPA) is also effective in producing benzimidazoles (15). Benzimidazoles (12) can also be prepared from o-phenylenediamineε and 20 . aldehyde (16) using cupric salt as an oxidant [R. eidenhagen, Chem. Ber,, ££, 2263 (1936)]. 25 30 - 114 - REACTION SCHEME 1-10 (R= H, OH, Cl) CK 1 = aryl, heteroaryl) 18 19 21 -114A- REACTION SCHEME 1-10 cont'd 10 22 15 20 25 30 -115- Although some benzimidazoles having aryl and heteroaryl groups at the 2 position can be prepared using the methods described in Reaction Scheme 1-9, Reaction Scheme 1-10 outlines methods which are more suitable for the synthesiε of thiε class of compounds. N'-aryl-N-hydroxyamidines (lfi; RsOH) are cyclized under mild conditions using benzene- εulfonyl chloride in pyridine or triethylamine to give 12 in good yield [M. W. Partridge and H. A. Turner, J. Chem. Soc. 2086 (1958)]. Parent amidineε (IS; R*=H) can also be oxidized with sodium hypochlorite under basic conditions to form 12 [V. J. Grenda, R. E. Jones, G. Gal and M. Sletzinger, J. Org. Chem... 30. 259, (1965)]. Alternatively, as shown in Reaction Scheme 1-10, o-phenylenediamines (11) can be reacted with N-ethoxycarbonylthioamides (2Q) to give 2-subεtituted benzimidazoles (21) in excellent yields. This method avoids the use of acidic catalysts. The reagents (2A) are easily obtained in one step from ethoxy- carbonyl isothiocyanate and simple aromatic or heterocyclic compounds or alkylmagneεium halides [B. George and E. P. Papadopoulos. , J. Org. Chem.. 41. 3233(1976); E. P. Papadopoulos., J. Org. Chem.. 4_l, 962(1976)]. Heterocyclic compounds containing reactive methyl groups (e.g., 2-picoline) can also be reacted with o-phenylenediamines in the preεence of εulfur at elevated temperatureε to give 2-heteroaryl benzimidazoles (22)- -116- REACTION SCHEME 1-11 21 Ctf= C -C 6 alkyl) 26 29 30 -117- As outlined in Reaction Scheme 1-11, benzimidazoles containing 2-alkoxy and thioalkyl substituents (22 and 22) can be prepared from the corresponding benzimidazolones (25) or benzimidazol- ethiones (2δ)- Benzimidazolones are conveniently prepared rom o-phenylenediamines and phoεgene or urea [K. Hofmann, "Imidazole and its Derivatives, Part 1," Wiley-Interscience, New York, 1953, pp. 285-291]. Carbonate esters, diethylpyrocarbonate, N,N-carbonyldiimidazole and N,N-diethylcarbamyl chloride may also be used in this reaction. The reaction of phoεgene iε apparently facilitated by the uεe of N.N'-biε-trimethylεilyl (TMS) derivative (23) inεtead of the parent diamine [L. Birkhofer, Ξ. P. uhlthau, and A. Ritter, Chem. Ber.. 22, 2810 (I960) -118- REACTION SCHEME 1-12 ,3 a 11 30 15 32 30 -119- Aε deεcribed in Reaction Scheme 1-12, 2-alkylthioalkyl substituted benzimidazoles (31) can be prepared from the reaction of RS-M (where M iε sodium, potasεium or lithium) with 2-chloroalkyl benzimidazoleε (3A). 2-Chloroalkyl benzi idazoleε (3Q) can be conveniently prepared from the diamineε and the chloroalkyl carboxylic acids using PPA [W. Knobloch, Chem. Ber.. 21, 2557 (1958)]. Alternatively, compound 31 can also be prepared from the readily available 2-thioalkyl derivative (32) [E. S. Milner, S. Snyder, and M. M. Joullie, . Chem. Soc. 4151 (1964)]. IMIPAZQ-6-FUSEP SSTSRPCYC ES CH 2 Ar (FORMULA I, wherein A 5 iε a εingle bond and -A-J'-A-Z-AS-A 4 - iε a 4-atom sequence as defined in the Detailed Description of the Invention) -120- The compounds of Formula I, wherein _A* ** -A 2 -A 3 -A 4 - are defined by (ak) to (bw) in the Detailed Description of the invention can be synthesized using the reactions and techniques described herein below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected. It is understood by those skilled in the art of organic syntheεiε that the functionality present on the heterocycle and in the reactants being employed should be consistent with the chemical transformationε being conducted. Depending upon the reactionε and techniques employed, optimal yieldε may require changing the order of synthetic stepε or uεe of protecting groups followed by deprotection. As shown in Reaction Scheme 1, compounds of Formula I can be prepared by carrying-out direct alkylation of alkali-metal salts of heterocycles (1) (preparation of heterocycles are described in Reaction Schemes 3-6) using appropriately protected benzyl halide, tosylate (OTs) or meεylate (OMε) derivatives (2). The εalt is prepared preferably using MH (where M iε lithium, sodium or potasεium) in anhydrous dimethylformamide (DMF), or by treating it with a metal alkoxide such as sodium or potasεium methoxide, ethoxide or t-butoxide in an appropriate alcohol εuch aε methanol, ethanol or t-butanol as the εolvent. The alkylation iε generally carried-out by dissolving the metal εalt of the heterocycle in a dipolar aprotic solvent εuch as DMF or dimethylεulfoxide (DMSO) and reacting it with the alkylating agent at 20'C to reflux temperature of the solvent for 1-24 hours. -121- If substituents and/or the heteroatom poεitionε in the six membered ring are not symmetrically disposed, the alkylation on the imidazole nitrogen(s) generally produces a mixture of two regioisomerε. as products arising rom N 1 and N 3 alkylation. These regioisomers I and la possess distinct physico-chemical and biological properties and in most caseε can be separated and purified by using conventional separation techniques such aε chromatography (flash column chromatography, medium-pressure liquid chromatography, high performance liquid chromatography) and/or crystallization. In those cases where separation of regioisomerε iε difficult by conventional techniques, the mixture can be tranεformed into εuitable derivatives that can be separated by the above separation methods. The structural asεignmentε of the iεomerε can be made using Nuclear Overhauser Effect (NOE), 1 H- 13 C coupled NMR experiments or X-ray crystallography. When there iε potential for alkylation of the 6-membered heterocyclic ring, this can be avoided by the use of suitable protecting groups. The heterocycles of type (1) can be prepared by any of the standard procedures described in the literature [J.A. Montgomery and J.A. Secriεt III in "Comprehensive Heterocyclic Chemistry," Vol. 5, A.R. Katritεky and C.W. Rees Eds., Pergamon Presε 1984; pp 567-597 and 631-656 and referenceε cited therein]. As shown in Reaction Scheme 1-13, the most widely uεed εtarting materialε are εix member heterocyclic vicinal diamines (9). Fuεed imidazoles (10) can be -122- prepared by condensation of (9) with an appropriate carboxylic acid, nitrile, imidate ester, or orthoester, either neat, or in a solvent appropriate and compatible with the starting materials and 5 reagents, such as polyphosphoric acid, ethanol, methanol, hydrocarbon solvents, and with a catalytic amount of acid if required. Oxidation of an imine formed by reaction of diamine (9) with an appropriate aldehyde using oxidants such as Cu (II), nitrobenzene, 0 or 2,3-dichloro-5,6-d*icyano-l,4-benzoquiήone (DDQ) also affords heterocycles (1Q). Aminoamideε (11, W - H) or diamideε (11, W = R 6 C0) can be converted to fuεed imidazoleε (11) by heating neat, or at an elevated temperature in a solvent εuch aε xylene 1 under acidic or neutral conditions. Halogenation of the imidazo[4,5-b]pyridine ring at the 6-position can be accomplished using Br , or N-bromoεuccinimide. Halogenation of the 7-position can be accomplished by reaction of the corresponding 20 imidazopyridine-4-oxide (prepared by reaction of the imidazopyridine with peracids εuch as m-chloroperben- zoic acid) with POCI3. When the 7-position iε εubεtituted other than hydrogen halogenation at the 5-position of the 4(N)-oxide precursor occurs on 25 treatment with POCI3. Chlorides-may be substituted * * by bromides or iodides by treatment with either HBr or HI, respectively, in a solvent such as HOAc. 30 -123- 2-Alkyl-imidazo[4,5-b]ρyridines can be subεtituted at the 5, 6, or 7 poεitionε by displace¬ ment of a halogen at that position by nucleophiles such as cyanide (followed by hydrolysis to obtain carboxylic acids), amines, copper alkoxides, trialkyl- phoεphiteε, and thiolateε. Also, substitution of the halogens, in particular bromides or iodides, can be accomplished by reaction with a coupling partner εuch as alkylzinc or arylzinc halides, or monoalkylaryl- phosphonites in the preεence of an appropriate metal catalyεt εuch aε nickel, palladium, ruthenium, or platinum. In caεes where the displacement of a halogen is slυggiεh or otherwise complicated due to an acidic proton, the imidazopyridine may be protected at the 1, 3, or 4 poεitionε by benzyl or other arylmethyl groups. 7-Methyl-2-propylimidazo[4,5-b]pyridine-5- carboxylic acid or the 2-ethyl analog iε prepared from 7-methyl-2-propylimidazo[4,5-b]pyridine or the 2-ethyl analog by treatment with m-chloro- peroxybenzoic acid to obtain the N-oxide which iε then treated with P0C1 3 to give 5-chloro-7- methyl-2-propylimidazo-[4,5-b]pyridine or 2-ethyl analog . The chloride is then exchanged for a bromide by reaction of 5-chloro-7-methyl- 2-propylimidazo[4,5-b]pyridine or the 2-ethyl analog with HBr in acetic acid. The resulting 5-bromo-7-methyl-2-propylimidazo[4,5-b]- pyridine or 2-ethyl analog iε treated with NaH in DMF followed by benzyl bromide to obtain 3-benzyl-5-bromo- 7-methyl-2-ρropylimidazo[4,5-b]pyridine or itε correεponding 2-ethyl analog which iε in turn treated -124- with CuCN in hot pyridine to obtain 3-benzyl- 5-cyano-7-methyl-2-propylimidazo[4,5-b]pyridine or the corresponding 2-ethyl analog. The cyano compound is hydrolyzed to 3-benzyl-7-methyl-2-propylimidazo- [4,5-b]pyridine-5-carboxylic acid or the corresponding 2-ethyl analog by treatment with H2SO4-B2O. Thiε acid is esterified by reaction with MeOH-HCl. The benzyi group iε removed by hydrogenation at 1 atm. in MeOH-HCl solution uεing Pd(0H) 2 aε catalyεt. Thiε compound can be alkylated as described earlier and the product methyl ester iε converted to the carboxylic acid by treatment with hydroxide. As shown in Reaction Scheme 1-14, methods of preparing heterocycles of types 12 and 13 involve treatment of diamines (2) with reagents such as urea, phosgene, potassium cyanate, alkyl chloroformates, dialkylcarbonates, or carbon diεulfide in the presence of bases such as potasεium hydroxide or potassium carbonate. Amino acids 14 or 15_ can be converted to 13 via Curtiuε or Hoffman rearrangement of εuitable derivativeε εuch aε acyl azides, hydroxy- amideε, or N-haloamides. Bicyclic compoundε of type (li, E = sulfur or oxygen) are formed from 12 by reaction under neutral or basic conditions with alkyl halides, alkyl meεylateε, alkyl toεylateε, trialkyl- oxonium salts, or witfa an appropriate diazoalkane. Compounds of type (16; B = oxygen or sulfur) are prepared by displacement reactions using alkoxides or alkyl mecaptides with chloro intermediateε aε indicated. -125- Diamineε of type 2. can be prepared by a wide variety of methods such as hydrolysis of bis-amideε or amino amides, reduction of dinitro or aminonitro or hydrazino or azido groups, displacement of heteroaromatic halides or. alkoxy or thio or alkylthio or hydroxy or alkyl sulfonyl groups with ammonia or amines, or rearrangement of acyl azides or amides or acids (Curtiuε, Hoffman, or Schmidt rearrangements). [A.S. Tomcufcik, L.N. Starker in "Heterocyclic Compounds, Pyridine and it's Derivativeε" Pt 3, E. Klingsberg Ed., Wiley Interscience, 1962, pp 59-62, and references cited therein; T. Nakagome in "Heterocyclic Compounds, Pyridazines" Vol. 28, R.N. Castle, Ed., Wiley Interscience, 1973, pp 597-601, and references cited therein; "Heterocyclic Compounds, The Pyrimidines" Vol. 16, D.J. Brown Ed., Wiley Interscience 1985, pp 299-325; E. Schipper, and A.R. Day J. Am. Chem. Soc. (1952) 2A, 350; "Comprehensive Heterocyclic Chemistry," Vol. 5, A.R. Katritsky and C.W. Reeε Eds., Pergamon Press 1984; pp 567-597 and 631-656 and references cited therein] . In caseε wherein heterocycleε of type 1Q or 16 are not easily prepared from their corresponding dia ines, or when these diamines cannot be prepared then alternative routeε involving fuεion of the εix member heterocycle onto an appropriately εubεtituted imidazole, are used. Two of these routes are illustrated in Reaction Scheme 1-15. For example, imidazo[4,5-d][l,2,3]triazineε (13) are preferentially prepared by treatment of amino carboxamido imidazoles (11) with sodium nitrite in aqueous acid. Precursor imidazoles (12) are prepared -126- by degradation of an appropriately substituted xanthine or by condensation of an appropriate imidate ester with aminocyanoacetamide. Imidazo[4,5-b]- pyridazines (20.) can be prepared from imidazodi- carboxylate esters (li) by treatment with hydrazine. Oxidation of (2.) gives pyridazinediones (21). The oxygen(ε) in (2Q) or (21) can be converted to other functionalitieε εuch aε halideε or thioneε, which are themselves precursors for the synthesis of more elaborate systems ["Comprehensive Heterocyclic Chemistry," Vol. 5, A.R. Katritsky and C.W. Rees Eds., Pergamon Presε 1984; pp 567-597 and 631-656 and references cited therein]. -127- REACTION SCHEME 1-13 Alternate reagents and reaction conditions: R -CN, PPA R 1 -C-COC 2 K 5 ). C j HsOH, i NH" HCl 20 R 1 CCOCH 3 ) 3 , toluene. H * . Δ R 1 CHO, CjHgOH, Cu(OCH 3 ) 2 25 30 * -128- REACTION SCHEME 1-14 10 20 12 or 13 •+ E 1 Q H 16 30 -129- REACTION SCHEME 1-15 17 ιe As shown in Reaction Scheme 1-16 amino imidazole esters and amides are versatile intermediates for the preparation of purines. Thiε scheme alεo . illuεtrateε the εyntheεiε of the 6-membered heterocyclic ring after the alkylating agent 2 has been reacted with a suitably substituted imidazole to afford 22 or 24. -130- REACTION SCHEME 1-16 The preparation of reduced forms of hetero¬ cycles can be achieved by catalytic reduction, or by synthesis from a suitable imidazole precursor. For example, hiεtidine and derivativeε thereof react with formaldehyde to afford partially saturated imidazo(4,5-c) pyridines [cf. Neuberger, A. Biochem. J., (1944), 3_8_, 309]. -131- IMIDA2Q-7-MEMBERED FUSED HETEROCYCLES Compounds of.FORMULA I, wherein represents a 5-atom sequence as defined in the Detailed Description of the Invention are prepared as described below in Schemes 1-17 to 1-23 SCBSMS 1-17 -132- The imidazoles (7) required in alkylation Scheme 1-17 can be prepared by a number of methods well known in the literature including those described in EPO publication 253,310. A useful method of generating compound (7) wherein A* and A** are NH2 a nd CONHR 6 or CO2 7 is illustrated in Scheme 1-18. -133- Scheme 1-18 C=N 10 l?im_. EtOH. Δ 20 DC CONHR" H 25 11 30 -134- The synthesis of intermediate (1) wherein A* iε NHR 6 and A** iε CONHR 6 or C0 2 R 7 (R 7 « ethyl) and B iε a εingle bond can be accomplished by the alkylation of the cyanoamidine (13) with a benzylic halide or pεeudohalide represented as "ArCB 2 -Q" where Q iε a leaving group aε outlined in Scheme 1-19. -135- NH N-C≡N R 1 -C-OEt + NH 2 C=N 5tOH* -C-OEt θ 12 10 H 2 C0 2 Et 13 14 20 25 30 -136- Seheme 1-19 (Cont ' d ^ Cyanoamidine (13) iε prepared according to the methods described by Edenhofer, Helv. Chim Acta. 58. 2192(1975). Alkylation of cyanoamidine 13. may require an alkylating reagent which incorporates functional groups. In such cases, protecting groups may be required for these functional groups during the alkylation step. For example, a carboxyl group can be conviently protected as a t-butyl ester and a tetrazole group as an N-trityl derivative. The alkylated cyanomidine (14) is purified by silica gel chromatography aε is the ring-cloεed product (15). Conversion of (15) to amide (16) iε accompliεhed by heating the ester with R & NH 2 in an inert solvent εuch as ethanol. Compound (15) can be alkylated on the amino moiety uεing a small excesε of R ** **-I in DMF in the presence of NaH. -137- Compoundε of Formula (7) wherein A* and A** are either Cl and CH 2 0H or CH2OH and Cl reεpectively are alεo uεeful intermediateε, and their preparationε are deεcribed in EPO publication 253,310. The primary alcohol (CH2OH) moiety in their alkylation productε (18) can be oxidized directly to the correεponding -CO2CH3 eεter groupε uεing MnC>2 in the presence of NaCN and acetic acid in methanol as illustrated in Scheme 1-20. Scheme 1-20 1 8 19 CHjOH Cp j CH 3 tf. B ι o -' NaCN ■ R ι. B A eι CH,Ar ∞Ac * >*∞ CI^Ar 20 21 Compounds (19) and (21) from Scheme 1-20 can be further converted to thiol compounds as illustrated by the methodology of Scheme 1-21. Scheme 1-21 also illustrates an alternate route to amino compoundε (22) which involves azide displacement of Cl followed by hydrogenation. -138- Scheme 1-21 21 23 21 22 Formation of the products (I) wherein the fused ring A represented by AI-A^-A^-A^-A * - ** contains 3 = NR 6 is carried out from intermediates (1) wherein A* and A** are (NHR 6 , CONHR 6 ) or (CONHR 6 , NHR 6 ) respectively by treating (1) in DMF with Q-C(0)-C(R 7 )(R 8 )-Q in the presence of a tertiary amine such aε triethylamine. Q is a leaving group which preferably iε a halo group. When A* or A** is CO2 7 and R 7 = H then*! in the resultant products iε oxygen. The transformations illustrated in Scheme 1-22 with intermediate (16) are.analogous to tranεformationε which can be"employed to synthesize similarly substituted benzodiazepines. -139- Seheme 1-22 ,ι Scheme. 1-22 also provides an alternate route to generate products (I ) wherein Y iε NR 6 . In thiε εequence N-protected amino acidε are uεed to acylate intermediate (1 ) wherein A* or A** iε NR 6 , by employing either an acyl halide , or a εtandard carboxyl activating reagent εuch aε dicyclohexyl- carbodimide (DCC ) or (benzotriazol-l-yl )oxytris- (dimethylamino) phoεphonium hexafluorophoεphate (BOP) . The N-protecting group of the amino acid εuch as the carbobenzyloxy (Cbz) , t-butoxycarbonyl (t-BOC ) or the fluorenylethylmethoxyloxycarbonyl (FMOC ) group -140- iε removed according to standard peptide synthetic conditions. The final ring forming step is made by heating this intermediate in an alcoholic solvent or by εaponifying the imidazole CO2R 7 group to yield a carboxylic acid which is treated with a carboxyl activating reagent εuch aε DCC or polyphosphoric acid Following the methodology of the above described transformation of Scheme 1-22, if A* and A** are SH and CO2R 7 , as illustrated by intermediate (23), and the ring forming reagent iε HNR 6 C(R 7 )(R 8 )CH 2 C1, it iε poεεible to form products of formula (I) whereiiϊ the A- * --A 2 -A 3 -A 4 -A 5 element iε -CON(R 6 )-C(R 7 )(R 8 )-CH 2 S -SCH 2 C(R 7 )(R 8 )-N(R 6 )-C0- -C0N(R 6 )-C(R 14 )(R 15 )-CH 2 S- -SCH 2 C(R 14 )(R 15 )-N(R 16 )C0- The preparation of productε of Formula I, wherein - r \ 1 -A 2 -A-'-A fy -A 5 is -CON(R 6 )-C(R 7 )(R 8 )-C(R 9 )= N- is carried out in Scheme 1-23. The final ring closure, which involves a dehydration to yield an amine, can be aεεiεted by heating in the preεence of molecular εieves and acetic acid in an inert solvent εuch as dioxane, or by employing polyphoεphoric acid as the dehydrating agent. -141- 26 20 25 30 - 142 - * PART II: Preparation of substituted benzyl derivatives of the general Formula I. Preparation of compounds of Formula I εtarting from the heterocycleε or benzyl-subεtituted heterocycleε 5 deεcribed in Part I iε illuεtrated in the following εchemes and descriptions. The εyntheεis of Angiotensin II Antagonistε incorporating a εubεtituted benzyl group aε εhown in 10 Formula I may be accompliεhed by reactions in the presence of a base of a heterocyclic compound (as described in Part I) with a benzylic compound bearing a good leaving group, and the appropriate substituents R 9 , R 10 , R 11 , R 12 , X, Y and Z as shown 15 in Formula I. Alternatively, compounds with structures according to Formula I may also be synthesized in stages from a benzyl-εubεtituted heterocycle which contains the substituents R 9 , R**-* 1 -* 1 and X, followed by reaction with an intermediate 20 (such aε a substituted alpha-bromophenylacetic ester) which introduces the substituents at R *** - 1 , R* * -* 2 and Z. Examples of this latter methodology in which a benzyl-substituted heterocyclic intermediate is prepared first, and then elaborated to afford 25 compounds with structures described by Formula I, are shown in the Schemes II-l, II-2 and II-3. The preparation of compound 5 of Formula I wherein: 30 - 143 - « A 1_A 2 -A 3 -A 4 - = -CH=CH-CH=CH-, B= a ingle bond, R 1 * butyl, R 9 , R 10 and R 11 are H, X= 0, Y= a single bond, Z= C0 2 H and R * ^ 2 = phenyl appears in Scheme II-l and in Example 1 of the experimental section. Deprotonation of 2-butylbenzimidazole with strong bases such as sodium hydride or potasεium tert-butoxide in DMF for a period of 1-24 hourε at temperatureε of 20-100'C, followed by alkylation with 4-benzyloxybenzyl chloride affordε the protected ether 2. The benzyl ether iε next removed by hydrogenolyεis using hydrogen and an appropriate catalyst such as Pd/C, Pd(0H) 2 /C or Pt/C which affords the intermediate phenol 3. The phenolic proton is then abstracted, and the phenolate is alkylated with methyl 2-bromophenylacetate to furnish eεter 4. Finally, the ester is hydrolyzed and the free acid 5 is obtained. - 144 - SCHEME II-l The synthesis of compound 10 of Formula I wherein: -A-**-A 2 -A 3 -A 4 - = -C(CH 3 )=CH-CH=N-, B= a single bond, R* * -= a-propyl, R 9 , R 10 and R 11 are H, X= 0, Y= a single bond, Z= C0 2 H and R 12 = phenyl is presented in Scheme II-2 and in Example 2 of the experimental section. Deprotonation of 7-methyl-2- - 145 - propylimidazo[4,5-b_]pyridine (6) with εodium hydride in DMF, followed by treatment with 4-benzyloxybenzyl chloride giveε compound 7. The benzyl ether iε removed by hydrogenolysis to give the phenol 8, which is then deprotonated with potasεium hydride and 18-crown-6 in DMF and alkylated with methyl 2-bromophenylacetate to give the eεter 9. Baεic hydrolysis of 9 gives the free acid 10. Alkylation of the phenol 8 with εubεtituted 2-bromophenylacetic esters, followed by ester hydrolysiε leadε to compounds of Formula I where R- ** - 2 iε a εubεtituted phenyl group εuch as those shown in Examples 6 (R* ** - 2 = 2,6-dichlorophenyl), 7 (R 12 = 2-nitrophenyl), 8 (R 12 = cyclohexyl), 9 (R 12 = n-propyl), and 10 (R 12 = o-carboxyphenyl) in the experimental section. - 146 - gCBEME H-2 The synthesis of compound 15 of Formula I wherein: -A 1 -A 2 -A 3 -A 4 - = -C(CH 3 )=CH-C(CH 3 )=N-, B= a single bond, R 1 -* ethyl, R 9 , R 10 and R 11 are H, X= 0, Y= a single bond, Z= C0 2 H and R 12 = 2-methylphenyl iε shown in Scheme II-3 and in Example 24 of the - 147 - experimental section. Deprotonation of 5,7-dimethyl-2-ethylimidazo[4,5-b_3pyridine (11) with a strong baεe such as εodium hydride in DMF, followed by treatment with 4-benzyloxybenzyl chloride produceε the ether 12. The benzyl ether iε removed by hydrogenolyεiε to give the phenol 13, which iε then deprotonated with potaεεium hydride and 18-crown-6 in DMF and alkylated with methyl 2-bromo-2'-methylphenyl- acetate to give the eεter 14. Alkaline hydrolyεis of 14 gives the free acid 15. Reaction of the phenol 13 with other substituted alpha-bromophenylacetic esters followed by alkaline hydrolysiε leadε to additional derivatives in thiε heterocycle εeries, such as Examples 25 (R 12 = 2-chlorophenyl), 26 (R 12 = 2-bromophenyl) and 40 (R 12 = 2-phenylethyl) in the experimental section. - 148 - SCHEME II-3 10 25 B, 30 SUBSTITUTE SHEET -148A - Substituted 2-bromophenylacetic esters are typically employed in the synthesis of compounds of general Formula I when it is desired that R^ 2 be a substituted phenyl group, R 11 is hydrogen, Y is a single bond and Z is a carboxylic acid. These substituted 2-bromophenylacetic esters are readily prepared from substituted phenyl acetic acids (16) by a Hell-Volhard-Zelinsky reaction as shown in Scheme II-4. Alternatively, substituted 2-bromophenylacetic esters may also be obtained from benzaldehydes (18) as shown in Scheme II-5. Reaction of the substituted SUBSTITUTE SHEET - 149 - benzaldehydes (18) with trimethylsilyl cyanide affords the trimethylsilyl-cyanohydrins 19. Treatment of 19 with acidic ethanol produces the hydroxy eεterε 20, and εubεequent reaction with carbon tetrabromide and triphenylphoεphine provides the εubεtituted 2-bromophenylacetic eεterε 17. 1 B 1 9 20 17 - 150 - The εyntheεiε of Angiotensin II Antagonists incorporating a substituted benzyl element defined by Formula I may also be accomplished by the alkylation reaction of a heterocycle (as described in Part I) with a benzylic intermediate bearing a good leaving group, and with all of the appropriate εubεtituentε R 9 , R 10 , R 11 , R 12 , X, Y and Z in place. Thiε approach which iε generally preferred when either R 9 or R ****0 are non-hydrogen, is illustrated in Scheme II-6 and in Examples 3, 4, 27-31, 33, and 46 of the experimental section. Deprotonation of p-creεol (21) with εtrong bases εuch aε potaεεium hydride or potassium tert-butoxide in DMF and alkylation with methyl 2-bromo-2-phenylacetate gives the ether 22. Bromination of 22 at the benzylic methyl group with N-bromosuccinimide gives the alkylating agent 23. Deprotonation of 5,7-dimethyl-2-ethylimidazo[4,5-b]- pyridine (11) with sodium hydride in DMF, followed by reaction with bromide 23, and subεequent eεter hydrolysis provides the acid 24. - 151 - SCHEME ι -e SUBSTITUTE SHξET -151A- A strategy similar to that of Scheme II-6 is applied when substitution at R ***** --- is desired as shown in Scheme II-7. Intermediate ethers such as 22 in Scheme II-6 are deprotonated with strong bases such as lithium bis(trimethylsilyl)amide in THF and can then be reacted with an alkylating agent such as an alkyl halide or mesylate. In this case, reaction of the anion derived from ether 22 with methyl iodide affords the alkylated product 25. Reaction of 25 with N-bromosuccinimide gives bromide 26, which is in turn used for alkylation of a heterocyclic compound from Part I. Scheme II-7 illustrates the alkylation of heterocycle 6 with bromide 26 which after ester hydrolysis affords acid 27. SUBSTITUTESHEET -152- SCHEME II-7 22 10 30 -152A- The synthesis of compound 32 of Formula I wherein: -A * - * -A 2 -A 3 -A 4 - = -C(CH 3 )=CH-C(CH 3 )=N-, B= a single bond, R x = ethyl, R 9 , R 10 and R 11 are H, X= 0, Y= CH , Z= C0 H and ^ 2 = phenyl is shown in Scheme II-8. In this example, p-hydroxybenzyl alcohol (28) is selectively alkylated at the phenolic hydroxyl group with methyl bromoacetate when they are refluxed with potassium carbonate in acetone. After the remaining hydroxyl group is protected as a tert-butyldimethylsilylether, this ether (29) may then be deprotonated with a strong base such as potassium bis(trimethylsilyl)amide and reacted with an alkylating agent in a manner similar to that shown for intermediate 22 in Scheme II-7. Alkylation of ether 29 with benzyl bromide provides 30. Silylether hydrolysis of 30 and bromination of the resulting alcohol affords an alkylating agent (31) which is then used to alkylate a heterocyclic compound from Part I. Alkylation of the anion derived from heterocycle 11, followed by ester hydrolysis affords the acid 32 shown in Scheme II-8 and described in Example 41 of the experimental section. -153- SCHEME II-8 * 30 SUBSTITUTE SHEET -153A- Scheme II-9 illustrates the preparation of an antagonist of Formula I wherein: -A 1 -A 2 -A 3 -A 4 -= -C(CH 3 )=CH-CH=N-, B= a single bond, Rl= propyl, R 9 , R 10 and R 11 are H, X is a single bond, Y= 0, Z= C0 2 H and, R 12 = phenyl. In this example, the Hell-Volhard- Zelinsky reaction converts 4'-methylphenylacetic acid (33) to the alpha-bromoester 34, which is in turn reacted with the potassium salt of phenol to yield 35. Benzylic bromination of 35 provides alkylating agent 36 which is then reacted with a heterocyclic species described in Part I. When the sodium salt of heterocycle 6 is alkylated with the bromide 36 in DMF, ester 37 is obtained. Alkaline hydrolysis of ester 37 then provides acid 38, which is also the product of Example 17 in the experimental section. SUBSTITUTESHEET -154- SCHEME I 1-9 - 155 - Schemes 11-10 and 11-11 illuεtrate the preparation of analogε where -A- * ---A 2 -A 3 -A 4 - = -C(CH 3 )=CH-CH=N-, B= a εingle bond, R *** -= n-propyl, R 9 and RIO are H, Y= a εingle bond, R 12 is phenyl, Z= C02H and X iε either methyne or methylene. A Reformatεky reaction iε firεt employed to prepare methyl 3-hydroxy-3-(4-methylphenyl)-2-phenyl- propanoate (39) from the εtarting materialε shown in Scheme 11-10. When heated in the preεence of p-tolueneεulfonic acid in benzene 39 iε dehydrated to the trans-stilbene derivative 40, and then benzylic bromination of 40 gives the alkylating agent 41. Deprotonation of heterocycle 6 with sodium hydride in DMF and treatment with 41 gives ester 42. Alkaline hydrolyεiε of 42 affordε the product 43, in which X is a methyne group (R- ** - *** - iε abεent) doubly bonded to the carbon atom bearing εubstituents R-^ 2 and Z as shown in Scheme 11-11 and in Example 11. Catalytic hydrogenation of 43 gives the derivative 44 where X is a methylene group and R ** -- ** *- is a hydrogen atom (Scheme 11-11; Example 12 in the experimental section). - 156 - SCHEME 11-10 SCHEME 11-11 30 - 157 - The εynthesiε of compound 47 of Formula I which haε the same subεtitυentε aε compound 10 (Scheme II-2) with the exception that Z iε a tetrazol-5-yl group, iε illuεtrated in Scheme 11-12 Expoεure of eεter 9 to excess ammonia in methanol produceε the correεponding amide which is then dehydrated with phosphorous oxychloride and triethylamine to give the nitrile 45. Reaction of the nitrile 45 with trimethylstannyl azide in refluxing toluene provides the tetrazole derivative 46. SCHEME 11-12 1 ) MB s snN 3 toluβrβ rβflu 2) HOAc - 158 - Scheme 11-13 illustrates the preparation of a tetrazole analog (52) similar to structure 46 wherein R 12 is a 2-chlorophenyl group. In this synthesiε, the eεter group of intermediate 47 is converted to a nitrile prior to alkylating a heterocycle (Part I) with this substituted benzyl element. Thus, reaction of ester 47 with ammonia in methanol, followed by dehydration of amide 48 produces nitrile 49. Benzylic bromination affords 50, which is then reacted with the sodium salt of heterocycle 6 in DMF to give intermediate 51. Finally, reaction of nitrile 51 with trimethylstannyl azide in refluxing toluene gives the tetrazole 52 shown in Scheme 11-13 (Example 15). SUBSTITUTESHEET -158A- Scπ Mr: ττ-1 20 30 - 159 - The preparation of a derivative of Formula I analogouε to tetrazole 47 (Scheme 11-12) which has a methylene group for the X subεtituent, iε shown in Scheme 11-15 and in Example 16 of the experimental section. In this synthesis, phenylacetonitrile iε deprotonated with lithium biε(trimethylεilyl)amide and then alkylated with the tert-butyldimethylεilyl- ether of p-hydroxymethylbenzyl bromide (preparation of bromide 53 iε εhown in Scheme 11-14 and Example 16 of the experimental εection) to yield nitrile 54. The εilylether group in compound 54 iε directly converted to the bromide 55 with carbon tetrabromide, triphenylphoεphine and acetone in dichloromethane (Mattes, H.; Benezra, C. Tetrahedron Lett., 1987, 1697). Alkylation of the sodium salt of heterocycle 6 with bromide 55, followed by reaction of 56 with trimethylstannyl azide in refluxing toluene yields the tetrazole 57. SCHEME 11-14 Br jy °> » „, Br or ° H - 160 - SCHEME 11-15 Scheme 11-16 illustrateε the preparation of a derivative of Formula I where -A ** --A 2 -A 3 -A^- = -C(CH 3 )=CH-C(CH 3 )=N-, R 1 iε ethyl, B iε a εingle bond, R 9 , R 10 and R 11 are H, X= 0, Y= a εingle bond, R 12 i s 2-methylphenyl, and Z is a phosphonic acid group. Reaction of o-tolualdehyde (58) with dimethylphosphite in the presence of triethylamine affords the phosphonate ester 59. Bromination of the hydroxyl group of 59 with carbon tetrabromide and triphenylphoεphine in dichloromethane giveε bromide 60. Deprotonation of p-hydroxybenzyl alcohol with - 161 - εodium hydride in DMF followed by addition of bromide 60 affords intermediate 61. A second bromination reaction (C r , PPh 3 , CH2CI2) converts alcohol 61 to the bromide 62 which is then used to alkylate a heterocyclic compound described in Part I. Scheme 11-16 illustrates the case where the anion of heterocycle 11 is reacted withgbromide 62 to give upon workup, the phoεphonate mono-eεter 63 (Example 67). Phosphonic acid 64 may be obtained by treatment of ester 63 with trimethylsilyl bromide. SCHEME 11-16 - 162 - The εyntheεiε of a derivative of Formula I where Z iε an acyl-εulfonamide group iε illuεtrated in Scheme 11-17. Alkylation of the anion derived from heterocycle 11 with bromide 65 (εyntheεiε deεcribed in Example 28 of the experimental section) and alkaline hydrolyεiε of the reεulting ester (66) affords the acid 67 (Example 29). Reaction of acid 67 with l,l*-carbonyldiimidazole in THF at elevated temperatureε giveε an acylimidazolide which may be reacted with a εulfonamide (benzeneεulfonamide in this example) and DBU in THF to provide the target compound (68) where Z is the acyl-sulfonamide group. SCHEME 11-17 - 163 - Precursorε for the synthesis of All Antagonistε incorporating a substituted benzyl element wherein either substituentε R 9 or R- ** - 0 are non-hydrogen include subεtituted p-cresols (Scheme II-6), 4-hydroxybenzyl alcoholε, 4-hydroxybenz- aldehydeε, 4-hydroxybenzoic acidε and their esters as shown in Schemes 11-18-20. Commercially available benzyl alcohols εuch as 3-chloro-4-hydroxy-5-methoxybenzyl alcohol may be selectively alkylated by alpha-bromophenylacetic esters when they are refluxed together in the presence of bases such as anhydrous potassium carbonate, giving 2-phenoxyeεterε like 69 εhown in Scheme 11-18. Conversion of the benzyl alcohol group in 69 to a bromide (CBrή, PPh 3 , CH 2 C1 2 ) affordε an alkylating agent (70). A heterocyclic compound from Part I (11) is then alkylated with bromide 70; hydrolysis of the intermediate ester affordε 71, the product of Example 37 in the experimental εection. Alternatively, a heterocyclic compound from Part I may be directly coupled with benzyl alcohols like 69 using Mitsunobu reaction conditions (diethyl azodicarboxylate, PPh , THF). Again, hydrolysis of the resulting ester completes the εyntheεiε. - 164 - SCHEME 11-18 Scheme 11-19 illustrates the use of commercially available 3-ethoxy-4-hydroxybenzaldehyde (72) to prepare an All Antagonist of Formula I bearing a 3-ethoxy group (R 9 ) on the εubεtituted benzyl element. Alkylation of the phenolic group of 72 with methyl 2-bromophenylacetate gives the - 165 - aldehyde 73 which is then reduced to a benzyl alcohol with sodium borohydride in methanol or ethanol. The alcohol iε converted to the bromide 74, and the εyntheεiε of product 75 (Example 34) iε completed as previously deεcribed. SCHEME 11-19 - 166 - Subεtituted 4-hydroxybenzoic eεterε are alεo convenient precurεorε for the synthesis of the subεtituted benzyl element defined in All Antagoniεtε of Formula I. In this approach, the phenolic hydroxyl group iε uεually firεt protected with a εuitable protecting group, the ester iε then reduced to a hydroxymethyl group, and deprotection affordε a 4-hydroxybenzyl alcohol derivative. Scheme 11-20 illuεtrates the preparation of derivative 80 using thiε sequence starting from methyl 3,5-dichloro- 4-hydroxybenzoate (76). Silylation of phenol 76 followed in turn by lithium aluminum hydride reduction of the eεter and εilylether deprotection affordε 3,5-dichloro-4-hydroxybenzyl alcohol (77). Phenol 77 waε then εelectively alkylated with methyl 2-bromophenylacetate, and the εyntheεiε of derivative 80 (Example 38) was completed using the previously described methods. - 167 - SCHEME 11-20 5 A variety of 2-subεtituted phenols are selectively carboxylated when refluxed with carbon tetrachloride, 507. aqueous sodium hydroxide and powdered copper (European Patent Application #193,853, 10-Sept-86) to afford the corresponding 0 substituted 4-hydroxybenzoic acids. This reaction may be added to the synthetic sequence when it is convenient to derive the desired substituent on the benzyl portion of the target All Antagonist from a readily available 2-substituted phenol. This strategy is illustrated for the preparation of derivative 84 shown in Scheme 11-21. Carboxylation of 2-ethylphenol provides 3-ethyl-4-hydroxybenzoic acid (81). Acid 81 is then esterified, silylated, reduced and desilylated to give the 3-ethyl-4- - 168 - hydroxybenzyl alcohol 82. Alcohol 82 may then be used to complete the synthesis of All Antagonist 84 shown in Scheme 11-21 using the previously discussed methodology. SCHEME 11-21 1 ) MsOH, H 2 S0 4 82 SUBSTITUTE SHEET - 169 The Claisen rearrangement of phenyl-allyletherε offerε another uεeful technique for the introduction of alkyl substitutents (R 9 or R- ** * 0 ) at the meta position of the εubεtituted benzyl element. In Scheme 11-22, Claisen rearrangement at 185 β C of allyl ether 85 provides the allylphenol 86. Silylation of this phenol (86), followed by reduction of the ester group and bromination leads to the benzyl bromide 87. Alkylation of a heterocyclic species from Part I, εuch as imidazopyridine 11, followed by εilylether removal giveε intermediates related to 88. Alkylation of 88 with methyl 2-bromophenylacetate followed by alkaline hydrolysis gives a derivative of Formula I (89) wherein R 9 iε a meta-allyl group (Example 42). Hydrogenation of intermediate 88 followed by the εame εequence provides derivative 90 where R 9 iε the meta-propyl group as εhown in Scheme 11-22 and described in Example 43 of the experimental section. - 170 - SCHEME 11-22 The Claisen rearrangement strategy for the o introduction of a meta-alkyl substituent onto the εubεtituted benzyl element of an All Antagoniεt of Formula I may be exerciεed twice when it iε desired that both R 9 and R 10 be meta-alkyl substituents. Thus, allyl phenol 86 may be converted to its 5 0-allylether and subjected to a second Claisen rearrangement to provide the phenol (91) shown in Scheme 11-23. Silylation of phenol 91, followed by catalytic hydrogenation and reduction of the ester group with lithium aluminum hydride gives the benzyl alcohol 92. A Mitεunobu reaction of the benzyl alcohol 92 with a heterocyle (11) deεcribed in Part - 171 - I, followed by silylether deprotection gives an intermediate related to 93. The phenolic hydroxyl group of 93 may then be alkylated with a substituted alpha-bromoester and the ester hydrolyzed to yield the acid 94 in which R 9 and R O are meta-propyl groups as shown in Scheme 11-23 and Example 52. -171A- SCHEME 11-23 25 30 -171B- SCHEME 11-23 cont'd - 172 - The synthesis of compounds of Formula I wherein: -A- * -A 2 -A 3 -A 4 - = -C(CH 3 )=CH-C(CH 3 )=N-, B= a single bond, R 1 - ethyl, R 9 , R 10 and R 11 are H, Y= a single bond, Z= CO2H R- ** -2= phenyl, and X= NR, are presented in the following two Schemes. To access these analogs, a heterocycle (ie. 11) defined in Part I is alkylated with p-nitrobenzyl bromide to yield nitro compounds such as 95 in Scheme 11-24. Catalytic hydrogenation of the nitro group provides an aniline derivative (96) which is then alkylated by an alpha-bromoester. The ester 97 is subsequently hydrolyzed to afford a derivative of Formula I (98) where X= NH (Example 57). SUBSTITUTESHEET -172A- SCHEME 11-24 11 SUBSTITUTE SHEET - 173 - The preparation of All Antagonists of Formula I similar to 98 in Scheme 11-24 but having X= NR may be accomplished by methodology shown in Scheme 11-25. The εubεtituted aniline (96) preεented above, iε readily converted to the N-tert-butylcarbamate (BOC) 99. Carbamateε such as 99 may be deprotonated at the amide nitrogen atom when reacted with baseε εuch aε εodium hydride in DMF, and then reacted with an alkyl halide. Subsequent treatment of the intermediate with trifluoroacetic acid removes the BOC group providing the mono-alky1ated aniline derivative 100. The aniline nitrogen in 100 may be deprotonated again with sodium hydride in DMF and alkylated a εecond time with a εubεtituted alpha-bromoeεter to provide eεterε εuch as 101. Alternatively, the order of introduction of the substituents on the nitrogen atom may be reversed. Intermediate 97 (Scheme 11-24) may alεo be deprotonated by εtrong baεes such as lithium bis(trimethylεilyl)amide in THF and then reacted with an alkyl halide to yield εimilar productε (101). Ester 101 prepared by either synthetic route, is then hydrolyzed to afford the targeted All Antagonists (102) of Formula I where X= NR. - 174 - SCHEME 11-25 10 20 25 30 -174A- SCHEME 11-25 cont'd i> -175- » The compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention. Such salts include ammonium saltε, alkali metal εaltε 5 like sodium and potasεium εaltε, alkaline earth metal εalts like the calcium and magnesium saltε, saltε with organic baεeε; e.g., dicyclohexylamine saltε, N-methyl-D-glucamine, salts with amino acidε like arginine, lysine, and the like. Also, saltε with 10 organic and inorganic acidε may be prepared; e.g., HC1, HBr, H2SO4, H3PO4, methane-εulfonic, tolueneεulfonic, maleic, fumaric, camphorεulfonic. The non-toxic, phyεiologically, acceptable εalts are preferred, although other salts are also useful; 15 e.g., in isolating or purifying the product. The εalts can be formed by conventional means such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium 20 in which the salt iε inεoluble, or in a εolvent εuch as water which iε then removed in vacuo or by freeze-drying or by exchanging the cations of anexisting εalt for another cation on a εuitable ion exchange resin. 25 Angiotensin II (All) is a powerful arterial vasoconstrictor, and it exerts its action by interacting with specific receptors present on cell membranes. The compoundε described in the present invention act as competitive " antagonists of All at 30 the receptors. In order to identify All antagonists and determine their efficacy in vitro, the following two ligand-receptor binding assays were established. -176- Receptor binding aεεay using rabbit aortae membrane preparation Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) were suspended in 5 mM Tris-0.25M Sucroεe, pH 7.4 buffer (50 mL) homogenized, and then centrifuged. The mixture waε filtered through a cheeεecloth and the supernatant was centrifuged for 30 minutes at 20,000 rpm at 4'C. The pellet thus obtained was reεuεpended in 30 mL of 50 mM Triε-5 mM MgCl2 buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/mL Bacitracin and the εuεpenεion waε uεed for 100 aεsay tubes. Samples tested for screening were done in duplicate. To the membrane preparation (0.25 mL) there was added 125 I-Sar 1 Ile 8 - angiotenεin II [obtained from New England Nuclear] (10 mL; 20,000 cpm) with or without the teεt εample and the mixture was incubated at 37 β C for 90 minutes. The mixture was then diluted with ice-cold 50 mM Triε-0.97. NaCl, pH 7.4 (4 mL) and filtered through a glaεs fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in scintillation cocktail (10 mL) and counted for radioactivity using Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC50) of potential All antagonist which giveε 50% displacement of the total specifically bound •■■■2* -- i I-Sar 1 Ile 8 -angiotensin II was presented as a measure of the efficacy of εuch compounds as All antagonists. -177- 1 * Receptor assay using Bovine adrenal cortex ** preparation . Bovine adrenal cortex was selected aε the εource of All receptor. Weighed tiεεue (0.1 g iε 5 needed for 100 assay tubes) was suspended in Tris HCl (50 mM), pH 7.7 buffer and homogenized. The homogenate waε centrifuged at 20,000 rp for 15 minutes. Supernatant was diεcarded and pellets resuspended in buffer [Na 2 HP0 (10 mM)-NaCl (120 10 mM)-disodium EDTA (5 mM) containing phenylmethane εulfonyl fluoride (PMSF)(0.1 mM)]. (For screening of compounds, generally duplicates of tubes are used). To the membrane preparation (0.5 mL) there was added 3H-angiotenεin II (50 mM) (10 mL) with or without the 15 test sample and the mixture waε incubated at 37'C for 1 hour. The mixture was then diluted with Tris buffer (4 mL) and filtered through a glasε fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in scintillation cocktail (10 L) and counted 20 for radioactivity using Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration IC50) of potential All antagonist which gives 50% displacement of the total specifically bound 3 H-angiotensin II was presented as a measure of the 25 efficacy of εuch compoundε as All antagonists. The potential antihypertensive effectε of the compounds described in the present invention may be evaluated using the methodology described below: Male Charles River Sprague-Dawley rats (300-375 gm) 30 were anesthetized with methohexital (Brevital; 50 mg/kg i.p.) and the trachea was cannulated with PE -178- 205 tubing. A stainleεε steel pithing rod (1.5 mm thick, 150 mm long) was inserted into the orbit of the right eye and down the spinal column. The rats were immediately placed on a Harvard Rodent Ventilator (rate - 60 εtrokeε per minute, volume - 1.1 cc per 100 gramε body weight). The right carotid artery waε ligated, both left and right vagal nerveε were cut, and the left carotid artery waε cannulated with PE 50 tubing for drug adminiεtration, and body 0 temperature was maintained at 37 β C by a thermostati¬ cally controlled heating pad which received input from a rectal temperature probe. Atropine (1 mg/kg i.v.) was then adminiεtered, and 15 minuteε later propranolol (1 mg/kg i.v.). Thirty minuteε later 5 angiotensin II or other agoniεtε were adminiεtered intravenously at 30 minute intervals and the increase in the diastolic blood preεεure was recorded before and after drug or vehicle adminiεtration. ϋεing the methodology deεcribed above, o repreεentative compoundε of the invention were evaluated and found to exhibit an activity of at least IC50 < 50 mM thereby demonstrating and confirming the utility of the compounds of the invention as effective All antagonists. 5 Thus, the compounds of the invention are uεeful in treating hypertenεion. They are alεo of value in the management of acute and chronic congeεtive heart failure, in the treatment of εecondary hyperaldoεteroniεm, primary and εecondary pulmonary hyperaldosteronism, primary and εecondary pulmonary hypertension, renal failure and renal -179- vaεcular hypertension, and in the management of vaεcular diεorderε such as migraine or Raynaud'ε diεeaεe. The application of the compounds of this invention for these and εimilar diεorderε will be apparent to thoεe εkilled in the art. The compoundε of thiε invention are also useful to treat elevated intraocular pressure and can be administered to patients in need of εuch treatment with typical pharmaceutical formulations such as tablets, capsules, injectables, as well aε topical ocular formulations in the form of. solutions, ointments, inserts, gels and the like. Pharmaceutical formulations prepared to treat intraocular presεure would typically contain about 0.1% to 15% by weight, and preferably 0.5% to 2.0% by weight of a compound of thiε invention. In the management of hypertension and the clinical conditions noted above, the compounds of this invention may be utilized in compositions εuch as tablets, capsules or elixirs for oral administra¬ tion, εuppoεitorieε for rectal adminiεtration, sterile solutions or suεpensions for parenteral or intramuscular administration, and the like. The compounds of this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factorε which thoεe εkilled in -180- the art will recognize, the dosage range will generally be about 1 to 1000 mg per patient per day which can be administered in single or multiple doseε. Perferably, the dosage range will be about 2.5 to 250 mg per patient per day; more preferably about 2.5 to 75 mg per patient per day. The compounds of this invention can also be administered in combination with other antihyperten- sives and/or diuretics and/or angiotensin converting enzyme inhibitors and/or calcium channel blockers. For example, the compounds of thiε invention can be given in combination with such compounds as amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene εulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydro¬ chloride, minoxidil, pargyline hydrochloride, polythiazide, prazoεin, propranolol, rauwolfia εerpentina, reεcinnamine, reεerpine, εodium nitropruεside, spironolactone, timolol maleate, trichlormethiazide, trimethophan camεylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furoεemide, merethoxy11ine procaine, εodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, foεinopril εodium, liεinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, difluniεal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, niεoldipine, nitrendipine, and the like, aε well aε admixtureε and combinationε thereof. -181- Typically, the individual daily doεages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly. To illustrate these combinations, one of the angiotenεin II antagonists of this invention effective clinically in the 2.5-250 milligrams per day range can be effectively combined at levels at the 0.5-250 milligrams per day range with the following compounds at the indicated per day dose range: hydrochlorothiazide (15-200 mg), chlorothiazide (125-2000 mg), ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg), propranolol (20-480 mg), timolol maleate (5-60 mg), methyldopa (65-2000 mg), felodipine (5-60 mg), nifedipine (5-60 mg), and nitrendipine (5-60 mg). In addition, triple drug combinations of hydrochlorothiazide (15-200 mg) plus miloride (5-20 mg) plus angiotensin II antagonist of this invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plus timolol maleate (5-60) plus an angiotensin II antagonist of thiε invention (0.5-250 mg) or hydrochlorothiazide (15-200 mg) and nifedipine (5-60 mg) pluε an angiotenεin II antagoniεt of thiε invention (0.5-250 mg) are effective combinations to control blood presεure in hypertensive patients. Naturally, these dose ranges can be adjusted on a unit basis as necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity of the diseaεe, weight of patient, εpecial dietε and other factors. -182- Typically, these combinations can be formulated into pharmaceutical compositionε as discussed below. About 1 to 100 mg of compound or mixture of compounds of Formula I or a phyεiologically acceptable εalt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preεervative, εtabilizer, flavor, etc., in a unit doεage form aε called for by accepted pharmaceutical practice. The amount of active εubεtance in theεe compositions or preparations is such that a suitable dosage in the range indicated is obtained. Illustrative of the adjuvants which can be incorporated in tablets, capsules and the like are the following: a binder such aε gum tragacanth, acacia, corn εtarch or gelatin; an excipient εuch as microcrystalline celluloεe; a diεintegrating agent εuch as corn starch, pregelatinized starch, alginic acid and the like; a lubricant εuch aε magnesium stearate; a εweetening agent εuch aε εucroεe, lactose or saccharin; a flavoring agent εuch aε peppermint, oil of wintergreen or cherry. When the doεage unitform is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the phyεical form of the doεage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose aε a sweetening agent, methyl and propyl parabenε aε preεervatives, a dye and a flavoring εuch as cherry or orange flavor. -183- Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suεpending the active εubεtance in a vehicle εuch k aε water for injection, a naturally occuring vegetable oil like sesame oil, ϋ coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidantε and the like can be incorporated as required. The compounds of thiε invention are alεo useful to treat elevated intraocular preεsure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such aε tablets, capsules, injectables, as well as topical ocular formulations in the form of εolutionε, ointments, inserts, gels and the like. Pharmaceutical formulations prepared to treat intraocular presεure would typically contain about 0.1% to 157. by weight, and preferably 0.5% to 2.0% by weight of a compound of this invention. Thus, the compounds of the invention are useful in treating hypertension. They are also of value in the management of acute and chronic congestive heart failure, in the treatment of secondary hyperaldoεteroniεm, primary and εecondary pulmonary hypertension, renal failure such as diabetic nephropathy, glomerulonephritiε, εcleroderma, and the like, renal vascular hypertension, left ventricular dysfunction, diabetic retinopathy, and in the management of vascular disorders εuch aε migraine or Raynaud's diseaεe. The application of the -184- compoundε of thiε invention for these and similar disorderε will be apparent to thoεe skilled in the art. The useful central nervous system (CNS) activities of the compounds of thiε invention are demonεtrated and exemplified by the enεuing aεεayε. COGNITIVE FUNCTION ASSAY The efficacy of theεe compoundε to enhance cognitive function can be demonεtrated in a rat paεsive avoidance asεay in which cholinomimeticε εuch as phyεoεtigmine and nootropic agentε are known to be active. In thiε aεεay, ratε are trained to inhibit their natural tendency to enter dark areaε. The teεt apparatus used consiεtε of two chamberε, one of which is brightly illuminated and the other iε dark. Rats are placed in the illuminated chamber and the elapsed time it takes for them to enter the darkened chamber is recorded. On entering the dark chamber, they receive a brief electric shock to the feet. The teεt animals are pretreated with 0.2 mg/kg of the muscarinic antagonist εcopolamine which diεruptε learning or are treated with εcopolamine and the compound which iε to be teεted for poεεible reverεal of the εcopolamine effect. Twenty-four hourε later, the ratε are returned to the illuminated chamber. Upon return to the illuminated chamber, normal young ratε who have been εubjected to thiε training and who have been treated only with control vehicle take longer to re-enter the dark chamber than teεt animals who have been exposed to the apparatus but who have -185- not received a shock. Rats treated with scopolamine before training do not εhow thiε hesitation when tested 24 hours later. Efficacious test compoundε can overcome the diεruptive effect on learning which εcopolamine produceε. Typically, compoundε of thiε invention εhould be efficaciouε in thiε paεεive avoidance aεεay in the doεe range of from about 0.1 mg/kg to about 100 mg/kg. ANXIOLYTIC ASSAY The anxiolytic activity of the invention compounds can be demonεtrated in a conditioned emotional response (CER) assay. Diazepa is a clinically useful anxiolytic which is active in this assay. In the CER protocol, male Sprague-Dawley rats (250-350 g) are trained to press a lever on a variable interval (VI) 60 second schedule for food reinforcement in a εtandard operant chamber over weekly (five days per week) training sessions. All animals then receive daily 20 minute conditioning sessions, each εeεεion partitioned into alternating 5 minute light (L) and 2 minute dark (D) periodε in a fixed L1D1L2D2L3 εequence. During both periods (L or D), presεing a lever delivers food pelletε on a VI 60 εecond εchedule: in the dark (D), lever preεεes also elicit mild footshock (0.8 mA, 0.5 sec) on an independent shock presentation schedule of VI 20 seconds. Lever pressing is suppressed during the dark periods reflecting the formation of a conditioned emotional response (CER) . -186- Drug testing in thiε paradigm iε carried out under extinction conditionε. During extinction, animalε learn that reεponding for food in the dark iε no longer puniεhed by shock. Therefore, response rates gradually increase in the dark periods and animalε treated with an anxiolytic drug show a more rapid increaεe in reεponεe rate than vehicle treated animalε. Compoundε of thiε invention should be efficacious in this teεt procedure in the range of from about 0.1 mg/kg to about 100 mg/kg. DEPRESSION ASSAY The antidepreεεant activity of the compounds of this invention can be demonstrated in a tail suspension test using mice. A clinically useful antidepressant which εerveε as a positive control in thiε asεay iε deεipramine. The method iε baεed on the obεervations that a mouse suεpended by the tail εhows alternate periods of agitation and immobility and that antidepresεantε modify the balance between theεe two formε of behavior in favor of agitation. Periods of immobility in a 5 minute teεt period are recorded using a keypad linked to a microcomputer which allows the experimenter to aεεign to each animal an identity code and to measure latency, duration and frequency of immobile periods. Compounds of this invention should be efficacious in this teεt procedure in the range of from about 0.1 mg/kg to about 100 mg/kg. -187- SCHIZOPHRENIA ASSAY >* The antidopa inergic activity of the compoundε of thiε invention can be demonεtrated in an 5 apomorphine-induced εtereotypy model. A clinically uεeful antipεychotic drug that iε uεed aε a positive control in this aεεay iε haloperidol. The aεεay method iε based upon the obεervation that stimulation of the dopaminergic εyεtem in rats produces stereo- 10 typed motor behavior. There is a εtrong correlation between the effectiveneεε of claεεical neuroleptic drugs to block apomorphine-induced stereotypy and to prevent εchizophrenic εymptoms. Stereotyped behavior induced by apomorphine, with and without pretreatment 5 with test compounds, iε recorded using a keypad linked to a microcomputer. Compounds of the inven¬ tion should be efficaciouε in this asεay in the range of from about 0.1 mg/kg to about 100 mg/kg. In the treatment of the clinical conditions 20 noted above, the compoundε of thiε invention may be utilized in compoεitionε εuch as tablets, capεuleε or elixirs for oral administration, suppoεitories for rectal administration, εterile εolutionε or εuεpen- εions for parenteral or intramuεcular adminiεtration, 25 and the like. The compoundε of thiε invention can be administered to patients (animalε and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary from patient to patient depending upon the 0 nature and εeverity of disease, the patient's weight, εpecial diets then being followed by a patient, concurrent medication, and other factors -188- which those εkilled in the art will recognize, the doεage range will generally be about 5 to 6000 mg. per patient per day which can be adminiεtered in εingle or multiple doses. Perferably, the dosage range will be about 10 to 4000 mg. per patient per day; more preferably about 20 to 2000 mg. per patient per day. In order to obtain maximal enhancement of cognitive function, the compounds of this invention may be combined with other cognition-enhancing agents . These include acetylcholinesteraεe inhibitors εuch as heptylphysoεtigmine and tetrahydroacridine (THA; tacrine), muεcarinic agoniεts εuch aε oxotremorine, inhibitors of angiotenεin-converting enzyme such as octylramipril, captopril, ceranapril, enalapril, liεinopril, foεinopril and zofenopril, centrally-acting calcium channel blockerε εuch aε nimodipine, and nootropic agentε εuch aε piracetam. In order to achieve optimal anxiolytic activity, the compoundε of thiε invention may be combined with other anxiolytic agentε εuch aε alprazola , lorazepam, diazepam, and buεipirone. In order to achieve optimal antidepreεεant activity, combinationε of the compounds of this invention with other antidepresεantε are of use. These include tricyclic antidepresεantε such as nortriptyline, amitryptyline and trazodone, and monoamine oxidase inhibitors εuch as tranylcypromine. In order to obtain maximal antipsychotic activity, the compounds of this invention may be combined with other antipsychotic agents εuch as promethazine, fluphenazine and haloperidol. -189- The following examples, illustrate the preparation of the compounds of Formula I and their incorporation into pharmaceutical compositionε and aε such are not to be considered as limiting the invention set forth in the claims appended hereto. Example 1 2-Butyl-l-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl- 0 benzimidazole Step A: Preparation of l-(4-benzyloxyρhenyl)-methyl- 2-butvlbenzim.idazole A suspension of 1.50 g (8.62 mmol) of 5 2-butylbenzimidazole (described in European Patent Application #400,835, 12-May-90) and NaH (272 mg, 1.05 eq) in DMF (20 mL) was stirred 25 minutes. Next, 4-benzyloxybenzyl chloride (2.10 g, 1.05 eq) was added to the reaction mixture. After stirring o overnight, the reaction mixture was concentrated in vacuo and the residue was chromatographed on a medium presεure liquid chromatograph eluted with 30% ethyl acetate/hexane to yield 3.08 g (96%) of the title compound. 5 1 H NMR (300 MHz, CDCI3, ppm): δ 0.9-1.0 (t, 3H), 1.35 (m, 2H), 1.75-1-9 ( , 2H), 2.8-2.9 (t, 2H), 5.0 (ε, 2H), 6.85-6.95 (d, 2H), 6.95-7.05 (d, 2H), 7.15-7.45 (m, 8H),7.75-7.80 (d, IH) . FAB-MS: m/e 371 (M+H). 0 -190- Step B: Preparation of 2-butyl-l-(4-hydroxyphenyl)- methvlbenzimidazole A εolution of the product of Step A (1.00 g, 2.70 mmol) diεεolved in 20 mL of MeOH, waε added 0.100 g of a 10% Pd/C catalyεt and the reaction mixture waε εtirred under an H2 atmoεphere (1 atm) for 6.5 hours. The reaction mixture was filtered through MgSθ and the filtrate concentrated in vacuo to yield 0.628 g (83%) of the title compound. --E NMR (300 MHz, CD3OD, ppm): δ 0.9-1.0 (t, 3H), 1.35-1.50 (m, 2H), 1.65-1.8 (m, 2H), 2.9-3.0 (t, 2H) , 5.4 (s,2H),6.7-6.8 (d, 2H), 6.9-7.0 (d, 2H), 7.25-7.35 (m, 2H), 7.4-7.5 (m, IH), 7.6-7.7 (m, IH; FAB-MS: m/e 281 (M+H). Step C: Preparation of 2-butyl-l-[4-(l-carbomethoxy- l-phenvl)methoxvphenvl1methvlbenzimidazole To a solution of the product of Step B (100 mg, 0.357 mmol) in DMF (1 mL) was added NaH (11 mg, 1.0 eq). After stirring the reaction mixture for 15 minutes, a solution of methyl 2-bromophenylacetate (82 mg, 1.0 eq) in DMF (500 mL) waε added and the reaction mixture was εtirred for 60 hourε. The reaction mixture was quenched with saturated ammonium chloride solution and the organic layer was concentrated in vacuo. The residue waε diεεolved in ethyl acetate and waεhed with water and then brine. The organic layer was dried (MgS0 ), filtered and concentrated in vacuo and the residue was purified on a silica gel flash chromatography column (120 x 40 mm) eluted with 50% ethyl acetate/hexane to yield 26 mg (17%) of the title compound. -191- l E NMR (300 MHz, CDCI3, ppm): δ 0.9-1.0 (t, 3H), 1.35-1.50 (m, 2H), 1.65-1.75 (m, 2H), 2.75-2.85 (t, 2H), 3.7 (s, 3H), 5.25 (ε, 2H), 5.6 (ε, IH) , 6.8-6.9 (d, 2H), 6.9-7.0 (d, 2H), 7.15-7.25 (m, 3H), 7.35-7.45 (m, 3H), 7.5-7.6 (m, 2H), 7.7-7.8 (d, 2H). FAB-MS: m/e 429 (M+H). Step D: Preparation of 2-butyl-l-[4-(l-carboxy-l- phenvl^methoxvnhenvllmethvlbenzimidazole 0 To a εolution of the product of Step C (25 mg, 0.058 mmol) in 2.0 mL of MeOH waε added 1 N KOH (0.5 mL). The reaction mixture was εtirred for 1 hour and then concentrated i vacuo■ The residue was disεolved in water, acidified to pH 4 with 1 N HCl, 5 and the reεulting precipitate waε extracted into chloroform. The organic extracts were dried (M S04), filtered and evaporated in vacuo. and then precipitated from HCl/EtOAc to yield 7.1 mg (30%) of the title compound. o X H NMR (300 MHz, CDCI3, ppm): δ 0.55-0.65. (t, 3H), 1.05-1.2 (m, 2H), 1.40-1.50 (m, 2H), 2.75-2.85 (t, 2H), 5.15-5.30 (q, 2H), 5.6 (ε, IH), 6.85-7.00 (m, 4H), 7.2-7.4 (m, 6H), 7.65-7.75 (m, 2H), 7.75-7.85 ( , IH). 5 FAB-MS: m/e 415 (M+H). 0 -192- Example 2 3-[4-(1-carboxy-l-phenyl)methoxyphenyl]methy1-7- methvl-2-propyl-3H-imidazor4.5-b1pvridine Step A: Preparation of 2,3-diamino-4-picoline (cf. Lappin, G. R. ; Slezak, F. B. J. Am. Chem. Soc. 1950. 72. 2806-7) To a εlurry of 2-amino-4-methyl-3-nitropyri- dine (10.0 g, 65.3 mmol) in 350 mL of 95% EtOH waε added 500 mg of a 10% Pd/C catalyεt. The mixture was εtirred under a H2 atmoεphere (1 atm) for 36 hourε. Filtration and evaporation gave 8.05 g of a black εolid which waε uεed directly in the next εtep. Step B: Preparation of 7-methyl-2-propylimidazo [4,5-b]pyridine (cf. Lappin, G. R. ; Slezak, F. B. J. Am. Chem. Soc. 1950. 72. 2806-7^) A mixture of butyric acid (6.57 mL, 71.9 mmol), 2,3-diamino-4-picoline (8.05 g, 65.4 mmol), and polyphoεphoric acid (50 g) was heated to 100 β C with stirring for 3 hours, and monitored by tic of NH4OH neutralized aliquots. Baεification (NH4OH), extraction (CH 2 C1 2 » 4 x 50 mL), drying (K 2 C0 3 ), purification (by filtering through 100 g εilica gel, EtOAc elution), and concentration gave 10.0 g (87%) of the title compound aε an amorphouε tan εolid which was judged pure by ~-E NMR and tic: mp 110-112 β C (without recryεtallization). --E NMR (300 MHz, CDCI3, ppm): δ 8.13 (d, IH, J=5 Hz), 7.01 (d, IH, J=5 Hz), 3.01 (t, 2H, J=7.8 Hz), 2.67 (ε, 3H), 2.07-1.93 (m, 2H), 1.06 (t, 3H, J=7.5 Hz). -193- Step C: Preparation of 3-(4-benzyloxyphenyl)methyl- 7-methvl-2-proτ?vl-3H-imidazor4.5-b1pvridine A suspenεion of 7-methyl-2-propylimidazo- [4,5-b]ρyridine (1.00 g, 5.71 mmol) and NaH (189 mg, 1.1 eq) in DMF (25 L) was stirred for 1 hour and then cooled to 0*C. 4-Benzyloxybenzyl chloride (1.46 g; 1.1 eq) was then added and the ice bath removed. The reaction mixture was εtirred for 2.5 hourε and was then concentrated in vacuo. The reεidue waε chromatographed on a silica gel flash chromatography column (30 x 100 mm) eluted with 30% ethyl acetate/hexane to yield 1.07 g (50%) of product. 1 H NMR (300 MHz, CDCI3, ppm): δ 0.9-105 (m, 3H), 1.7-1.85 (m, 2H), 2.65-2.85 (m, 5H), 5.0-5.1 (m, 2H), 5.4-5.5 (m, 2H), 6.8-6.95 (m, 2H), 6.95-7.15 (m, 3H) , 7.2-7.5 (m, 5H), 8.15-8.25 (m, IH) . Step D: Preparation of 3-(4-hydroxyphenyl)methyl-7- methvl-2-proPvl-3H-imidazor4.5-b1nvri ine To a solution of the product of Step C (0.60 g, 1.62 mmol) in 10 mL of MeOH was added 60 mg of a 10% Pd/C catalyεt and waε εtirred under a H 2 atmoεphere (1 atm) for 7 hourε. The reaction mixture waε then filtered through magneεium εulfate and the filtrate waε concentrated in vacuo to yield 0.372 g (82%) of the title compound. λ E NMR (300 MHz, CD3OD, ppm): δ 0.95-1.05 (t, 3H) , 2.65-2.8 (m, 2H), 2.7 (s, 3H), 2.9-3.0 (t, 2H) , 5.5 (s, 2H), 6.7-6.8 (d, 2H), 7.0-7.1 (d, 2H), 7.2-7.5 (d, IH), 8.25-8.3 (d, IH). •194- Step E: Preparation of 3-[4-(l-carbomethoxy-l- pheny1)-methoxyphenyl]methyl-7-methyl-2- propvl-3H-imidazor4.5-b1pvridine To a suεpension of H (45 mg, 1.1 eq) in DMF (0.5 mL) was added the product of Step D (100 mg, 0.365 mmol) followed by 18-crown-6 (20 mg, 0.2 eq). After stirring the reaction mixture for 0.5 hour until the foaming subεided, a εolution of methyl 2-bromophenylacetate (81 mg, 1.0 eq) in DMF (0.5 mL) was added and the reaction mixture was εtirred 2 hours and was then concentrated in vacuo. The residue was purified on a εilica gel flash chromato¬ graphy column (120 x 20 mm) eluted with 50% ethyl acetate/hexane to yield 67 mg (44%) of the title compound. - ■ E NMR (300 MHz, CDC1 3 , ppm): δ 0.9-1.0 (t, 3H) 1.65-1.80 (m, 2H), 2.65 (ε, 3H), 2.7-2.8 (t, 2H), 3.7 (s, 3H), 5.4 (s, 2H), 5.6 (s, IH), 6.8-6.9 (d, 2H) , 6.95-7.1 (m, 3H), 7.35-7.45 (m, 3H), 7.5-7.6 (m, 2H) , 8.2 (d, IH). Step F: Preparation of 3-[4-(l-carbomethoxy-l- phenyl)methoxyphenyl]methyl-7-methyl-2- propvl-3H-imidazor4.5-b1pvridine To a εolution of the product of Step E (21 mg, 0.0490 mmol) in MeOH (1 mL) was added IN NaOH (1 mL) . The reaction mixture was stirred for 1.5 hours, and was then concentrated in vacuo. The residue was partitioned between brine and THF. The organic layer was separated from the aqueouε layer, dried (MgS04), filtered, and evaporated in vacuo. The reεidue was purified on a silica gel flash chromatography column -195- (15 x 130 mm) eluted first with 20% methanol/ethyl acetate, and later with 50% methanol/ethyl acetate. The product fractions were concentrated in vacuo. redissolved in ethyl acetate and filtered to yield 16 mg (76%) of the title compound. l E NMR (300 MHz, CDCI3, ppm): δ 0.8-0.9 (t, 3H), 1.5-1.7 (m, 2H), 2.2-2.3 (m, 5H), 5.1 (ε, IH), 5.25 (ε, 2H), 6.6-6.6 (d,. 2H), 6.7-6.8 (d, 2H), 6.9-7.0 (m, 4H), 7.15-7.25 (m, 2H), 8.1 (d, IH). FAB-MS: m/e 438 (M+H). Example 3 3-[ -(1-Carboxy-1-(4-chlorophenyl)methoxyphenyl]- methyl-7-methvl-2-propvl-3H-imidazor4.5-b1pvridine Step A: Preparation of methyl 2-bromo-2-(4-chloro- phenvl^acetate A mixture of 4-chlorophenylacetic acid (5.00 g, 29.3 mmol) and thionyl chloride (2.67 mL, 1.25 eq) were heated at reflux while bromine (1.51 mL, 1.0 eq) was added from a dropping funnel over 15 minutes. The reaction mixture was heated at reflux 19.5 hours, and then cooled to room temperature. Methanol (30 mL, 25 eq) was then added slowly, aε an exotherm and violent bubbling reεulted. The reaction mixture was then concentrated in vacuo. The residue was partitioned between water and ether and the aqueous phase was then extracted twice with ether. The combined ether portions were washed with 5% NaHS0 3 , dried ( gSθ ), filtered, and concentrated in vacuo. The residue was purified on a εilica gel flaεh -196- chromatography column (170 x 45 mm) eluted with 15% ethyl acetate/hexane to yield 2.89 g (37%) of the title compound. ■ -E NMR (300 MHz, CDCI3, ppm): δ 3.8 (ε, 3H), 5.35 (ε, IH), 7.2-7.3 (d, 2H), 7.45-7.55 (d, 2H). EI-MS: m/e 262, 264, 266 (M + , 10:13:3 ratio). Step B: Preparation of methyl 2-(4-methylphenoxy)- 4-chlorophenylacetate To a 0 β C εuεpenεion of KH (530 mg, 1.0 eq) in DMF (10 mL) was quickly added p-cresol (500 mg, 4.63 mmol), and the reaction mixture waε εtirred at room temperature. After stirring 10 minutes hydrogen evolution had subεided, and 50 mg of 18-crown-6 was added followed by the product of Step A (1.22 g, 1.0 eq). The reaction mixture was εtirred 2.5 hourε and was then concentrated in vacuo. The reεidue was purified on a silica gel flash chromatography column (140 x 30 mm) eluted with 5% ethyl acetate/hexane to yield 0.744 g (55%) of the title compound. - ■ E NMR (300 MHz, CDCI3, ppm): δ 2.3 (ε, 3H), 3.75 (ε, 3H), 5.6 (S, IH), 6.8-6.9 (d, 2H), 6.9-7.1 (d, 2H) , 7.3-7.4 (d, 2H), 7.5-7.6 (d, 2H) . EI-MS: m/e 290, 292 (M + , 3:1 ratio). Step C: Preparation of methyl 2-(4-bromomethyl- henoxv)-4-chlorophenvlacetate A solution of the product of Step B (200 mg, 0.690 mmol), NBS (117 mg, 0.95 eq) and AIBN (10 mg, catalytic amount) in CCI4 (5 mL) was heated at reflux for 2 hours and then cooled and concentrated in vacuo. The residue waε purified on a εilica gel flaεh -197- * chromatography column (30 x 130 mm) eluted with 5% ethyl acetate/hexane to yield 128 mg (50%) of the title compound. λ E NMR (300 MHz, CDCI3, ppm): δ 3.75 (s, 3H), 4.5 (s, 5 2H), 5.6 (s, IH), 6.8-6.9 (d, 2H), 7.25-7.35 (d, 2H), 7.35-7.45 (d, 2H) x 7.5-7.6 *(d, 2H). Step D: Preparation of l-[4-(l-carbomethoxy-l-(4- chlorophenyl))methoxyphenyl]methyl-7-methyl- 10 2-propyl-3H-imidazor4.5-b1pvridine To a suspension of NaH (4.3 mg, 1.0 eq) in DMF (1 mL) was added 7-methyl-2-propylimidazo[4,5-b] pyridine (25 mg, 0.143 mmol). Next a solution of product from Step C (53 mg, 1.0 eq) in DMF (1 mL) was 5 added. The reaction mixture was εtirred for 2 hours and then concentrated in vacuo. The residue was purified on a silica gel flash chromatography column (20 x 230 mm) eluted with 50% ethyl acetate/hexane to yield 17 mg (26%) of the title compound. 20 l NMR (300 MHz, CDCI3, ppm): δ 0.9-1.0 (t, 3H) , 1.65-1.8 (m, 2H), 2.65 (ε, 3H), 2.7-2.8 (t, 2H), 3.7 (ε, 3H), 5.4 (s, 2H), 5.55 (ε, IH), 6.8-6.9 (d, 2H), 7.0-7.1 (m, 3H), 7.3-7.4 (d, 2H), 7.45-7.5 (d, 2H) , 8.2 (d, IH). 25 FAB-MS: m/e 464, 466 (M+l, 3:1 ratio). Step E: Preparation of l-[4-(l-carboxy-l-(4- chlorophenyl))methoxyphenyl]methyl-7-methyl- 2-propyl-3H-imidazor4.5-b1pvridine 3 0 To a εolution of product from Step D (16 mg, 0.035 mmol) in MeOH (1 mL) waε added IN NaOH (1 mL). The reaction mixture was stirred 10 minutes, and then -198- concentrated in vacuo. Water was added to the residue and the mixture waε acidified to pH 2 with 1 N HCl. The aqueouε layer waε then extracted 3 times with chloroform, the combined organic layers were dried (MgSθ ), filtered and concentrated in vacuo to yield 12 mg (70%) of the titled product. l E NMR (300 MHz, CDCI3, ppm): δ 0.75-0.85 (t, 3H), 1.55-1.7 (m, 2H), 2.65 (ε, 3H), 2.9-3.0 (t, 2H), 5.4 (ε, 2H), 5.55 (ε, IH), 6.85-6.95 (d, 2H), 7.05-7.1 0 (d, 2H), 7.15 (d, IH) 7.3-7.4 (d, 2H), 7.5-7.6 (d, 2H), 8.3 (d, IH). FAB-MS: m/e 450, 452 (M+l, 3:1 ratio). Example 4 ' 5 3_[ _(l-Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-7-methvl-2-propvl-3H-imidazor4.5-blpvridine Step A: Preparation of methyl 2-bromo-(2'-chloro)- 0 phenylacetate Commercially available 2-chlorophenylacetic acid (5.00 g, 29.3 mmol) waε converted to 2.13 g (28%) of the title compound in a procedure εimilar to that deεcribed in Step A of Example 3. 5 λ E NMR (300 MHz, CDCI3, ppm): δ 3.8 (s, 3H), 5.95 (ε, IH), 7.25-7.45 (m, 3H), 7.7-7.8 (m, IH) . Step B: Preparation of methyl 2-(2-chlorophenyl)-2- (^-methylphenoxv)acetate 0 The product of Step A (1.22 g, 4.63 mmol) waε uεed to alkylate p-creεol (0.5 g, 4.63 mmol) uεing the procedure described in Step B of Example 3, and afforded 1.03 g (77%) of the title compound. -199- ■ -E NMR : (300 MHz , CDC1 3 , ppm) : δ 2.25 (s , 3H) , 3 .8 (s , 3H) , 6.12 (s , IH) , 6.85 (d , 2H) , 7.05 (d , 2H) , 7 .28-7 .35 (m, 2H) , 7 .40-7 .45 (m, IH) , 7 .63-7 .70 (m , IH) . EI-MS : m/e 290 , 292 (M+) . Step C: Preparation of methyl 2-(4-bromomethylphen- oxy)-2-(2-chloroρhenyl)acetate The product of Step B (0.200 g, 0.69 mmol) was brominated with NBS (117 mg, 0.66 mmol) and purified using the procedure described in Step C of Example 3, and afforded 0.186 g (73%) of the title compound. -Ε NMR (300 MHz, CDCI3, ppm): δ 3.8 (s, 3H), 4.5 (ε, 2H), 6.15 (ε, IH), 6.85-6.95 (d, 2H), 7.25-7.35 (m, 4H); 7.4-7.5 (m, IH), 7.6-7.7 (m, IH). EI-MS: m/e 368, 370, 372 (M+l, 10:13:3 ratio). Step D: Preparation of 3-[4-(l-carbomethoxy-l- (2-chlorophenyl))methoxyphenyl]methyl-7- methvl-2-propvl-3H-imidazor4.5-b1pvridine The product of Step C (0.100 g, 0.27 mmol) was used to alkylate 0.047 g of 7-methyl-2-propyl- imidazo[4,5-b]pyridine (Example 2, Step B) according to the procedure described for Step D of Example 3, which after purification afforded 0.040 g (32%) of the title compound. λ E NMR (300 MHz, CDCI3, ppm): δ 0.9-1.0 (t, 3H) , 1.65-1.8 (m, 2H), 2.65 (s, 3H), 2.7-2.8 (t 2H), 3.75 (s, 3H), 5.4 (s, 2H), 6.1 (s, IH), 6.8-6.9 (d, 2H), 7.0-7.1 (m, 3H), 7.25-7.35 On, 2H), 7.35-7.45 (m, IH), 7.55-7.65 (m, IH), 8.2 (d, IH). FAB-MS: m/e 464, 466 (M+l, 3:1 ratio). -200- Step E: Preparation of 3-[4-(l-carboxy-l-(2-chloro- phenyl))methoxyphenyl]methyl-7-methyl-2- propyl-3H-imidazor4.5-b1pvridine The product of Step D (0.040 g, 0.086 mmol) was dissolved in 1.0 mL of methanol and 1.0 mL of 1 N NaOH was added. The hydrolysiε was complete in 5 minutes, and the εolution waε then concentrated in vacuo. The reεidue waε chromatographed on εilica gel (130 x 20 mm) eluted with ethyl acetate/hexane/ acetic acid (19:5:1) to afford 33 mg (85%) of the title compound. - ■ E NMR (300 MHz, CD3OD, ppm): δ 0.85-0.95 (t, 3H), 1.55-1.75 ( , 2H), 2.65 (s, 3H), 2.8-2.9 (t, 2H), 5.5 (s, 2H), 6.05 (s, IH), 6.85-6.95 (d, 2H), 7.05-7.20 ( , 3H), 7.25-7.35 (m, 2H), 7.35-7.45 (m, IH), 7.55-7.65 (m IH), 8.2 (d, IH). FAB-MS: m/e 450,452 (M+l). Exam le 5 3_[ _(l-Carboxy-l-(3-chlorophenyl))methoxyphenyl]- methyl-7-methyl-2-propvl-3H-imidazor .5-blpvridine Step A: Preparation of methyl 2-bromo-2-(3-chloro- phenyl)acetate Commercially available 3-chlorophenylacetic acid (5.00 g, 29.3 mmol) was converted to 1.70 g (22%) of the title compound in a procedure similar to that described in Step A of Example 3. - ■ E NMR (300 MHz, CDCI3, ppm): δ 3.80 (s, 3H) 5.30 (s, IH) 7.25-7.60 (m, 4H). -201- * Step B: Preparation of 3-[4-(l-carbomethoxy-l-(3- chlorophenyl))methoxyphenyl]methyl-7-methyl- 2-propvl-3H-imidazor4.5-blpvridine To a solution of 0.150 g (0.54 mmol) of the 5 product of Step D of Example 2 disεolved in 1.0 mL of DMF was added 61 mg of KH, and 0.141 g of 18-crown-6. The reaction was stirred under an N 2 atmosphere for 20 minutes, and then 0.155 g of the product of Step A dissolved in 0.5 mL of DMF was added. The reaction 10 was εtirred an additional 30 minuteε, then partitioned between water and ethyl acetate. The organic layer was washed with water, dried (MgSθ4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column 15 eluted first with 30% ethyl acetate/hexane then with 50% ethyl acetate/hexane to afford 0.087 g (35%) of the title compound. l E NMR (300 MHz, CDCI3, ppm): δ 0.90-1.00 (t, 3H), 1.65-1.85 (m, 2H), 2.65 (s, 3H), 2.70-2.85 (t, 2H), 2 0 3.75 (s, 3H), 5.45 (s, 2H), 5.55 (ε, IH), 6.80-6.90 (d, 2H), 7.00-7.10 (m, 3H), 7.25-7.35 (m, 2H), 7.30-7.35 (m, IH), 7.55 (br s, IH), 8.15-8.25 (d, IH) , Step C: Preparation of 3-[4-(l-carboxy-l-(3-chloro- 25 phenyl))methoxyphenyl]methyl-7-methyl-2- ropvl-3H-imidazor4.5-blpvridine To a solution of 0.087 g (0.19 mmol) of the product of Step B dissolved in 2 mL of methanol was added 1 mL of 2 N NaOH and the reaction was stirred 30 for 2 hours at room temperature. The reaction mixture was concentrated in vacuo and applied to a -202- εilica gel flaεh chromatography column eluted with CHCl 3 /MeOH/HOAc (100:3:1) to afford 0.049 g (58%) of the title compound. - ■ E NMR (300 MHz, CD3OD, ppm): δ 0.90-1.00 (t, 3H), 1.60-1.75 (m, 2H), 2.65 (ε, 3H), 2.80-2.90 (t, 2H), 5.50 (ε, 2H), 5.70 (ε, IH), 6.90-6.95 (d, 2H), 7.05-7.20 (m, 3H), 7.30-7.35 (m,2H), 7.45-6.50 (m, 2H), 7.45-7.50 (m, IH), 7.55 (br ε, IH), 8.15-8.25 (d, IH). FAB-MS: m/e 450,452 (M+l). Example 6 3_[ _(l-carboxy-1-(2,6-dichlorophenyl))methoxyphenyl]- methyl-7-methvl-2-propvl-3H-imidazor4.5-blpvridine Step A: Preparation of methyl 2-bromo-2' ,6'-dichloro- phenvlacetate Commercially available 2,6-dichlorophenyl- acetic acid (5.00 g, 24.4 mmol) waε converted to 2.60 g (357.) of the title compound in a procedure εimilar to that described in Step A of Example 3. 1 H NMR (300 MHz, CDCI3, ppm): δ 3.80 (ε, 3H) , 6.70 (s, IH), 7.20-7.30 ( , IH), 7.35-7.40 (d, 2H) . Step B: Preparation of 3-[4-(l-carbomethoxy-l-(2,6- dichlorophenyl))methoxyphenyl]methyl-7- τnethyl-2-propyl-3H-imidazor4.5-blpyridine The product of Step D of Example 2 (0.100 g, 0.36 mmol) was deprotonated (41 mg KH, 94 mg 18-crown-6, 1.0 mL DMF) and alkylated with 0.117 g (0.39 mmol) of the product of Step A according to the procedure described in Step B of Example 5. Purifica- -203- » tion on a silica gel flash chromatography column eluted with 40% ethyl acetate/hexane afforded 0.085 g (48%) of the title compound. λ E NMR (300 MHz, CDCI3, ppm): δ 0.90-1.00 (t, 3H), 5 1.60-1.80 ( , 2H), 2.65 (s, 3H), 2.70-2.80 (t, 2H), 3.80 (ε, 3H), 5.40 (s, 2H), 6.40 (s, IH), 6.60-6.65 (d, IH), 6.85-6.90 (d, IH), 6.90-7.05 (m, 5H), 7.15-7.35 (m, 2H), 8.15-8.35 (d, IH) . 10 Step C: Preparation of 3-[4-(l-carboxy-l-(2,6- dichlorophe*iiyl))methoxyphenyl]methyl-7- methyl-2-propvl-3H-imidazor4.5-blpvridine To a solution of 0.085 g (0.17 mmol) of the product of Step B diεεolved in 1.0 mL of methanol was 1 added 1.0 mL of 1 N NaOH and the reaction waε εtirred for 3 hourε at room temperature. The reaction mixture was concentrated in vacuo and applied to a silica gel flash chromatography column eluted with CHCl 3 /MeOH/NH 4 OH (80:15:1) to afford 0.070 g (84%) of 20 the title compound. -Ε NMR (300 MHz, CD3OD, ppm): δ 0.90-1.00 (t, 3H), 1.55-1.75 (m, 2H), 2.65 (s, 3H), 2.80-2.90 (t, 2H), 5.50 (s, 2H), 6.30 (s, IH), 6.95-7.10 (m, 2H) , 7.30-7.40 (d, 2H), 8.20 (d, IH). 2 5 FAB-MS: m/e 484 (M+l). Example 7 3-[4-(l-carboxy-l-(2-nitrophenyl))methoxyphenyl]- 30 methyl-7-methvl-2-τronvl-3H-imidazor4.5-b1pvridi-nP Step A: Preparation of methvl 2'-nitrophc vlacPfatP To a flask charged with 5 mL of methanol was introduced a fine stream of hydrogen chloride gas -204- until the solution waε εaturated. The hydrogen chloride waε stopped, and 0.50 g (2.7 mmol) of 2'-nitrophenylacetic acid waε added and the reaction mixture waε εtirred for 1.5 hourε. The reaction mixture waε then partitioned between ethyl acetate and water, the organic layer waε washed with saturated NaHC0 3 , brine, dried ( gSθ ), filtered and evaporated to afford 0.529 g (98%) of the title compound. X H NMR (300 MHz, CDC1 3 , ppm): δ 3.75 (ε, 3H), 4.05 (s, 2H), 7.25-7.30 (d, IH), 7.45-7.55 (m, IH), 7.55-7.65 (m, IH), 8.20-8.25 (d, IH). FAB-MS: m/e 196 (M+l). Step B: Preparation of methyl 2-bromo-2'-nitrophenyl- cetate To a εolution of the product of Step A diεsolved in 10 mL of carbon tetrachloride was added 0.441 g of N-bromosuccinimide and 25 mg of AIBN and the reaction was heated at reflux for 14 hours. The mixture waε then cooled and evaporated and the residual oil was purified on a silica gel flaεh chromatography column eluted with 5% ethyl acetate. Evaporation of the purified fractions afforded 0.335 g (50%) of the title compound. l E NMR (300 MHz, CDCI3, ppm): δ 3.80 (ε, 3H), 6.10 (ε, IH), 7.50-7.60 (m, IH) , 7.70-7.80 (m, IH), 8.00-8.10 (m, 2H). -205- Step C: Preparation of 3-[4-(l-carbomethoxy-l-(2- nitrophenyl))methoxyphenyl]methyl-7-methyl- 2-propylimidazor4.5-blpvridine A εolution of 0.364 g (1.30 mmol) of 3-(4- hydroxyphenyl)methyl-7-methyl-2-propyl-3H-imidazo [4,5-b]pyridine (Step D, Example 2) dissolved in 5 mL of DMF was deprotonated (0.163 g KH, 0.376 g 18-crown-6) and alkylated with 0.355 g (1.30 mmol) of the product of the previous step εimilarly to the procedure described in Example 2, Step E. Purifi¬ cation on a silica gel flash chromatography column eluted with 40% ethyl acetate/hexane afforded 0.296 g (48%) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 0.95-1.05 (t, 3H), 1.70-1.80 (m, 3H), 2.65 (s, 3H), 2.70-2.80 (t, 2H), 3.75 (s, 3H), 5.40 (s, 2H), 6.65 (s, IH), 6.85-6.95 (d, 2H), 7.00-7.10 (m,3H), 7.50-7.55 (t, IH), 7.60-7.65 (t, IH), 7.80-7.85 (d, IH), 8.05-8.10 (d, IH), 8.20-8.25 (d, IH). Step D: Preparation of 3-[4-(l-carboxy-l-(2-nitro- phenyl))methoxyphenyl]methyl-7-methyl-2- propvl-3H-imidazor4.5-blpvridine Hydrolysis of 0.030 g (0.063 mmol) of the ester prepared in the previous step waε performed in a manner similar to that described in Example 2, Step F. Purification on a silica gel flash chromatography column eluted with CHCl 3 /MeOH/HOAc (100:3:1) afforded 0.023 g (74%) of the title compound. Ϊ R NMR (300 MHz, CD3OD, ppm): δ 0.90-1.00 (t, 3H), 1.60-1.75 ( , 2H), 2.65 (ε, 3H), 2.80-2.90 (t, 2H) , -206- 5.50 (s, 2H), 6.45-6.60 (br ε, IH), 6.90-7.00 (d, 2H), 7.05-7.15 (d, 2H), 7.15-7.20 (d, 2H), 7.50-7.60 (t, IH), 7.60-7.70 (t, IH), 7.75-7.80 (t, IH), 8.00-8.05 (d, IH), 8.20-8.25 (d, IH). FAB-MS: m/e 461 (M+l). Example 8 3-[4-(1-Carboxy-1-cyclohexyl)methoxyphenyl]methyl-7- methyl-2-propvl-3H-imidazor4.5-b1pvridine Step A: Preparation of 3-[4-(l-carbomethoxy-l-cyclo- hexyl)methoxyphenyl]methyl-7-methyl-2-propyl- 3H-imidazor4.5-blpvridine A solution of 0.200 g (0.71 mmol) of 3-(4- hydroxyphenyl)methyl-7-methyl-2-propyl-3H-imidazo [4,5-b]pyridine (Step D, Example 2) diεεolved in 0.5 mL of DMF waε deprotonated (82 mg KH, 0.188 g 18-crown-6) and alkylated with 0.184 g (0.78 mmol) of commercially available methyl 2-bromo-2-cyclohexyl- acetate εimilarly to the procedure described in Example 2, Step E. Purification on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane afforded 0.029 g (10%) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 0.97 (t, J=8 Hz, 3H), 1.10-1.90 (m, 13H), 2.66 (s, 3H), 2.78 (t, J=8 Hz, 2H), 3.70 (ε, 3H), 4.31 (d, J=6 Hz, IH), 5.40 (s, 2H), 6.77 (d, J=10 Hz, 2H), 7.02-7.10 (m, 3H), 8.10 (d, J=6 Hz, IH). -207- Step B: Preparation of 3-[4-(l-carboxy-l-cyclohexyl)- methoxyphenyl]methyl-7-methyl-2-propyl-3H- imidazor4.5-blpvridine Hydrolysis of 0.029 g (0.066 mmol) of the 5 ester prepared in Step A was performed in a manner similar to that described in Example 2, Step F. Purification on a εilica gel flaεh chromatography column eluted with CHCl 3 /MeOH/HOAc (100:3:1) afforded 0.017 g (61%) of the title compound. 10 --E NMR (300 MHz, CD3OD, ppm): δ 0.95 (t, J=8 Hz, 3H) , 1.10-1.90 (m, 13H), 2.65 (ε, 3H), 2.85 (t, J=8 Hz, 2H), 4.38 (d, J=6 Hz, IH), 5.48 (ε, 2H), 6.84 (d, J=10 Hz, 2H), 7.06 (d, J=10 Hz, 2H) , 7.15 (d, J=6 Hz, IH), 8.20 (d, J=6 Hz, IH). 15 FAB-MS: m/e 422 (M+l). Example 9 3-[4-(l-Carboxy-l-propyl)methoxyphenyl]methyl-7- 20 methyl-2-propvl-3H-imidazor4.5-blpvridine Step A: Preparation of 3-[4-(l-carbomethoxy-l- propyl)methoxyphenyl]methyl-7-methyl-2- ropvl-3H-iffiidazor4.5-blpvridine 25 To a suspension of H (22 mg, 1.1 eq) in 0.25 mL of DMF under N was added 0.050 g (0.18 mmol) T of the product of Step D in Example 2, and the reaction mixture was εtirred for 15 minutes. When the KH had dissolved, 18-crown-6 (10 mg, 0.2 eq) was 3 0 added, followed by ethyl 2-bromopentanoate (30 uL, 1.0 eq). After 5 minutes, tic showed that the bromide had disappeared, but that εome of the εtarting -208- phenolic intermediate remained. The reaction mixture waε quenched with εaturated ammonium chloride and concentrated in vacuo. The residue was chromato¬ graphed on εilica gel (120 x 20 mm) eluted with 30% ethyl acetate/hexane. The product waε isolated in a 19% yield (14 mg). - • B. NMR (300 MHz, CDCI3 ppm): δ 0.9-1.0 (m, 6H), 1.15-1.25 (t, 3H), 1.4-1.6 (m, 2H), 1.7-2.0 (m, 4H), 2.65 (ε, 3H), 2.7-2.8 (t, 2H), 4.1-4.2 (m, 2H), 4.5-4.6 (m, IH), 5.4 (s, 2H), 6.7-6.8 (d, 2H), 7.0-7.1 (m, 3H), 8.2 (d, IH). FAB-MS: m/e 410 (M+l). Step B: Preparation of 3-[4-(l-carboxy-l-propyl)- methoxyphenyl]methyl-7-methyl-2-propyl-3H- imidaspr ,5-b1pyridine To a solution of 21 mg (0.049 mmol) of the product of Step B diεsolved in 1 mL of ethanol was added 0.25 mL of 1 N NaOH. The reaction mixture was stirred overnight, after which time tic indicated the consumption of the starting material. The reaction mixture was neutralized with 1 N HCl and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column (90 x 10) eluted with ethyl acetate/hexane/acetic acid (76:20:4). The product fractions were combined and evaporated, redissolved in ethyl acetate and reconcentrated in vacuo several timeε to remove reεidual acetic acid. Drying in vacuo afforded 13 mg (93%) of the title compound. -209- - ■ E NMR (300 MHz, CD3OD, ppm): δ 0.9-1.0 (m, 6H), 1.4-1.6 (m, 2H), 1.6-1.8 (m, 2H), 1.8-1.9 (m, 2H), 2.65 (ε, 3H), 2.8-2. (t, 2H), 4.5-4.6 (t, IH), 5.5 (ε, 2H), 6.8-6.9 (d, 2H), 7.0-7.1 (d, 2H), 7.15 (d, IH), 8.2 (d, IH). FAB-MS: m/e 382 (M+l). Example 10 3-[4-(l-Carboxy)-l-(2-carboxyphenyl)methoxyphenyl]- methyl-7-methvl-2-propvl-3H-imidazor4.5-blpvridine Step A: Preparation of dimethyl homophthalate To homophthalic acid (500 mg, 2.78 mmol) cooled to 0 β C was added a saturated solution of HCI/CH3OH (20 mL). The εolution was gradually warmed to room temperature and stirred for 3 days. The reaction was concentrated in vacuo. the residue was partitioned between ethyl acetate and water, and the organic layer washed with saturated NaHCU3 an< * brine. The organic layer was concentrated in vacuo. then redisεolved in ethyl acetate, dried (MgS0 ), filtered and evaporated to afford 0.470 g (81%) of the title compound. -Ε NMR (300 MHz, CDCI3, ppm): δ 3.7 (ε, 3H) , 3.9 (ε, 3H), 4.0 (ε, 2H), 7.2-7.2 (m, IH), 7.25-7.35 (m, IH) , 7.45-7.55 <m, IH), 8.0-8.1 (m, IH). EI-MS: m/e 208 (M + ). Step B: Preparation of methyl 2-bromo-(2'-carbo- methoxv)phenvlacetate To a εolution of the product of Step A (464 mg, 223 mmol) in 10 mL CC1 were added NBS (377 mg, -210- 0.95 eq) and a catalytic amount of AIBN. The reaction mixture was refluxed overnight, and then concentrated in vacuo. The residue was chromatogra¬ phed on εilica gel (140 x 40 mm) eluted with 8% ethyl acetate/hexane. The product waε isolated in a 65% yield (398 mg). 1 H NMR (300 MHz, CDCI3, ppm): δ 3.8 (ε, 3H), 3.9 (ε, 3H), 6.6 (ε, IH), 7.35-7.45 (t, IH), 7.55-7.65 (t, IH), 7.8-7.9 (d, IH), 7.95-8.0 (d, IH) . Step C: Preparation of 3-[4-(l-carbomethoxy-l-(2- carbornethoxyphenyl))methoxyphenyl]methyl-7- methvl-2-propvl-3H-imidazor4.5-blpvridine To a suspenεion of KH (22 mg, 1.1 eq) in 250 uL DMF under N 2 waε added 50 mg (0.178 mmol) of 3-(4-hydroxyphenyl)methyl-7-methyl-2-propyl-3H- imidazo[4,5-b]pyridine (Example 2, Step D), and the reaction mixture waε εtirred for 1 hour. To thiε εolution were added 18-crown-6 (47 mg, 1.1 eq) and the product of Step B (56 mg, 1.1 eq) . The reaction mixture waε εtirred at room temperature overnight. The reaction mixture waε then quenched with εaturated ammonium chloride and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the organic layer extracted with saturated NaHCθ3 and concentrated in vacuo. The product waε purified on a silica gel flash chromatography column (130 x 20 mm) eluted with 40% ethyl acetate/hexane to afford 33 mg (38%) of the title compound. -211- -•E NMR (300 MHz, CDC1 3 , ppm): δ 0.9-1.0 (t, 3H), 1.65-1.8 (m, 2H), 2.65 (s, 3H), 2.7-2.8 (t, 2H), 3.7 (ε, 3H), 3.9 (ε, 3H), 5.2 (s, 2H), 6.8-6.95 (m, 3H), 7.0-7.1 (m, 3H), 7.35-7.45 (m, IH), 7.45-7.55 (m, 5 IH), 7.7 (m, IH), 7.9-8.0 (m, IH), 8.2 (d, IH). FAB-MS: m/e 488 (M+l). Step D: Preparation of 3-[4-(l-carboxy)-l-(2- carboxyphenyl)methoxyphenyl]methyl-7-methyl- 1 0 2-propvl-3H-imidazor4.5-blpvridine To a methanol solution (1.5 mL) of the product of Step C (33 mg, 0.068 mmol) was added 1.5 mL of 1 N NaOH. The reaction mixture was εtirred at room temperature for 4.5 hourε, and was then 15 neutralized with 1 N HCl and concentrated in vacuo. The residue was chromatographed on silica gel (120 x 20 mm) eluted with CHCl 3 /MeOH/HOAc (100:10:2) to afford 32 mg (94%) of the title compound. l E NMR (300 MHz, CD3OD, ppm): δ 0.85-0.95 (t, 3H), 20 1.5-1.7 (m, 2H), 2.6 (s, 3H), 2.7-2.8 (t, 2H), 5.35 (s, 2H), 6.3 (ε, IH), 6.8-7.0 (m, 4H) , 7.05-7.30 (m, 3H), 7.55-7.7 (m, 2H), 8.15 (d, 2H) . Ex&FΦle U 25 (Z)-3-[(4-((2-Carboxy~2-phenyl)ethenyl)phenyl)- *1 methyl1-7-methvl-2-propvl-3H-imidazor .5-blpvridine Step A: Preparation of methyl 3-hydroxy-3-(4-methyl- 30 phenyl)-2-phenvlpropionate To a solution of methyl 2-bromophenylacetate (473 mg; 2.065 mmol) and 4-methylbenzaldehyde (188 -212- mg, 1.57 mmol) in dry THF (5 mL) under N 2 waε added powdered zinc (201 mg, 3.09 mmol). After stirring at reflux for 10 min, a few crystals of iodine were added. The mixture was refluxed under N 2 for 4 hourε, then allowed to stand at room temperature overnight. The next day the mixture waε diluted in Et 2 0 and 1 N HCl waε added. The biphaεic mixture waε εtirred until the zinc had completely diεεolved in the aqueouε layer. The organic layer waε εeparated, washed with brine, dried (MgSU ), filtered, and concentrated in vacuo. The residue which contained two diastereomerε (Rf=0.22, 0.17 in 15% EtOAc/hexane), was purified on a εilica gel flaεh chromatography column eluted with 15% ethyl acetate/hexane. A total of 283 mg (67%) of both diaεtereomerε was isolated. The 300 MHz --E NMR εpectra of each diaεtereomer waε conεiεtent with its structure. Step B: Preparation of methyl (Z)-3-(4-methylphenyl)- 2-phenylpropenoate To a εolution of a mixture of the diaεtereo- iεomerε from Step A (34 mg, 0.126 mmol) in dry benzene (3 mL) waε added a few cryεtalε of p-TεOH and the mixture waε heated to reflux. After εeveral minuteε tic analyεis indicated complete reaction. The mixture was diluted with Et 2 0, washed with εaturated NaHCU3, brine, dried (MgSθ4), filtered and concentrated in vacuo to provide 31 mg (98%) of the title compound. X H NMR (300 MHz, CDCI3, ppm): δ 2.27 (s, 3H), 3.79 (s, 3H), 6.92 (q, 4H), 7.25 (m, 2H), 7.40 (m, 3H), 7.82 (ε, IH). -213- Step C: Preparation of methyl (Z)-3-(4-bromomethyl- To a solution of the product of Step B (31 mg, 0.123 mmol) in dry CCI4 (1 mL) under 2 were added NBS (20 mg, 0.9 eq) and a catalytic amount of AIBN. The mixture was t εtirred at reflux under N 2 for 1.5 hours. The mixture was cooled to room tempera¬ ture, diluted with Et 2 0 and filtered to remove the precipitated εuccinimide. The filtrate waε concen- trated in vacuo and the reεidue was purified on a silica gel flash chromatography column eluted with 15:1 hexane/EtOAc to afford 27.4 mg (67%) of the title compound. ■ -E NMR (300 MHz, CDCI3, ppm): δ 3.80 (ε, 3H) , 4.49 (s, 2H), 7.02 (d, 2H) r 7.18 (d, 2H) , 7.24 (d, IH), 7.39 (m, 4H), 7.82 (ε, IH). Step D: Preparation of (Z)-3-[(4-(2-carbomethoxy-2- phenylethen-l-yl)phenyl)methyl]-7-methyl-2- propvl-3H-imidazor4.5-blpvridine To a εolution of 30 mg (0.171 mmol) of 2-propyl-7-methylimidazo[4,5-b]pyridine (Example 2, Step D) diεεolved in 1 mL of dry DMF waε added 11 mg of a 60% oil diεperεion of NaH (1.5 eq) and the reaction mixture waε εtirred under an N 2 atmoεphere. After εtirring at room temperature for 30 minuteε the product from Step C (27.4 mg, 0.082 mmol) diεεolved in 0.5 mL DMF waε added via syringe. The reaction mixture was quenched with εaturated NH4CI εolution, and the εolvent was removed under in vacuo. The reεidue was diεεolved in EtOAc and washed with H 2 0 and brine. The organic layer was dried (MgS04), -214- filtered, and concentrated in 2&£n£. The residue waε purified on a silica gel flash chromatography column eluted with 50% ethyl acetate/hexane to provide 13.2 mg (38%) of the title compound. --E NMR (300 MHz, CDCI3, ppm): δ 0.95 (t, 3H), 1.72 (q, 2H), 2.68 (s, 3H), 2.71 (q, 2H), 3.78 (s, 3H) , 5.40 (S, 2H), 6.91 (q, 4H), 7.02 (d, IH), 7.19 (dd, IH), 7.32 (m, 3H), 7.79 (ε, IH), 8.16 (d, IH) . Step E: Preparation of (Z)-3-[(4-((2-carboxy-2- phenyl)ethen-1-yl)pheny1)methyl]-7-methyl-2- prσpyl-3H-imidazor4.5-blpvridine To a εolution of the product of Step D (13.2 mg, 0.031 mmol) in MeOH (1 mL) was added 1 N NaOH (0.138 mL, 4.5 eq). After stirring overnight the mixture waε quenched with 0.5 mL of acetic acid and concentrated in vacuo. The product was purified on a silica gel flash chromatography column eluted with hexane/EtOAc/HOAc (75:50:1) to afford 10.8 mg (85%) of the title compound. 1 H NMR (300 MHz, CD3OD, ppm): δ 0.91 (t, 3H), 1.63 (q, 2H), 2.62 (s, 3H), 2.79 (t, 2H), 5.47 (ε, 2H), 6.87 (d, 2H), 6.96 (d, 2H), 7.12 ( , 3H), 7.31 (m, 3H), 7.79 (ε, IH), 8.12 (d, IH) . Example 12 3-[(4-((2-Carboxy-2-ρhenyl)ethyl)phenyl)methyl]-7- methyl-2-propvl-3H-imidazor4.5-blpvridine -215- Step A: Preparation of 3-[(4-((2-carboxy-2-phenyl)- ethylphenyl)methyl]-7-methyl-2-propyl-3H- To a solution of 2.2 mg (0.0054 mmol) of the product of Step E of Example 11 in 1 mL of EtOAc was added a catalytic amount of 10% Pd on carbon. A hydrogen atmosphere was secured with a balloon and the mixture was εtirred for 1 hour. The catalyεt waε removed by filtering the mixture through a pad of celite, and the filtrate waε concentrated in vacuo to provide 1.3 mg (597.) of the title compound. - ■ E NMR (300 MHz, CDCI3, ppm): δ 0.87 (t, 3H), 1.63 (q, 2H), 2.62 (s, 3H), 2.67 (t, 2H), 5.30 (s, 2H), 6.80 (s, 4H), 6.92 (d, IH) , 7.01 (m, 5H) , 8.12 (d, IH). Example 13 3-[ -(1-carboxy-l-methyl-l-phenyl)methoxyphenyl]- methvl-7-methvl-2-propvl-3H-imidazor4.5-b1pvridine Step A: Preparation of methyl 2-(4-methylphenoxy)- phenylacetate a To a cooled (0 β C) εuεpenεion of KH (2.12 g, 1.0 eq) in DMF (30 mL) waε added a εolution of p-creεol (2.00 g, 18.5 mmol) in 20 mL of DMF. The reaction mixture was stirred 15 minutes, then 18-crown-6 (200 mg) was added followed by a solution of 4.24 g (18.5 mmol) of methyl 2-bromophenylacetate diεεolved in 10 mL of DMF. The reaction mixture was stirred 45 minutes, then partitioned between ethyl acetate and water. The organic layer was washed with -216- water, brine, dried (MgS0 ), filtered and evaporated in vacuo. The residue was purified on a εilica gel flaεh chromatography column (150 x 40 mm) eluted with 5% ethyl acetate/hexane to yield 2.63 g (58%) of the title compound. NMR (300 MHz. CDCI3): δ 2.3 (ε, 3H), 3.75 (ε, 3H), 5.6 (ε, IH), 6.8-6.9 (d, 2H), 7.0-7.1 (d, 2H), 7.3-7.45 (m, 3H), 7.5-7.6 (d, 2H). FAB-MS: m/e 257 (M+l). Step B: Preparation of methyl 2-(4-methylphenoxy)- 2-phenylpropanoate A εolution of the product of Step A (50 mg, 0.195 mmol) in 500 uL of THF waε cooled to -78"C. A εolution of lithium biε(trimethylεilyl)amide (195 uL, 1.0 M in THF) waε added and the reaction was εtirred for 15 minuteε. Methyl iodide (12 uL, 1.0 eq) was added and the cooling bath removed. After 8 minutes, the reaction mixture was quenched with saturated NH4CI and concentrated in vacuo. The residue was purified on a on a silica gel flash chromatography column (140 x 20 mm) eluted with 2.5% ethyl acetate/hexane to yield 26 mg (49%) of the title compound. --E NMR (300 MHz, CDCI3, ppm): δ 1.9 (ε, 3H), 2.3 (ε, 3H), 3.75 (ε, 3H), 6.7-6-8 (d, 2H), 7.0-7.1 (d, 2H), 7.3-7.45 (m, 3H), 7.6-7.7 (d, 2H) . FAB-MS: m/e 271 (M+l). Step C: Preparation of methyl 2-(4-bromomethyl- phenoxy)-2-phenvlpropanoate A solution of the product of Step B (26 mg, 0.096 mmol) NBS (16 mg, 0.95 eq) and AIBN (2 mg, -217- catalytic amount) in CCI4 ,(2 mL) waε heated to reflux for 1 hour and then concentrated in vacuo. The reεidue waε purified on a εilica gel flaεh chromato¬ graphy column (125 x 20 mm) eluted with 5% ethyl acetate/hexane to yield 21 mg (62%) of the title compound. ■ -E NMR (300 MHz, CDCI3, ppm): δ 1.9 (ε, 3H), 3.75 (ε, 3H), 4.5 (s, 2H), 6.9-6.9 (d, 2H), 7.2-7.3 (d, 2H), 7.3-7.5 (m, 3H), 7.6-7.7 (d, 2H) . 10 Step D: Preparation Df l-[4-(l-carbomethoxy-l- methyl-l-phenyl)methoxyphenyl]methyl-7- methvl-2-propvl-3H-imidazor4.5-blpvridine To a εuεpension of NaH (2.0 mg, 1 eq) in DMF 15 (0.25 mL) was added 10 mg (1.0 eq) of 7-methyl-2- propylimidazo[4,5-b]p-yridine (Example 2, Step B), and the reaction mixture was εtirred 15 minutes. Next, a solution of the product of Step C (20 mg, 0.057 mmol) in DMF (0.5 mL) was added. After εtirring 1.5 hourε, 20 the reaction mixture waε concentrated in vacuo. The residue was purified on a silica gel flash chromato¬ graphy column (140 x 15 mm) eluted with 507. ethyl acetate/hexane to yield 12 mg (48%) of the titled product. 25 1 H NMR (300 MHz, CDCI3, ppm): δ 0.9-1.0 (t, 3H), 1.65-1.8 (m, 2H), 1.85 (s, 3H), 2.7 (ε, 3H), 2.75-2.85 • (t, 2H), 3.7 (s, 3H), 7.55-7.65 (m, 2H),8.2 (d IH) . FAB-MS: m/e 444 (M+l). c 30 -218- Step E: Preparation of 3-[4-(l-carboxy-l-methyl-l- phenyl)methoxyphenyl]methyl-7-methyl-2- propyl-3H-imidazor4.5-blpvridine To a εolution of the product of Step D (12 mg, 0.027 mmol) in MeOH (2 mL) was added 2 mL of a 1 N NaOH εolution. The reaction mixture waε stirred for 45 minutes, and waε then concentrated in vacuo. The reεidue waε taken up in water and acidified to pH 2 with 1 N HCl. Next, the aqueous layer was diluted with water and extracted 3 times with chloroform. The combined organic layers were dried (MgS04), filtered, and concentrated in vacuo to yield 8.3 mg (70%) of the title compound. l E NMR (300 MHz, CDCI3, ppm): δ 0.9-1.0 (t, 3H), 1.7-1.85 (m, 2H), 1.8 (s, 3H), 2.8 (ε, 3H), 3.1-3.2 (t, 2H), 5.5 (ε, 2H), 6.75-6.85 (d, 2H), 7.0-7.1 (d, 2H), 7.25-7.4 (m, 4H), 7.5-7.6 (m, 2H), 8.45 (d, IH). FAB-MS: m/e 450, 452 (M+l, 3:1 ratio). Example 1 7-Methyl-2-propyl-3-[4-(l-(tetrazol-5-yl)-l-ρhenyl)- methoxyphenvnmethvl-3H-imidazor4.5-blpvridine Step A: Preparation of 3-[4-(l-carboxamido-l-phenyl)- methoxyphenyl]methyl-7-methyl-2-propyl-3H- midazor4.5-blpvridine A εolution of the product of Example 2, Step E (125 mg, 0.291 mmol) in MeOH (10 mL) waε cooled to 0°C and ammonia was bubbled through the mixture for 1.5 hours. The flask was stoppered and εtirred for 6 hourε, during which time the product precipitated. -219- The reaction mixture was concentrated in vacuo to yield 105 mg (88%) of product (Rf=0.50 5% methanol/ ethyl acetate) which was uεed in the next step without further purification. - ■ E NMR (300 MHz, CDCI3, ppm): δ 0.9-1.0 (t, 3H), 1.7-1.8 (m, 2H), 2.65 (ε, ' 3H), 2.7-2.8 (t, 2H), 5.4 (ε, 2H), 5.45 (ε, IH), 5.5-5.6 (ε, IH), 6.55-6.65 (ε, IH), 6.8-6.9 (d, 2H), 7.0-7.1 (m, 3H), 7.3-7.4 (m, 3H), 7.45-7.55 (m, 2H), 8.2 (d, IH). 10 Step B: Preparation of 3-[4-(l-cyano-l-phenyl)- methoxyphenyl]methyl-7-methyl-2-propyl-3H- imidazor4.5-blpvridine To a 0 β C εuspensiόn of the product of Step A 15 (83 mg, 0.20 mmol) in phosphorouε oxychloride (0.51 mL, 27 eq) was added Et3N (61 uL, 2.2 eq) over 55 minutes. After the addition was complete, the reaction mixture was warmed to room temperature over 2 hours and then heated to reflux for 45 minutes . 20 Next, the reaction mixture was concentrated in vacuo. and the residue was partitioned between ice water and toluene. The aqueous layer was extracted three times with toluene. The combined extracts were washed with 0.5 N NaOH and then with water. The organic layer 25 was separated and concentrated in vacuo to yield 59 mg (74%) of crude product (Rf=0.35 in 50% ethyl *» acetate/hexane), which was used in the next step without purification. 30 -220- Step C: Preparation of 7-methyl-2-propyl-3-[4-(l- (tetrazol-5-yl)methoxyphenyl]methyl-3H- imidazo-r4.5-b1Pvridine To a εolution of the product of Step B (29 mg, 0.073 mmol) diεεloved in 0.5 mL of toluene waε added 15 mg (1.2 eq) of Me 3 SnN 3 and the reaction mixture waε refluxed for 22 hourε. An additional 15 mg (1.2 eq) of Mβ3SnN3 waε then added, and the refluxing continued for another hour. The reaction mixture waε then poured into ethyl acetate/ether and waεhed with εaturated NH4CI and brine. The organic layer was εeparated and concentrated in vacuo. The reεidue was purified on a silica gel flash chromato¬ graphy column (120 x 30 mm) eluted with chloroform/ methanol/acetic acid (100:5:1) to yield 5 mg (16%) of the title compound. l E NMR (300 MHz, CD3OD, ppm): δ 0.9-1.0 (t, 3H) , 1.6-1.7 (m, 2H), 2.65 (ε, 3H), 2.8-2.9 (t, 2H), 5.5 (s, 2H), 6.8 (s, IH), 6.95-7.1 (m, 5H), 7.1-7.2 (d, IH), 7.3-7.4 (m, 2H), 7.45-7.55 (m, 2H), 8.2 (d, IH). FAB-MS: m/e 440 (M+l). Example 15 7-Methyl-2-proρyl-3-[4-(l-(tetrazol-5-yl )-l-(2-chloro- phenvl ^methoxvphenvl1methvl-3H-imidazor4.5-blpvridine Step A : Preparation of 2-(4-methylphenoxy)-2-(2- hlorophenvDacetamide To a εolution of 0.700 g (2.41 mmol ) of methyl 2-(2-chlorophenyl )-2-(4-methylphenoxy)acetate (Example 4 , Step B) in 10 mL of methanol , εtirred at -221- 0°C (ice-bath) was added anhydrous NH3 for 45 minutes. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture waε then concentrated in vacuo and afforded 0.658 g (99%) of title compound. - ■ E NMR (300 MHz, CD3OD, ppm): δ 2.25 (ε, 3H), 6.0 (ε, IH), 6.8-6.9(d, 2H), 7.0-7.1 (d, 2H), 7.25-7.35 (m, 2H), 7.4-7.5 (m, IH), 7.55-7.6 (m, IH) FAB-MS: m/e 276, 278 (M+l, 3:1 ratio). Step B: Preparation of 2-(4-methylphenoxy)-2-(2'- chlorophenvDacetonitrile The product of Step A (0.650 g, 2.36 mmol) was added to phosphorous oxychloride (5.95 mL, 27 eq) at 0°C followed by εlow addition of 0.73 mL (2.2 eq) of triethylamine. The reaction mixture was warmed to room temperature for 10 minutes, refluxed for 50 minutes and then cooled to room temperature. The reaction mixture was concentrated in vacuo. and partitioned between ice water and toluene. The aqueous layer was extracted 3 times with toluene, and the combined toluene extracts were washed with 0.5 N NaOH and H 2 0. The crude product was concentrated in vacuo and purified on a silica gel flash chromato- graphy column (140 x 30 mm) eluted with 2% ethyl acetate/hexane to afford 0.555 g (91%) of the title compound. ■ -E NMR (300 MHz, CD3OD, ppm): δ 2.35 (s, 3H), 6.15 (s, IH), 6.95-7.05 (d, 2H), 7.1-7.2 (d, 2H), 7.4-7.6 (m, 3H), 7.8-7.9 (m, IH). EI-MS: m/e 257,259 (M+, 3:1 ratio). -222- Step C: Preparation of 2-(4-bromomethylphenoxy)-2- (2-chlorophenvl)acetonitrile To a CCI4 solution (5 mL) of the product (0.200 g) of Step B waε added NBS (0.132 g, 0.95 eq) 5 and a catalytic amount of AIBN. The reaction mixture waε refluxed overnight. TLC indicated clean conver- εion to product, and the reaction mixture waε cooled to room temperature and concentrated in vacuo. The crude product was purified on a silica gel flash 10 chromatography column (120 x 30 mm) eluted with 5% ethyl acetate in hexane to afford 0.178 g (72%) of the title compound. - ■ E NMR (300 MHz, CDCI3 ppm): δ 4.5 (s, 2H) , 6.2 (ε, IH), 7.05-7.15 (d, 2H), 7.35-7.55 (m, 5H), 7.8-7.9 15 ( , IH). Step D: Preparation of 3-[4-(l-cyano-l-(2-chloro- phenyl)methoxyphenyl]methyl-7-methyl-2- propyl-3H-imidazor4.5-blpvridine 20. To a DMF εuεpenεion (0.5 mL) of NaH (7.5 mg, 0.252 mmol) under N 2 waε added 0.040 g (0.23 mmol) of 7-methyl-2-propylimidazo[4,5-b]pyridine (Example 2, Step B) and the reaction mixture was εtirred at room temperature for 1.5 hourε. To the reεulting εodium 25 salt was added the product of Step C (84 mg, 1.1 eq) and the reaction mixture was εtirred for 5 hourε. The reaction mixture waε then quenched with εaturated NH4CI and concentrated in vacuo. The crude product waε purified on a εilica gel flaεh chromatography 0 column (130 x 20 mm) eluted with 30% ethyl acetate/hexane to afford 24 mg (24%) of the title compound. -223- l E NMR (300 MHz, CDC1 3 ., ppm): d 0.9-1.0 (t, 3H), 1.7-1.85 (m, 2H), 2.7 (ε, 3H), 2.75-2.85 (t, 2H), 5.45 (ε, 2H), 6.15 (ε, IH), 6.95-7.05 (m, 3H), 7.1-7.2 (d, 2H), 7.35-7.5 (m, 3H) , 7.75-7.85 (m, IH), 8.2 (d, IH). FAB-MS: m/e 431 (M+l). Step E: Preparation of 7-methyl-2-propyl-3-[4-(l- (tetrazol-5-yl)-l-(2-chlorophenyl)methoxy- phenynmethyl-3H-imidazor4.5-blpvridine To a toluene εolution (1 mL) of the product of Step D (24 g, 0.056 mmol) was added trimethyl¬ stannyl azide (14 mg, 1.2 eq) and the mixture was refluxed for 48 hours. The reaction mixture was then concentrated in vacuo and purified on a silica gel flash chromatography column (130 x 15 mm) eluted with CHCl 3 /MeOH/HOAc (100:3:1) to afford 13 mg (50%) of the title compound., --E NMR (300 MHz, CD3OD, ppm): δ 0.85-0.95 (t, 3H) , 2.55-2.7 (m, 2H) , 2.65 (s, 3H), 2.8-2.9 (t, 2H) , 5.5 (s, 2H), 6.9-7.0 (d, 2H), 7.05-7.2 (m, 4H), 7.3-7.5 (m, 3H), 7.55-7.65 (i/lH), 8.2 (d, IH) . FAB-MS: m/e 474, 476 (M+l). -Example 16 7-Methyl-2-propyl-3-[4-(2-phenyl-2-(tetrazol-5-yl)- ethyl)phenyltmethyl-3H-imidazor4.5-blpyridine -224- Step A: Preparation of 4-(bromomethvl)benzvl alcohol A εuspenεion of 4-bromomethylbenzoic acid (5.04 g, 23.3 mmol) in THF (30 mL) waε cooled to 0 β C and treated with borane/THF (35 mmol). The ice bath waε removed and the mixture waε allowed to warm to room temperature and εtirred for 1.5 hourε. The exceεε borane was quenched first with MeOH, then with water. The reaction mixture was then concentrated in vacuo and redissolved in ethyl acetate. The ethyl acetate layer was washed with 5% HCl, water-, aHCθ3, brine, dried (MgSU4), filtered, and evaporated in vacuo to afford 4.44 g (94%) of the titled product. - ■ E NMR: (300 MHz, CDCl 3 ,ppm): d 7.38 (q, 4H), 4.70 (ε, 2H), 4.51 (s, 2H). FAB MS: m/e 202 (M+l). Step B: Preparation of 4-(bromomethyl)-l-(tert-butyl- dimethylsilvloxvmethyDbenzen To a solution of the product of Step A (4.44 g. 22.1 mmol) in CH2CI2 were added N,N-diiεopropyl- ethylamine (1.2 eq.), 4-dimethylaminopyridine (0.1 eq), and tert-butyldimethylεilyl chloride (1.2 eq). The reaction mixture was stirred for 1.5 hours at room temperature, then concentrated in vacuo. The residue was disεolved in ethyl acetate and waεhed with water, brine, dried (MgSθ4), filtered, and concentrated in vacuo. The residue was chromatogra- phed on silica gel eluted with 2.5% ethyl acetate/ hexane to afford 5.0 g (71 %) of the titled product. 1H NMR (300 MHz, CDCI3, ppm): δ 7.34 (q, 4H), 4.74 (ε, 2H), 4.59 (ε, 2H), 0.95 (ε, 9H), 0.11 (ε, 6H). -225- Step C: Preparation of 3-[4-(tert-butyldimethyl- Bilyloxymethvl^phenvn-2-phenvlpropanonitrile A εolution of phenylacetonitrile (1.5 mL, 12.7 mmol) in THF (40 mL) containing HMPA (11 mL, 63.4 mmol) waε cooled to -78'C and treated with 16 mL (16 mmol) of a 1.0 M THF εolution of lithium biε(trimeth- ylsilyDa ide dropwise while the temperature was maintained at -78'C. The reaction was stirred at -78 C C for 1.5 hours, and a solution of the product of Step B (2.00 g, 6.34 mmol) in THF (8 mL) waε added dropwise with the temperature maintained below -70 β C. The reaction temperature was maintained below -68 β C for 3 hours. The reaction was quenched at thiε temperature by addition of 1 N NaHSθ4- After warming to room temperature, the mixture waε partitioned between EtOAc and water, and the combined organic layers were washed with water, εaturated aHCθ3, brine, dried (MgSU4), filtered, then concentrated s vacuo. The residue was chromatographed on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 1.5 g (67%) of the title compound. - ■ E NMR (300 MHz, CDCI3, ppm): δ 7.40-7.30 (m, 3H), 7.30-7.22 (m, 4H), 7.10 (d, 2H), 4.73 (ε, 2H), 3.98 (t, IH), 3,23-3.08 (m, 2H), 0.94 (s, 9H) , 0.10 (s, 6H). FAB MS: m/e 294 (M + less tert-Bu). -226- Step D: Preparation of 3-[4-(bromomethyl)phenyl]- 2-phenvlpropanonitrile To a cooled (0 β C) solution of 1.5 g ( 4.27 mmol) of the product of Step C disεolved in 20 mL of acetonitrile, waε added 2.12 g (6.4 mmol) of carbon tetrabromide, and 1.68 g (6.40 mmol) of triphenyl¬ phoεphine. The reaction mixture waε stirred 30 minutes at 0 β C, then allowed to warm to room tempera¬ ture and 0.5 mL (6.4 mmol) of acetone was added. The reaction mixture was stirred an additional 16 hours at room temperature, then filtered and evaporated in vacuo. The reεidue was purified on a εilica gel flash chromatography column eluted with 57. ethyl acetate/hexane to afford 0.575 g (45%) of the title compound. ■ -E NMR (300 MHz, CDCI3, ppm): δ 7.48-7.10 (m, 9H), 4.50 (s, 2H), 4.00 (t, IH), 3.26-3.10 (m, 2H). FAB MS: m/e 299, 301 (M+l). Step E: Preparation of 3-[4-(2-cyano-2-phenylethyl)- phenyl]methyl-7-methyl-2-propyl-3H-imidazo r4.5-b1pvridine To a εolution of 7-methyl-2-propylimidazo [4,5-b]pyridine (106 mg, 0.61 mmol) in DMF (3 mL) was added NaH (0.91 mmol). The εuεpension waε εtirred at room temperature for 30 minutes, at which time a solution of the product of Step D (200 mg, 0.667 mmol) in DMF (2 mL) was added. The mixture was stirred for 2 hours at room temperature, quenched with water, and then concentrated in vacuo. The residue was partitioned between water and EtOAc, and -227- the combined organic layers were washed with brine, dried ( 2CO3), filtered, and evaporated in vacuo. The residue was chromatographed on a silica gel flaεh chromatography column eluted with 50% ethyl acetate/ hexane to afford 46 mg (19%) of the title compound. ~Ε NMR (300 MHz, CD3OD, ppm): δ consistent with structure. FAB MS: m/e 395 (M+l). Step F: Preparation of 7-Methyl-2-propyl-3-[4-(2- phenyl-2-(tetrazol-5-yl)ethyl)phenyl]methyl- 3H-imidazor4.5-blpyridlne To a solution of the product of the product of Step E (46 mg, 0.12 mmol) in toluene (2 mL) was added 29 mg (0.14 mmol) of trimethylstannyl azide and the reaction mixture waε refluxed for 24 hours . The reaction mixture was concentrated in vacuo. The residue was dissolved in THF and treated with 12 N HCl (5 drops) for 5 minutes at room temperature. The mixture was concentrated in vacuo and purified on a silica gel flash chromatography column eluted with CHCl 3 /MeOH/NH 4 OH (80:20:2) to afford 19.6 mg (38%) of the title compound. - • E NMR (300 MHz, CD3OD, ppm): δ 8.18 (d, IH) , 7.28-7.12 (m, 6H), 7.05 (d, 2H), 6.93 (d, 2H) , 5.48 (s, 2H), 4.58 (t, IH), 3.59-3.49 (m, IH), 3.38-3.30 (m, IH), 2.78 (t, 2H) , 2.65 (s, 3H) , 1.68-1.52 (m, 2H), 0.89 (t, 3H). FAB MS: m/e 438 (M+l). -228- Exampie 17 3-[4-(l-carboxy-l-phenoxy)methylphenyl]methyl-7- methyl-2-propyl-3H-imidazor4.5-blpyridine Step A: Preparation of methyl 2-bromo-4'-methyl- phenylacetat A mixture of 4-methylphenylacetic acid (5.00 g, 33.3 mmol) and thionyl chloride (2.67 mL, 36.6 mmol) were heated to reflux. Bromine (1.51 mL, 29.3 mmol) was added dropwise to the reaction mixture over 10 minutes and then the mixture was refluxed overnight (17 hours). The reaction mixture was cooled to room temperature and 34 mL of methanol was added slowly. The reaction mixture was concentrated in vacuo and chromatographed on silica gel (45 x 120 mm) eluted with 2% ethyl acetate/hexane to afford 3.18 g (37%) of the titled compound. ~ -E NMR (300 MHz, CDCI3, ppm): d 2.35 (s, 3H), 3.8 (s, 3H), 5.35 (s, IH), 7.1-7.2 (d, 2H), 7.4-7.5 (d, 2H). FAB-MS: m/e 243, 241 (M+l, 1:1 ratio). Step B: Preparation of methyl 2-phenoxy-2-(4-methyl- henyDacetate To a εuspension of KH (244 mg, 2.13 mmol) in 2 mL of DMF at room temperature under N 2 was added a DMF solution (1 mL) of phenol (200 mg, 2.13 mmol). When the KH had completely diεεolved, the reaction mixture was cooled to 0 β C. A DMF εolution (1 mL) of the product of Step A (517 mg, 2.13 mmol) was then added by εyringe. After the addition was complete, -229- the reaction mixture was allowed to warm to room temperature, and waε then stirred for 2 hourε. The reaction mixture waε quenched with εaturated NH4CI and concentrated in 2&CJ1G- The reεidue waε purified on a silica gel flaεh chromatography column (130 x 40 mm) eluted with 5% ethyl acetate/hexane to afford 0.126 g (23%) of the title compound. - ■ E NMR (300 MHz, CDCI3, ppm): δ 2.35 (s, 3H), 3.75 (ε, 3H), 5.65 (s, IH), 6.9-7.0 (m, 3H), 7.1-7.3 (m, 4H), 7.4-7.5 (d, 2H) . EI-MS: m/e 256 (M + ). . Step C: Preparation of methyl 2-phenoxy-2-(4-bromo- methylphenvDacetate To a CCI4 εolution (1 mL) of the product of Step B (126 mg, 0.495 mmol) waε added N-bromoεuccin¬ imide (44 mg, 246 mmol) and a catalytic amount of AIBN. The εolution was refluxed for 30 minutes and then concentrated in vacuo. The reεidue waε purified on a εilica gel flash chromatography column (150 x 30 mm) eluted with 5% ethyl acetate/hexane to afford 27 mg (337.) of the title compound. λ E NMR (300 MHz, CDCl 3 ppm): δ 3.75 (s, 3H) , 4.5 (s, 2H), 5.65 (s, IH), 6.9-7.0 (m, 3H) , 7.25-7.35 (m, 2H), 7.4-7.5 (d, 2H), 7.55-7.6 (d, 2H). EI-MS: m/e 334, 336 (M*. 1:1 ratio). Step D: Preparation of 3-[4-(l-carbomethoxy-l- phenoxy)methylphenyl]methyl-7-methyl-2- propvl-3H-imida2or4.5-bTpvridine To a DMF suspension (0.1 mL) of NaH (2.4 mg; 0.081 mmol) under N 2 waε added 1.0 eq. of 7-methyl-2- -230- propylimidazo[4,5-b]pyridine (14 mg). After 15 minuteε, the NaH had completely reacted. The reaction mixture was then treated with a DMF solution (0.4 mL) of the product of Example 9, Step C (27 mg, 0.081 mmol). The reaction mixture was stirred for 5 hours, and then concentrated in vacuo. The crude product was chromatographed on εilica gel (140 x 20 mm) eluted firεt with 300 mL of 30% ethyl acetate/hexane, then with 50% ethyl acetate/hexane to afford 5.2 mg (15%) of the titled compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 0.9-1.0 (t, 3H), 1.65-1.85 ( , 2H), 2.7 (ε, 3H), 2.75-2.85 (t, 2H), 3.7 (s, 3H), 5.5 (s, 2H), 5.65 (s, IH), 6.9-7.1 (m, 4H), 7.1-7.2 ( , 2H), 7.2-7.3 (m, 2H), 7.5 (d, 2H), 8.2 (d, IH). Step E: Preparation of 3-[4-(l-carboxy-l-phenoxy)- methylphenyl]methyl-7-methyl-2-propyl-3H- imidazo-r4.5-blpvridine To a methanol εolution (50 uL) of the product of Example 9, Step D (5.2 mg, 0.012 mmol) was added 1 N NaOH (12.1 uL, 1.0 eq). The hydrolyεis was complete after stirring for 4 days. The reaction mixture was chromatographed on εilica gel (140 x 10 mm) eluted with ethyl acetate/hexane/acetic acid (30:20:1) to afford 3.0 mg (57%) of the title compound. - ■ E NMR (300 MHz, CD3OD, ppm): δ 0.9-1.0 (t, 3H), 1.6-1.8 (m, 2H), 2.65 (s, 3H), 2.8-2.9 (t, 2H), 5.4 (s, IH), 5.6 (s, 2H), 6.8-7.0 (m, 3H), 7.1-7.3 (m, 5H), 7.55-7.65 (d, 2H), 8.2 (d, IH). FAB-MS: m/e 416 (M+l). -231- Example 18 3-[4-(l-Carboxy-l-(2-methylphenyl))methoxyphenyl]- methyl-7-methyl-2-propvl-3H-imidazor4.5-blpvridine 5 General procedure fox the synthesis of 2-bromophenyl¬ acetic esters from benzaldehydes (Steps A-C): Step A: Preparation of 2-trimethylsilyloxy-2-(2- 10 methylphenylϊacetonitrile To a solution of 1.00 g (8.33 mmol) of 2-methylbenzaldehyde diεεolved in 20 mL of dichloro- methane waε added 1.33 mL (10.0 mmol) trimethylεilyl- cyanide, 1-2 mg of potasεium cyanide, 1-2 mg of 15 18-crown-6, and the reaction mixture was εtirred at room temperature for 3 hourε. The reaction mixture waε then diluted into diethyl ether, waεhed with 5% NaHC0 3 , brine, dried (HgSθ4), filtered and evaporated. The residual oil was used directly in the next εtep. 20 Step B: Preparation of ethyl 2-hydroxy-2-(2-methyl- phenvl^acetate To a εtirred 0 β C (ice-water bath) εolution of 1.83 g (8.35 mmol) of the product of Step A 25 disεolved in 10 mL of ethanol was introduced a εlow * stream of anhydrous hydrogen chloride gas. After 5 minutes the hydrogen chloride was turned off and the * reaction mixture was stoppered and εtirred at room temperature 14 hourε. The reaction was then poured 3 0 into ice-water and extracted into chloroform. The chloroform εolution was filtered through a 60 mL -232- εintered funnel filled with silica gel and the εilica gel waε waεhed with additional chloroform. The combined filtrate waε evaporated in vacuo to afford 0.437 g (27%) of the title compound. ~ -E NMR (300 MHz, CDCI3, ppm): δ 1.15-1.25 (t, 3H), 2.40 (ε, 3H), 3.35-3.45 (d, IH), 4.05-4.30 (m, 2H), 5.30-5.35 (d, IH), 7.05-7.20 (m, 4H). Step C: Preparation of ethyl 2-bromo-2-(2-methyl- phenvDacetate To a cooled (0 β C) εolution of 0.425 g (2.19 mmol) of the product of Step B diεεolved in 10 mL of dichloromethane waε added 0.717 g (2.74 mmol) of triphenylphoεphine followed by 0.908 g ( 2.74 mmol) of carbon tetrabromide. After 30 minutes the reaction was allowed to warm to room temperature and stirring was continued for 2 hours. The raction mixture was evaporated in vacuo and the residue was purified on a silica gel flaεh chromatography column eluted with 5% ethyl acetate/hexane to afford 0.373 g (66%) of the title compound. --E NMR (300 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H), 2.40 (ε, 3H), 4.15-4.30 (m, 2H), 5.60 (ε, IH), 7.10-7.25 (m, 3H) , 7.55-7.65 (m, IH). -233- General procedure fo the alkylation of inidazo[4,5-b] pyridines with 2-bromophenylacetic esters: Step D: Preparation of 3-[4-(l-carbomethoxy)-l-(2- 5 methylphenyl)methoxyphenyl]methy1-7-methyl- 2-propyl-3H-imidazor4.5-blpvridine To a suεpenεion of 37 mg (0.32 mmol) of a 35% oil diεperεiσn of potaεsium hydride in 0.5 mL of DMF waε added 0.090 g (0.32 mmol) of 3-(4-hydroxy- 1 0 phenyl)methyl-7-methyl-2-propyl-3H-imidazo[4,5-b] pyridine (Example 2, Step D) and the reaction waε εtirred under an N 2 atmoεphere. After εtirring for 15 minutes, 0.085 g of 18-crown-6 was added followed by addition of a εolution of 0.090 g (0.35 mmol) of 15 the product of Step C disεolved in 0.75 mL of DMF. The reaction mixture was stirred for 4 hours, then concentrated in vacuo. The reεidue waε purified on a εilica gel flaεh chromatography column eluted with 40% ethyl acetate/hexane to afford 0.099 g (68%) of 2o the title compound. --E NMR (300 MHz, CDCI3, ppm): δ 0.90-1.00 (t, 3H) , 1.15-1.25 (t, 3H), 1.65-1.80 (m, 2H), 2.45 (ε, 3H), 2.65 (ε, 3H) 2.70-2.80 (t, 2H), 4.05-4.25 (m, 2H), 5.35 (ε, 2H), 5.75 <s» IH), 6.75-6.85 (d, 2H), 25 6.95-7.05 (m, 3H), 7.10-7.25 (m, 3H), 7.45-7.55 (m, IH), 8.15-8.20 (d, IH) . FAB-MS: m/e 458 (M+U, ; » 30 -234- General procedure for ester hydrolysis: Step E: Preparation of 3-[4-(l-carboxy)-l-(2-methyl¬ phenyl)methoxyphenyl]methyl-7-methyl-2- propyl-3H-imidazor4.5-blpvridine To a solution of 0.097 g (0.21 mmol) of the product of Step D diεεolved in 3 mL of ethanol was added 1 mL of a 1 N NaOH solution. The reaction mixture was εtirred at room temperature for 1.5 hourε, neutralized to pH 7 with 1 N HCl and then concentrated in vacuo. The reεidue was purified on a silica gel flash chromatography column eluted with CHCl 3 /MeOH/NH4θH (80:15:1) to afford 0.076 g (84%) of the title compound. l E NMR (300 MHz, CDC1 3 , ppm): δ 0.90-1.00 (t, 3H) , 1.65-1.75 (m, 2H) , 2.50 (s, 3H), 2.70 (s, 3H), 2.85-2.95 (t, 2H), 5.50 (s, 2H), 5.85 (s, IH), 6.85-6.95 (d, 2H), 7.05-7.15 (d, 2H), 7.15-7.25 (m, 4H), 7.45-7.55 (d, IH), 8.20-8.25 (d, IH) . FAB-MS: m/e 430 (M+l). Example 19 3-[ -(1-Carboxy-l-(2-ethoxyphenyl))methoxyphenyl]- -ethyl-7-methyl-2-propyl-3H-imidazor4.5-b1pvririi*ne Step A: Preparation of ethyl 2-bromo-2-(2-ethoxy- phenvl)acetate Using the general procedure for the synthesis of 2-bromophenylacetic esters from benzaldehydes (Steps A-C, Example 18), 1.00 g (6.67 mmol) of -235- 2-ethoxybenzaldehyde was converted to 0.291 g (1.01 mmol) of the title compound in 15% overall yield. - • E NMR (300 MHz, CDC1 3 , ppm): d 1.30-1.40 (t, 3H), 1.45-1.55 (t, 3H), 4.00-4.10 (m, 2H), 4.15-4.30 (m, 2H), 5.85 (s, IH), 6.80-6.85 (d, IH), 6.90-7.00 (t, IH), 7.00-7.30 (t, IH), 7.55-7.65 (d, IH) . Step B: Preparation of 3-[4-(l-carbomethoxy)-l-(2- ethoxyphenyl)methoxyphenyl]methyl-7-methyl- 2-propvl-3H-imidagor .5-blpvridine Using the general procedure for the alkylation reaction described in Step D of Example 18, 0.089 g (0.32 mmol) of 3-(4-hydroxyphenyl)methyl- 7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine (Example 2, Step D) was alkylated with 0.100 g (0.35 mmol) of the product of Step A, to afford 0.107 g (69%) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 0.85-0.95 (t, 3H), 1.10-1.20 (t, 3H), 1.30-1.40 (t, 3H), 1.60-1.76 (m, 2H), 2.65 (s, 3H), 2.70-2.80 (t, 2H) , 4.00-4.25 (m, 4H), 5.35 (s, 2H), 6.05 (ε, IH), 6.80-7.05 (m, 6H), 7.20-7.30 (m, 2H), 7.40-7.50 (d, IH), 8.15-8.20 (d, IH). Step C: Preparation of 3-[4-(l-carboxy)-l-(2-ethoxy- phenyl)methoxyphenyl]methyl-7-methyl-2- ropvl-3H-imidazor4.5-b1pvridine Using the general procedure for eεter hydrolyεis deεcribed in Step E of Example 19, 0.107 g (0.22 mmol) of the product of Step B was converted to 0.087 g (86%) of the title compound. -236- ■-E NMR (300 MHz, CD3OD, ppm): δ 0.90-1.00 (t, 3H), 1.35-1.45 (t, 3H), 1.50-1.65 (m, 2H), 2.70 (ε, 3H), 2.80-2.90 (t, 2H), 4.05-4.20 (m, 2H), 5.50 (ε, 2H), 6.05 (ε, IH), 6.90-7.05 (m, 3H), 7.05-7.10 (m, 3H), 7.15-7.20 (d, IH), 7.25-7.35 (t, IH), 7.45-7.50 (d, IH), 8.20-8.25 (d, IH). FAB-MS: m/e 460 (M+l). Example 20 3-[4-(1-Carboxy-l-(2-(1-hexyloxy)phenyl))methoxy- phenyl]methyl-7-methyl-2-propyl-3H-imidazo[4,5-b] pyridine Step A: Preparation of ethyl 2-bromo-2-(2-(l- hexyloxy)phenvl)acetate Using the general procedure for the εyntheεiε of 2-bromophenylacetic eεterε from benzaldehydeε (Steps A-C, Example 18), 0.50 g (2.43 mmol) of 2-hexyloxybenzaldehyde was converted to 0.088 g (0.26 mmol) of the title compound in 117. overall yield. 1 H NMR (300 MHz, CDCI3, ppm): δ 0.85-0.95 (t, 3H), 1.20-1.55 (m, 9H), 1.75-1.85 (m, 2H), 3.95-4.05 (t, 2H), 4.15-4.30 (m, 2H), 5.85 (s, IH), 6.80-6.85 (d, IH), 6.90-7.00 (t, 3H), 7.20-7.30 (t, IH), 7.55-7.65 (d, IH). Step B: Preparation of 3-[4-(l-carbomethoxy)-l-(2-(l- hexyloxy)phenyl)methoxyphenyl]methyl-7- methvl-2-propvl-3H-imidazor4.5-blpvridine -237- Using the general procedure for the alkylation reaction described in Step D of Example 18, 0.065 g (0.23 mmol) of 3-(4-hydroxyphenyl)methyl- 7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine (Example 2, Step D) was alkylated with 0.088 g (0.25 mmol) of the product of Step A, to afford 0.090 g (71%) of the title compound. λ E NMR (300 MHz, CDCI3, ppm): d 0.80-0.90 (t, 3H), 0.90-1.00 (t, 3H), 1.15-1.50 (m, 9H), 1.65-1.80 (m, 4H), 2.65 (s, 3H), 2.70-2.80 (t, 2H), 3.95-4.05 (t, 2H), 4.05-4.25 (m, 2H), 5.35 (ε, 2H), 6.05 (ε, IH), 6.80-7.05 (m, 6H), 7.20-7.30 (m, 2H), 7.40-7.45 (d, IH), 8.15-8.20 (d, IH). Step C: Preparation of 3-[4-(l-carboxy)-l-(2-(l- hexyloxy)phenyl)methoxyphenyl]methyl-7- methvl-2-propvl-3H-imidazor4.5-b1pvricl-i-nP Uεing the general procedure for eεter hydrolyεiε deεcribed in Step E of Example 19, 0.090 g (0.17 mmol) of the product of Step B was converted to 0.072 g (85%) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 0.80-0.90 (t, 3H), 0.90-1.00 (t, 3H), 1.20-1.35 (m, 4H), 1.50-1.60 (m, 2H), 1.60-1.85 (m, 2H), 2.65 (ε, 3H), 2.80-2.90 (t, 2H), 3.95-4.05 (m, 2H), 5.50 (ε, 2H), 6.05 (s, IH), 6.90-7.05 (m, 4H), 7.05-7.15 (d, 2H), 7.15-7.20 (d, IH), 7.25-7.35 (t, IH), 7.40-7.45 (d, IH) , 8.20-8.25 (d, IH). FAB-MS: m/e 516 (M+l). -238- Example 21 3-[4-(1-Carboxy-l-(2-methoxyphenyl))methoxyphenyl]- methyl-7-methyl-2-propyl-3H-imidazor4.5-blpyridine Step A: Preparation of ethyl 2-bromo-2-(2-methoxy¬ phenyl)acetate Uεing the general procedure for the εyntheεis of 2-bromophenylacetic esterε from benzaldehydes (Steps A-C, Example 18), 1.00 g (7.35 mmol) of 2-methoxybenzaldehyde was converted to 0.736 g (2.69 mmol) of the title compound in 37% overall yield. l E NMR (300 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H), 3.85 (s, 3H), 4.15-4.30 (m, 2H), 5.85 (ε, IH), 6.80-6.90 (d, IH), 6.90-7.00 (t, IH) , 7.25-7.35 (t, IH), 7.55-7.65 (d, IH). Step B: Preparation of 3-[4-(l-carbomethoxy)-l-(2- methoxyphenyl)methoxyphenyl]methyl-7-methyl- 2-propvl-3H-imidazor4.5-blpvridine Using the general procedure for the alkylation reaction deεcribed in Step D of Example 18, 0.090 g (0.32 mmol) of 3-(4-hydroxyphenyl)methyl- 7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine (Example 2, Step D) waε alkylated with 0.096 g (0.35 mmol) of the product of Step A, to afford 0.126 g (83%) of the title compound. --E NMR (300 MHz, CDC1 3 , ppm): δ 0.90-1.00 (t, 3H), 1.15-1.25 (m, 3H), 1.65-1.80 ( , 2H), 2.65 (ε, 3H), 2.70-2.80 (t, 2H), 4.05-4.25 (m, 2H), 5.35 (ε, 2H) , 6.05 (ε, IH), 6.80-7.05 (m, 7H), 7.25-7.35 (m, IH), 7.45-7.50 (d, IH), 8.15-8.20 (d, IH). FAB-MS: m/e 474 (M+l). -239- Step C: Preparation of 3-[4-(l-carboxy)-l-(2-methoxy- phenyl)methoxyphenyl]methyl-7-methyl-2- ropvl-3H-imidazor4.5-b1-pvridine Using the general procedure for ester hydrolysis described'In Step E of Example 19, 0.123 g (0.26 mmol) of the product of Step B waε converted to 0.095 g (82%) of the -έitle compound. --E NMR (300 MHz, CD3OD, ppm): δ 0.90-1.00 (t, 3H), 1.60-1.80 (m, 2H), 2.60 (s, 3H), 2.80-2.90 (t, 2H), 10 3.90 (s, 3H), 5.50 (s, 2H), 6.00 (ε, IH), 5.90-7.15 (m, 6H), 7.15-7.20 (d, IH), 7.2Q-7.25 (t, IH), 7.45-7.55 (d, IH), 8.20-8.25 (d, IH). FAB-MS: m/e 446 (M+l). 15 Example 22 3-[4-(l-Carboxy-l-(naphth-l-yl))methoxyphenyl]methyl- 7-methyl-2-propvl-3H-imidazor4.5-b1pvridine 2 0 Step A: Preparation of ethyl 2-bromo-2-(naphth-l- yl~)acetate Uεing the general procedure for the εynthesis of 2-bromophenylacetic eεters from benzaldehydeε (Steps A-C, Example 18), 1.00 ' g (6.40 mmol) of 1-naph- 25 thaldehyde was converted to 0.694 g (2.69 mmol) of * the title compound in 37% overall yield. - ■ E NMR (300 MHz, CDCI3, ppm) δ 1.20-1.30 (t, 3H) , 4.15-4.35 (m, 2H), 6.15 (ε, IH), 7.40-7.65 (m, 3H), 7.75-7.95 (m, 3H), 8.05-8.15 (d, IH). 30 EI-MS: m/e 292, 294 (M + , 1:1 ratio). -240- Step B: Preparation of 3-[4-(l-carbomethoxy-l- (naphth-1-yl))methoxyphenyl]methyl-7-methyl- 2-propvl-3H-imidazor4.5-b1pvridine Using the general procedure for the alkyla- tion reaction deεcribed in Step D of Example 18, 0.090 g (0.32 mmol) of 3-(4-hydroxyphenyl)methyl-7-methyl-2- propyl-3H-imidazo[4,5-b]pyridine (Example 2, Step D) was alkylated with 0.103 g (0.35 mmol) of the product of Step A, to afford 0.132 g (84%) of the title compound. - ■ E NMR (300 MHz, CDC1 3 , ppm) δ 0.85-0.95 (t, 3H), 1.05-1.15 (t, 3H), 1.60-1.80 (m, 2H), 3.65 (s, 3H), 3.70-3.80 (t, 2H), 4.05-4.25 (m, 2H), 5.35 (ε, 2H), 6.20 (ε, IH), 6.80-6.90 (d, 2H), 6.95-7.05 (m, 3H), 7.40-7.60 (m, 3H), 7.65-7.75 (d, IH), 7.80-7.90 (m, 2H), 8.15-8.20 (d, 2H), 8.20-8.30 (d, IH). FAB-MS: m/e 494 (M+l). Step C: Preparation of 3-[4-(l-carboxy-l-(naphth-l- yl))methoxyphenyl]methyl-7-methyl-2-propyl- 3H-imidazor4.5-blpvridine Using the general procedure for ester hydrolysiε deεcribed in Step E of Example 19, 0.125 g (0.25 mmol) of the product of Step B waε converted to 0.108 g (91%) of the title compound. * - *■ _ NMR (300 MHz, CD3OD, ppm): δ 0.90-1.00 (t, 3H), 1.50-1.75 (m, 2H), 2.70 (ε, 3H), 2.80-2.90 (t, 2H), 6.50 (s, 2H), 6.20 (s, IH), 6.95-7.05 (d, 2H) , 7.05-7.15 (d, 2H), 7.15-7.20 (d, IH), 7.45-7.55 (m, 3H), 7.80-7.95 (m, 2H), 8.15-8.25 (d, IH), 8.35-8.45 (d, IH). FAB-MS: m/e 466 (M+l). -241- Ezample 23 3_[4_(l-Carboxy-l-(3-methylnaphth-2-yl))methoxy- phenyl]methyl-7-methyl-2-propyl-3H-imidazo[4,5-b] 5 pyridine Step A: Preparation of ethyl 2-bromo-2-(3-methyl- naphth-2-vl)acetate Using the general procedure for the syntheεis 10 of 2-bromophenylacetic eεterε from benzaldehydes (Steps A-C, Example 18), 1.00 g (5.88 mmol) of 3-methyl-2-naphthaldehyde was converted to 0.953 g (3.10 mmol) of the title compound in 53% overall yield. 15 1 H NMR (300 MHz, CDC1 3 , ppm): δ 1.20-1.30 (t, 3H) , 2.55 (s, 3H), 4.20-4.40 (m, 2H), 5.60 (s, IH), 7.40-7.50 (m, 2H) , 7.65 (s, IH), 7.70-7.75 (d, 2H) , 7.75-7.85 (d, IH), 8.10 (s, IH). EI-MS: m/e 306, 308 (M + , 1:1 ratio). 20 Step B: Preparation of 3-[4-(l-carbomethoxy-l-(3- methylnaphth-2-yl))methoxyphenyl]methyl-7- ethvl-2-propvl-3H-imidazor4.5-blpvridine Using the general procedure for the 25 alkylation reaction described in Step D of Example * 18, 0.090 g (0.32 mmol) of 3-(4-hydroxyphenyl)methyl- 7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine (Example 2, Step D) was alkylated with 0.108 g (0.35 mmol) of the product of Step A, to afford 0.121 g (75%) of the 30 title compound. -242- -•E NMR (300 MHz, CDCI3, ppm): δ 0.85-0.95 (t, 3H), 1.15-1.25 (m, 2H), 1.65-1.75 (m, 2H), 2.60 (s, 3H), 2.65 (ε, 3H), 2.70-2.80 (t, 2H), 4.05-4.30 (m, 2H), 5.40 (ε, 2H), 5.85 (ε, IH), 6.80-6.90 (d, 2H), 6.95-7.05 (m, 3H), 7.35-7.45 (m, 2H), 7.65 (s, IH), 7.70-7.80 (m, 2H), 8.00 (ε, IH), 8.15-8.20 (d, IH). FAB-MS: m/e 508 (M+l). Step C: Preparation of 3-[4-(l-carboxy-l-(3- methylnaphth-2-yl))methoxyphenyl]methyl-7- methyl-2-propyl-3H-imidazor4.5-blpvridine Uεing the general procedure for eεter hydrolysis described in Step E of Example 19, 0.090 g (0.32 mmol) of the product of Step B was converted to 0.121 g (75%) of the title compound. --E NMR (300 MHz, CD3OD, ppm): δ 0.85-0.95 (t, 3H), 1.60-1.75 (m, 2H), 2.60 (s, 3H), 2.54 (s, 3H), 2.80-2.90 (t, 2H), 5.50 (s, 2H), 5.85 (s, IH) , 6.95-7.05 (d, 2H), 7.05-7.15 (d, 2H), 7.35-7.50 (m, 2H), 7.65 (s, IH), 7.75-7.85 (t, 2H), 8.00 (s, IH), 8.15-8.25 (d, IH) FAB-MS: m/e Example 24 3-[4-(1-Carboxy-l-(2-methylphenyl))methoxyphenyl]- methyl-5.7-dimethyl-2-ethyl-3H-imidazor4.5-blpyridine -243- Step A: Preparation of 2-nitramino-4,6-dimethyl- pyridine 2-Amino-4,6-dimethylpyridine (10.0 g, 81.8 mmol) was added portion-wise to 65 mL of H2SO (cone. —c• d=1.84) which was εtir * r.ed (mechanical) at 0°C. After complete addition, the mixture waε warmed to room temperature until the mixture became homogeneouε. The solution was then cooled to -10°C and a pre-cooled (0 β C) mixture of cone _N0 3 (11.5 mL, d = 1.40) and 10 H2SO4 (8.2 mL, d = 1.84) was added at such a rate as not to raise the internal reaction temperature above -9 β C. Ten minutes after the addition was complete this cooled (-10 β C) mixture was poured onto 400 g of crushed ice. The resulting εlurry waε neutralized by 15 the addition of cone NH4OH (to pH 5.5) while cooling (ice bath). The εolid was isolated by filtration, and dried at room temperature to give 13.3 g of the title compound as a white εolid. 0 Step B: Preparation of 2-amino-3-nitro-4,6-dimethyl- pyridine : To 75 mL of εtirred cone H2SO 4 cooled to -5°C (ice-εalt bath) was added 4,6-dimethyl-2- nitraminopyridine (13.2 g, 79 mmol) portion-wise at 5 such a rate aε to maintain the internal temperature below -3 β C. The mixture waε warmed to 0 # C until homogeneous (30 minutes) at which time tic (Si0 2 , 1:1 EtOAc/hexanes on a NH4OH neutralized aliquot) indicated that the rearrangement was complete. The 0 mixture was poured onto 400 g of crushed ice and the pH waε adjuεted to 5.5 by the addition of cone -244- NH4OH. The resulting yellow slurry was cooled to 0 β C, filtered, washed with cold water (50 mL), and dried at room temperature to give 10.32 g of a mixture of the title compound and the 5-nitro isomer in a 55:45 ratio (determined by -^H NMR). This mixture was used directly in the next εtep. Step C: Preparation of 5,7-dimethyl-2-ethylimidazo T4,5-l>1pyr d ne To a mixture of 8.44 g of a 55:45 mixture of 2-amino-3-nitro-4,6-dimethylpyridine and 2-amino-5- nitro-4,6-dimethylpyridine in MeOH (1.2 L) waε added 10 % Pd/C (2.4 g). The reaction veεεel waε evacuated then purged with H 2 at 1 atm. and εtirred vigorously for 18 h. Filtration through a celite pad, and concentration gave 6.65 g of a mixture of 2,3-diamino- 4,6-dimethylpyridine and 2,5-diamino-4,6-dimethyl- pyridine as a dark εolid. To 5.40 g (39.4 mmol) of this mixture was added propionic acid (8.80 mL, 118 mmol) followed by polyphoεphoric acid (100 mL) . This εtirred mixture waε heated to 90 β C for 3 h then to 100 β C for 1 hour. The inεide walls of the flask were scraped with a spatula to asεiεt diεεolution of the εolidε. After the reaction waε complete, the warm mixture was poured onto 300 g of ice and the mixture was made basic with NH4OH. The mixture waε extracted (4 x 50 mL CH 2 C1 2 ), dried (K 2 C0 3 ) and concentrated to give a mixture of the title compound and 4,6-dimethyl- 2,5-bis(propionamido)pyridine. Purification (Si0 2 , 5% MeOH/ EtOAc) gave 1.66 g of the title compound as the εlower eluting component. -245- --E NMR (CD3OD, 300 MHz, ppm): δ 6.95 (s, IH), 2.92 (q, J=7.8 Hz, 2H), 2.54 (apparent s, 6H), 1.40 (t, J=7.8 Hz, 3H). 5 Step D: Preparation of 3-(4-(benzyloxy)phenyl)- methyl-5,7-dimethyl-2-ethyl-3H-imidazo T4.5-blpvridine To a εuspension of 0.503 g (12.5 mmol) of a 607. oil dispersion of sodium hydride in 20 mL of DMF 1 Q was added 2.0 g (11.4 mmol) of the product of Step C and the mixture was stirred at room temperature. After 25 minutes, 2.92 g (12.5 mmol) of 4-benzyloxy- benzyl chloride and a catalytic amount of sodium iodide were added and the reaction was stirred for an 5 additional 4 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgSθ4), filtered and evaporated. The residual oil was purified on a εilica gel flaεh 2 0 chromatography column eluted with 30% ethyl acetate/hexane to afford 3.33 g (79%) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H), 2.55 (s, 3H), 2.60 (s, 3H), 2.70-2.80 (m, 2H), 5.00 25 (ε, 2H), 5.35 (ε, 2H), 6.80-6.90 (m, 3H), 7.00-7.10 (d, 2H), 7.25-7.45 (m, 5H) . FAB-MS: m/e 372 (M+l). * 30 -246- Step E: Preparation of 5,7-dimethyl-2-ethyl-3-(4- hydroxyphenyl)methyl-3H-imidazo[4,5-b] pyridine A solution of 1.40 g (3.77 mmol) of the product of Step D dissolved in 38 mL of methanol waε placed in a Parr hydrogenation flask and 0.140 g of 10% Pd/C catalyεt waε added. The reaction mixture was placed in a Parr apparatus and rocked under a hydrogen atmoεphere (32 psig) for 2 hourε. The reaction mixture was then filtered through a plug of εilica gel eluted with 20% methanol/chloroform to remove the catalyεt. Evaporation of the filtrate and drying in vacuo afforded 0.650 g (61%) of the title compound. l E NMR (300 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H), 3.64 (s, 3H), 3.66 (ε, 3H), 2.85-2.95 (m, 2H), 5.45 (s, 2H), 6.70-6.80 (d, 2H), 6.95-7.05 (m, 3H) . FAB-MS: m/e 282 (M+l). Step F: Preparation of 3-[4-(l-carboethoxy-l-(2- methylphenyl)methoxyphenyl]methyl-5,7- dimethyl-2-ethyl-3H-imidazor4.5-b1pyridine To a εuεpension of 0.108 g (0.94 mmol) of potassium hydride in 2 mL of DMF was added 0.264 g (0.94 mmol) of the product of Step E and the reaction mixture was stirred under an N 2 atmosphere. After 10 minutes, 0.248 g (0.94 mmol) of 18-crown-6 and a solution of 0.266 g (1.03 mmol) of ethyl 2-bromo-2-(2- methylphenyl)acetate (Example 18, Step C) disεolved in 1 mL DMF were added and the reaction was then stirred an additional 15 minutes. The reaction -247- mixture waε then partitioned between ethyl acetate and water. The organic layer waε εeparated, waεhed with water, brine, dried (MgSU ), filtered and evaporated. The reεidual oil waε purified on a εilica gel flaεh chromatography column eluted with 40% ethyl acetate/hexane to afford 0.338 g (79%) of the title compound. ^ • H NMR (300 MHz, CDCI3, ppm): δ 1.10-1.20 (t, 3H), 1.20-1.30 (t, 3H), 2.45 (ε, 3H), 2.55 (ε, 3H), 2.60 (s, 3H), 2.70-2.80 (m, 2H), 4.05-4.25 (m, 2H), 5.35 (s, 2H), 5.70 (s, IH), 6.75-6.85 (d, 2H), 6.88 (s, IH), 6.95-7.05 (d, 2H) 7.15-7.25 (m, 3H), 7.45-7.55 (d, IH). FAB-MS: m/e 458 (M+l). Step G: Preparation of 3-[4-(l-carboxy-l-(2-methyl- phenyl)methoxyphenyl]methyl-5,7-dimethyl-2- ethvl-3H-imidazor4.5-blpvridine Using the general procedure for eεter hydrolyεis described in Step E of Example 19, 0.060 g (0.13 mmol) of the product of Step F was converted to 0.054 g (96%) of the title compound. ■ -E NMR (300 MHz, CD3OD, ppm): δ 1.20-1.30 (t, 3H) , 2.50 (s, 3H), 2.60 (ε, 3H), 2.65 (ε, 3H), 2.85-2.95 (m, 2H), 5.50 (ε, 2H), 5.85 (ε, IH), 6.90-7.00 (d, 2H), 7.05-7.15 (m, 3H), 7.15-7.25 (m, 3H), 7.50-7.55 (d, IH). FAB-MS: m/e 430 (M+l). -248- Example 25 3-[4-(1-Carboxy-l-(2-chlorophenyl))methoxyphenyl]- methyl-5.7-dimethvl-2-ethvl-3H-imidazor4.5-blpvridine Step A: Preparation of 3-[4-(l-carboethoxy-l-(2- chlorophenyl)methoxyphenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-blpvridine Using the procedure described in Step F of Example 24, 0.050 g (0.18 mmol) of 5,7-dimethyl-2- ethyl-3-(4-hydroxyphenyl)methyl-3H-imidazo[4,5-b] pyridine (Example 24, Step E) waε alkylated with 0.052 g (0.20 mmol) of methyl 2-bromo-(2'-chloro)- phenylacetate (Example 4, Step A) to afford 0.053 g (64%) of the title compound. Step B: Preparation of 3-[4-(l-carboxy-l-(2-chloro- phenyl)methoxypheny1]methy1-5,7-dimethyl-2- ethyl-3H-imidazor4.5-blpvridine Uεing the general procedure for eεter hydrolysis described in Step E of Example 19, 0.048 g (0.10 mmol) of the product of Step A was converted to 0.036 g (78%) of the title compound. 1 H NMR (300 MHz, CD3OD, ppm): δ 1.20-1.30 (t, 3H), 2.60 (ε, 3H), 2.63 (ε, 3H), 2.85-2.95 (m, 2H), 5.50 (ε, 2H), 6.05 (ε, IH), 6.90-7.00 (d, 2H), 7.05-7.15 (m, 3H), 7.30-7.40 (m, 2H), 7.40-7.50 (m, IH), 7.60-7.65 (m, IH) . FAB-MS: m/e 450, 452 (M+l, 3:1 ratio). -249- E-gample 26 3-[4-(1-Carboxy-1-(2-bromophenyl))methoxyphenyl]- methvl-5.7-dimethvl-2-ethvl-3H-imidazor4.5-blpvridine Step A: Preparation of methyl 2-bromo-2-(2-bromo¬ phenyl)acetat Commercially available 2-bromophenylacetic acid (5.00 g, 23.3 mmol) waε converted to 4.89 g (68%) of the title compound in a procedure similar to that described in Step A of Example 3. --E NMR (300 MHz, CDCI3, ppm): δ 3.80 (s, 3H) , 5.90 (ε, IH), 7.15-7.20 (t, IH), 7.20-7.25 (t, IH), 7.50-7.55 (d, IH), 7.70-7.75 (d, IH). FAB-MS: m/e 306, 308, 310 (M+l, 1:2:1 ratio). Step B: Preparation of 3-[4-(l-carbomethoxy-l-(2- bromophenyl)methoxyphenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-blpyridine Uεing the procedure deεcribed in Step F of Example 24, 0.050 g (0.18 mmol) of 5,7-dimethyl-2- ethyl-3-(4-hydroxyphenyl)methyl-3H-imidazo[4,5-b] pyridine (Example 24, Step E) waε alkylated with 0.060 g (0.20 mmol) of the product of Step A to afford 0.077 g (85%) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H), 2.55 (ε, 3H), 2.60 (s„ 3H), 2.65-2.75 (m, 2H), 3.75 (ε, 3H), 5.35 (s, 2H), 6.05 (s, IH), 6.80-6.90 (m, 3H), 6.95-7.05 (d, 2H), 7.15-7.35 (m, 2H), 7.50-7.60 (d, 2H). FAB-MS: m/e 508, 510 (M+l, 1:1 ratio). -250- Step C: Preparation of 3-[4-(l-carboxy-l-(2- bromophenyl)methoxyphenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-blpvridine Uεing the general procedure for ester hydrolyεiε deεcribed in Step E of Example 19, 0.077 g (0.15 mmol) of the product of Step B waε converted to 0.065 g (86%) of the title compound. ■ -E NMR (300 MHz, CD3OD, ppm): δ 1.20-1.30 (t, 3H), 2.64 (s, 3H), 2.66 (s, 3H), 2.85-2.95 (m, 2H), 5.50 (s, 2H), 5.95 (s, IH), 6.90-7.00 (d, 2H), 7.05-7.15 (m, 3H), 7.20-7.30 (t, IH), 7.30-7.40 (t, IH), 7.60-7.70 (m, 2H). FAB-MS: m/e 494, 496 (M+l, 1:1 ratio). Example 27 3-[4-(1-Carboxy-l-phenyl)methoxyphenyl]methy1-5,7- dimethyl-2-ethyl-3H-imidazor4.5-blpvridine Step A: Preparation of methyl 2-(4-bromomethyl- phenoxv)-2-ρhenvlacetate To a εolution of 0.710 g (2.77 mmol) of methyl 2-(4-methylphenoxy)phenylacetate (Step A of Example 13) diεεolved in 10 mL of CCI4, waε added 0.494 g (2.77 mmol) of N-bromosuccinimide, and 25 mg of AIBN (catalytic amount). The mixture waε stirred and heated to reflux for 4 hours, then cooled to room temperature and concentrated in vacuo. The residue was purified on a εilica gel flaεh chromatography column (25 x 170 mm) eluted with 5% ethyl acetate/ hexane to afford 0.509 g (55%) of the title compound. -251- -Ε NMR (300 MHz, CDCI3, ppm): δ 3.75 (ε, 3H), 4.5 (ε, 2H), 5.65 (s, IH), 6.9-7.0 (d, 2H), 7.3-7.35 (d, 2H), 7.35-7.5 (m, 3H), 7.5-7.6 (d, 2H). EI-MS: m/e 334, 336 (M+, 1:1 ratio). Step B: Preparation of 3-[4-(l-carbomethoxy-l- pheny1)methoxypheny1]methyl-5,7-dimethyl-2- ethyl-3B-imidazς>r .5-b1pyridine To a suεpenεion of 12 mg of a 60% oil dispersion of sodium hydride in 1 mL of DMF was added 0.050 g (0.29 mmol) of 5,7-dimethyl-2-ethylimidazo [4,5-b]pyridine (Example 24, Step C) and the mixture was stirred at room temperature under an N 2 atmosphere. After 15 minutes, a εolution of 0.105 g (0.32 mmol) of the product of Step A diεεolved in 1 mL of DMF waε added and the reaction was εtirred an additional 75 minutes. The mixture was then concentrated in vacuo and purified on a silica gel flash chromatography column eluted with 507. ethyl acetate/hexane to afford 0.068 g (55%) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H), 2.55 (ε, 3H), 2.60 (s, 3H), 2.70-2.80 (m, 2H), 3.70 (s, 3H), 5.35 (s, 2H), 5.55 (s, IH), 6.80-6.90 (m, 3H), 7.00-7.05 (d, 2H), 7.25-7.45 (m, 3H), 7.45-7.55 (m, 2H). FAB-MS: m/e 430 (M-+1). Step C: Preparation of 3-[4-(1-carboxy-l-phenyl)- methoxyphenyl]methyl-5,7-dimethyl-2-ethyl- 3H-imidazor4.5-blpvridine -252- Uεing the general procedure for eεter hydrolyεiε deεcribed in Step E of Example 19, 0.065 g (0.15 mmol) of the product of Step B waε converted to 0.044 g (70%) of the title compound. l E NMR (300 MHz, CD3OD, ppm): δ 1.20-1.30 (t, 3H), 3.60 (ε, 3H), 3.65 (ε, 3H), 2.85-2.95 (m, 2H), 5.50 (ε, 2H), 5.65 (8, IH), 6.90-7.00 (d, 2H), 7.05-7.15 (m, 3H), 7.35-7.45 (m, 3H), 7.55-7.65 (m, 2H) . FAB-MS: m/e 416 (M+l). Example 28 3-[3-Chloro-4-((1-carboxy-l-phenyl)methoxy)phenyl]- methvl-7-methvl-2-propvl-3H-imidazor4.5-blpvridine Step A: Preparation of methyl 2-(2-chloro-4-methyl- phenoxy)-2-phenvlacetate To a εuspenεion of 0.282 g (7.04 mmol) of a 607. oil diεperεion of εodium hydride in DMF waε added 1.00 g (7.04 mmol) of 2-chloro-4-methylphenol and the mixture was stirred under an N atmoεphere at room temperature. After 10 minutes, a solution of 1.94 g (8.45 mmol) of methyl 2-bromophenylacetate dissolved in 10 mL of DMF was added and the reaction was εtirred an additional 1.5 hourε. The reaction waε then diluted into ethyl acetate, waεhed with water, dried ( S04), filtered and evaporated. The reεidue waε purified on a εilica gel flash chromatography column eluted with 4% ethyl acetate/hexane to afford 1.70 g (83%) of the title compound. -253- l E NMR (300 MHz, CDCI3, ppm): δ 2.20 (s, " 3H), 3.70 (ε, 3H), 5.60 (ε, IH), 6.70-6.80 (d, IH), 6.85-6.95 (d, IH), 7.20 (br ε, IH), 7.20-7.30 (m, 3H), 7.55-7.65 (m, 2H). EI-MS: m/e 290 (M+). Step B: Preparation of methyl 2-(2-chloro-4-bromo- methylphenoxy)-2-phenylacetate To a εolution of 1.70 g (5.86 mmol) of the product from Step A diεsolved in 20 mL of CCI4 was added 1.04 g (5.86 mmol) of N-bromosuccinimide and 50 mg (catalytic amount)" of AIBN. The reaction mixture was stirred and heated at reflux for 7 hourε, then an additional 0.20 g of NBS was added. The reaction was refluxed for 48 hours, then cooled and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 10% ethyl acetate/hexane to afford 0.73O g (34%) of the title compound. X H NMR (300 MHz, CDCI3, ppm): δ 3.70 (s, 3H), 4.40 (s, 2H), 5.65 (ε, IH), 6.75-6.85 (d, IH), 7.10-7.20 (d, IH), 7.30-7.45 (m, 4H), 7.55-7.65 (m, 2H). FAB-MS: m/e 369 (M+l). Step C: Preparation of 3-[3-chloro-4-((l-carbo- methoxy-l-phenyl)methoxy)phenyl]methyl-7- τnethvl-2-prόpyl-3B-imidazor4.5-blpyridine The product of Step B (0.127 g, 0.34 mmol) was used to alkylate 0.050 g (0.29 mmol) of 7-methyl- 2-propylimidazo[4,5-b]pyridine (Example 2, Step B) according to the procedure described for Step D of Example 3, which after purification afforded 0.059 g (45%) of the title compound. -254- -Ε NMR (300 MHz, CDC1 3 , ppm): δ 0.90-1.00 (t, 3H), 1.65-1.80 (m, 2H), 2.65 (ε, 3H), 2.65-2.80 (t, 2H), 3.70 (ε, 3H), 5.35 (ε, 2H), 5.60 (s, IH), 6.70-6.75 (d, IH), 6.85-6.95 (d, IH), 7.00-7.05 (d, IH), 7.20 (br ε, IH), 7.30-7.45 (m, 3H), 7.50-7.60 (m, 2H), 8.15-8.20 (d, IH). FAB-MS: m/e 464 (M+l). Step D: Preparation of 3-[3-chloro-4-((l-carboxy-l- phenyl)methoxy)phenyl]methyl-7-methyl-2- propvl-3H-imidazor4.5-b1pvridine Uεing the general procedure for eεter hydrolyεiε described in Step E of Example 19, 0.059 g (0.13 mmol) of the product of Step C was converted to 0.040 g (70%) of the title compound. l E NMR (300 MHz, CD3OD, ppm): δ 0.90-1.00 (t, 3H), 1.65-1.80 (m, 2H) , 2.70 (s, 3H), 2.85-2.95 (t, 2H), 5.50 (s, 2H), 5.75 (s, IH), 6.95-7.10 (m, 2H), 7.15-7.20 (d, IH), 7.25 (br ε, IH), 7.35-7.45 ( , 3H), 7.60-7.70 (m, 2H), 8.20-8.25 (d, IH). FAB-MS: m/e 450 (M+l). Example 29 3-[3-Chloro-4-((1-carboxy-l-phenyl)methoxy)phenyl]- methyl-5.7-dimethvl-2-ethvl-3H-imidazor4.5-blpyridine Step A: Preparation of 3-[3-chloro-4-((l-carbo- methoxy-1-phenyl)methoxy)phenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-blpyridine -255- The product of Example 28, Step B (0.127 g, 0.34 mmol) was used to alkylate 0.050 g (0.29 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 24, Step C) according to the procedure 5 described for Step B of Example 27, which after purification afforded 0.080 g (61%) of the title compound. ^ ■ H NMR (300 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H), 2.55 (s, 3H), 2.60 (ε, 3H) , 2.65-2.80 (m, 2H), 3.70 10 (ε, 3H), 5.35 (ε, 2H), 5.60 (ε, IH), 6.80-6.85 (d, IH), 6.85-6.95 (m, 2H), 7.20-7.25 (d, IH), 7.30-7.45 (m, 3H), 7.50-7.60 (m f 2H). FAB-MS: m/e 464 (M+l). 15 Step B: Preparation of 3-[3-chloro-4-((1-carboxy-l- phenyl)methoxy)phenyl]methyl-5,7-dimethyl-2- ethvl-3H-imidazoT4.5-blpvridine Uεing the general procedure for eεter hydrolysis described in Step E of Example 19, 0.080 g 20 (0.17 mmol) of the product of Step A was converted to 0.047 g (60%) of the title compound. 1 H NMR (300 MHz, CD3OD, ppm): δ 1.25-1.35 (t, 3H), 2.60 (s, 3H), 2.65 (s, 3H) , 2.85-2.95 (m, 2H), 5.50 (s, 2H), 5.75 (s, IH), 6.95-7.10 (m, 3H) , 7.25 (s, 25 IH), 7.35-7.45 (m, 3H), 7.60-7.70 (m, 2H) . FAB-MS: m/e 450 (M+l). * 30 -256- Esample 30 3-[3-Benzoyl-4-((1-carboxy-l-phenyl)methoxy)phenyl]- methyl-5.7-dimethvl-2-ethvl-3H-imidazor4.5-b1pyririine Step A: Preparation of methyl 2-(2-benzoyl-4-methyl- phenoxv)-2-phenvlacetate To a εolution of 1.00 g (4.72 mmol) of 2-hydroxy-5-methylbenzophenone and 1.19 g (5.19 mmol) of methyl 2-bromophenylacetate in 10 mL of acetone was added 1.30 g (9.44 mmol) of CU3 and the mixture was stirred and refluxed for 14 hourε. The mixture was cooled, filtered and evaporated in vacuo and the residue was purified on a silica gel flash chromato- graphy column eluted with 5% ehtyl acetate/hexane to afford 0.320 g (19%) of the title compound. --E NMR (300 MHz, CDCI3, ppm): δ 2.30 (ε, 3H), 3.60 (s, 3H), 5.50 (s, IH), 6.65-6.75 (d, IH), 6.90-7.00 (d, 2H), 7.10-7.25 (m, 4H), 7.30 (ε, IH), 7.40-7.50 (m, 2H), 7.50-7.55 (m, IH), 7.80-7.90 (m, 2H). FAB-MS: m/e 361 (M+l). Step : Preparation of methyl 2-(2-benzoyl-4-bromo- methvlphenoxv)-2-phenvlacetate To a εolution of 0.314 g (0.87 mmol) of the product of Step A diεsolved in 10 mL of CCI4 was added 0.155 g (0.87 mmol) of N-bromoεuccinimide and 15 mg (catalytic amount) of AIBN. The mixture waε stirred at reflux for 7 hourε, then cooled filtered and evaporated in vacuo. The reεidue was purified on a εilica gel flaεh chromatography column eluted with -257- 15% ethyl acetate/hexane to afford 0.136 g (36%) of the title compound. ■ -E NMR (300 MHz, CDCI3, ppm): δ 3.65 (ε, 3H), 4.50 (ε, 2H), 5.55 (ε, IH), 6.75-6.85 (d, IH) 6.90-7.00 5 (d, 2H), 7.10-7.25 (m, 4H), 7.40-7.60 (m, 4H), 7.80-7.90 (d, 2H). FAB-MS: m/e 440 (M+l). Step C: Preparation of 3-[3-benzoyl-4-((l-carbo- 10 methoxy-l-phenyl)methoxy)phenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-blpvridine The product of Step B (0.136 g, 0.31 mmol) was used to alkylate 0.049 g (0.28 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 5 24, Step C) according to the procedure described for Step B of Example 27, which after purification afforded 0.066 g (44%) of the title compound. -J-H NMR (300 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H), 2.50 (s, 3H), 2.55 (s, 3H), 2.65-2.80 (m, 2H), 3.80 20 (s, 3H), 5.30 (s, 3H), 6.80-7.30 (m, 14H) . FAB-MS: m/e 534 (M+l). Step D: Preparation of 3-[3-benzoyl-4-((1-carboxy- l-phenyl)methoxy)phenyl]methyl-5,7-dimethyl- 25 2-ethvl-3H-imidazoT .5-blpvridine Using the general procedure for ester hydrolysiε deεcribed in Step E of Example 19, 0.060 g * (0.11 mmol) of the product of Step C waε converted to 0.031 g (537.) of the title compound. 30 --E NMR (300 MHz, CD3OD, ppm): δ 1.20-1.30 (t, 3H), 2.55 (s, 3H), 2.60 (s, 3H), 2.70-2.80 (m, 2H), 5.50 (s, 3H), 6.85-7.35 (m, 14H). FAB-MS: m/e 520 (M+l). -258- Egample 31 3-[3-Acetyl-4-((1-carboxy-l-phenyl)methoxy)phenyl]- methyl-5.7-dimethyl-2-ethyl-3H-imidazor4.5-blpyridine Step A: Preparation of methyl 2-(2-acetyl-4-methyl- phenoxy>-2-phenvlacetate Using the 2 C03/acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.67 mmol) of 2'-hydroxy-5'-methylaceto- phenone was alkylated with 1.68 g (7.34 mmol) of methyl 2-bromophenylacetate to afford 1.25 g (63%) of the title compound. 1 H NMR (400 MHz, CDCI3, ppm): δ 2.25 (s, 3H), 2.70 (s, 3H), 3.70 (ε, 3H), 5.70 (d, IH), 6.65-6.75 (d, IH), 7.10-7.20 (d, IH), 7.30-7.45 (m, 4H), 7.50-7.60 (m, 2H). FAB-MS: m/e 299 (M+l). Step B: Preparation of methyl 2-(2-acetyl-4-bromo- methylphenoxy)-2-phenylacetate To a solution of 1.25 g (4.19 mmol) of the product of Step A dissolved in 15 mL of CCI4 was added 0.821 g (4.61 mmol) of N-bromosuccinimide and 20 mg (catalytic amount) of AIBN. The mixture was εtirred at reflux for 3.5 hourε, then cooled, filtered and evaporated in vacuo. The residue was purified on a εilica gel flaεh chromatography column eluted with 15% ethyl acetate/hexane to afford 0.431 g (27%) yield of the title compound. -259- --E NMR (400 MHz, CDC1 3 , ppm): δ 2.75 (s, 3H), 3.75 (ε, 3H), 4.45 (ε, 2H), 5.70 (ε, IH), 6.75-6.80 (d, 2H), 7.35-7.45 (m, 4H), 7.50-7.60 (m, 2H), 7.75 (ε, IH). 5 Step C: Preparation of 3-[3-acetyl-4-((l-carbo- methoxy-l-phenyl)methoxy)phenyl]methyl-5,7- dimethyl-2-ethvl-3H-imidazor4.5-blpvridine The product of Step B (0.119 g, 0.31 mmol) 10 was used to alkylate 0.050 g (0.28 mmol) of 5,7- dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 24, Step C) according to the procedure deεcribed for Step B of Example 27, which after purification afforded 0.040 g (30%) of the title compound. 15 --E NMR (400 MHz, CDCI3, ppm): δ 1.20 (ε, 3H), 1.20-1.30 (t, 3H), 2.55 (8, 3H), 2.60 (s, 3H), 2.70-2.80 ( , 2H), 3.75 (ε, 3H), 5.35 (ε, 3H), 6.85 (s, IH), 6.95-7.00 (d, IH), 7.05-7.10 (ε, IH), 7.15 (s, IH), 7.20-7.30 (m, 3H) , 7.50-7.55 (m, 2H) . 20 FAB-MS: m/e 472 (M+l). Step D: Preparation of 3-[3-acetyl-4-((l-carboxy-l- phenyl)methoxy)phenyl]methyl-5,7-dimethyl-2- thvl-3H-imidazor4.5-blpvridine 25 Uεing the general procedure for eεter hydrolysis described in Step E of Example 19, 0.038 g (0.08 mmol) of the product of Step C was converted to 4. 0.016 g (43%) of the title compound. * -•E NMR (400 MHz, CD3OD, ppm): δ 1.15 (s, 3H), 30 1.20-1.30 (t, 3H), 2.55 (s, 3H), 2.60 (s, 3H), 2.85-2.95 (m, 2H) , 5.50 (s, 3H), 6.95-7.05 (m, 2H), 7.05 (8, IH), 7.10 (s, IH), 7.25-7.35 (m, 3H), 7.60-7.70 (m, 2H) . FAB-MS: m/e 458 (M+l). -260- Example 32 3-[4-((l-Carboxy-l-phenyl)methoxy)-3-methoxyphenyl]- methyl-5.7-dimethyl-2-ethyl-3H-imidazoT4.5-blpvridine Step A: Preparation of methyl 2-(4-hydroxymethyl-2- methoxyphenoxv^-Σ-phenvlacetate Using the K 2 CU3/acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.49 mmol) of 4-hydroxy-3-methoxybenzyl alcohol was alkylated with 1.64 g (7.14 mmol) of methyl 2-bromophenylacetate to afford 0.495 g (257.) of the title compound. --E NMR (300 MHz, CDCI3, ppm): δ 1.20-1.30 (t, IH), 3.70 (s, 3H), 3.85 (s, 3H), 4.60 (d, 2H), 5.65 (s, IH), 6.75-6.85 (m, 2H), 6.95 (ε, IH), 7.30-7.40 (m, 3H), 7.50-7.60 (m, 2H). FAB-MS: m/e 303 (M+l). Step B: Preparation of methyl 2-(4-bromomethyl-2- methoxyphenoxv)-2-phenvlacetate To a cooled (0 β C) εolution of 0.490 g (1.62 mmol) of the product of Step A diεεolved in 8 mL of CH 2 C1 2 waε added 0.673 g (2.03 mmol) of carbon tetrabromide and 0.531 g (2.03 mmol) of triphenyl- phosphine. The reaction mixture was εtirred for 1.5 hours and was allowed to εlowly warm to room temper¬ ature. The reaction mixture waε then concentrated in vacuo. and purified on a εilica gel flaεh chromato- graphy column eluted with 15% ethyl acetate/hexane to afford 0.478 g (81%) of the title compound. -261- X H NMR (300 MHz, CDCI3, ppm): δ 3.75 (ε, 3H), 3.85 (ε, 3H), 4.40 (ε, 2H), 5.60 (s, IH), 6.75-6.85 (m, 2H), 6.90 (ε, IH), 7.30-7.40 (m, 3H), 7.50-7.60 (m, 2H). Step C: Preparation of 3-[4-((l-carbomethoxy-l- phenyl)methoxy)-3-methoxyphenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-blpvridine The product of Step B (0.115 g, 0.31 mmol) waε uεed to alkylate 0.050 g (0.28 mmol) of 5,7- dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 24, Step C) according to the procedure described for Step B of Example 27, which after purification afforded 0.084 g (64%) of the title compound. 1 H NMR (300 MHz, CDC1 3 , ppm): δ 1.20-1.30 (t, 3H) , 2.55 (s, 3H), 2.60 (s, 3H), 2.70-2.80 (m, 2H), 3.70 (ε, 3H), 3.75 (s, 3H), 5.35 (s, 2H), 5.55 (s, IH), 6.50-6.60 (d, IH), 6.70-6.75 (d, IH) , 6.80 (s, IH), 6.85 (s, IH), 7.30-7.40 (m, 3H) , 7.45-7.55 (m, 2H). FAB-MS: m/e 460 (M+l). Step D: Preparation of 3-[4-((l-carboxy-l-phenyl)- methoxy)-3-methoxyphenyl]methyl-5,7-dimethyl- 2-ethvl-3H-imidazor4.5-blpvridine Using the general procedure for ester hydrolysiε deεcribed in Step E of Example 19, 0.080 g (0.17 mmol) of the product of Step C waε converted to 0.064 g (82%) of the title compound. - ■ E NMR (300 MHz, CD3OD, ppm): δ 1.20-1.30 (t, 3H), 2.60 (ε, 3H), 2.62 (s, 3H), 2.85-2.95 (m, 2H), 3.80 (s, 3H), 5.50 (s, 3H), 6.50-6.60 (d, IH), 6.80-6.90 (d, IH), 6.95 (ε, IH), 7.05 (ε, IH), 7.30-7.40 (m, 3H), 7.55-7.65 (m, 2H). FAB-MS: m/e 446 (M+l). -262- Example 33 3-[3-tert-Butyl-4-((1-carboxy-l-phenyl)methoxy)- ρhenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pvridine Step A: Preparation of methyl 2-(2-tert-butyl-4- methylphenoxv Σ-phenvlacetate To a suspension of 1.05 g (9.15 mmol) of a 0 35% oil dispersion of KH in 15 mL of DMF was added 1.50 g (9.15 mmol) of 2-tert-butyl-4-methylphenol and the mixture was εtirred under N at room temperature. After 10 minuteε, 2.41 g (91.5 mmol) of 18-crown-6 and then a εolution of 2.30 g (10.1 mmol) of methyl 5 2-bromophenylacetate diεsolved in 10 mL of DMF were added. THe reaction mixture waε εtirred 17 hourε, then partitioned between ethyl acetate and water. The organic layer waε εeparated, waεhed with water, dried (MgSU4), filtered and evaporated. The reεidue o was purified on a εilica gel flaεh chromatography column eluted with 5% ethyl acetate/hexane to afford 0.750 g (26%) of the title compound. l E NMR (300 MHz, CDCI3, ppm): δ 1.43 (ε, 9H), 2.24 (s, 3H), 3.68 (s, 3H), 5.64 (s, IH), 6.56 (d, J=10 5 Hz, IH), 6.86 (dd, J=2, 10 Hz, IH), 7.12 (d, J=2 Hz, IH), 7.30-7.44 (m, 3H), 7.54-7.62 (m, 2H). Step B: Preparation of methyl 2-(2-tert-butyl-4- bromomethvlphenoxy)-2-phenylacetat.e To a solution of 0.494 g (1.58 mmol) of the product of Step A dissolved in 10 mL of CCI4 was -263- added 0.310 g (1.74 mmol) of N-bromosuccinimide and 15 mg (catalytic amount) of AIBN and the mixture was heated at reflux for 3.5 hourε. The reaction waε cooled, filtered and evaporated in vacuo. The reεidue waε purified on a εilica gel flaεh chromato¬ graphy column eluted with 3% ethyl acetate/hexane to afford 0.134 g (22%) of the title compound. - ■ E NMR (300 MHz, CDC1 3 , ppm): δ 1.44 (ε, 3H), 3.70 (ε, 3H), 4.45 (ε, 2H), 5.64 (ε, IH), 6.70 (d, J=10 Hz, IH), 7.12 (dd, J=2, 10 Hz, IH), 7.22 (d, J=2 Hz, IH), 7.32-7.42 (m, 3H) , 7.53-7.60 (m, 2H) . Step C: Preparation of 3-[3-tert-butyl-4-((l-carbo- methoxy-1-phenyl)methoxy)phenyl]methyl-5,7- dimethyl-2-ethvl-3H-imidazor4.5-blpvridine The product of Step B (0.128 g, 0.33 mmol) was used to alkylate 0.052 g (0.30 mmol) of 5,7- dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 24, Step C) according to the procedure described for Step B of Example 27, which after purification afforded 0.088 g (62%) of the title compound. - ■ E NMR (300 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H), 1.40 (s, 9H), 2.55 (ε, 3H), 2.60 (s, 3H) , 2.75-2.85 (m, 2H), 3.65 (ε, 3H), 5.30 (ε, 2H), 5.60 (ε, IH), 6.45-6.55 (d, IH), 6.70-6.80 (d, IH), 6.85 (br s, IH), 7.25-7.40 (m, 4H), 7.50-7.55 (m, 2H). FAB-MS: m/e 486 (M+l). Step D: Preparation of 3-[3-tert-butyl-4-((l-carboxy- l-phenyl)methoxy)phenyl]methyl-5,7-dimethyl- -ethvl-3H-imidazor4.5-blpvridine -264- Uεing the general procedure for ester hydrolysiε deεcribed in Step E of Example 19, 0.080 g (0.16 mmol) of the product of Step C waε converted to 0.056 g (73%) of the title compound. --E NMR (300 MHz, CD3OD, ppm): δ 1.25-1.35 (t, 3H), 1.40 (ε, 9H), 2.63 (ε, 3H), 2.65 (ε, 3H), 2.85-2.95 (m, 2H), 5.50 (ε, 2H), 5.65 (ε, IH), 6.75-6.85 (d, IH), 6.90-6.95 (d, IH), 7.05 (ε, IH), 7.30 (ε, IH), 7.35-7.45 (m, 3H), 7.60-7.70 (m, 2H) . FAB-MS: m/e 472 (M+l). Example 34 3-[ -((1-carboxy-l-phenyl)methoxy)-3-ethoxyphenyl]- methyl-5.7-dimethvl-2-ethvl-3H-imidazor4.5-blpyridine Step A: Preparation of methyl 2-(2-ethoxy-4-formyl- phenoxy)phenvlacetate Uεing the K 2 C03/acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.02 mmol) of 3-ethoxy-4-hydroxybenzaldehyde was alkylated with 1.52 g (6.62 mmol) of methyl 2-bromophenylacetate to afford 1.74 g (92%) of the title compound. ~-E NMR (300 MHz, CDCI3, ppm): δ 1.40-1.50 (t, 3H), 3.85 (s, 3H), 4.10-4.20 (m, 2H), 5.75 (ε, IH), 6.95 (s, IH), 7.20-7.35 (m, 5H), 7.50-7.60 ( , 2H) , 9.85 (s, IH). FAB-MS: m/e 315 (M+l). -265- Step B: Preparation of methyl 2-(2-ethoxy-4-hydroxy- ethylphenoxv)phenvlacetate A εtirred εolution of 1.74 g (5.54 mmol) of the product of Step A disεolved in 22 mL of methanol waε treated with 0.105 g (2.8 mmol) of sodium borohydride at room temperature. After 5 minutes the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid, and the organic layer was separated. The product waε waεhed with water, brine, dried (MgS04), filtered and evaporated in vacuo. The reεidue was purified on a εilica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 1.15 g (66%) of the title compound. l E NMR (300 MHz, CDCI3, ppm): δ 1.20-1.30 (t, IH), 1.35-1.45 (t, 2H), 3.70 (s, 3H), 4.05-4.15 (m, 2H), 4.60 (s, 2H), 5.65 (ε, IH) , 6.75-6.80 (d, IH) , 6.85-6.95 (m, 2H), 7.30-7.40 (m, 3H), 7.50-7.60 (m, 2H). FAB-MS: m/e 317 (M+l). Step C: Preparation of methyl 2-(4-bromomethyl-2- ethoxyphenoxv phenylacetate To a εtirred and cooled (0°C) εolution of 1.15 g (3.64 mmol) of the product of Step B dissolved in 18 mL of CH 2 C1 2 was added 1.51 g (4.55 mmol) of carbon tetrabromide and 1.19 g (4.55 mmol) of triphenylphosphine. After the addition the reaction mixture was stirred 30 minutes and allowed to warm to room temperature. The mixture was then evaporated in vacuo and purified on a εilica gel flaεh chromato¬ graphy column eluted with 15% ethyl acetate/hexane to afford 1.21 g (88%) of the title compound. -266- -Ε NMR (300 MHz, CDCI3, ppm): δ 1.35-1.45 (t, 3H), 3.75 (ε, 3H), 4.05-4.15 (m, 2H), 4.40 (ε, 2H), 5.65 (ε, IH), 6.80-6.90 (m, 2H), 6.95 (ε, IH), 7.35-7.45 (m, 3H), 7.50-7.60 (m, 2H). FAB-MS: m/e 378, 380 (M+l). Step D: Preparation of 3-[4-((l-carbόmethoxy-l- phenyl)methoxy)-3-ethoxyphenyl]methyl-5,7- dimethyl-2-ethvl-3H-imidazor4.5-blpvridine The product of Step C (0.119 g, 0.31 mmol) was used to alkylate 0.055 g (0.28 mmol) of 5,7- dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 24, Step C) according to the procedure described for Step B of Example 27, which after purification afforded 0.084 g (62%) of the title compound. - NMR (400 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H) , 1.30-1.40 (t, 3H), 2.55 (ε, 3H), 2.60 (ε, 3H), 2.70-2.80 (m, 2H), 3.70 (ε, 3H), 3.90-4.00 (m, 2H), 5.30 (s, 2H), 5.60 (s, IH), 6.50-6.55 (d, IH) , 6.75-6.80 (m, 2H), 6.85 (ε, IH), 7.30-7.40 (m, 3H) , 7.50-7.55 (m, 2H) . FAB-MS: m/e 474 (M+l). Step E: Preparation of 3-[4-((l-carboxy-l-phenyl)- methoxy)-3-ethoxyphenyl]methyl-5,7-dimethyl- 2-ethvl-3H-imi zo^4■5-b^pvridine Uεing the general procedure for eεter hydrolyεis described in Step E of Example 19, 0.080 g (0.17 mmol) of the product of Step D was converted to 0.069 g (88%) of the title compound. -267- λ E NMR (400 MHz, CD3OD, ppm): δ 1.20-1.30 (t, 3H), 1.30-1.40 (t, 3H), 2.55 (ε, 3H), 2.60 (ε, 3H), 2.80-2.90 (m, 2H), 3.95-4.05 (m, 2H), 5.45 (ε, 2H), 5.50 (ε, IH), 6.50-6.55 (d, IH), 6.80-6.85 (m, 2H), 5 7.25-7.35 (m, 3H), 7.50-7.55 (m, 2H). Example 35 3-C4-((l-Carboxy-l-pheny1)methoxy)-3-methylpheny1]- 10 methyl-5.7-dimethvl-2-ethvl-3H-imidazor4.5-blpvridine Step A: Preparation of methyl 2-(4-formyl-2-methyl- henoxy)phenylacetate Using the K2C03/acetone conditionε for 15 phenol alkylation deεcribed in Step A of Example 30, 0.50 g (3.68 mmol) of 4-hydroxy-3-methylbenzaldehyde was alkylated with 0.926 g (4.05 mmol) of methyl 2-bromophenylacetate to afford 1.00 g (96%) of the title compound. 2o X H NMR (400 MHz, CDCI3, ppm): δ 2.40 (s, 3H), 3.70 (s, 3H), 5.70 (s, 1H>, 6.80 (d, IH), 7.35-7.45 (m, 3H), 7.55-7.60 (m, 2H), 7.65 (d, IH), 7.70 (ε, IH), 9.85 (s, IH). FAB-MS: m/e 285 (M+l). 25 Step B: Preparation of methyl 2-(4-hydroxymethyl-2- methvlphenoxv)phenvlace te \ A εtirred εolution of 1.00 g (3.52 mmol) of the product of Step A diεεolved in 14 mL of methanol 30 waε treated with 0.067 g (1.8 mmol) of εodium borohydride at room temperature. After 15 minuteε -268- the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid, and the organic layer was separated. The product waε washed with water, brine, dried (MgSθ ), filtered and evaporated in vacuo. The residue waε purified on a εilica gel flaεh chromatography column eluted with 30% ethyl acetate/hexane to afford 0.660 g (66%) of the title compound. - ■ E NMR (400 MHz, CDCI3, ppm): δ 2.10 (ε, IH), 2.35 (s, 3H), 3.70 (s, 3H), 4.55 (ε, 2H), 5.65 (ε, IH), 6.70 (d, IH), 7.05 (d, IH), 7.15 (ε, IH), 7.35-7.45 (m, 3H), 7.55-7.65 (m, 2H). FAB-MS: m/e 287 (M+l). Step C: Preparation of methyl 2-(4-hydroxymethyl-2- methvlphenoxv)phenvlacetate To a εtirred and cooled (0 β C) εolution of 0.660 g (2.31 mmol) of the product of Step B diεεolved in 12 mL of CH 2 C1 2 waε added 0.957 g (2.89 mmol) of carbon tetrabromide and 0.756 g (2.89 mmol) of triphenylphoεphine. After the addition the reaction mixture waε allowed to warm to room temperature and waε stirred overnight. The mixture was then evaporated in vacuo and purified on a εilica gel flash chromatography column eluted with 15% ethyl acetate/hexane to afford 0.704 g (87%) of the title compound. - • E NMR (400 MHz, CDCI3, ppm): δ 2.30 (ε, 3H) , 3.70 (s, 3H), 4.45 (s, 2H), 5.60 (s, IH) , 6.65 (d, IH) , 7.10 (d, IH), 7.20 (s, IH) , 7.35-7.45 (m, 3H), 7.55-7.60 (m, 2H). FAB-MS: m/e 269 (M+l). -269- Step D: Preparation of 3-[4-((l-carbomethoxy-l- phenyl)methoxy)-3-methylphenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-blpvridine The product of Step C (0.110 g, 0.31 mmol) 5 was used to alkylate 0.050 g (0.28 mmol) of 5,7- dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 24, Step C) according to the procedure deεcribed for Step B of Example 27, which after purification afforded 0.041 g (33%) of the title compound. 10 X H NMR (400 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H) , 2.25 (s, 3H), 2.55 (s, 3H), 2.60 (s, 3H), 2.70-2.80 ( , 2H), 3.65 (s, 3H), 5.35 (s, 2H), 5.55 (ε, IH), 6.60 (d, IH), 6.80 (d, IH), 6.85 (ε, IH), 6.95 (ε, IH), 7.30-7.40 (m, 3H), 7.50-7.55 (m, 2H). 15 FAB-MS: m/e 444 (M+l). Step E: Preparation of 3-[4-((1-carboxy-l-phenyl)- methoxy)-3-methylphenyl]methyl-5,7-dimethyl- 2-ethyl-3H-imidazor4.5-b1pyridine 20 Uεing the general procedure for eεter hydrolyεiε described in Step E of Example 19, 0.040 g (0.09 mmol) of the product of Step D was converted to 0.023 g (60%) of the title compound. ■-E NMR (400 MHz, CD3OD, ppm): δ 1.15-1.25 (t, 3H), 25 2,25 (s, 3H), 2.58 (ε, 3H), 2.60 (ε, 3H), 2.80-2.90 (m, 2H), 5.45 (ε, 2H), 5.60 (ε, IH), 6.75 (d, IH), *, 6.85 (d, IH), 6.95 (ε, IH), 7.05 (ε, IH), 7.30-7.40 ( , 3H), 7.55-7.65 (m, 2H) . « FAB-MS: m/e 430 (M+l). 30 - 270 - Example 36 3-[4-((l-Carboxy-l-(2-methylphenyl))methoxy)-3-chloro- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]- pvridine Step A: Preparation of methyl 4-tert-butyldimethyl- εilyloxy-3-chlorobenzoate To a εolution of 5.00 g (26.8 mmol) of methyl 3-chloro-4-hydroxybenzoate diεεolved in 40 mL of CH 2 C1 2 was added 6.55 g (53.6 mmol) of 4-dimethyl- aminopyridine, 4.85 g (32.2 mmol) of tert-butyl- dimethylchlorosilane and the mixture waε εtirred at room temperature for 3.5 hours. The reaction mixture was filtered, diluted with ethyl acetate, washed with 0.1 N HCl, saturated aHCU3, and brine. The product layer was then dried (MgSU4), filtered and evaporated in vacuo to afford 8.05 g (100%) of the title compound. λ E NMR (300 MHz, CDCI3, ppm): δ 0.25 (s, 6H), 1.00 (ε, 9H), 3.85 (ε, 3H), 6.85 (d, IH), 7.80 (d, IH), 8.05 (s, IH). FAB-MS: m/e 301, 303 (M+l). Step B: Preparation of 4-tert-butyldimethylsilyloxy- 3-chlorobenzvl alcohol To a εtirred and cooled (0°C) εolution of 8.00 g (26.7 mmol) of the product of Step A diεsolved in 50 mL of anhydrous THF was added 53.3 mL (53.3 mmol) of a 1 M εolution of lithium aluminum hydride in THF. After the addition waε complete the reaction - 271 - mixture was allowed to warm to room temperature and εtirred 2 hourε. The εtirred reaction waε then quenched by dropwise addition of 2.5 mL water, then 2.5 mL of 15% NaOH, and finally 7.5 mL water. The reaction mixture waε then filtered and concentrated in vacuo. The reεidue waε dissolved in ethyl acetate, washed with 1 N HCl, sturated aHC03» dried (MgS04), and evaporated in vacuo to afford 4.0 g (53%) of the title compound. --E NMR (300 MHz, CDC1 3 , ppm): δ 0.20 (ε, 6H), 1.00 (ε, 9H), 1.80 (br ε, IH), 4.55 (ε, 2H), 6.85 (d, IH), 7.10 (d, IH), 7.35 (ε, IH). FAB-MS: m/e 255, 257 (M+l). Step C: Preparation of 4-tert-butyldimethylεilyl- oxv-3-chlorobenzvl btomide To a εtirred and cooled (0°C) εolution of 4.00 g (14.1 mmol) of the product of Step B diεεolved in 70 mL of CH 2 C1 2 waε added 5.84 g (17.6 mmol) of carbon tetrabromide and 4.61 g (17.6 mmol) of triphenylphoεphine. After the addition the reaction mixture waε allowed to warm to room temperature and waε εtirred 3 hourε. The mixture waε then evaporated in vacuo and purified on a εilica gel flaεh chromato- graphy column eluted with 2% ethyl acetate/hexane to afford 4.50 g (92%) of the title compound. --E NMR (300 MHz, CDCI3, ppm): δ 0.20 (ε, 6H), 1.00 (8, 9H), 4.40 (ε, 2H), 6.80 (d, IH), 7.15 (d, IH), 7.35 (ε, IH). - 272 - Step D: Preparation of 3-(4-tert-butyldimethyl- silyloxy-3-chlorophenyl)methyl-5,7- imethyl- 2~ethvl-3H-imidazor4.5-blpvridine The product of Step C (1.79 g, 5.15 mmol) was uεed to alkylate 0.750 g (4.29 mmol) of 5,7- dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 24, Step C) according to the procedure deεcribed for Step B of Example 27, which after purification afforded 0.294 g (15%) of the title compound. --E NMR (300 MHz, CDCI3, ppm): δ 0.20 (ε, 6H), 1.00 (ε, 9H), 1.20-1.30 (t, 3H), 2.58 (s, 3H), 2.60 (s, 3H), 2.70-2.80 (m, 2H), 5.35 (s, 2H), 7.75 (d, IH), 7.85-7.90 (m, 2H), 7.15 (s, IH). FAB-MS: m/e 430, 432 (M+l). Step E: Preparation of 3-(3-chloro-4-hydroxyphenyl)- methyl-5,7-dimethyl-2-ethyl-3H-imidazo T4.5-blpyridine To a εolution of 0.294 g (0.661 mmol) of the product of Step D diεsolved in 4 mL of THF was added 0.69 mL (0.69 mmol) of a 1.0 M εolution of tetra-n- butylammonium fluoride in THF, and the reaction mixture was stirred 2 hourε at room temperature. The reaction was then concentrated in vacuo and purified by filtration through a εilica gel pad eluted with chloroform. Evaporation of the filtrate and drying in vacuo afforded 0.188 g (87%) of the title compound. --E NMR (300 MHz, CD3OD, ppm): δ 1.25-1.35 (t, 3H), 2.65 (ε, 3H), 2.67 (ε, 3H), 2.85-2.95 (m, 2H), 5.45 (ε, 2H), 6.90 (d, IH), 6.95 (d, IH), 7.05 (ε, IH), 7.15 (s, IH). FAB-MS: m/e 316, 318 (M+l). - 273 - Step F: Preparation of 3-[4-((l-carbomethoxy-l-(2- methylphenyl))methoxy)-3-chlorophenyl]methyl- 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine 5 To a suspension of 7 mg of a 60% oil disper¬ sion of sodium hydride in 0.75 mL of DMF was added 0.050 g (0.16 mmol) of the product of Step E and the reaction mixture was stirred 10 minutes under an N 2 atmosphere. A εolution of methyl 2-bromo-2'-methyl- 0 phenylacetate (prepared from 2'-methylphenylacetic acid via a Hell-Volhard-Zelinεky reaction εimilar to Step A of Example 17) diεsolved in 0.75 mL of DMF was then added and the reaction was stirred for 2 hourε at room temperature. The reaction mixture waε then 15 partitioned between ethyl acetate and water, the organic layer was separated, dried (MgS04), filtered and evaporated. The reεidue waε purified on a εilica gel flaεh chromatography column eluted with EtOAc/ hexane/CHCl 3 (50:40:10) to afford 0.070 g (92%) of 20 the title compound. - • E NMR (300 MHz, CDCI3, ppm): δ 1.25-1.35 (t, 3H), 2.45 (ε, 3H), 2.60 (ε, 3H), 3.65 (ε, 3H), 2.75-2.85 (m, 2H), 3.70 (ε, 3H), 5.35 (ε, 2H), 5.60 (ε, IH), 6.75 (d, IH), 6.85-6.95 (m, 2H), 7.15-7.40 (m, 4H) , 25 7.55-7.65 (m, IH). FAB-MS: m/e 478, 480 (M+l, 3:1 ratio). * 30 - 274 - Step G: Preparation of 3-[4-((1-carboxy-l-(2-methy1- phenyl))methoxy)-3-chlorophenyl]methyl-5,7- dimethyl-2-ethyl-3H-imidazor4.5-blpvridine Using the general procedure for ester hydrolysiε deεcribed in Step E of Example 19, 0.040 g (0.15 mmol) of the product of Step F waε converted to 0.066 g (97%) of the title compound. l E NMR (300 MHz, CD3OD, ppm): d 1.25-1.35 (t, 3H), 2.50 (ε, 3H), 2.63 (ε, 3H), 2.65 (ε, 3H), 2.85-2.95 (m, 2H), 5.50 (ε, 2H), 5.80 (ε, IH), 6.95-7.10 (m, 3H), 7.20-7.30 (m, 4H), 7.60 (d, IH). FAB-MS: m/e 464, 466 (M+l, 3:1 ratio). Example 37 3-[4-((1-Carboxy-l-phenyl)methoxy)-3-chloro-5- methoxyphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo ■T4.5-blpvridine Step A: Preparation of methyl 2-(2-chloro-4-hydroxy- methvl-6-methoxvphenoxv)-2-phenvlacetate Uεing the K 2 Cθ3/acetone conditionε for phenol alkylation described in Step A of Example 30, 0.50 g (2.65 mmol) of 3-chloro-4-hydroxy-5-methoxy- benzaldehyde was alkylated with 0.668 g (2.92 mmol) of methyl 2-bromophenylacetate to afford 0.570 g (64%) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 1.65-1.75 (t, IH), 3.70 (s, 3H), 3.80 (ε, 3H), 4.55 (d, 2H), 5.75 (ε, IH), 6.80 (S, IH), 6.90 (s, IH) , 7.30-7.40 (m, 3H), 7.50-7.60 (m, 2H) . FAB-MS: m/e 337, 339 (M+l, 3:1 ratio). - 275 - Step B: Preparation of 2-(4-bromomethyl-2-chloro-6- methoxvphenoxv)-2-phenvlacetate To a εtirred and cooled (0°C) solution of 0.570 g (1.69 mmol) of the product of Step A dissolved in 6 mL of CH C1 was added 0.702 g (2.11 mmol) of carbon tetrabromide and 0.555 g (2.11 mmol) of triphenylphosphine. After the addition the reaction mixture was allowed to warm to room temperature and was stirred 4 hourε. The mixture was then evaporated in vacuo and purified on a silica gel flash chromato¬ graphy column eluted with 20% ethyl acetate/hexane to afford 0.580 g (86%) of the title compound. -Ε NMR (300 MHz, CDC1 3 , ppm): δ 3.75 (s, 3H), 3.80 (s, 3Ξ), 4.35 (S, 2H), 5.65 (ε, IH), 6.80 (s, IH), 6.95 (ε, IH), 7.30-7.40 (m, 3H), 7.50-7.60 (m, 2H). FAB-MS: m/e 398, 400, 402 (M+l). Step C: Preparation of 3-[4-((l-carbomethoxy-l- phenyl)methoxy)-3-chloro-5-methoxyphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine The product of Step B (0.126 g, 0.31 mmol) was used to alkylate 0.050 g (0.29 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 24, Step C) according to the procedure described for Step B of Example 27, which after purification afforded 0.092 g (65%) of the title compound. ■-E NMR (300 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H), 2.55 (s, 3H), 2.60 (ε, 3H), 2.70-2.80 (m, 2H) , 3.65 (s, 3H), 3.70 (ε, 3H) , 5.30 (ε, 2H), 5.70 (s, IH) 6.63 (ε, IH), 6.68 (ε, IH), 6.90 (s, IH), 7.25-7.35 (m, 3H), 7.45-7.55 (m, 2H). FAB-MS: m/e 494, 496 (M+l). - 276 - Step D: Preparation of 3-[4-((1-carboxy-l-phenyl)- methoxy)-3-chloro-5-methoxyphenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-blpvridine Using the general procedure for ester hydrolyεiε deεcribed in Step E of Example 19, 0.090 g (0.18 mmol) of the product of Step C waε converted to 0.070 g (80%) of the title compound. - ■ E NMR (300 MHz, CD3OD, ppm): δ 1.20-1.30 (t, 3H), 2.60 (ε, 3H), 2.65 (s, 3H), 2.80-2.90 (m, 2H), 3.75 (s, 3H), 5.45 (s, 2H), 5.70 (ε, IH), 6.60 (ε, IH), 6.85 (ε, IH), 7.05 (ε, IH), 7.35-7.45 (m, 3H), 7.45-7.55 (m, 2H). FAB-MS: m/e 480, 482 (M+l, 3:1 ratio). Example 38 3-[4-((l-Carboxy-l-phenyl)methoxy)-3,5-dichloro¬ phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine Step A: Preparation of methyl 4-tert-butyldimethyl- silvloxv-3.5-dichlorobenzoate To a εolution of 10.00 g (45.2 mmol) of methyl 3,5-dichloro-4-hydroxybenzoate diεεolved in 100 mL of CH 2 C1 2 waε added 11.06 g (90.2 mmol) of 4-dimethylaminopyridine and 8.18 g (54.2 mmol) of tert-butyldimethylchlorosilane and the mixture waε εtirred under N 2 for 5 hourε. The reaction mixture waε then filtered and the filtrate waε diluted with ethyl acetate. The εolution was washed with water, 1 N HCl, εaturated NaHC03, dried (MgS04), filtered and - 277 - evaporated. The residue was purified on a silica gel flaεh chromatography column eluted with 5% ethyl acetate/hexane to afford 7.70 g (51%) of the title compound. l E NMR (300 MHz, CDCI3, ppm): δ 0.30 (ε, 6H), 1.00 (ε, 9H), 3.90 (ε, 3H), 7.95 (ε, 2H). FAB-MS: m/e 335, 337, 339 (M+l). Step B: Preparation of 4-tert-butyldimethylεilyloxy- 3.5-dichlorobenzvl alcohol To a εtirred and cooled (0°C) solution of 7.70 g (23.0 mmol) of the product of Step A diεεolved in 50 mL of anhydrous THF was added 23.0 mL (23.0 mmol) of a 1 M εolution of lithium aluminum hydride in THF. After the addition waε complete the reaction mixture was allowed to warm to room temperature and εtirred 3.5 hours. The εtirred reaction was then quenched by dropwise addition of 0.88 mL water, then 0.88 mL of 15% NaOH, and finally 2.62 mL water. The reaction mixture waε then filtered and concentrated in vacuo. " The reεidue waε diεsolved in ethyl acetate, washed with 1 N HCl, εturated NaHCθ3, dried (M Sθ4), and evaporated in vacuo to afford 1.83 g (267.) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 0.30 (ε, 6H), 1.05 (s, 9H), 1.80 (br ε, IH), 4.55 (s, 2H), 7.22 (s, 2H). FAB-MS: m/e 306 (M+l). - 278 - Step C: Preparation of 3,5-dichloro-4-hydroxybenzyl alcohol To a solution of 1.83 g (5.96 mmol) of the product of Step B dissolved in 6 mL of THF was added 5.96 mL (5.96 mmol) of a 1 M solution of tetra-n- butylammonium fluoride in THF and the reaction mixture was εtirred at room temperature 30 minuteε. The εolution waε then evaporated in vacuo and the reεidue waε purified on a εilica gel flaεh chromato- graphy column eluted with 4% methanol/chloroform to afford 0.733 g (64%) of the title compound. ■ -E NMR (300 MHz, CDCI3, ppm): δ 1.90-4.10 (br, 2H) 4.60 (ε, 2H), 7.27 (ε, 2H). FAB-MS: m/e 192 (M+l). Step D: Preparation of methyl 2-(2,6-dichloro-4- hydroxvmethvlphenoxv)-2-phenvlacetate Using the 2CO3/acetone conditions for phenol alkylation described in Step A of Example 30, 0.400 g (2.07 mmol) of the product of Step C was alkylated with 0.522 g (2.28 mmol) of methyl 2-bromophenylacetate to afford 0.144 g (20%) of the title compound. - ■ E NMR (300 MHz, CDCI3, ppm): δ 1.70-1.80 (t, 3H), 3.75 (s, 3H), 4.55 (d, 2H), 5.75 (s, IH), 7.22 (s, 2H), 7.30-7.40 (m, 3H), 7.45-7.55 (m, 2H). FAB-MS: m/e 341, 343, 345 (M+l, 10:6:1 ratio). - 279 - Step E: Preparation of methyl 2-(4-bromomethyl-2,6- ichlorophenoxv^-2-phenvlacetate To a stirred and cooled (0°C) solution of 0.140 g (0.41 mmol) of the product of Step D 5 diεεolved in 2 mL of CH 2 C1 2 was added 0.170 g (0.51 mmol) of carbon tetrabromide and 0.135 g (0.51 mmol) of triphenylphosphinfe. After the addition the reaction mixture was allowed to warm to room temper¬ ature and waε εtirred overnight. The mixture waε 10 then evaporated in vacuo and purified on a εilica gel flash chromatography column eluted with 15% ethyl acetate/hexane to afford 0.130 g (78%) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 3.75 (ε, 3H), 4.30 15 (ε, 2H), 5.75 (ε, IH), 7.27 (ε, 2H), 7.30-7.40 (m, 3H), 7.45-7.55 (m, 2H) . FAB-MS: m/e 405 (M+l). Step F: Preparation of 3-[4-((l-carbomethoxy-l- 20 phenyl)methoxy)-3,5-dichlorophenyl]methyl- 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine The product of Step E (0.126 g, 0.31 mmol) waε uεed to alkylate 0.050 g (0.29 mmol) of 5,7- 25 dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 24, Step C) according to the procedure deεcribed for Step B of Example 27, which after purification afforded 0.096 g (68%) of the title compound. ψ - ■ E NMR (300 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H), 30 2.58 (ε, 3H), 2.62 (ε, 3H), 2.65-2.75 (m, 2H), 3.75 (s, 3H), 5.30 (ε, 2H), 5.75 (ε, IH), 6.90 (ε, IH), 7.00 (8, 2H), 7.25-7.35 (m, 3H), 7.45-7.55 (m, 2H) . FAB-MS: m/e 498, 500, 502 (M+l). - 280 - Step 6: Preparation of 3-[4-((1-carboxy-l-phenyl)- methoxy)-3,5-dichloroρhenyl]methyl-5,7- dimethyl-2-ethvl-3H-imidazor4.5-blpyridine Using the general procedure for ester hydrolysiε deεcribed in Step E of Example 19, 0.092 g (0.18 mmol) of the product of Step F waε converted to 0.080 g (90%) of the title compound. - • E NMR (300 MHz, CD3OD, ppm): δ 1.20-1.30 (t, 3H), 2.61 (ε, 3H), 2.65 (s, 3H), 2.80-2.95 (m, 2H), 5.45 (ε, 2H), 5.65 (ε, IH), 7.05 (ε, 2H), 7.25-7.35 (m, 3H), 7.45-7.55 (m, 2H). FAB-MS: m/e 484, 486, 488 (M+l, 10:6:1 ratio). Example 39 3-[4-((1-Carboxy-l-phenyl)methoxy)-2-chlorophenyl]- methyl-5.7-dimethvl-2-ethvl-3H-imidazor4.5-blpvridine Step A: Preparation of methyl 2-(3-chloro-4-formyl- phenoxy -2-phenylacetate Uεing the K2CO3/acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.41 mmol) of 2-chloro-4-hydroxybenzaldehyde was alkylated with 1.61 g (7.05 mmol) of methyl 2-bromophenylacetate to afford 1.49 g (76%) of the title compound. --E NMR (300 MHz, CDCI3, ppm): δ 3.75 (s, 3H), 5.68 (s, IH), 6.90 (d, IH), 7.00 (s, IH), 7.35-7.45 ( , 3H), 7.50-7.60 (m, 2H), 7.85 (d, IH), 10.30 (ε, IH). FAB-MS: m/e 305, 307 (M+l). - 281 - Step B: Preparation of methyl 2-(3-chloro-4-hydroxy- methvlphenoχy)-2-phenvlacetate A stirred solution of 1.49 g (4.90 mmol) of the product of Step A dissolved in 20 L of methanol was treated with 0.093 g (2.46 mmol) of sodium borohydride at room temperature. After 5 minutes the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid, and the organic layer waε separated. ,,, The product waε waεhed with water, brine, dried ( SU4), filtered and evaporated in vacuo. The reεidue waε purified on a εilica gel flash chromatography column eluted with 25% ethyl acetate/hexane to afford 1.380 g (92%) of the title compound. λ E NMR (400 MHz, CDCI3, ppm): δ 1.80-1.85 (t, IH), 3.75 (s, 3H), 4.70 (d, 2H), 5.60 (ε, IH), 6.85 (d, IH), 7.00 (ε, IH), 7.30-7.45 (m, 4H), 7.50-7.60 (m, 2H). Step C: Preparation of methyl 2-(4-bromomethyl-3- chlorophenoxv)-2-phenvlacetate To a εtirred and cooled (O'C) εolution of 1.38 g (4.51 mmol) of the product of Step D diεsolved in 18 mL of CH 2 C1 2 was added 1.87 g (5.64 mmol) of carbon tetrabromide and 1.48 g (5.64 mmol) of triphenylphosphine. After the addition the reaction mixture waε allowed to warm to room temperature and waε εtirred 3 hourε. The mixture waε then evaporated in vacuo and purified on a εilica gel flash chromato- graphy column eluted with 10% ethyl acetate/hexane to afford 1.60 g (96%) of the title compound. - 282 - l E NMR (400 MHz, CDCI3, ppm): δ 3.75 (ε, 3H), 4.55 (ε, 2H), 5.60 (ε, IH), 6.80 (d, IH), 7.00 (ε, IH), 7.30 (d, IH), 7.35-7.45 (m, 3H), 7.50-7.60 (m, 2H). FAB-MS: m/e 369, 371, 373 (M+l). Step D: Preparation of 3-[4-((l-carbomethoxy-l- phenyl)methoxy)-2-chlorophenyl]methyl-5,7- dimethvl-2-ethvl-3B-imidazor4.5-blpvridine The product of Step C (0.116 g, 0.31 mmol) was used to alkylate 0.050 g (0.29 mmol) of 5,7- dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 24, Step C) according to the procedure described for Step B of Example 27, which after purification afforded 0.094 g (69%) of the title compound. 1 H NMR (400 MHz, CDCI3, ppm): δ 1.20-1.30 (t, 3H), 2.55 (s, 3H), 2.62 (s, 3H), 2.65-2.75 (m, 2H), 3.70 (s, 3H), 5.45 (s, 2H), 5.55 (s, IH), 6.45 (d, IH), 6.65 (d, IH), 6.90 (s, IH) , 7.05 (s, IH), 7.35-7.40 (m, 3H), 7.45-7.55 (m, 2H). FAB-MS: m/e 464, 466 (M+l, 3:1 ratio). Step E: Preparation of 3-[4-((1-carboxy-l-phenyl)- methoxy)-2-chlorophenyl]methyl-5,7-dimethyl- ?-ethvl-3H-imidazor4.5-blpvridine Uεing the general procedure for eεter hydrolyεis described in Step E of Example 19, 0.090 g (0.18 mmol) of the product of Step D was converted to 0.030 g (34%) of the title compound. λ E NMR (300 MHz, CD3OD, ppm): δ 1.25-1.35 (t, 3H) , 2.60 (s, 3H), 2.65 (s, 3H), 2.80-2.90 (m, 2H), 5.55-5.65 (m, 3H), 6.50 (d, IH), 6.85 (d, IH), 7.05 (ε, IH), 7.15 (ε, IH), 7.35-7.45 (m, 3H), 7.55-7.65 (m, 2H). FAB-MS: m/e 450, 452 (M+l, 3:1 ratio). - 283 - -Example 40 3-[4-((l-Carboxy-l-(3-phenyl)propyloxy)phenyl]methyl- 5.7-dimethvl-2-ethvl-3H-imidazor4.5-blpvridine Step A: Preparation of 3-[4-((l-carboethoxy-l-(3- phenyl)propoxy)phenyl]methyl-5,7- imethyl-2- ethyl-3fi-iffiidaapr ,5-blpyridine To a suspenεion of 20 mg (0.18 mmol) of a 0 35% oil diεpersion of KH in 0.4 mL of anhydrouε DMF was added 0.050 g (0.18 mmol) of 5,7-dimethyl-2-ethyl- 3-(4-hydroxyphenyl)methyl-3H-imidazo[4,5-b]pyridine (Example 24, Step E) and the reaction mixture waε εtirred under N 2 at room temperature. After 15 5 minuteε, 0.050 g (0.18 mmol) of 18-crown-6 and a εolution of 0.053 g (0.20 mmol) of ethyl 2-bromo-4- phenylbutanoate diεεolved in 0.4 mL of DMF were added. The reaction mixture waε εtirred at room temperature 4 hourε, then partitioned between ethyl o acetate and water. The organic layer waε εeparated, waεhed with water, dried (MgS04), filtered and evaporated. The reεidue waε purified on a εilica gel flaεh chromatography column eluted with 50% ethyl acetate/hexane to afford 0.063 g (75%) of the title 5 compound. l E NMR (300 MHz, CDCI3, ppm): δ 1.17 (t, J=8 Hz, 3H), 1.27 (t, J=8 Hz, 3H), 2.11-2.30 (m, 2H) , 2.56 (ε, 3H), 2.60 (ε, 3H), 2.70-2.90 (m, 4H), 4.15 (q, J=8 Hz, 2H), 4.50 (dd, J=6, 7 Hz, IH), 5.35 (ε, 2H), 6.74 (d, J=10 Hz, 2H), 6.86 (ε, IH), 7.04 (d, J=10 Hz, 2H), 7.10-7.28 (m, 5H). FAB-MS: m/e 472 (M+l). - 284 - Step B: Preparation of 3-[4-((l-carboxy-l-(3-phenyl)- propoxy)phenyl]methyl-5,7-dimethyl-2-ethyl- 3H-imidazor4.5-blpvridine Using the general procedure for ester hydrolysiε deεcribed in Step E of Example 19, 0.063 g (0.13 mmol) of the product of Step A waε converted to 0.047 g (80%) of the title compound. --E NMR (300 MHz, CD3OD, ppm): δ 1.27 (t, J=8 Hz, 3H), 2.16 (m, 2H), 2.63 (ε, 3H), 2.66 (ε, 3H), 2.80-2.95 (m, 4H), 4.55 (t, J=6 Hz, IH), 5.52 (ε, 2H), 6.86 (d, J=10 Hz, 2H), 7.07 (s, IH), 7.12 (d, J=10 Hz, IH), 7.15-7.32 (m, 5H). FAB-MS: m/e 444 (M+l). Example 41 3-t4-((l-Carboxy-l-(2-phenyl)ethoxy)phenyl]methyl-5,7- dimethyl-2-ethyl-3H-imidazor4.5-blpyridine Step A: Preparation of methyl 2-(4-hydroxymethyl- phenoxv^acetate Uεing the 2 Cθ3/acetone conditionε for phenol alkylation described in Step A of Example 30, 8.00 g (64.5 mmol) of 4-hydroxybenzyl alcohol was alkylated with 11.84 g (77.4 mmol) of methyl bromo- acetate to afford 6.00 g (48%) of the title compound. - ■ E NMR (300 MHz, CDCI3, ppm): δ 1.74 (br ε, IH), 3.76 (ε, 3H), 4.61 (br s, 4H), 6.86 (d, J=10 Hz, 2H) , 7.26 (d, J=10 Hz, 2H). FAB-MS: m/e 305 (M+l). - 285 - Step B: Preparation of methyl 2-(4-tert-butyl- dimethvlsilvlo-vmethvlphenoxv)acetate To a εolution of 4.00 g (20.4 mmol) of the product of Step A dissolved in 30 mL of CH C1 was added 5.00 g (40.8 mmol) of 4-dimethylaminopyridine and 3.69 g (24.5 mmol) of tert-butyldimethylchloro- εilane and the mixture waε εtirred under N for 5 hourε. The reaction mixture waε then filtered and the filtrate waε diluted with ethyl acetate. The εolution waε waεhed with water, 1 N HCl, εaturated aHCθ3, dried (M Sθ4), filtered and evaporated. Drying in vacuo afforded 6.30 g (99%) of the title compound. l E NMR (300 MHz, CDC1 3 , ppm): δ 0.09 (ε, 6H), 0.94 (ε, 9H), 3.80 (ε, 3H), 4.63 (s, 2H) , 4.68 (ε, 2H), 6.86 (d, J=10 Hz, 2H), 7.26 (d, J=10 Hz, 2H) . FAB-MS: m/e 311 (M+l). Step C: Preparation of methyl 2-(4-tert-butyl- dimethylεilyloxymethylphenoxy)-3-phenyl- ropanoate A solution of 1.00 g (3.23 mmol) of the product of Step B disεolved in 4 mL of toluene was stirred under a N 2 atmosphere and cooled to 0 β C with an ice-water bath. To thiε εolution was added 9.68 mL (4.85 mmol) of a 0.5 M solution of potasεium bis(trimethylεilyl)amide in toluene. After a 15 minute interval, 0.46 mL (3.88 mmol) of benzyl bromide was added and the reaction mixture was allowed to warm to room temperature and εtirred 1 hour. Several milliliterε of methanol were added to conεume exceεε baεe, and the reaction waε partitioned - 286 - between ethyl acetate and 1 N HCl. .The organic layer waε separated, waεhed with saturated aHC03, brine, dried (MgS0 ), filtered and evaporated. The reεidue waε purified on a εilica gel flaεh chromatography column eluted with 15% ethyl acetate/hexane to afford 0.540 g (42%) of the title compound. --E NMR (300 MHz, CDC1 3 , ppm): δ 0.09 (ε, 6H), 0.94 (ε, 9H), 3.24 (m, 2H), 3.70 (ε, 3H), 4.64 (ε, 2H), 4.80 (dd, J=6,7 Hz, IH), 6.80 (d, J=10 Hz, 2H), 7.09-7.35 (m, 7H). FAB-MS: m/e 401 (M+l). Step D: Preparation of methyl 2-(4-hydroxymethyl- phenoxv)-3-phenvlpropanoate To a εolution of 0.520 g (1.30 mmol) of the product of Step C diεsolved in 3 mL of anhydrous THF was added 1.3 mL (1.3 mmol) of a 1 N solution of tetra-n-butylammonium fluoride in THF and the mixture was stirred at room temperature 1.5 hours. The mixture was then concentrated in vacuo and the reεidue waε purified on a εilica gel flash chromato¬ graphy column eluted with 707. ethyl acetate/hexane to afford 0.230 g (62%) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 1.55 (br s, IH), 3.23 (m, 2H), 3.66 (s, 3H), 4.56 (d, J=9 Hz, 2H), 4.74 (dd, J=6,7 Hz, IH), 6.83 (d, J=10 Hz, 2H), 7.10-7.30 (m, 7H). FAB-MS: m/e 285 (M+l). - 287 - Step E: Preparation of methyl 2-(4-bromomethyl- henoxy)-3-phenylpropanoate To a cooled (0 # C) solution of 0.230 g (0.80 mmol) of the product of Step D dissolved in 4 mL of CH 2 C1 2 was added 0.263 g (1.00 mmol) of carbon tetrabromide and 0.333 g (1.00 mmol) of triphenyl¬ phosphine. After 15 minutes at 0*C, the reaction mixture was allowed to warm to room temperature and waε εtirred for an additional 6 hourε. The reaction was then concentrated in vacuo and purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 097 g (35%) of the title compound. l E NMR (300 MHz, CDCI3, ppm): δ 3.20 (m, 2H), 3.80 (s, 3H), 4.44 (s, 2H), 4.77 (dd, J=6,7 Hz, IH), 6.76 (d, J=10 Hz, 2H), 7.17-7.35 (m, 7H). Step F: Preparation of 3-[4-((l-carboethoxy-l-(2- phenyl)ethoxy)phenyl]methyl-5,7-dimethyl-2- ethyl-3H-imidazor4.5-b1pyridine The product of Step E (0.094 g, 0.27 mmol) was used to alkylate 0.040 g (0.23 mmol) of 5,7- dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 24, Step C) according to the procedure described for Step B of Example 27, which after purification afforded 0.054 g (53%) of the title compound. l E NMR (300 MHz, CDCI3, ppm): δ 1.26 (t, J=8 Hz, 3H), 2.55 (s, 3H), 2.60 (ε, 3H), 2.74 (q, J=8 Hz, 2H) , 3.20 (m, 2H), 3.65 (ε, 3H), 4.72 (dd, J=6,7 Hz, IH), 5.34 (ε, 2H), 6.70 (d, J«10 Hz, 2H), 6.83 (s, IH), 7.02 (d, J=10 Hz, 2H), 7.16-7.30 (m, 5H). FAB-MS: m/e 444 (M+l). - 288 - Step G: Preparation of 3-[4-((l-carboxy-l-(2-phenyl)- ethoxy)phenyl]methyl-5,7-dimethyl-2-ethyl-3H- imidazo .5-blpvridine Using the general procedure for ester hydrolyεiε described in Step E of Example 19, 0.054 g (0.12 mmol) of the product of Step A was converted to 0.042 g (81%) of the title compound. -Ε NMR (300 MHz, CD3OD, ppm): δ 1.25 (t, J=8 Hz, 3H), 2.60 (s, 3H), 4.63 (ε, 3H), 4.85 (q, J=8 Hz, 2H), 3.18-3.25 (m, 2H), 4.78 (dd, J=6,7 Hz, IH), 5.45 (s, 2H), 6.80 (d, J=10 Hz, 2H), 7.02-7.10 (m, 3H), 7.15-7.35 (m, 5H). FAB-MS: m/e 430 (M+l). Example 42 3-[4-((1-Carboxy-l-phenyl)methoxy)-3-(2-propen-l-yl)- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine Step A: Preparation of methyl 4-(2-propen-l-yl)oxy- benzoate A 2 L flask was equipped with a mechanical stirrer, a reflux condenser and a stopper, then charged with 50.05 g (0.329 mol) of methyl 4-hydroxy- benzoate, 960 mL of acetone, 22.50 g (1.625 mol) of anhydrous potasεium carbonate, 80.5 mL (112.6 g, 0.932 mol) of allyl bromide and the mixture was εtirred and refluxed for 14 hourε. The mixture waε cooled to room temperature, filtered and concentrated to an oil. The reεidual oil waε purified by distillation (97 β C § 0.03 mm Hg) to afford 53.52 g (86%) of the title compound. - 289 - - ■ E NMR (300 MHz, CDCI3, ppm): δ 3.84 (ε, 3H), 4.56 (d, J=7 Hz, 2H), 5.28 (dd, J=3,12 Hz, IH), 5.40 (dd, J=3,19Hz, IH), 5.96-6.10 (m, IH), 6.90 (d, J=10 Hz, 2H), 7.96 (d, J=10 Hz, 2H). FAB-MS: m/e 193 (M+l). Step B: Preparation of methyl 4-hydroxy-3-(prop-2- en-l-vDbenzoate A solution of 15.05 g (78.3 mmol) of the product of Step A in 25 mL of 1,2-dichlorobenzene was magnetically εtirred an*d refluxed (183 # C) under an argon atmoεphere for 18 hourε. At this point, the reaction mixture was cooled to room temperature and applied to a 6 cm diameter by 18 cm silica gel flash chromatography column and eluted with 25% ethyl acetate-hexane to εeparate the 1,2-dichlorobenzene, then with 407. ethyl acetate-hexane to elute the product. The product fractionε were concentrated in vacuo and the reεidual oil waε cryεtallized from hexane to afford 13.70 g (91%) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 3.42 (d, J=8 Hz, 2H), 3.88 (ε, 3H), 5.14-5.20 (m, 2H), 5.48 (ε, IH), 5.94-6.06 (m, IH) , 6.82 (d, J=12 Hz, IH), 7.80-7.85 (m, 2H). FAB-MS: m/e 193 (M+l). Step C: Preparation of methyl 4-(tert-butyldimethyl- silvloxv)-3-(2-propen-l-vl)benzoate To a εolution of 5.168 g (26.9 mmol) of the product of Step B in 50 mL of ichloromethane was added 4.40 mL (2.95 mmol) of triethylamine, 4.46 g - 290 - (2.95 mmol) of tert-butyldimethylchloroεilane,0.100 g of 4-dimethylaminopyridine, and the reaction mixture waε εtirred at room temperature for 2 hourε. The mixture waε then diluted with 50 mL dichloromethane, waεhed with 100 mL 1 N hydrochloric acid, dried (MgS04), filtered and evaporated. The reεidual oil (7.993 g, 97%) waε uεed in the next step without further purification. - ■ E NMR (300 MHz, CDCI3, ppm): δ 0.24 (ε, 6H), 1.02 (ε, 9H), 3.36 (d, J=8 Hz, 2H), 3.84 (ε, 3H), 4.98-5.08 (m, 2H), 5.88-6.03 (m, IH), 6.78 (d, J=ll Hz, IH), 7.76-8.40 (m, 2H) . FAB-MS: m/e 307 (M+l). Step D: Preparation of 4-(tert-butyldimethyl- silvloxv 3-(2-propen-l-vl)benzvl alcohol To a magnetically εtirred εolution of 8.523 g (28.0 mmol) of the product from Step C in 35 mL of anhydrous THF was added 15.0 mL of a 1.0 M solution of lithium aluminum hydride in THF, and the reaction mixture was stirred under a nitrogen atmosphere for 2 hourε. At thiε point, the reaction waε quenched by cautious addition of 10 mL water, the resulting precipitate was disεolved by addition of 1.0 N hydrochloric acid and the product waε extracted into ethyl acetate. The organic layer waε εeparated, dried (MgS0 4 ), filtered and evaporated in vacuo to afford 7.258 g (93%) of the title compound. - ■ E NMR (300 MHz, CDCI3, ppm): δ 0.20 (s, 6H), 1.00 (s, 9H), 3.34 (d, J=8 Hz, 2H) , 3.84 (s, IH), 4.57 (ε, 2H), 4.97-5.07 (m, 2H), 5.88-6.03 (m, IH), 6.86 (d, J=10 Hz, IH), 7.05-7.14 (m, 2H). FAB-MS: m/e 279, 261 (M+l). - 291 - Step E: Preparation of 4-(tert-butyldimethyl- Bilvl')3-( , 2-propen-l-vl)benzvl bromide To a magnetically stirred solution of 7.258 g (26 mmol) of the product from Step D and 10.281 g (31 mmol) of carbon tetrabromide in 50 mL of dry dichloromethane waε slowly added 8.131 g (31 mmol) of triphenylphoεphine at 0°C under a nitrogen atmoεphere The reaction mixture waε εtirred 45 minuteε and allowed to warm to room temperature. At thiε point, 0 the reaction mixture waε applied to a εilica gel flaεh chromatography column and was eluted with dichloromethane. Evaporation of the product fractions and drying in vacuo afforded 7.651 g (86%) of the title compound as a viεcouε oil. 15 X H NMR (300 MHz, CDCI3, ppm): δ 0.23 (s, 6H), 1.00 (s, 9H), 3.34 (d, J=8 Hz, 2H), 4.45 (ε, 2H), 4.98-5.09 (m, 2H), 5.86-6.02 (m, IH), 6.74 (d, J.10 Hz, IH), 7.08-7.16 (m, 2H). FAB-MS: m/e 343, 341 (M+l). 20 Step F: Preparation of 5,7-dimethyl-2-ethyl-3-[4- tert-butyldimethylεilyloxy-3-(2-propen-l-yl)- phenvl1methvl-3H-imidazor4.5-b1pvridine To a εolution of 1.029 g (5.9 mmol) of 25 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (Example 24, Step C) diεεolved in 10 mL of dry DMF waε added 0.258 g (6.5 mmol) of a 60% oil diεperεion of εodium hydride and the reaction mixture waε εtirred under a * * nitrogen atmoεphere for 1 hour. At this point, 30 hydrogen evolution had ceased, and a solution of 2.210 g of the product of Step E dissolved in 2.0 mL - 292 - of dry DMF waε added via syringe. The reaction waε εtirred an additional 2 hourε at room temperature and then partitioned between ethyl acetate and water. The organic layer waε extracted, waεhed with brine, dried ( gSθ4), filtered and evaporated. The reεidual oil waε purified on a εilica gel flash chromatography column eluted with 50% ethyl acetate-hexane. Evaporation of the purified fraction and drying in vacuo afforded 1.519 g (59%) of the title compound. l E NMR (300 MHz, CDCI3, ppm): δ 0.16 (s, 6H), 0.96 (s, 9H), 1.27 (t, J=9 Hz, 3H), 2.57 (s, 3H), 2.60 (s, 3H), 2.76 (q, J=9 Hz, 2H), 3.28 (d, J=8 Hz, 2H), 4.93-5.03 (m, 2H), 5.33 (s, 2H), 5.81-5.95 (m, IH), 6.64 (d, J=10 Hz, IH), 6.76 (dd, J=3,10 Hz, IH), 6.86 (s, IH), 7.00 (d, J=3 Hz, IH). FAB-MS: m/e 436 (M+l). Step G: Preparation of 5,7-dimethyl-2-ethyl-3-[4- hydroxy-3-(2-propen-l-yl)phenyl]methyl-3H- imidazo .5-blpvridine To a solution of 1.519 g (3.48 mmol) of the product of Step F in 8.0 mL of anhydrous THF was added 3.6 mL of a 1.0 M solution of tetra-n-butyl¬ ammonium fluoride in THF and the reaction mixture was εtirred for 2.5 hours at room temperature. The reaction mixture was then evaporated in vacuo and the residual oil was chromatographed on a silica gel flash chromatography column eluted with ethyl acetate. The purified fractions were combined, evaporated and dried in vacuo to afford the title compound. - 293 - - ■ E NMR (300 MHz, CDCI3, ppm): δ 1.24 (t, J=9 Hz, 3H), 2.57 (ε, 3H), 2.60 (ε, 3H), 2.73 (q, J-9 Hz, 2H), 3.31 (d, J=8 Hz, 2H), 5.03-5.10 (m, 2H), 5.33 (s, 2H), 5.88-6.02 (m, IH), 6.36 (d, J=10 Hz, IH), 6.48 (dd, J=3,10 Hz, IH), 6.84-6.89 (m, 2H), 7.37 (br s, IH). FAB-MS: m/e 322 (M+l). Step H: Preparation of 5,7-dimethyl-2-ethyl-3-[4- ((l-carbomethoxy-l-phenyl)methoxy)-3- (2-propen-l-yl)phenyl]-methyl-3H-imidazo[4,5- bl pyridine ; To a εolution of 0.171 g (0.53 mmol) of the product of Step G diεεolved in 2.5 mL of anhydrouε DMF was added 0.023 g (0.58 mmol) of a 60% oil dispersion of εodium hydride and the reaction mixture was εtirred under a nitrogen atmoεphere for 30 minuteε at room temperature. A solution of 0.134 g of methyl a-bromophenylacetate in 1.0 mL of DMF waε then added via εyringe and the reaction mixture waε εtirred an additional 1.5 hourε. The reaction mixture waε then partitioned between ethyl acetate and water, the organic layer waε εeparated, dried (MgSU ), filtered and evaporated. The reεidual oil was purified on a εilica gel flaεh chromatography column eluted with 75% ethyl acetate-hexane to afford after evaporation of the purified fractions and drying in vacuo 0.212 g (85%) of the title compound. - ■ E NMR (300 MHz, CDCI3, ppm): δ 1.26 (t, J=9 Hz, 3H), 2.57 (s, 3H), 2.60 (s, 3H), 2.76 (q, J=9 Hz, 2H), 3.45 (d, J=8 Hz, 2H), 3.66 (s, 3H), 4.99-5.07 (m, - 294 - 2H) , 5.34 (ε , 2H) , 5.57 (ε , IH) , 5.88-6.04 (m, IH) , 6.59 (d , J=10 Hz , IH) , 6.79 (dd , J * 3 , 10 Hz , IH) , 6.86 (ε , IH) , 7.05 (d , J=3 Hz , IH) , 7.30-7.40 (m, 3H) , 7 .48-7.56 (m, 2H) . FAB-MS : m/e 470 (M+l) . Step I: Preparation of 3-[4-((1-carboxy-l-phenyl)- methoxy)-3-(2-propen-l-yl)phenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-blpvridine 0 To a εolution of 0.141 g (0.30 mmol) of the product of Step H diεεolved in 2.0 mL of methanol was added 0.25 mL of a 1.0 N solution of sodium hydroxide and the reaction was εtirred at room temperature for 2 hourε. The reaction mixture waε then adjusted to pH 7 with 1.0 N hydrochloric acid and then partitioned between ethyl acetate and water. The organic layer was εeparated, dried (MgS04), filtered, evaporated and then purified on a εilica gel flaεh chromatography column eluted with chloroform-methanol-conc. ammonium o hydroxide (80:15:1). Evaporation of the purified fractionε and drying in vacuo afforded 0.092 g (69%) of the title compound as a white amorphous solid. --E NMR (300 MHz, CD 3 0D, ppm): δ 1.27 (t, J=9 Hz, 3H), 2.61 (s, 3H), 2.64 (ε, 3H), 2.89 (q, J=9 Hz, 2H), 5 3.40-3.52 (m, 2H), 4.95-5.06 (m, 2H), 5.53 (ε, 2H), 5.73 (s, IH), 5.94-6.13 ( , IH), 6.84 (d, J=10 Hz, IH), 6.95 (dd, J=3,10 Hz, IH), 7.06 (br ε, 2H), 7.36-7.44 (m, 3H), 7.57-7.64 (m, 2H). FAB-MS: m/e 456 (M+l). - 295 - Example 43 3-[4-((l-Carboxy-1-phenyl)methoxy)-3-propylphenyl]- methvl-5.7-dimethvl-2-ethvl-3H-imidazor4.5-blpyridine 5 Step A: Preparation of 5,7-dimethyl-2-ethyl-3-[4- hydroxy-3-propylphenyl]methyl-3H-imidazo T4.5-blpvridine A εolution of 0.255 (0.79 mmol) of the 10 product of Example 1, Step G in 10 mL ethanol waε placed in a εmall Parr' hydrogenation flaεk and 50 mg of a 10% palladium on carbon catalyεt waε added. The reaction mixture waε then εhaken in a Parr apparatus under a 45 psig hydrogen atmosphere for 1 hour at 15 room temperature. The reaction mixture was then removed from the flask, filtered, evaporated and dried in vacuo to afford 0.239g (93%) of the title compound which waε uεed in the next εtep without further purification. 2o 1 H NMR (300 MHz, CDC1 3 , ppm): δ 0.90 (t, J=9 Hz, 3H), 1.24 (t, J=10 Hz, 3H), 1.50-1.62 (m, 2H), 2.48 (t, J=8 Hz, 2H), 2.56 (ε, 3H), 2.59 (ε, 3H), 2.72 (q, J=9 Hz, 2H), 5.32 (ε, 3H), 6.23 (d, J=10 Hz, IH) , 6.38 (dd, J=3,10 Hz, IH), 6.79 (d, J=3 Hz, IH), 6.87 (ε, 25 IH), 7.68 (br ε, IH) . FAB-MS: m/e 324 (M+l). * * 30 - 296 - Step B : Preparation of 5 , 7-dimethyl-2--ethyl-3-[4- ( (l-carbomethoxy-l-phenyl )methoxy)-3-propyl- phenvnmethvl-3H-imidazor4.5-blpvridine To a εolution of 0.062 g (0.19 mmol) of the product of Step A in 1.5 mL of anhydrouε DMF waε added 8.4 mg of a 60% oil dispersion of sodium hydride and the reaction mixture was stirred under a nitrogen atmosphere. After the reaction mixture had εtirred 30 minuteε at room temperature, hydrogen evolution had ceaεed, and a εolution of 0.048 g of methyl 2-bromophenylacetate in 0.5 mL of dry DMF was added via syringe. The reaction mixture was εtirred an additional 1.5 hourε and then partitioned between ethyl acetate and water. The organic layer waε εeparated, waεhed with brine, dried (MgSU4), filtered, evaporated and then chromatographed on a silica gel flash chromatography column eluted with 50% ethyl acetate-hexane. The purified fractions were combined, evaporated and dried in vacuo to afford 59 mg (66%) of the title compound as a viscous oil. l E NMR (300 MHz, CDCI3, ppm): δ 0.90 (t, J=9 Hz, 3H), 1.25 (t, J=9 Hz, 3H), 1.54-1.68 (m, 2H), 2.56-2.66 (m, 2H), 2.58 (s, 3H), 2.62 (s, 3H), 2.76 (q, J=9 Hz, 2H), 3.66 (s, 3H), 5.35 (s, 2H), 5.57 (s, IH) , 6.59 (d, J=10 Hz, IH), 6.81 (dd, J=3,10 Hz, IH), 6.87 (s, IH), 6.99 (d, J=3 Hz, IH), 7.28-7.40 (m, 3H), 7.49-7.56 (m, 2H) . FAB-MS: m/e 472 (M+l). - 297 - Step C: Preparation of 3-[4-((1-carboxy-l-phenyl)- ethoxy)-3-propylphenyl]methyl-5,7- imethyl- 2-ethvl-3H-imidazor4.5-blpvridine To a solution of 0.042 g (0.09 mmol) of the product of Step B dissolved in 1.0 mL of methanol waε added 0.1 mL of a 1.0 N εolution of sodium hydroxide and the reaction mixture waε εtirred for 3 hourε at room temperature. The reaction mixture waε then adjuεted to pH 7 with 1.0 N hydrochloric acid and then partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSU ), filtered, evaporated and then purified on a εilica gel flash chromatography column eluted with chloroform-methanol-conc. ammonium hydroxide (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 0.021 g (51%) of the title compound as a white amorphous solid. --E NMR (300 MHz, CD3OD, ppm); δ 0.90 (t, J=8 Hz, 3H), 1.26 (t, J=9 Hz, 3H), 1.53-1.67 (m, 2H), 2.61 (ε, 3H), 2.65 (ε, 3H), 2.66-2.80 (m, 2H), 2.86 (q, J=8 Hz, 2H), 5.49 (ε, 2H), 5.54 (ε, IH), 6.80 (d, J=10 Hz, IH), 6.90 (dd, J=2, 10 Hz, IH), 6.98 (d, J=2 Hz, IH), 7.06 (ε, IH), 7.30-7.44 (m, 3H), 7.60-7.66 (m, 2H). FAB-MS: m/e 458 (M+l). Example 44 3-[4-((l-Carboxy-l-(2-methylρhenyl))methoxy)-3-propyl- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine . - 298 - Step A: Preparation of 5,7-dimethyl-2-ethyl-3-[4-((l- carbomethoxy-l-(2-methylphenyl))methoxy)- 3-propylphenyl]-methyl-3H-imidazo[4,5-b] pyridine To a εuεpenεion of 5.9 mg (2.45 mmol) of a 60% oil diεperεion of NaH in 0.8 mL of DMF waε added 0.066 g (0.20 mmol) of 5,7-dimethyl-2-ethyl-3-[4- hydroxy-3-propylphenyl]methyl-3H-imidazo[4,5-b] pyridine (Example 43, Step A) and the mixture waε εtirred at room temperature. After 20 minuteε, a solution of 0.060 g (2.45 mmol) of methyl 2-bromo-2'- methylphenylacetate (prepared from 2'-methylphenyl- acetic acid via a Hell-Volhard-Zelinεky reaction εi ilar to Step A of Example 17) diεεolved in 0.5 mL of DMF waε added and the reaction mixture waε εtirred an additional 1.5 hourε. The reaction waε then partitioned between ethyl acetate and water, the organic layer waε εeparated, waεhed with water, dried (MgSθ4), filtered and evaporated in vacuo. The reεidue waε purified on a εilica gel flaεh chromato¬ graphy column eluted with 50% ethyl acetate/hexane to afford 0.082 g (83%) of the title compound. λ E NMR (300 MHz, CDCI3, ppm): δ 0.90 (t, J=9 Hz, 3H) , 1.25 (t, J=8 Hz, 3H), 1.50-1.65 (m, 2H), 2.44 (ε, 3H), 2.56 (ε, 3H), 2.60 (ε, 3H), 2.52-2.65 (m, 2H), 2.75 (q, J=8 Hz, 2H), 3.67 (ε, 3H), 5.34 (ε, 2H), 5.74 (s, IH), 6.55 (d, J=10 Hz, IH), 6.78 (dd, J=2, 10 Hz, IH), 6.86 (s, IH), 6.98 (d, J=2 Hz, IH), 7.15-7.28 (m, 3H), 7.50-7.56 (m, IH). FAB-MS: m/e 486 (M+l). - 299 - Step B: Preparation of 3-[4-((1-carboxy-l-(2-methyl¬ phenyl))methoxy)-3-propylρhenyl]methyl-5,7- imethvl-2-ethvl-3H-imidazor4.5-blpvridine Using the general procedure for ester hydrolysiε described in Step E of Example 19, 0.076 g (0.16 mmol) of the product of Step A was converted to 0.040 g (54%) of the title compound. - ■ E NMR (300 MHz, CD3OD, ppm): δ 0.88 (t, J * 9 Hz, 3H), 1.27 (t, J=8 Hz, 3H), 1.50-1.65 (m, 2H), 2.49 (ε, 3H), 2.62 (8, 3H), 2.65 (ε, 3H), 2.55-2.70 (m, 2H), 2.88 (q, J=8 Hz, 2H), 5.48 (ε, 2H), 5.83 (s, IH) , 6.78 (d, J=10 Hz, IH), 6.90 (dd, J=2,10 Hz, IH), 6.99 (d, J=2 Hz, IH), 7.06 (ε, IH), 7.20-7.27 (m, 3H), 7.54-7.60 (m, IH). FAB-MS: m/e 472 (M+l). Example 45 3-[4-((l-Carboxy-l-(2-chlorophenyl))methoxy)-3-propyl- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine Step A: Preparation of 5,7-dimethyl-2-ethyl-3-[4-((l- carbomethoxy-l-(2-chlorophenyl))methoxy)- 3-propylphenyl]-methyl-3H-imidazo[4,5-b] pyridine To a εuεpenεion of 6.3 mg (2.63 mmol) of a 60% oil diεpersion of NaH in 1.0 mL of DMF waε added 0.071 g (0.22 mmol) of 5,7-dimethyl-2-ethyl-3-[4- hydroxy-3-propylphenyl]methyl-3H-imidazo[4,5-b] pyridine (Example 43, Step A) and the mixture was - 300 - stirred at room temperature. After 20 minutes, a solution of 0.069 g (0.26 mmol) of methyl 2-bromo-2'- chlorophenylacetate (Example 4, Step A) dissolved in 0.75 mL of DMF was added and the reaction mixture waε εtirred an additional 2 hourε. The reaction waε then partitioned between ethyl acetate and water, the organic layer waε εeparated, waεhed with water, dried (MgSU 4 ), filtered and evaporated in vacup. The reεidue was purified on a εilica gel flaεh chromato- graphy column eluted with 50% ethyl acetate/hexane to afford 0.098 g (88%) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 0.89 (t, J=9 Hz, 3H), 1.26 (t, J=8 Hz, 3H), 2.55 (s, 3H), 2.59 (ε, 3H), 2.52-2.63 (m, 2H), 2.74 (q, J=8 Hz, 2H), 3.70 (ε, 3H), 5.34 (s, 2H), 6.03 (s, IH), 6.62 (d, J=10 Hz, IH), 6.78 (dd, J=2,10 Hz, IH), 6.86 (s, IH), 6.97 (d, J=2 Hz, IH), 7.24-7.32 (m, 2H), 7.34-7.42 (m, IH), 7.57-7.64 (m, IH). FAB-MS: m/e 506 (M+l). Step B: Preparation of 3-[4-((l-carboxy-l-(2- chlorophenyl))methoxy)-3-propylphenyl]methyl- 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine _______ Using the general procedure for ester hydrolysis described in Step E of Example 19, 0.098 g (0.19 mmol) of the product of Step A was converted to 0.072 g (76%) of the title compound. --E NMR (300 MHz, CD3OD, ppm): δ 0.85 (t, J=9 Hz, 3H), 1.25 (t, J=8 Hz, 3H), 1.60-1.74 (m, 2H), 2.61 (s, 3H), 2.64 (s, 3H), 2.52-2.60 (m, 2H), 2.88 (q, J=8 - 301 - Hz, 2H), 5.49 (ε, 2H), 6.04 (ε, IH), 6.80 (d, J=10 Hz, IH), 6.92 (dd, J=2, 10 Hz, IH), 6.98 (d, J=2 Hz, IH), 7.06 (ε, IH), 7.33-7.39 (m, 2H), 7.44-7.50 (m, IH), 7.64-7.70 (m, IH). FAB-MS: m/e 492 (M+l). Exampl 46 3-[4-((1-Carboxy-l-phenyl)methoxy)-3-(l-methylcyclo- hex-l-yl)phenyl]methyl-5,7-dimethyl-2-ethyl-3H- imidazor4.5-b1pvridine Step A: Preparation of methyl 2-(2-(l-methylcyclohex- l-yl)-4-methvlphenoxv)-2-phenvlacet te Uεing the K 2 CU3/acetone conditionε for phenol alkylation deεcribed in Step A of Example 30, 0.496 g (2.43 mmol) of 2-(l-methylcyclohex-l-yl)- 4-methylphenol was alkylated with 0.834 g (3.64 mmol) of methyl 2-bromophenylacetate to afford 0.780 g (91%) of the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 1.41 (s, 3H), 1.36-1.80 (m, 8H) , 2.20-2.34 (m, 2H), 2.27 (s, 3H), 3.70 (s, 3H), 5.64 (ε, IH), Hz, IH), 6.87 (dd, J=2, 10 Hz, IH) , z, IH), 7.32-7.44 (m, 3H), 7.55-7.63 (m, 2H). FAB-MS: m/e 353 (M+l). Step B: Preparation of methyl 2-(4-bromomethyl-2-(l- methvlcvclohex-l-vl)phenoxv ) -2-phenylacetat:e To a solution of 0.780 g (2.21 mmol) of the product of Step A diεsolved in 12 mL of CCI4 was - 302 - added 0.394 g (2.21 mmol) of N-bromosuccinimide and 20 mg (catalytic amount) of AIBN. The mixture waε εtirred and refluxed under a N 2 atmoεphere for 6 hourε. The mixture waε then cooled, filtered and evaporated in vacuo. The reεidue waε purified on a εilica gel flaεh chromatography column eluted with 7% ethyl acetate/hexane to afford 0.203 g (21%) of the title compound. • -E NMR (300 MHz, CDC1 3 , ppm): δ 1.36 (ε, 3H), 1.34-1.80 (m, 8H), 2.18-2.30 (m, 2H) , 3.70 (s, 3H), 4.46 (s, 2H), 5.65 (ε, IH), 6.71 (d, J=10 Hz, IH) , 7.10 (dd, J=2, 10 Hz, IH), 7.35 (d, J=2 Hz, IH) , 7.32-7.44 (m, 3H), 7.50-7.58 (m, 2H). FAB-MS: m/e 433 (M+l). Step C: Preparation of 3-[4-((l-carbomethoxy-l- phenyl)methoxy)-3-(l-methylcyclohex-l-yl)- phenyl]methyl-5,7-dimethyl-2-ethyl-3H- imidazor4.5-blpvridine To a εuspenεion of 18 mg (0.47 mmol) of a 60% oil diεperεion of NaH in 1.0 mL of DMF waε added 0.083 g (0.47 mmol) of 5,7-dimethyl-2-ethyl-3-[4- hydroxy-3-propylphenyl]methyl-3H-imidazo[4,5-b] pyridine (Example 43, Step A) and the mixture was εtirred at room temperature. After 20 minutes, a solution of 0.203 g (0.47 mmol) of the product of Step B disεolved in 0.75 mL of DMF was added and the reaction mixture was εtirred an additional 2 hours. The reaction was then partitioned between ethyl acetate and water, the organic layer was separated, washed with water, dried (MgS04), filtered and - 303 - evaporated in vacuo. The residue was purified on a εilica gel flash chromatography column eluted with 50% ethyl acetate/hexane to afford 0.097 g (39%) of the title compound. λ E NMR (300 MHz, CDCI3, ppm): δ 1.28 (t, J=8 Hz, 3H), 1.33 (s, 3H), 1.20-1.70 (m, 8H), 2.13-2.24 (m, 2H), 2.55 (ε, 3H), 2.60 (s, 3H), 2.82 (q, J=8 Hz, 2H), 3.66 (m, 3H), 5.34 (ε, 2H), 5.58 (ε, IH), 6.53 (d, J=10 Hz, IH), 6.77 (dd, J=2, 10 Hz, IH) , 6.85 (s, IH), 7.26-7.40 (m, 4H), 7.50-7.58 (m, 2H). FAB-MS: m/e 526 (M+l). Step D: Preparation of 3-[4-((1-carboxy-l-phenyl)- methoxy)-3-(1-methylcyclohex-l-yl)phenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine Using the general procedure for ester hydrolysis described in Step E of Example 19, 0.097 g (0.18 mmol) of the product of Step C was converted to 0.056 g (59%) of the title compound. τ E NMR (300 MHz, CD3OD, ppm): δ 1.01 (t, J=8 Hz, IH), 1.34 (ε, 3H), 1.20-1.70 (m, 8H), 2.08-2.20 ( , 2H), 2.40 (s, 3H), 2.54 (s, 3H), 2.88 (q, J=8 Hz, 2H), 5.25 (d, J=16 Hz, IH), 5.37 (d, J=16 Hz, IH) , 5.60 (s, IH), 6.73-6.86 (m, 3H), 7.32-7.47 (m, 4H), 7.64-7.74 (m, 2H). FAB-MS: m/e 512 (M+l). - 304 - Example 47 3-[4-((l-Carboxy-l-(4-chlorophenyl))methoxy)-3-propyl- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine . Step A: Preparation of 5,7-dimethyl-2-ethyl-3-[4- ((l-carbomethoxy-l-(4-chlorophenyl))methoxy)- 3-propylphenyl]methyl-3H-imidazo[4,5-b] pyridine Using the K 2 Cθ3/acetone conditions for phenol alkylation described in Step A of Example 30, 5,7-dimethyl-2-ethyl-3-[4-hydroxy-3-propylphenyl]methy l-3H-imidazo[4,5-b]pyridine (Step A, Example 43) was alkylated with methyl 2-bromo-2-(4-chlorophenyl)- acetate (Step A, Example 3). Standard workup and purification by flash chromatography afforded a 507. yield of the title compound. λ E NMR (200 MHz, CDCI3, ppm): δ 7.49 (d, 2H), 7.36 (d, 2H), 7.02 (d, IH), 6.90 (s, IH), 6.82 (dd, IH), 6.57 (d, IH), 5.54 (ε, IH), 5.38 (br s, 2H), 3.67 (s, 3H), 2.86 (q, 2H), 2.66 (ε, 3H), 2.6 (s, 3H), 2.5 (t, 2H), 1.7-1.5 (m, 2H), 1.15 (t, 3H), 0.9 (t, 3H) . FAB-MS: m/e 506 (M+l). Step B: Preparation of 5,7-dimethyl-2-ethyl-3-[4- ((l-carboxy-l-(4-chlorophenyl))methoxy)-3- propvl p henvl1methvl-3H-imidazor4.5-b1pyridi-ne Using the general procedure for ester hydrolysiε deεcribed in Step E of Example 19, the product of Step A waε converted to the title compound in 77% yield. - 305 - l E NMR (200 MHz, CDC1 3 , ppm): 7.56 (d, 2H), 7.25 (d, 2H), 7.15 (d, IH), 6.988 (d, ,2H), 6.8 (br 6, IH), 5.44 (ε, IH), 5.41 (ε, 2H), 2.9-2.72 (q, 2H), 2.6 (ε, 3H), 2.56 (ε, 3H), 2.3-1.95 (br m, 2H), 1.65-1.44 (m, 5 2H), 1.27 (t, 3H), 0.84 (t, 3H). FAB-MS: m/e 492 (M+l), 530 (M+K). Example 48 10 3-[4-((l-Carboxy-l-(2-methoxyphenyl))methoxy)-3- propylphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo T4.5-blpyridine Step A: Preparation of 5,7-dimethyl-2-ethyl-3-[4- 15 ((1-carbomethoxy-1-(2-methoxyphenyl))- methoxy)-3-propylphenyl]methyl-3H-imidazo T4.5-blpvridine Uεing the K 2 CU3/acetone conditionε for phenol alkylation described in Step A of Example 30, 20 5,7-dimethyl-2-ethyl-3-[4-hydroxy-3-propylphenyl]methy l-3H-imidazo[4,5-b]pyridine (Step A, Example 43) was alkylated with methyl 2-bromo-2-(2-methoxy)acetate. Standard workup and purification by flash chromato¬ graphy afforded a 69% yield of the title compound. 25 - ■ E NMR (400 MHz, CDCI3, ppm): δ 7.6 (d, IH), 7.38 (dd, IH), 6.98 (dd, IH), 6.875 (s, IH) , 6.866 (dd, t * IH), 6.8-6.75 (m, 2H), 6.62 (d, IH), 5.975 (ε, IH) , 5.35 (ABq, 2H), 3.85 (ε, 3H), 3.68 (ε, 3H), 2.79 (q, * 2H), 2.62(s 3H), 2.57 (ε, 3H), 2.466 (dd, IH), 30 1.65-1.47 (m, 2H), 1.27 (t, 3H) , 0.9 (t, 3H) . FAB-MS: m/e 502 (M+l). - 306 - Step B: Preparation of 5,7-dimethyl-2-ethyl-3-[4- ((1-carboxy-l-(2-methoxyphenyl))methoxy)-3- propylphenvnmethvl-3H-imidazor4.5-blpvridine Uεing the general procedure for eεter hydrolyεiε deεcribed in Step E of Example 19, the product of Step A waε converted to the title compound in 58% yield. ■ -E NMR (400 MHz, CDCI3, ppm): δ 7.8 (d, IH), 7.4 (dd, IH), 7.16 (d, IH), 6.99 (d, IH), 6.875 (ε, IH), 6.825 (d, IH), 6.775 (d, IH), 6.72 (d, IH), 6.02 (br ε, IH), 5.33 (ABq, 2H), 3.83 (ε, 3H), 2.72 (q, 2H), 2.575 (s, 3H), 2.49 (s, 3H), 1.7-1.47 (m, 2H), 0.97 (t, 3H), 0.9 (t, 3H). FAB-MS: m/e 488 (M+l). Example 49 3-[4-((l-Carboxy-l-(2,5-dibromo-3,4-dimethoxyphenyl))- methoxy)-3-propylphenyl]methyl-5,7-dimethyl-2-ethyl- 3H-imidazor4.5-blpvridine Step A: Preparation of methyl 2,2' ,5 ! -tribromo-3,4- dimethoxyphenvlacetate A mixture of 5.0 g (25 mmol) of 3' ,4'-dimeth- oxyphenylacetic acid and thionyl chloride 2.32 mL (1.25 eq.) was stirred and refluxed while bromine (4.5 mL, 3.5 eq.) was added dropwise to the reaction mixture. The reaction was refluxed overnight then cooled. Methanol (30 mL) was cautiously added and the reaction mixture was εtirred an additional 1 hour at room temperature. The mixture waε then evaporated - 307 - in vacuo. and the reεidue waε purified on a εilica gel flash chromatography column eluted with 10% ethyl acetate/hexane to afford 0.80 g (7%) of the title compound. - NMR (400 MHz, CDCI3, ppm): δ 7.37 (s, IH), 5.94 (s, 2H), 3.88 (ε, 3H), 3.85 (s, 3H), 3.79 (s, 3H). FAB-MS: m/e 445 (M+l). Step B: Preparation of 5,7-dimethyl-2-ethyl-3-[4- ((l-carbomethoxy-l-(2,5-dibromo-3,4-dimeth- oxyphenyl))methoxy)-3-propylphenyl]methyl-3H- imidazoU.5-blpvridine Uεing the 2 Cθ3/acetone conditionε for phenol alkylation deεcribed in Step A of Example 30, 5,7- dimethyl-2-ethyl-3-[4-hydroxy-3-propylphenyl]methyl- 3H-imidazo[4,5-b]pyridine (Step A, Example 43) was alkylated with the product of Step A. Standard workup and purification by flash chromatography afforded a 65% yield of the title compound. X H NMR (400 MHz, CDCI3, ppm): δ 7.15 (ε, IH), 6.98 (dd, IH), 6.86 (s, IH), 6.79 (dd, IH), 6.5485 (d, IH, 8.42 Hz), 6.042 (ε, IH), 5.33 (ABq, 2H), 3.825 (ε, 3H), 3.8 (s, 3H), 3.713 (s, 3H), 2.76 (q, 2H, 7.6 Hz), 2.592 (s, 3H), 2.561 (s, 3H), 2.477 (dd, 2H, 7.65 Hz, 7.6 Hz), 1.675-1.45 (m, 2H), 1.268 (t, 3H) , 0.889 (t, 3H). FAB-MS: m/e 688, 690, 692 (M+l). Step C: Preparation of 5,7-dimethyl-2-ethyl-3-[4- ((1-carboxy-l-(2,5-dibromo-3,4-dimethoxy- phenyl ) ) methoxy)-3-propylphenyl]methyl-3H- imidazo -S-bTpyridine - 308 - Using the general procedure for ester hydrolysiε deεcribed in Step E of Example 19, the product of Step B waε converted to the title compound in 72% yield. --E NMR (400 MHz, CDCI3, ppm): δ 7.25 (br ε, IH), 6.97 (ε, IH), 6.94 (ε, IH), 6.82 (br ε, IH), 6.68 (br ε, IH), 5.41 (s, 3H), 3.80 (ε, 3H), 3.78 (ε, 3H), 2.80 (m, 2H), 2.58 (ε, 3H), 2.56 (ε, 3H), 2.22 (m, 2H), 1,8-1.45 (m, 2H), 1.25 (t, 3H), 0.84 (t, 3H). FAB-MS: m/e 675 (M+l). Example 50 3-[4-((l-Carboxy-l-(3,4-dimethoxyphenyl))methoxy)-3- propylphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo T4.5-blpyridine Step A: Preparation of 5,7-dimethyl-2-ethyl-3-[4- ((l-carbomethoxy-l-(3,4-dimethoxyphenyl))- methoxy)-3-propylphenyl]methyl-3H-imidazo T4.5-blpvridine To a εolution of 63 mg (0.09 mmol) of the product of Step A of Example 49 in methanol was added 5 mg of palladium chloride, 20 mg of εodium boro- hydride and the mixture waε εtirred at room temper¬ ature for 2 hourε. The reaction mixture waε evapor¬ ated in vacuo, and the reεidue waε purified on a εilica gel flash chromatography column eluted with 50% ethyl acetate/hexane to afford 22 mg (45%) of the title compound. - 309 - λ E NMR (400 MHz, CDCI3, ppm): δ 7.07 (s, IH), 7.04 (d, IH, 8.13 Hz), 6.97 (s, IH), 6.85 (s, IH), 6.85 (d, IH), 6.78 (dd, IH), 6.57 (d, IH), 5.48 (ε, IH), 5.33 (ε, IH), 3.86 (ε, 3H), -3.85 (ε, 3H), 3.65 (ε, 3H), 2.75 (q, 2H, 7.52 Hz), 2.59 (ε, 3H), 2.56 (s, 3H), 2.65-2.5 (m, 2H), 1.72-1.47 (m, 2H), 1.252 (t, 3H, 7.69 Hz), 0.89 (t, 3H, 7.34 Hz). FAB-MS: m/e 532 (M+l). Step B: Preparation of 5,7-dimethyl-2-ethyl-3-[4- ((1-carboxy-l-(3,4-dimethoxyphenyl))methoxy)■ 3-propylphenyl]methyl-3H-imidazo[4,5-b] pyridine Using the general procedure for ester hydrolysis described in Step E of Example 19, the product of Step A was converted to the title compound in 90% yield. - ■ E NMR (400 MHz, CDCI3, ppm): δ 7.2 (s, IH) , 7.14 (d, IH), 6.98 (s, IH), 6.84 (d, IH), 6.82 (s, IH), 6.74 (d, IH), 6.65 (d, IH), 5.5 (ε, IH), 5.3 (ABq, 2H), 3.86 (ε, 3H), 3.84 (ε, 3H), 2.62 (q, 2H), 2.7-2.55 (m, 2H), 2.52 (s, 3H), 2.39 (ε, 3H), 1.7-1.47 (m, 2H), 1.22 (t, 3H), 0.89 (t, 3H). FAB-MS: m/e 518 (M+l). Example 51 3-[4-((1-Carboxy-l-phenyl)methoxy)-3,5-dipropyl- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pvridine Step A: Preparation of methyl 3-(2-propen-l-yl)-4- (2-propen-l-yloxy)benzoate - 310 - A εolution of 3.04 g (15.8 mmol) of methyl 4-hydroxy-3-ρropenylbenzoate (Example 42, Step B) was refluxed with anhydrous potasεium carbonate (4.37 g, 2 equiv) and allyl bromide (3.5 mL, 2.5 equiv) in acetone overnight. The mixture was filtered through Celite and the filter cake was washed with more acetone and dichloromethane. After removing the εolventε, the reεulting oil waε distilled under high vacuum to give 3.2 g (87%) of the title compound. λ E NMR (400 MHz, CDCI3, ppm): δ 7.87 (dd, IH), 7.83 (d, IH), 6.83 (d, IH), 6.07-5.92 (m, 2H), 5.41 (dd.lH), 5.27 (dd, IH) , 5.07 (dd, IH), 5.05 (dd, IH), 4.58 (d, 2H), 3.83 (s, 3H), 3.4 (d, 2H) . Step B: Preparation of methyl 4-hydroxy-3,5-di(2- propen-1-vl)benzoate The product of Step A (3.2g, 13.8 mmol) was refluxed in 1,2-dichlorobenzene for 3 days in the presence of a catalytic amount of BHT (10 mg). Flash column chromatography of the mixture using hexane and then 10% and 20% ethyl acetate in hexane afforded 3.1 g (97%) of the title compound. -Ε NMR (200 MHz, CDCI3, ppm): δ 7.73 (s, 2H), 6.12-5.92 (m, 2H), 5.63 (s, IH), 5.21 (dd, 2H), 5.15 (dd, 2H), 3.87 (s, 3H), 3.43 (dd, 4H). FAB-MS: m/e 232 (M+l). Step C: Preparation of methyl 4-tert-butyldimethyl- silvloxv-3.5-di(2-propen-l-vl)benzoate The product of Step B (3.1 g, 13.36 mmol) was treated with tert-butyldimethylsilyl chloride - 311 - (2.22 g, 1.1 equiv), triethylamine (3 mL) and DMAP (0.1 equiv) in dichloromethane overnight. The mixture was concentrated and flaεh chromatographed with 5% and then 10% ethyl acetate in hexane to furniεh 4.5 g (97%) of the title compound. 1 H NMR (200 MHz, CDCI3, ppm): δ 7.72 (s, 2H), 6.02-5.30 (m, 2H), 5.12 (dd, 2H), 5.07 (dd, 2H), 3.86 (s, 3H), 3.38 (dd, 4H, 7 Hz), 1.02 (ε, 9H), 0.21 (ε, 6H). Step D: Preparation of methyl 4-tert-butyldimethyl- silyloxy-3.5-dipropvlbenzoate A εolution of 5.0 g (14.45 mmol) of the product of Step C in 250 mL ethanol containing 5% Rh/C (0.25 g) waε shaken under a 40 psi preεsure of hydrogen. Upon completion of reduction, the mixture was filtered through Celite, the filter cake was washed with methanol and dichloromethane. Removal of solvents afforded 4.55 g (90%) of the title compound. 1 H NMR (200 MHz, CDCI3, ppm): δ 7.66 (s, 2Ξ), 3.84 (ε, 3H), 2.54 (dd, 4H, 7.91 Hz, 7.41 Hz), 1.56 (sextet, 4H), 0.98 (ε, 9H), 0.899 (t, 6H), 0.18 (ε, 6H). Step E: Preparation of 4-tert-butyldimethylεilyl- oxv-3.5-dipEopvlbenzvl alcohol Lithium aluminum hydride (9 mL of a 1 M εolution in THF) was added cautiously to a solution of the product of Step D at 0 β C, and the reaction mixture was stirred overnight. Ethyl acetate was added to the mixture, cooled to 0 β C and treated with - 312 - cold 1 N HCl. After separating the organic phase, the aqueous phaεe waε extracted with a mixture of ethyl acetate-ether-dichloromethane. The combined organic extractε were dried and concentrated. The concentrated material waε purified by flash column chromatography using 20% ethyl acetate in hexane to afford 4.2 g (92%) of the title compound. --E NMR (400 MHz, CDC1 3 , ppm): δ 6.95 (ε, 2H), 4.54 (ε, 2H), 2.52 (dd, 4H), 1.55 (εextet, 4H), 0.99 (ε, 9H), 0.90 (t, 6H), 0.16 (ε, 6H). Step F: Preparation of 5,7-dimethyl-2-ethyl-3-[4- tert-butyldimethylsilyloxy-3,5-dipropyl- phenvnmethvl-3H-imidazor4.5-blpvridine To a εolution of 4.2 g (13.0 mmol) of the product of Step E, 2.5 g (14.0 mmol) of 5,7-dimethyl- 2-ethylimidazo[4,5-b]pyridine (Example 24, Step C), and 5.62 (20.0 mmol) of triphenylphosphine dissolved in 40 mL of THF, was added 3.396 g (20.0 mmol) of diethyl azodicarboxylate and the mixture was stirred for 1 hour. The reaction mixture waε then concentra¬ ted in vacuo and the reεidual oil waε purified on a εilica gel flaεh chromatography column eluted with 25-40% ethyl acetate/hexane to afford 5 g (80%) of the title compound. - ■ E NMR (400 MHz, CDCI3, ppm): δ 6.84 (ε, IH), 6.71 (s, 2H), 5.29 (ε, 2H), 2.75 (q, 2H), 2.57 (s, 3H),2.55 (s, 3H), 2.4 (dd, 4H), 1.42 (sextet, 4H), 1.27 (t, 3H), 0.94 (s, 9H), 0.8 (t, 6Ξ), 0.10 (s, 6H) . - 313 - Step G: Preparation of 5,7-dimethyl-2-ethyl-3-[4- hydroxy-3,5- ipropylphenyl]methyl-3H- imidazo .5-blpvridine A THF solution of 5.0 g (10.44 mmol) of the product of Step F was treated with tetrabutylammonium fluoride (1.2 equiv, 1M εolution in THF) overnight. THF waε removed in vacuo and the residue was flaεh chromatographed uεing 30-50% ethyl acetate in hexane aε eluent to afford 3.35 g (88%) of the title compound. X H NMR (400 MHz, CDCI3, ppm): δ 6.86 (ε, IH) , 6.81 (s, IH), 6.73 (s, 2H), 5.37 (ε, IH), 5.30 (ε, 2H), 2.76 (q, 2H), 2.6 (ε, 3H), 2.56 (ε, 3H), 2.44 (dd, 4H), 1.52 (εextet, 4H), 1.23 (t, 3H), 0.88 (t, 6H) . Step H: Preparation of 5,7-dimethyl-2-ethyl-3-[4- ((l-carbomethoxy-l-phenyl)methoxy)-3,5- dipropylphenyl]methyl-3H-imidazo[4,5-b] pyridine Uεing the 2 Cθ3/acetone conditionε for phenol alkylation described in Step A of Example 30, the product of Step G was alkylated with methyl 2-bromophenylacetate. Standard workup and purifica¬ tion by flash chromatography afforded a 96% yield of the title compound. - ■ E NMR (400 MHz, CDCI3, ppm): δ 7.44-7.42 (m, 2H), 7.37-7.31 (m, 3H), 6.88 (ε, IH), 6.74 (ε, 2H), 5.38 (s, IH), 5.33 (s, 2H), 3.7 (s, 3H), 2.80 (q, 2H), 2.62 (ε, 3H), 2.57 (s, 3H), 2.38 (dd, 2H) , 2.3-2.25 (m, 2H), 1.55-1.47 (m, 2H) , 1.46-1.37 (m, 2H), 1.36 (t, 3H), 0.86 (t, 3H), 0.72 (t, 3H) . FAB-MS: m/e 514 (M+l). - 314 - Step I: Preparation of 3-[4-((1-carboxy-l-phenyl)- methoxy)-3,5-dipropylphenyl]methyl-5,7- dimethyl-2-ethvl-3H-imidazor4.5-b1pvridine Using the general procedure for ester hydrolyεiε deεcribed in Step E of Example 19, the product of Step H waε converted to the title compound in 80% yield. --E NMR (400 MHz, CDCI3, ppm): δ 7.47-7.34 (m, 2H), 7.33-7.22 (m, 3H), 6.92 (ε, IH), 6.69 (ε, 2H), 5.35 (br ε, 3H), 2.78 (q, 2H), 2.58 (s, 3H), 2.55 (s, 3H) , 2.62-2.25 (m, 4H), 1.45-1.28 (m, 4H), 1.2 (t, 3H), 0.7 (t, 6H). FAB-MS: m/e 500 (M+l). Example 52 3-[ -((1-Carboxy-l-(2-methoxyphenyl))methoxy)-3,5- dipropylphenyl]methyl-5,7-dimethyl-2-ethyl-3H- imidazo .5-blpvridine Step A: Preparation of 3-[4-((l-carbomethoxy-l-(2- methoxyphenyl))methoxy)-3,5-dipropylphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo T .5-blpvridine Using the K 2 Cθ3/acetone conditions for phenol alkylation described in Step A of Example 30, the product of Step G was alkylated with methyl 2-bromo-(2 * -methoxy)phenylacetate. Standard workup and purification by flash chromatography afforded the title compound. - 315 - « *• * --E NMR (400 MHz, CDCI3, ppm): δ 7.62 (dd, IH, J=2.1, 1.9 Hz), 7.40 (dd, IH), 7.30 (dd, IH), 6.86 (ε, IH), 6.72 (ε, 2H), 6.70 (dd, IH), 5.37 (ε), 5.35 (ε), 5.32 (ε, 2H), 3.69 (ε, 3H), 3.68 (ε, 3H), 2.74 (q, 2H, 5 J=7.5 Hz), 2.61 is ] 3H), 2.56 (ε, 3H), 2.34-2.19 (m, 4H), 1.50-1.29 (m, 4H), 1.23 (t, 3H, 7.54 Hz), 0.74 (t, 6H, J=7.3 Hz). FAB-MS: m/e 544 (M+l). 10 Step B: Preparation of 3-[4-((1-carboxy-l-(2-methoxy¬ phenyl))methoxy)-3,5-dipropylphenyl]methyl- 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyri- dine Uεing the general procedure for eεter 5 hydrolysiε deεcribed in Step E of Example 19, the product of Step A waε converted to the title compound in 77% yield. λ E NMR (400 MHz, CDCI3, ppm): δ 7.72-7.66 (m), 7.55 (br ε, IH), 7.52-7.48 (m) , 7.35 (dd, IH), 6.86 (s, 20 IH), 6.72 (s, 2H), 6.69 (dd, IH), 5.38 (s, IH), 5.30 (ABq, 2H), 3.64 (s, 3H), 2.76 (q, 2H, 7.6 Hz), 2.55 (s, 3H), 2.52 (ε, 3H), 2.28 (m, 4H), 1.50-1.18 (m, 4H), 1.13 (t, 3H), 0.74 (t, 6H) . FAB-MS: m/e 608 (M+2K). 25 Example 53 3-[4-((l-Carboxy-l-(2,5-dibromo-3,4-dimethoxyphenyl))- methoxy)-3,5-dipropylphenyl]methyl-5,7-dimethyl-2- 30 ethyl-3H-imidazor4.5-blpvridine - 316 - Step A: Preparation of 3-[4-((l-carbomethoxy-l-(2,5- dibromo-3,4-dimethoxyphenyl))methoxy)-3,5- dipropylphenyl]methyl-5,7-dimethyl-2-ethyl- 3B-imiflagpr4,5-blpyridine Using the K 2 Cθ3/acetone conditions for phenol alkylation deεcribed in Step A of Example 30, the product of Step G waε alkylated with methyl 2,2',5'- tribromo-3' ,4'-dimethoxyphenylacetate (Step A, Example). Standard workup and purification by flaεh chromatography afforded a 60% yield of the title compound. - ■ E NMR (400 MHz, CDCI3, ppm): δ 7.36 (ε, IH), 6.89 (ε, IH), 6.75 (ε, 2H), 5.55 (ε, IH), 5.34 (ABq, 2H) , 3.88 (ε, 3H), 3.84 (s, 3H), 3.69 (ε, 3H), 2.78 (q, 2H), 2.62 (ε, 3H), 2.41-2.20 (m, 4H), 1.45-1.32 (m, 4H), 0.85 (t, 3H), 0.74 (t, 6H) . FAB-MS: m/e 732 (M+l). Step B: Preparation of 3-[4-((l-carboxy-l-(2,5- dibromo-3,4-dimethoxyphenyl))methoxy)-3,5- dipropylphenyl]methyl-5,7-dimethyl-2-ethyl- 3H-imidazor4.5-blpyridine Using the general procedure for ester hydrolysis described in Step E of Example 19, the product of Step A was converted to the title compound. - ■ E NMR (400 MHz, CD3OD, ppm): δ 7.45 (br s, IH), 7.01 (S, IH), 6.75 (s, 2H), 5.51 (s, IH), 5.44 (ABq, 2H), 3.88 (s, 3H), 3.78 (s, 3H), 3.34 (s, 3H), 2.82 (q, J=7.5 Hz, 2H), 2.59 (ε, 3H), 2.57 (s, 3H), 2.24-2.40 (m, 4H), 1.38-1.52 (m, 2H), 1.24-1.36 (m, 2H) , 1.20 (t, J=7.5 Hz, 3H), 0.74 (t, J=7.5 Hz, 6H). FAB-MS: m/e 716 (M+l). - 317 - Example 5 3-[4-N-((1-Carboxy-l-phenyl)methy1)-N-methylamino- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] 5 pyridine Step A: Preparation of 5,7-dimethyl-2-ethyl-3-(4- nitrophenvl)methvl-3H-imidazor4.5-blpyridine To a solution of 5.0 g (1.0 eq, 28.6 mmol) 10 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine in 30 mL DMF under N 2 at rt was added 1.37 g (1.2 eq, 34.3 mmol) of a 60% oil diεperεion of NaH. After εtirring for 5 minutes, 8.64 g (1.4 eq, 40.0 mmol) of p-nitro- benzyl bromide waε added. The dark brown mixture waε 15 εtirred for 2 hourε under a blanket of N 2 at rt. The mixture waε diluted with 1 L CH 2 C1 2 and waεhed with 500 mL H 2 0 and 500 mL saturated aqueous NaCl. The organic phase was dried over MgSU4 and concentrated to a yellow oil. The oil was flash chromatographed 2 0 with 50% ethyl acetate/hexane. The product containing fractions were combined and concentrated to a yellow oil which crystallized on standing, yielding 6.81 g (76.8%) of the title compound. - ■ E NMR (300 MHz, CDCI3, ppm): δ 8.15 (d, 2H), 7.27 25 (d, 2H), 6.92 (ε, IH), 5.55 (ε, 2H), 2.77 (q, 2H) , 2.64 (ε, 3H), 2.57 (s, 3H), 1.32 (t, 3H). FAB-MS: m/e 325 (M+l). % 30 - 318 - Step B: Preparation of 5,7-dimethyl-2-ethyl-3-(4- aminophenyl)methvl-3H-imida2or4.5-blpvridine To a εolution of 6.81 g (21.0 mmol) of the product of Step A diεεolved in 75 mL methanol in a high preεεure reaction veεεel waε added 0.3 g 5% palladium on carbon. The reεulting suεpenεion waε preεεurized to 40 pεi with H 2 and shaken for 2 hourε. The εolution waε filtered through a pad of celite and the filtrate concentrated to a gray-green oil which cryεtallized on standing. The crude material was flash chromatographed with 50% ethyl acetate/hexane and 3% methanol/ethyl acetate to yield 5.0 g (85%) of the title compound. - ■ E NMR (300MHz, CD3OD, ppm): δ 6.85 (s, IH), 6.80 (d, 2H), 6.52 (d, 2H), 5.26 (ε, 2H) , 2.72 (q, 2H), 2.49 (s, 3H), 2.49 (s, 6H), 1.12 (t, 3H) . FAB-MS: m/e 281 (M+l). Step C: Preparation of 5,7-dimethyl-2-ethyl-3-(4-N- (tert-butyloxycarbonyl)aminophenyl)methyl- 3H-imidazor4.5-blpvridine To a εolution of 1.0 g (3.57 mmol) of of the product of Step B diεεolved in 20 mL CH 2 C1 2 was added 0.75 mL (5.36 mmol, 1.5 eq) of triethylamine and 1.23 mL (5.36 mmol, 1.5 eq) of di-tert-butyl dicarbonate. The resulting solution waε εtirred for 18 hourε. The productε had cryεtallized out of εolution after that time period. The εuspenεion was diluted with 500 mL of CH 2 C1 2 (which promoted dissolution of the products) and washed with 200 mL H 2 0 at pH 9 (NaOH). The organic phase was dried over Na 2 SU4, filtered and - 319 - r* concentrated to a pale yellow oil. The oil was flash chromatographed with 50% ethyl acetate/hexane to yield 450mg (33%) of the title compound as a white powder. ■ J-H NMR (300 MHz, CDCI3, ppm): δ 7.26 (d, 2H), 7.04 (d, 2H), 6.89 (ε, IH), 6.63 (br s, IH), 5.39 (s, 2H), 2.77 (q, 2H), 2.62 (ε, 3H), 2.59 (s, 3H), 1.49 (s, 9H), 1.29 (t, 3H). FAB-MS: m/e 381 (M+l). 10 General procedure for alkylation of H-BOC protected amines: Step D: Preparation of 5,7-dimethyl-2-ethyl-3-(4-N- 15 (tert-butyloxycarbonyl)-N-methylaminophenyl)- methvl-3H-imidazor4.5-blpvridine To a solution of 100 mg of the product of Step C dissolved in 4 mL of DMF was added 16 mg (0.39 mmol, 1.5 eq) of a 60% oil dispersion of NaH. This 20 . mixture was εtirred for 5 minuteε until evolution of hydrogen ceaεed, and then 32.8 mL (73.8 mg, 0.52 mmol, 2.0 eq) of methyl iodide was added. The solution was then εtirred for 18 hours. The excess NaH was quenched with methanol and then all volatiles 25 were removed in vacuo. The resultant brown oil was purified on a εilica gel flaεh chromatography column eluted with 50% ethyl acetate/hexane. The product fractions were combined and concentrated to give a pale yellow oil which was used directly in the next 30 εte P- - 320 - ■ -E NMR (400 MHz, CDC1 3 , ppm): δ 7,12 (d, 2H), 7.04 (d, 2H), 6.87 (s, IH), 5.40 (ε, 2H), 3.18 (ε, 3H), 2.77 (q, 2H), 2.60 (ε, 3H), 2.56 (ε, 3H), 1.49 (ε, 9H),1.27 (t, 3H). FAB-MS: m/e 395 (M+l). General procedure for deprotection of N-BOC amines: Step E: Preparation of 5,7-dimethyl-2-ethyl-3-(4-N- methylaminophenyl)methyl-3H-imidazo[4,5-b] pyridine Diεεolved the product of Step D in 2.0 mL CH 2 C1 2 and added 2.0 mL TFA. Solution waε εtirred for 3 hours. Volatiles were removed in vacuo and the compound was disεolved in methanol. 2.0 mL saturated aqueous NaHCθ3 was added to neutralize the excess TFA. The methanol was then concentrated and the H 2 0 azeotroped with toluene. The compound was taken up in CHCI3 and the excess NaHCU3 was filtered out through a celite pad. The solution was concentrated yield 9 mg (94%) of a pale yellow oil. 1 H NMR (400 MHz, CDCI3, ppm): δ 6.97 (d, 2H), 6.85 (s, IH), 6.48 (d, 2H), 5.32 (s, 2H), 3.73 (br s, 3H) , 2.79 (q, 2H), 2.76 (s, 3H), 2.61 (s, 3H), 2.59 (s, 3H), 1.28 (t, 3H). FAB-MS: m/e 295 (M+l). - 321 - General procedure for phenylaminophenylacetic acid synthesis: Ste p F: Preparation of 3-[4-N-((l-carbomethoxy-l- phenyl)methyl)-N-methylaminophenyl]methyl- 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine To a solution of 72.3 mg (0.25 mmol) of the product of Step E diεεolved in 2.0 mL DMF waε added 15 mg (0.37 mmol, 1.5 eq) of a 60% oil diεperεion of NaH, and the reaction mixture waε εtirred at room temperature. After evolution of hydrogen had ceaεed, 95.5 mL (0.49 mmol, 2.0 eq) of methyl-2-bromophenyl- acetate waε added. The reεulting εolution was stirred for 80 hours under N 2 at rt. The excess NaH was quenched with methanol and the volatiles were removed in vacuo. The resultant oil was purified on a εilica gel flash chromatography column eluted with 50% ethyl acetate/hexane to yield 80.7 mg (73%) of the title compound as a pale yellow oil. - ■ E NMR (400 MHz, CDC1 3 , ppm): δ 7.29-7.38 (m, 3H), 7.22 (d, 2H), 7.05 (d, 2H), 6.87 (ε, IH), 6.74 (d, 2H), 5.69 (s, IH), 5.36 (s, 2H), 3.74 (ε, 3H), 2.82 (q, 2H), 2.73 (ε, 3H), 2.61 (s, 3H), 2.59 (s, 3H), 1.51 (t, 3H). FAB-MS: m/e 443 (M+l). - 322 - Step G: Preparation of 3-C4-N-((1-carboxy-l-phenyl)- methyl)-N-methylaminophenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-blpyridine To a solution of the product of Step F disεolved in 3.0 mL methanol, waε added 3.0 mL of 3 N NaOH, and the εolution waε stirred for 7 days. The methanol was removed in vacuo and the H 0 waε removed by azeotropic diεtillation with toluene. The product was taken up in CHCI3 and the exceεε NaOH filtered through a celite pad. The CHCI3 was concentrated and the resultant oil was purified on a 20 cm x 20 cm x 500 mm εilica gel preparatory TLC plate, developed with a εolution of CHCl 3 /Me0H/NH 0H (80:20:2). The product was extracted from the silica gel with 100 mL of 10% methanol/CHCI3. The solution was concentrated and the resultant oil triturated with ether to yield 61 mg (78.27.) of the title compound aε a white powder. l E NMR (400 MHz, CDCI3, ppm): δ 7.00 (ε, 5H), 6.77 (s, IH), 6.70 (d, 2H), 6.43 (d, 2H), 5.15 (s, IH), 5.12 (ε, 2H), 2.68 (q, 2H), 2.57 (ε, 3H), 2.40 (ε, 6H), 1.20 (t, 3H). FAB-MS: m/e 429 (M+l). Example 55 3_[4-N-((1-Carboxy-l-phenyl)methyl)-N-ethylamino- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine - 323 - t* Step A: Preparation of 5,7-dimethyl-2-ethyl-3-(4-N- (tert-butyloxycarbonyl)-N-ethylaminophenyl)- methyl-3H-imidazor4.5-b1pyridine Uεing the general procedure for the alkyla- 5 tion of N-BOC protected amineε deεcribed in Step D of Example 54, 5,7-dimethyl-2-ethyl-3-(4-N-(tert- butyloxycarbonyl)aminophenyl)methyl-3H-imidazo[4,5-b] pyridine (Step C, Example 54) waε alkylated with ethyl iodide. Standard workup and purification by 10 flaεh chromatography afforded the title compound. - ■ E NMR (300 MHz, CDCI3, ppm): δ 7.09 (ε, 4H), 6.90 (ε, IH), 5.44 (ε, 2H), 3.62 (q, 2H), 2.80 (q, 2H) , 2.64 (s, 3H), 2.59 (s, 3H), 1.40 (s, 9H), 1.28 (t, 3H), 1.09 (t, 3H). 15 FAB-MS: m/e 409 (M+l). Step B: Preparation of 5,7-dimethyl-2-ethyl-3-(4-N- ethylaminophenyl)methyl-3H-imidazo[4,5-b] pyridine 2 0 Using the general procedure for deprotection of N-BOC amines described in Step E of Example 54, the product of Step A was converted to the title compound. --E NMR (300 MHz, CDCI3, ppm): δ 6.97 (d, 2H) , 6.87 2 5 (S, IH), 6.49 (d, 2H), 3.10 (q, 2H), 2.80 (q, 2H), 2.62 (ε, 3H), 2.60 (ε, 3H), 1.29 (t, 3H), 1.21 (t, 3H). FAB-MS: m/e 308 (M+l). 30 - 324 - Step C: Preparation of 3-[4-N-((l-carbomethoxy-l- phenyl)methyl)-N-ethylaminophenyl]methyl- 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine Uεing the general procedure for the phenyl- aminophenylacetic acid εynthesiε deεcribed in Step F of Example 54, the product of Step B waε alkylated with methyl 2-bromophenylacetate. Standard workup and purification by flaεh chromatography afforded the title compound. - ■ E NMR (200 MHz, CDCI3, ppm): δ 7.24-7.40 (m 5H), 7.05 (d, 2H), 6.88 (ε, IH), 6.72 (d, 2H), 5.49 (ε, IH), 5.37 (ε, 2H), 4.73 (ε, 3H), 3.28 (q, 2H) , 2.83 (q, 2H), 2.62 (s, 3H), 2.60 (ε, 3H), 1.31 (t, 3H), 0.86 (t, 3H). FAB-MS: m/e 457 (M+l). Step D: Preparation of 3-[4-N-((1-carboxy-l-phenyl)- methyl)-N-ethylaminophenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-b1pvridine Uεing the general procedure for eεter hydrolyεiε deεcribed in Step E of Example 19, the product of Step C waε converted to the title compound, 1 H NMR (400 MHz, CDCI3, ppm): δ 7.05 (m, 5H), 6.75 (s, IH), 6.72 (d, 2H), 6.42 (d, 2H), 5.21 (s, IH), 5.14 (s, 2H), 3.12 (q, 2H), 2.73 (q, 2H), 2.58 (s, 3H), 2.37 (s, 3H), 1.24 (t, 3H) . FAB-MS: m/e 443 (M+l). - 325 - Example 56 3_[4-N-((1-Carboxy-l-phenyl)methyl)-N-propylamino- pheny1]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine Step A: Preparation of 5,7-dimethyl-2-ethyl-3-(4-N- (tert-butyloxycarbonyl)-N-propylaminophenyl)- methvl-3H-imidazor .5-b1pvridine Using the general procedure for the alkyla¬ tion of N-BOC protected amines described in Step D of Example 54, 5,7-dimethyl-2-ethyl-3-(4-N-(tert- butyloxycarbonyl)aminophenyl)methyl-3H-imidazo[4,5-b] pyridine (Step C, Example 54) was alkylated with propyl bromide. Standard workup and purification by flash chromatography afforded the title compound. 1 H NMR (300 MHz, CDCI3, ppm): δ 7.09 (s,4H), 6.89 (s, IH), 5.44 (ε, 2H), 3.52 (t, 2H), 2.79 (q, 2H), 2.63 (s, 3H), 2.59 (s, 3H), 1.50 (m, 2H), 1.40 (s, 9H), 1.28 (t, 3H), 0.84 (t, 3H) . FAB-MS: m/e 423 (M+l). Step B: Preparation of 5,7-dimethyl-2-ethyl-3-(4-N- propylaminophenyl)methyl-3H-imidazo[4,5-b] pyridine Uεing the general procedure for deprotection of N-BOC amines described in Step E of Example 54, the product of Step A was converted to the title compound. λ E NMR (300 MHz, CDCI3, ppm): δ 6.97 (d, 2H), 6.88 (ε, IH), 6.49 (d, 2H), 5.33 (ε, 2H), 3.02 (t, 2H), 2.80 (q, 2H), 2.62 (ε, 3H),2.60 (s, 3H), 1.60 (m, 2H), 1.30 (t, 3H), 0.98 (t, 3H) . FAB-MS: m/e 323 (M+l). - 326 - Step C: Preparation of 3-[4-N-((l-carbomethoxy-l- phenyl)methyl)-N-propylaminophenyl]methyl- 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine Uεing the general procedure for the phenyl- aminophenylacetic acid εyntheεiε deεcribed in Step F of Example 54, the product of Step B waε alkylated with methyl 2-bromophenylacetate. Standard workup and purification by flaεh chromatography afforded the title compound. --E NMR (400 MHz, CDCI3, ppm): δ 7.22-7.38 (m, 5H), 7.04 (d, 2H), 6.88 (ε, IH) , 6.70 (d, 2H), 5.49 (ε, IH), 5.37 (ε, 2H), 3.72 (t, 2H), 2.83 (q, 2H), 2.62 (s, 3H), 2.60 (s, 3H), 1.44 (m, 2H), 1.33 (t, 3H), 0.89 (t, 3H). FAB-MS: m/e 471 (M+l). Step D: Preparation of 3-[4-N-((1-carboxy-l-phenyl)- methyl)-N-propylaminophenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-blpvridine Uεing the general procedure for eεter hydrolyεiε deεcribed in Step E of Example 19, the product of Step C waε converted to the title compound. • -E NMR (400 MHz, CDCI3, ppm): δ 7.20 (br ε, 2H), 7.06 (br ε, 3H), 6.78 (s, IH), 6.73 (d, 2H), 6.52 (d, 2H), 5.11 (br ε, 3H), 2.97 (m, 2H), 2.71 (q, 2H), 2.57 (ε, 3H), 2.42 (ε, 3H), 1.23 (t, 3H), 0.87 (m, 2H), 0.46 (t, 3H). FAB-MS: m/e 457 (M+l). - 327 - ** Example 57 3_[4-N-((l-Carboxy-1-phenyl)methyl)aminophenyl]methyl- 5.7-dimethvl-2-ethvl-3H-imidazor4.5-blpvridine 5 Step A: Preparation of 3-[4-N-((l-carbomethoxy-l- pheny1)methy1)aminophenyl]methy1-5,7- dimethyl-2-ethyl-3B-imidazpr ,5-blpyridine To a solution of 0.50 g (1.79 mmol) of 5,7- 10 dimethyl-2-ethyl-3-(4-aminophenyl)methyl-3H-imidazo [4,5-b]pyridine (Step B, Example 54) in 4.0 mL DMF, was added 143 mg (3.57 mmol, 2.0 eq) of a 60% oil disperεion of NaH. When evolution of hydrogen ceaεed (approximately 5 min.), 1.04 mL (5.36 mmol, 3.0 eq) 15 of methyl 2-bromophenylacetate was added, and the mixture was stirred for 18 hourε. The DMF waε removed in vacuo and the reεultant brown oil was flash chromatographed with 2:1 ethyl acetate/hexane to yield 0.690 g (90%) of a yellow-green powder. 20 1 H NMR (400 MHz, CDCI3, ppm): δ 7.42 (d, 2H), 7.23-7.35 (m, 3H), 6.89 (d, 2H), 6.85 (ε, IH), 6.43 (d, 2H), 5.28 (ε, 2H), 4.97-5,01 (m, IH), 3.69 (ε, 3H), 2.77 (q, 2H), 2.60 (s, 3H), 2.56 (ε, 3H), 1.25 (t, 3H). 25 FAB-MS: m/e 429 (M+l). Step B: Preparation of 3-[4-N-((1-carboxy-l-phenyl)- « methyl)aminophenyl]methyl-5,7-dimethy1-2- ethvl-3H-im-dazor4.5-blpyridine 3 0 To a εolution of 0.45 g of the product of Step A diεεolved in 5.0 mL methanol, waε added 3.0 mL - 328 - of 3 N NaOH solution, and the mixture was stirred for 30 minutes. The methanol was removed in vacuo and the water was removed by azeotropic diεtillation with toluene. The toluene waε removed in vacuo, then the product waε rediεεolved in CHCI3 and excess NaOH was removed by filtration of the suspension through a celite pad. The filtrate was concentrated to a clear oil andpurified on a εilica gel flaεh chromatography column eluted with CHCl 3 /MeOH/NH 4 OH (80:15:1). The product fractionε were combined and concentrated. The reεultant oil was triturated with ether to yield 396 mg (91%) of the title compound as a white powder. ■ -E NMR (300 MHz, CDCI3, ppm): δ 7.48 (d, 2H) , 7.40 (s, IH), 7.20-7.34 (m, 4H), 6.91 (s, IH), 6.87 (d, 2H), 5.31 (ε, 2H), 4.89 (br ε, IH), 2.78 (q, 2H) , 2.59 (s, 6H), 1.24 (t, 3H). FAB-MS: m/e 415 (M+l). Example 58 3_[4_N-((1-Carboxy-l-phenyl)methyl)-N-allylamino- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine General procedure for alkylation of secondary amines with LiN(TMS) 2 : Step A: Preparation of 3-[4-N-((l-carbomethoxy-l- phenyl)methyl)-N-allylaminophenyl]methyl- 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine - 329 - «* To a solution of 0.30 g (0.70 mmol) of 3-[4-N-((l-carbomethoxy-l-phenyl)methyl)aminophenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine (Step A, Example 57) in 1.5 mL THF, 0.84 mL (0.84 mmol, 1.2 eq) of 1 M lithium biε(trimethylsilyl)amide in THF waε added producing a dark brown solution with evolution of hydrogen gaε. After εtirring the εolution for 5 minuteε, 96.1 mL (1.05 mmol, 1.5 eq) of allyl iodide waε added. The reεultant yellow 10 εolution waε εtirred for 18 hourε. The εolution was concentrated to a yellow oil which was flash chromato¬ graphed with 50% ethyl acetate/hexane. The product fractions were combined and concentrated to yield 173 mg (53%) of a pale yellow oil. 15 l E NMR (400 MHz, CDC1 3 , ppm): δ 7.52 (d, 2H), 7.22-7.33 (m, 3H), 6.98 (s, IH), 6.78 (d, 2H), 6.23 (d, 2H), 5.52-5.65 (ddd, IH), 5.26 (ε, IH), 5.23 (s, 2H), 5.03 (dd, IH), 4.96 (dd, IH) , 3.62 (ε, 3H), 3.18 (d, 2H), 2.71 (q, 2H), 2.57 (ε, 3H), 2.54 (ε, 3H), 20 1.21 (t, 3H). FAB-MS: m/e 469 (M+l). Step B: Preparation of 3-[4-N-((l-carboxy-l-phenyl)- methyl)-N-allylaminophenyl]methyl-5,7- 25 dimethvl-2-ethvl-3H-imidazor4.5-blpyridine Uεing the general procedure for eεter hydrolysiε deεcribed in Step E of Example 19, the product of Step A waε converted to the title compound. -Ε NMR (400 MHz, CD3OD, ppm): δ 7.53 (d, 2H), 7.22 30 (t, 3H), 7.12 (t, IH), 6.97 (s, IH), 6.68 (d, 2H), 6.22 (d, 2H), 5.67-5.74 (m, IH), 5.29 (ε, 2H), 3.36 (dd, IH), 3.07 (dd, IH), 2.78 (q, 2H), 2.57 (ε, 3H), 2.56 (ε, 3H), 1.15 (t, 3H). FAB-MS: m/e 455 (M+l). - 330 - Example 59 3_[4-N-((1-Carboxy-l-phenyl)methyl)-N-iso-butylamino- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine Step A: Preparation of 3-[4-N-((l-carbomethoxy-l- phenyl)methyl)-N-iεo-butylaminophenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo T4.5-blpvridine Using the general procedure for the alkyla¬ tion of εecondary amineε with LiN(TMS) 2 deεcribed in Step A of Example 58, 3-[4-N-((l-carbomethoxy-l- pheny1)methyl)aminophenyl]methy1-5,7-dimethy1-2- ethyl-3H-imidazo[4,5-b]pyridine (Step A, Example 57) waε alkylated with iso-butyl bromide. Standard workup and purification by flash chromatography afforded the title compound. - ■ E NMR (400 MHz, CDCI3, ppm): δ 7.49 (d, 2H), 7.18-7.30 (m, 3H), 6.83 (s, IH), 6.77 (d, 2H), 6.20 (d, 2H), 5.49 (s, IH), 5.22 (s, 2H), 3.61 (ε, 3H), 2.70 (q, 2H), 2.57 (ε, 3H), 2.54 (ε, 3H), 2.45 (d, 2H), 1.63 (m, IH), 1.18 (t, 3H), 0.81 (d, 3H),0.75 (d, 3H). FAB-MS: m/e 485 (M+l). Step B: Preparation of 3-[4-N-((l-carboxy-l-phenyl)- methyl)-N-iso-butylaminophenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-Mpvrirfi * -P Using the general procedure for ester hydrolysiε deεcribed in Step E of Example 19, the product of Step A waε converted to the title compound - 331 - l E NMR (400 MHz, CD3OD, ppm): δ 7.49 (d, 2H), 7.17 (t, 2H), 7.08 (t, IH), 6.96 (s, IH), 6.68 (d, 2H), 6.21 (d, 2H), 5.27 (ε, 2H), 2.76 (q, 2H), 2.57-2.63 (m, IH), 2.56 (s, 3H), 2.55 (ε, 3H), 2.31 (dd, IH), 1.65-1.71 ( , IH), 1.12 (t, 3H), 0.93 (d, 3H), 0.76 (d, 3H). FAB-MS: m/e 471 (M+l). Example 60 3-[4-N-((1-Carboxy-l-phenyl)methyl)-N-cyclopropyl- methylaminophenyl]methyl-5,7-dimethyl-2-ethyl-3H- imidazor4.5-b1pvridine Step A: Preparation of 3-[4-N-((l-carbomethoxy-l- phenyl)methyl)-N-cyclopropylmethylamino- phenyl]methyl-5,7-dimethyl-2-ethyl-3H- imidazor4.5-blpvridine Using the general procedure for the alkyla- tion of εecondary amines with LiN(TMS) 2 described in Step A of Example 58, 3-[4-N-((l-carbomethoxy-l- phenyl)methyl)aminophenyl]methyl-5,7-dimethyl-2- ethyl-3H-imidazo[4,5-b]pyridine (Step A, Example 57) was alkylated with cyclopropylmethyl bromide. Standard workup and purification by flaεh chromato¬ graphy afforded the title compound. - ■ E NMR (400 MHz, CDCI3, ppm): δ 7.49 (d, 2H) , 7.29 (t, 2H), 7.24 (d, IH), 6.83 (ε, IH) , 6.78 (d, 2H), 6.22 (d, 2H), 5.52 (ε, IH), 5.23 (ε, 2H), 3.63 (s, 3H), 2.73 (q, 2H), 2.67 (dd, IH), 2.57 (s, 3H), 2.55 (ε, 3H), 2.09 (dd, IE), 1.22 (t, 3H), 0.55-0.65 (m, IH), 0.36 (dt, 2H), -0.06 (m, 2H) . FAB-MS: m/e 483 (M+l). - 332 - Step B: Preparation of 3-[4-N-((l-carboxy-l-phenyl)- methyl)-N-cyclopropylmethylaminophenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo r4.5-blpvridine Using the general procedure for ester hydrolysiε deεcribed in Step E of Example 19, the product of Step A waε converted to the title compound. FAB-MS: m/e 485 (M+l). Example 61 3-[4-N-((1-Carboxy-l-phenyl)methyl)-N-εec-butylamino- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine Step A: Preparation of 3-[4-N-((l-carbomethoxy-l- phenyl)methyl)-N-sec-butylaminophenyl] methyl-5,7-dimethyl-2-ethyl-3H-imidazo T4.5-blpvridine Using the general procedure for the alkyla¬ tion of secondary amines with LiN(TMS) 2 described in Step A of Example 58, 3-[4-N-((l-carbomethoxy-l- phenyl)methyl)aminophenyl]methyl-5,7-dimethyl-2- ethyl-3H-imidazo[4,5-b]pyridine (Step A, Example 57) was alkylated with sec-butyl bromide. Standard workup and purification by flash chromatography afforded the title compound. l E NMR (400 MHz, CDCI3, ppm): δ 7.53-7.59 (m, 3H) , 7.20-7.30 (a, 2H), 6.82 (s, IH), 6.79 (d, 2H), 6.24 (d, 2H), 5.23 (s, 2H), 4.36 (s, IH) , 3.55 (s, 3H), 2.72 (q, 2H), 2.58 (s, 3H), 2.55 (ε, 3H), 2.10 (m, IH), 1.20 (t, 3H), 0.82-0.90 (m, 5H), 0.80 (d, 3H). FAB-MS: m/e 485 (M+l). - 333 - Step B: Preparation of 3-[4-N-((1-carboxy-l-phenyl)- methyl)-N-sec-butylaminophenyl]methyl-5,7- dimethyl-2-ethvl-3H-imidazor4.5-blpvridine Using the general procedure for ester hydrolysiε described in Step E of Example 19, the product of Step A can be converted to the title compound. Example 62 3-[4-N-((1-Carboxy-l-phenyl)methyl)-N-iεo-propylamino- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine Step A: Preparation of 3-[4-N-((l-carbomethoxy-l- phenyl)methyl)-N-iso-propylaminophenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo T4.5-blpyridine Using the general procedure for the alkyla¬ tion of εecondary amineε with LiN(TMS) 2 deεcribed in Step A of Example 58, 3-[4-N-((l-carbomethoxy-l- pheny1)methyl) minophenyl]methy1-5,7-di ethy1-2- ethyl-3H-imidazo[4,5-b]pyridine (Step A, Example 57) was alkylated with iεo-propyl bromide. Standard workup and purification by flaεh chromatography afforded the title compound. --E NMR (400 MHz, CDCI3, ppm): δ 7.57 (d, 2H) , 7.21-7.30 (m, 3H), 6.90 (br ε, IH), 6.81 (d, 2H) 6.25 (d, 2H), 5.27 (ε, 2H) , 4.42 (ε, IH), 3.56 (ε, 3H), 2.73-2.82 ( , 2H), 2.64 (s, 3H) , 2.57 (ε, 3H), 2.49 (m, IH), 1.24 (m, 3H) , 0.88 (d, 3H), 0.80 (d, 3H). FAB-MS: m/e 471 (M+l). - 334 - Step B: Preparation of 3-[4-N-((l-carboxy-l-phenyl)- methyl)-N-iso-propylaminophenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-b1pyridine Using the general procedure for ester hydrolysiε deεcribed in Step E of Example 19, the product of Step A can be converted to the title compound. Example 63 3-[4-N-((l-(Tetrazol-5-yl)-l-phenyl)methyl)-N-methyl- aminophenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo T4.5-blpvridine Step A: Preparation of 3-[4-N-((l-cyano-l-phenyl)- methyl)-N-methylaminophenyl]methyl-5,7- dimethvl-2-ethvl-3H-imidazor4.5-blpvridine To a εolution of 75 mg (0.26 mmol) of 5,7- dimethyl-2-ethyl-3-(4-N-methylaminophenyl)methyl-3H- imidazo[4,5-b]pyridine (Step E, Example 54) diεεolved in 1.0 mL methanol and 1.0 mL acetic acid was added 51.9 uL (0.51 mmol) benzaldehyde and 25 mg (0.38 mmol) potassium cyanide. The mixture was εtirred for 24 hourε at room temperature, then evaporated in vacuo. The reεidual oil was purified on a εilica gel flaεh chromatography column to afford 101 mg (97%) of the title compound. - ■ E NMR (400 MHz, CDCI3, ppm): δ 7.32-7.40 (m, 3H) , 7.24 (d, 2H), 7.08 (d, 2H), 6.90 (ε, IH) , 6.75 (d, 2H), 5.65 (ε, IH), 5.35 (ε, 2H), 2.88 (q, 2H), 2.75 (ε, 3H), 2.62 (s, 3H), 2.58 (ε, 3H), 1.50 (t, 3H). FAB-MS: m/e 410 (M+l). - 335 - ψ* Step B: Preparation of 3-[4-N-((l-(tetrazol-5-yl)-l- phenyl)methyl)-N-methylaminophenyl]methyl- 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b] pyridine To a solution of 101 mg (0.25 mmol) of the product of Step A dissolved in 5.0 mL toluene was added 154 mg (0.75 mmol) of trimethylstannyl azide, and the mixture was stirred and heated at reflux for 24 hours. The reaction mixture waε evaporated 10 in vacuo. the reεidue was redisεolved in 5.0 mL THF and then treated with 0.5 mL of a 1.0 N HCl εolution at 0 β C. After εtirring for 10 minutes, the reaction mixture was concentrated in vacuo t and the water was removed by azeotropic distillation with toluene. 15 After evaporation, the residue was purified on a εilica gel preparative layer chromatography plate eluted with CHCl 3 /Me0H/NH 4 0H (80:20:2). The product bands were collected and the product removed from the silica gel by elution with 10% methanol/chloroform. 20 Evaporation of the filtrate and recrystallization of the residue from dichloromethane/hexanes afforded 90 mg (80%) of the title compound aε a white powder. 1 H NMR (400 MHz, CD3OD, ppm): δ 7.20-7.30 (m, 3H) , 7.10 (d, 2H), 6.97 (d, 2H), 6.82 (d, 2H), 6.52 (ε, 25 IH), 5.40 (s, 2H), 2.83 (q, 2H), 2.80 (s, 3H) , 2.58 (ε, 3H), 2.57 (ε, 3H), 1.22 (t, 3H). FAB-MS: m/e 453 (M+l). 30 - 336 - Example 64 3_[4_(1-Carboxy-l-phenyl)methoxy-3-propylphenyl]- methyl-5-carbomethoxy-2-ethyl-7-methyl-3H-imidazo [4, -blpyridine Step A: Preparation of 2-ethyl-7-methylimidazo r4.5-b1pvridine-4-oxide A εolution of 28 g (174 mmol) of 2-ethyl-7- methylimidazo[4,5-b]pyridine (deεcribed in European Patent Application #400,974, 12-May-90) and m-chloro- perbenzoic acid (80-90%, 44.6 g) in CHCI3 (300 mL) waε heated at reflux for 0.5 hourε. The mixture was concentrated and purified (Si0 2 , 100% CH 2 C1 gradient to 30% CH 2 Cl 2 /MeOH) to give 29.8 g of the title compound as a solid. 1 H NMR (300 MHz, CD3OD, ppm): δ 8.13 (d, IH, J=6 Hz), 7.13 (d, IH, J=6 Hz), 3.01 (q, 2H, J=7.5 Hz), 2.60 (s, 3H), 1.46 (t, 3H, J=7.5 Hz). Step B: Preparation of 5-chloro-2-ethyl-7-methyl- imidazor4.5-blpvridine A mixture of 29.75 g (0.168 mol) of the product of Step A, CHCI3 (25 mL) and POCI3 (160 mL) was heated to 80°C for 1 hour. After pouring over ice, the mixture was neutralized by careful addition of NH4OH and extracted with EtOAc. Concentration gave 23.8 g of the title compound aε a εolid. --E NMR (250 MHz, CDCI3, ppm): δ 7.07 (ε, IH) 3.10 (q, 2H, J=7.5 Hz), 2.67 (ε, 3H), 1.48 (t, 3H, J=7.5 Hz). - 337 - ** Step C: Preparation of 5-bromo-2-ethyl-7-methyl- imidazor4.5-blpyridine A mixture of 22.2 g (0.113 mol) of the product of Step B in 30% HBr-HOAc waε heated to 100*C for 19 hourε. The mixture waε poured onto ice, neutralized with NH4OΞ, extracted (5 x EtOAc), and the organic layerε were concentrated to give 15 g (1 st crop) of the title compound aε a solid after cryεtallization from EtOAc. 10 1 H NMR (300 MHz, CDCI3, ppm): δ 7.22 (s, IH) 3.13 (q, 2H, J=7.5 Hz), 2.66 (ε, 3H), 1.47 (t, 3H, J=7.5 Hz). Step D: Preparation of 3-benzyl-5-bromo-2-ethyl-7- methvlimidazo .5-blpvridine 15 To a εolution of 10 g (39 mmol) of the product of Step C in DMF (70 mL) at rt waε added NaH (1.3 g of an 80% oil diεperεion, 43 mmol). After 20 minuteε benzyl bromide (5.15 mL, 43 mmol) was added and the reaction was stirred for 16 hourε. The 20 mixture was poured onto 500 g of ice and the solid residue was filtered, washed with water and air dried to give 13 g of the title compound. λ E NMR (300 MHz, CDCI3, ppm): δ 7.33-7.22 (m, 3H), 7.19 (ε, 1 H), 7.11-7.07 (m, 2H), 5.42 (s, 2H), 2.76 25 (q, 2H, J=7.5 Hz), 2.63 (ε, 3H), 1.29 (t, 3H, J=7.5 Hz). 30 - 338 - Step E: Preparation of 3-benzyl-5-cyano-2-ethyl-7- methylimidazo .5-blpvridine A mixture of 620 mg (1.8 mmol) of the product of Step D and CuCN (806 mg, 9.0 mmol) was heated in pyridine (4 mL) at reflux for 10 hours under nitrogen. The reaction was cooled, then water (50 mL), KCN (1.17 g), and EtOAc (20 mL) were added and the mixture was heated to 50 β C for 5 min. Cooling and extraction with EtOAc (2 x 50 mL) gave 467 mg of the title compound as a tan εolid. - ■ E NMR (400 MHz, CDCI3, ppm): δ 7.40 (ε, IH), 7.35-7.20 (m, 3H), 7.18-7.07 (m, 2H), 5.44 (ε, 2H), 2.83 (q, 2H, J=7.5 Hz), 2.67 (ε, 3H), 1.32 (t, 3H, J=7.5 Hz). Step F: Preparation of methyl 3-benzyl-2-ethyl-7- methvlimidazo .5-b1Pvridine-5-carboxvlate A solution of 440 mg (1.59 mmol) of the product of Step E in H 2 SU4 (4 mL) and H 2 0 (4 mL) was heated to 80 β C for 8 hours. The reaction was cooled, MeOH (150 mL) was added, then cone NH4OH was added until the mixture turned baεic. The white solid (NH4) 2 S0 was filtered and washed with MeOH. The water and MeOH were removed in vacuo and and the residue was taken up in MeOH and then filtered to remove any remaining (NH4) 2 S04- After concentrating, and removal of water from the residue by evaporation from toluene, anhydrous 3% HCl-MeOH (50 mL) was added and the mixture was εtirred overnight at rt. Filtra¬ tion, concentration, and extraction from 5% aqueouε Na 2 C0 3 with CH 2 C1 2 gave 750 mg of the crude title compound as a solid. - 339 - - ■ E NMR (300 MHz, CDCI3, ppm): δ 7.93 (s " , IH) 7.38-7.29 (m, 3H), 7.12-7.03 (m, 2H), 5.53 (s, 2H), 3.96 (s, 3H), 2.78 (q, 2H, J=7.5 Hz), 2.70 (ε, 3H), 1.29 (t, 3H, J=7.5 Hz). Step G: Preparation of methyl 2-ethyl-7-methylimidazo r4.5-b1pyridine-5-carboxvlate A mixture of 750 mg of the crude product of Step F in MeOH (30 mL), concentrated aqueouε HCl (1 mL) , and 100 mg of moist Pearlman's catalyεt were shaken under 1 atm. H 2 for 24 hourε. The reaction was incomplete so 100 mg more of the catalyεt was added and the reaction was shaken as deεcribed above for an additional 24 hourε. Filtration, concentra- tion, and extraction from dilute NH4OH with EtOAc followed by drying (Na SU4), concentration, and purification (Si0 2 , 5% MeOH/EtOAc) gave 250 mg of the title compound aε a εolid. λ E NMR (400 MHz, CDCI3, ppm): δ 7.90 (ε, IH) , 4.00 (s, 3H), 3.10 (q, 2H, J=7.5 Hz), 2.71 (ε, 3H), 1.38 (t, 3H, J=7.5 Hz). Step H: Preparation of 4-hydroxy-3-(2-propen-l-yl)- benzvl alcohol To a εolution of approximately 7.26 g (2.6 mmol) of crude 4-tert-butyldimethylεilyloxy-3-(prop-2- enyDbenzyl alcohol (Step D of Example 42) disεolved in 50 mL of anhydrouε THF was added 26 mL (2.6 mmol) of tetra-n-butylammonium fluoride and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then evaporated in vacuo and the - 340 - residual oil was purified on a εilica gel flaεh chromatography column eluted with 5% methanol/chloro¬ form to afford 3.386 g (79%) of the title compound aε a colorless oil. --E NMR (300 MHz, CDCI3, ppm): δ 2.12 (br s, IH), 3.35 (d, J=8 Hz, 2H), 4.54 (s, 3H), 5.05-5.15 (m, 2H), 5.90 (br s, IH), 5.90-6.05 (m, IH), 6.70 (d, J=10 Hz, IH), 7.02-7.10 (m, 2H). FAB-MS: m/e 165 (M+l). Step I: Preparation of 4-hydroxy-3-propylbenzyl alcohol To a εolution of 0.370 g (2.25 mmol) of the product of Step H diεsolved in 25 mL of absolute ethanol was added 53 mg of a 5% rhodium on carbon catalyst and the mixture was shaken under a 40 psig presεure of hydrogen on a Parr apparatus. After 30 minutes, the reaction mixture was removed, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 35% ethyl acetate/hexane to afford the title compound. - ■ E NMR (300 MHz, CDCI3, ppm): δ 0.95 (t, J=8 Hz, 3H), 1.55-1.68 (m, 2H), 2.22 (br s, IH), 2.57 (t, J=8 Hz, 2H), 4.56 (ε, 2H), 5.93 (br ε, 1), 6.66 (d, J=10 Hz, IH), 7.00 (dd, J=2, 10 Hz, IH), 7.08 (d, J=2 Hz, IH) . FAB-MS: m/e 167 (M+l). Step J: Preparation of methyl (4-hydroxymethyl-2- propvlphenoxv)-2-phenvlacetate To a εolution of 0.484 g (2.91 mmol) of the product of Step I diεsolved in 12 mL of acetone were - 341 - ** added 0.667 g (2.91 mmol) of methyl 2-bromophenyl¬ acetate, 0.804 g (5.82 mmol) of anhydrous K 2 C0 3 and the mixture was εtirred and heated at reflux for 5 hours. The mixture was then cooled, filtered and evaporated in vacuo. The residual oil was purified on a εilica gel flaεh chromatography column eluted with 30% ethyl acetate/hexane to afford 0.756 g (83%) of the title compound. --E NMR (300 MHz, CDCI3, ppm): δ 0.95 (t, J=8 Hz, 3H), 10 1.58 (br ε, IH), 1.60-1.75 (m, 2H), 2.70 (t, J=8 Hz, 2H), 3.68 (s, 3H), 4.57 ( , 2H), 5.62 (s, IH), 6.68 (d, J=10 Hz, IH), 7.07 (dd, J=2, 10 Hz, IH), 7.16 (d, 3=1 Hz, IH), 7.32-7.44 (m, 3H), 7.55-7.60 (m, 2H). FAB-MS: m/e 315 (M+l). 15 Step K: Preparation of methyl 2-(4-tert-butyldi- methylεilyloxymethyl-2-propylphenoxy)-2- henvlacetate To a solution of 2.34 g (7.45 mmol) of the 20 product of Step J in DMF (30 mL) were added imidazole (609 mg, 8.94 mmol) and tert-butyldimethylchlorosilane (1.35 g, 8.94 mmol) at 0 β C. The εolution waε stirred at room temperature for 18 hours, and was then poured into 100 mL of ethyl acetate and washed with H 2 0 (2x). 25 The water layer waε extracted with ethyl acetate (2x). The combined organic layer waε waεhed with H 2 0 (3x) % and brine, and waε dried over anhydrouε M S04. After concentration the mixture was purified by flash * chromatography (hexane : EtOAc = 10:1) to give 1.96 g 30 of the title compound as a clear oil. - 342 - ■ -E NMR (400 MHz, CDCI3, ppm): δ 7.58 (dd, 2H, J=8.4, 1.8 Hz), 7.42-7.30 (m, 3H) , 7.09 (d, IH, J=1.8 Hz), 7.03 (dd, IH, J=8.4, 1.8 Hz), 6.67 (d, IH, J=8.3 Hz), 5.61 (ε, IH), 4.63 (ε, 2H), 3.68 (ε, 3H), 2.69 (t, 2H, J=7.8 Hz), 1.72-1.60 (m, 2H), 0.94 (t, 2H, J=7.4 Hz), 0.90 (s, 9H), 0.06 (ε, 6H). Step L: Preparation of 2-(4-tert-butyldimethylεilyl- θ3r * -ιethyl-2-propvlphenoxv')-2-phenvlacetic acid To a εolution of 1.875 g (4.38 mmol) of the product of Step K in methanol (20 mL) waε added 1 N NaOH (4.82 mL, 4.82 mmol) at rt. The εolution waε εtirred at rt for 3 hourε. After the εolvent was evaporated under reduced pressure, the residue was dissolved in H 0 (30 mL) and washed with ethyl acetate (30 mL). The aqueous layer was acidified to pH=3 with 2 N HCl. A milky emulsion was extracted with ethyl acetate (3x). The combined organic layer was washed with brine, and was dried over anhydrous Sθ - Concentration afforded 0.929 g of the title compound as a colorless glass. l E NMR (400 MHz, CDCI3, ppm): δ 7.56 (d, 2H, J=6.2 Hz), 7.42-7.32 (m, 3H), 7.09 (s, IH), 7.02 (d, IH, J=8.3 Hz), 6.67 (d, IH, J=8.2 Hz), 5.60 (s, IH), 4.62 (s, 2H), 2.67 (t, 2H, J=7.4 Hz), 1.70-1.57 (m, 2H), 0.93 (t, 3H, J=7.2 Hz), 0.90 (s, 9H), 0.05 (s, 6H). - 343 - Step M: Preparation of tert-Butyl 2-(4-tert-butyl- dimethylsilyloxymethyl-2-propylρhenoxy)- 2-phenvlacetate To a solution of 929 mg (2.24 mmol) of the product of Step L in benzene were added oxalyl chloride (234 mL, 2.69 mmol) and one drop of DMF at 0 β C. The solution waε εtirred at rt for 45 minuteε. After concentration the reεidue waε dissolved in CH C1 2 (10 mL) . The εolution was added to a εolution of tert-butyl alcohol (253 mL, 2.69 mmol) and Et3N in CH 2 C1 2 (10 mL) at 0*C. The εolution waε εtirred at rt for 3 hourε. The mixture waε poured into EtOAc (50 mL) and washed with H 0 (lx) and brine, and dried over anhydrous MgS04- Concentration gave 778 mg of the title compound as a slightly yellow glass. 1 H NMR (300 MHz, CDCI3, ppm): δ 7.60-7.30 (m, 5H) , 7.09 (s, IH), 7.03 (d, IH, J=8.3 Hz), 6.68 (d, IH, J=8.2 Hz), 5.49 (ε, IH), 4.62 (ε, 2H), 2.80-2.60 (m, 2H), 1.80-1.55 (m, 2H), 1.33 (ε, 9H), 0.93 (t, 3H), 0.90 (s, 9H), 0.05 (s, 6H). Step N: Preparation of tert-butyl 2-(4-hydroxymethyl- 2-propvlphenoxv)-2-phenvlacetate To a εolution of 778 mg (1.59 mmol) of the product of Step J in THF (5 mL) waε added 1 N tetra- n-butylammonium fluoride εolution in THF (2.69 mL, 2.69 mmol). After the εolution waε εtirred at rt for 2 hourε, it waε poured into EtOAc (50 mL) and washed with H 0 and brine, and dried over anhydrous M SU4. Concentration afforded 839 mg of the title compound as a yellow glass. - 344 - l E NMR (400 MHz, CDCI3, ppm): δ 7.60-7.30 (m, 5H), 7.20-7.08 (m, 2H), 6.68 (d, IH, J=8.2 Hz), 5.18 (ε, IH), 4.52 (ε, 2H), 2.75-2.60 (m, 2H), 1.75-1.60 (m, 2H), 1.33 (ε, 9H), 0.93 (t, 3H). Step 0: Preparation of tert-butyl 2-(4-bromomethyl-2- propylphenoxy)-2-phenvlacetate To a εolution of 839 mg of the crude product from Step N in CH 2 C1 2 (20 mL) were added triphenyl¬ phoεphine (525 mg, 2 mmol) and carbon tetrabromide (663 mg, 2 mmol) at 0 β C. The εolution waε εtirred at 0°C for 1 hour and at rt for 15 hours. The εolution was poured into EtOAc (100 mL). After the precipitate was removed, the filtrate was washed with H 2 0 and brine, and dried over anhydrous MgS04- Concentration afforded 302 mg of the title compound as a white solid. - ■ E NMR (400 MHz, CDCI3, ppm): δ 7.57 (d, 2H, J=6.2 Hz), 7.41-7.33 (m, 3H), 7.17 (d, IH, J=2.0 Hz), 7.10 (dd, IH, J=8.3, 2.0 Hz), 6.67 (d, IH, J=8.2 Hz), 5.49 (s, IH), 4.52 (ε, 2H), 2.75-2.65 (m, 2H), 1.76-1.62 (m, 2H), 1.34 (ε, 9H), 0.96 (t, 3H, J=7.2 Hz). Step P: Preparation of 3-[4-((l-carbo-tert-butoxy-l- phenyl)methoxy)-3-propylphenyl]methyl-5- carbomethoxy-2-ethyl-7-methyl-3H-imidazo T4.5-blpvridine To a 25 mL round bottom flaεk were placed 41.8 mg (0.19 mmol) of methyl 2-ethyl-7-methylimidazo [4,5-b]pyridine-5-carboxylate (the product of Step G of this Example) and a 60% oil disperεion of NaH (5 - 345 - t* mg, 0.21 mmol). The flask was evacuated and filled with nitrogen. Dry DMF (2 mL) was added to the mixture dropwise at O'C. The solution was stirred at rt for 5 minutes. To the solution was added 80 mg (0.19 mmol) of tert-butyl 2-(4-bromomethyl-2-propyl- phenoxy)-2-phenylacetate (Step 0) in dry DMF (2 mL) at rt. After the solution waε stirred at rt for 15 hourε, it waε poured into EtOAc (10 mL) and washed with H 2 0 and brine, and dried over anhydrous MgSθ4- 10 Concentration followed by purification by flash chromatography (hexane : EtOAc = 2:1) afforded 63.6 mg of the title compound aε a colorleεε glaεs. λ E NMR (400 MHz, CDCI3, ppm): δ 7.92 (s, IH), 7.52 (d, 2H, J=7.0 Hz), 7.40-7.30 (m, 3H), 6.99 (d, IH, 15 J=2.0 Hz), 6.83 (dd.lH, J=8.3, 2.0 Hz), 6.61 (d, IH, J=8.4 Hz), 5.44 (s, 2H) , 5.43 (s, IH), 3.97 (s, 3H), 2.79 (q, 2H, J=7.5 Hz), 2.70 (s, 3H), 2.65-2.55 (m, 2H), 1.70-1.55 (m, 2H), 1.3 (ε, 9H), 1.25 (t, 3H, J=8.3 Hz), 0.89 (t, 3H. J=7.3 Hz). 20 Step 0: Preparation of 3-[4-((1-carboxy-l-phenyl)- methoxy)-3-propylphenyl]methyl-5-carbometh- oxy-2-ethyl-7-methyl-3H-imidazo[4,5-b] pyridine - 25 To a εolution of 21.4 mg (0.038 mmol) of the product of Step P in CH 2 C1 2 (1 mL) waε added TFA (0.4 mL, 5.19 mmol) at rt. The εolution waε εtirred at rt for 2 hourε. The crude mixture was directly purified by flaεh chromatography eluted with CHCl3/MeOH/N_ θH 30 (100:10:1) to give 11 mg of the title compound aε a white εolid. - 346 - --E NMR (400 MHz, CD3OD ppm): δ 7.84 (s, IH), 7.55-7.42 (br m, 2H), 7.25-7.13 (m, 3H), 6.96 (s, IH), 6.88-6.62 (br m, 2H), 5.43 (ε, 3H), 3.87 (ε, 3H), 2.81 (q, 2H, J=7.5 Hz), 2.58 (ε, 3H), 2.50-2.40 (m, 2H), 1.53-1.37 (m, 2H), 1.16 (t, 3H, J=7.5 Hz), 0.74 (t, 3H, J=6.6 Hz). FAB-MS: m/e 524 (M+Na), 540 (M+K). Example 65 3-[4-((1-carboxy-l-phenyl)methoxy)-3-propylphenyl]- methyl-5-carboxy-2-ethyl-7-methyl-3H-imidazo[4,5-b] pyridine Step A: Preparation of 3-[4-((l-carbo-tert-butoxy-l- phenyl)methoxy)-3-propyl phenyl]methyl-5- carboxy-2-ethyl-7-methyl-3H-imidazo[4,5-b] pyridine To a εolution of 63 mg ( 0.113 mmol) of 3-[4-((l-carbo-tert-butoxy-l-phenyl)methoxy)-3-propyl- phenyl]methyl-5-carbomethoxy-2-ethyl-7-methyl-3H- imidazo[4,5-b]pyridine (from εtep M of Example 64) in MeOH (2 mL) waε added 1 N NaOH (136 mL, 0.136 mmol) at rt. The εolution waε refluxed for 3 hourε. After the evaporation of the εolvent the reεidue waε taken up in H 2 0 and acidified to pH=3 with 2 N hydrochloric acid. A white precipitate waε collected and dried in a vacuum oven (60 β C) for 3 hours to afford 47 mg of the title compound as a white solid. - 347 - ■ -E NMR (400 MHz, CDCI3, ppm): δ 8.0 (ε, IH), 7.52 (d, 2H, Js6.9 Hz), 7.38-7.32 (m, 3H), 6.93 (s, IH), 6.79 (dd, IH, J=6.8, 1.1 Hz), 6.63 (d, IH, J«8.4 Hz), 5.44 (S, IH), 5.37 (ε, 2H), 2.85 (q, 2H, J=6.7 Hz), 2.72 (ε, 3H), 2.67-2.60 (m, 2H), 1.68-1.56 (m, 2H), 1.30 (8, 9H), 1.30 (t, 3H, J-8.3 Hz), 0.90 (t, 3H, J=6.5 Hz). FAB-MS: m/e 544 (M+l). Step B: Preparation of 3-[4-((1-carboxy-l-phenyl)- methoxy)-3-propylphenyl]methyl-5-carboxy-2- ethvl-7-methvl-3H-imidazor4.5-blpvridine To a εolution of 3-[4-((l-carbo-t-butoxy-l- phenyl)methoxy)-3-propylphenyl]methyl-5-carboxy-2- ethyl-7-methyl-3H-imidazo[4,5-b]pyridine (47 mg, 0.087 mmol) in CHCI3 (3 mL) was added TFA (0.5 mL) at -20 β C. The εolution waε warmed to rt and was stirred at rt for 12 hours. After evaporation of the solvent the crude mixture waε purified by flash chromato- graphy eluted with CHCl 3 /Me0H/Ac0H (90:5:5) to give 31 mg of the title compound as a white solid. l E NMR (400 MHz, CD3OD, ppm): δ 7.90 (br ε, IH), 7.52 (d, 2H, J=7.1 Hz), 7.30-7.20 (m, 3H) , 6.97 (ε, IH), 6.90-6.80 (m, IH), 6.78-6.68 (m, IH), 5.49 (br ε, 2H), 5.47 (ε, IH), 2.90-2.75 (m, 2H), 2.61 (ε, 3H), 2.54-2.45 (m, 2H), 1.55-1.45 (m, 2H), 1.17 (t, 3H, J=7.5 Hz), 0.77 (t, 3H, J=7.3 Hz). FAB-MS: m/e 510 (M+Na), 526 (M+K). - 348 - Example 66 3_[4-(1-Carboxy-l-phenyl)methoxy)-3-propylphenyl]- methyl-5-carbobenzyloxy-2-ethyl-7-methyl-3H-imidazo T4.5-blpvridine Step A: Preparation of 3-[4-((l-carbo-tert-butoxy-l- phenyl)methoxy)-3-propylphenyl]methyl-5- carbobenzyloxy-2-ethyl-7-methyl-3H-imidazo T4.5-blpvridine To a εolution of 23.3 mg (0.043 mmol) of 3-[4-(l-carbo-tert-butoxy-l-phenyl)methoxy-3-propyl- phenyl]methyl-5-carboxy-2-ethyl-7-methyl-3H-imidazo [4,5-b]pyridine (from step A of Example 65) and bis(2-oxo-3-oxazolidinyl)phoεphinic chloride (13.1 mg, 0.052 mmol) in CH 2 C1 2 (2 mL) were added triethyl¬ amine (7.2 mL, 0.052 mmol) and benzyl alcohol (5.4 L, 0.052 mmol) at rt. The solution was stirred at rt for 15 hours. The solution was poured into EtOAc (20 mL) and was washed with H 2 0 and brine, and dried over anhydrouε MgS04- After evaporation of the solvent, the mixture was purified by flash chromato¬ graphy (hexanes : EtOAc ■= 2:1) to afford 9.3 mg of the title compound as a colorless glass. - ■ E NMR (400 MHz, CDCI3): d 7.91 (ε, IH), 7.53-7.29 (m, 10H), 7.40-7.30 (m, 3H) , 6.99 (ε, IH), 6.87 (d, IH, J=8.4 Hz), 6.61 (d, IH, J=8.4 Hz), 5.43 (s, 5H), 2.79 (q, 2H, J=7.5 Hz), 2.68 (ε, 3H), 2.65-2.55 (m, 2H), 1.70-1.55 (m, 2H), 1.3 (ε, 9H), 1.28 (t, 3H, J=8.3 Hz), 0.88 (t, 3H. J=7.3 Hz). - 349 - Step B: Preparation of 3-[4-((l-ca_ oxy-l-phenyl)- methoxy)-3-proρylphenyl]methyl-5-carbobenzyl- oxy-2-ethyl-7-methyl-3H-imidazo[4,5-b] pyridine [ To a solution of 3-[4-(l-carbo-tert-butoxy-l- phenyl)methoxy-3-propylphenyl]methyl-5-carbobenzy1- oxy-2-ethyl-7-methyl-3H-imidazo[4,5-b]ρyridine (9 mg, 0.014 mmol) in CH 2 C1 2 (1 mL) waε added TFA (0.4 mL) at rt dropwiεe. The solution was stirred at rt for 2.5 hours. After evaporation of the solvent the crude mixture was purified by flaεh chromatography eluted with CHCl 3 /MeOH/NH 4 OH (80:15:1), to give 3.8 mg of the title compound aε a white εolid. l E NMR (400 MHz, CD3OD, ppm): δ 7.90 (ε, IH), 7.54 (d, 2H, J=7.0), 7.43 (d, 2H, J=7.1 Hz), 7.35-7.20 (m, 6H), 7.0 (ε, IH), 6.95-6.85 (m, IH), 6.75-6.70 (m, IH), 5.46 (ε, 2H), 5.38 (s, 3H), 2.86 (q, 2H, J=7.6 Hz), 2.61 (s, 3H), 2.70-2.60 (m, IH), 2.50-2.40 (m, IH), 1.48-1.37 (m, 2H), 1.20 (t, 3H, J=8.3 Hz), 0.73 (t, 3H. J=7.3 Hz). FAB-MS: m/e 600 (M+Na), 616 (M+K). .Example 67 3-[4-(l-(Hydroxymethoxyphoεphoryl)-l-(2-methyl- phenyl))methoxyphenyl]methyl-5,7-dimethyl-2-ethyl- H-imidazor4.5-b1pyridine - 350 - Step A: Preparation of dimethyl 2-hydrbxy-2-(2'- methvlphenvl)methvlphosphonate To a solution of dimethyl phosphite (1.340 g, 12.18 mmol) and o-tolualdehyde (1.50 mL, 1.06 equiv) at rt was added Et3 (3 dropε). After εtanding at rt for 48 h the reaction mixture, containing the product which had solidified, waε diεεolved in CH 2 C1 2 and waεhed with H 0, dried over anhydrouε MgSθ4 and concentrated in vacuo. The product was recrystallized from a mixture of Et 2 0/Hex providing 2.21 g (79%) of the titled compound. Rf = 0.5 (9:1 CH 2 Cl 2 /Me0H). --E NMR (200 MHz, CDCI3, ppm): δ 2.36 (ε, 3H), 3.63 (d, 3H), 3.68 (d, 3H), 4.57 (bm, IH), 5.29 (dd, IH), 7.09-7.30 (comp m, 3H), 7.67 (bd, IH) . Step B: Preparation of dimethyl 2-bromo-2-(2'- ethylphenyl)methylphosphonate To a solution of the product from step A (0.284 g, 1.23 mmol) and CBr (0.410 g, 1.0 equiv) in CH 2 C1 2 (5 mL) at rt was added PPh 3 (0.322 g, 1.0 equiv) . After εtanding at rt for 2 days the mixture was concentrated in vacuo and the residue waε purified by flash chromatography on a silica column using Hex/EtOAc (1:1) providing 0.174 g (48%) of the titled compound. Rf = 0.48 (2:1 EtOAc/Hex). 1 H NMR (300 MHz, CDCI3, ppm): δ 2.38 (ε, 3H), 3.61 (d, 3H), 3.86 (d, 3H), 5.16 (d, IH) , 7.12-7.28 (comp m, 3H), 7.86 (bd, IH). - 351 - • tr* Step C: Preparation of dimethyl 2-(4-hydroxymethyl- phenoxy)-2-(2'-methvlphenvl)methvlphosphonate To a solution of p-hydroxybenzyl alcohol (0.315 g, 2.54 mmol) in dry DMF (3 mL) under N 2 at rt was added 80% NaH in oil (76 mg, 1.0 equiv). After H 2 evolution ceased, a solution of the product of Step B (0.324 g, 1.11 mmol) in DMF (1 mL) was added. The mixture was stirred overnight at rt and the next day the blue-green solution was quenched with a 10 solution of sat'd NH4CI and the εolvent removed in vacuo. The residue was partially disεolved in EtOAc, dried over anhydrous MgS04, filtered and concentrated in vacuo. The product waε purified by flaεh chromatography on a εilica column uεing 15 Hex/EtOAc (1:3) to afford 85 mg (23%) of the titled compound. Rf = 0.17 (1:1 EtOAc/Hex). ■ -E NMR (200 MHz, CDCI3, ppm): δ 2.53 (dd, 3H), 3.72 (d, 3H), 3.80 (d, 3H), 4.57 (ε, 2H), 5.69 (d, IH), 6.81 (d, 2H), 7.13-7.26 (comp m, 5H), 7.59 (bm, IH). 20 Step D: Preparation of dimethyl 2-(4-bromomethyl- phenoxv ~)-2- (2'-methvlphenvl)methvlphosphonate To a εolution of the product of Step C (0.112 g, 0.333 mmol) and CBr 4 (0.253 g, 2.28 equiv) 25 in dry CH 2 C1 2 (1 mL) waε added PPh 3 (0.200 g 2.29 equiv) . The reaction mixture waε εtirred at rt overnight and then concentrated in vacuo. The product waε purified by flaεh chromatography on a εilica column uεing Hex/EtOAc (1:1) to afford 78 mg 30 (59%) of the titled compound. Rf = 0.46 (2:1 EtOAc/Hex). - 352 - - ■ E NMR (300 MHz, CDCI3, ppm) δ 2.48 (ε, 3H), 3.68 (d, 3H), 3.76 (d, 3H), 4.39 (s, 2H), 5.63 (d, IH), 6.71 (d, 2H), 7.12-7.25 (comp m, 5H), 7.59 (bm, IH). Step E: Preparation of 3-[4-(l-(Hydroxymethoxy- phoεphoryl)-!-(2-methylphenyl))methoxy¬ phenyl]methyl-5,7-dimethyl-2-ethyl-3H- imidazo[4,5-b]pyridine and 3-[4-(l- (dimethoxyphoεphoryl)-l-(2-methylphenyl))- methoxyphenyl]methyl-5,7-dimethyl-2-ethyl- 3H-imidazor4.5-blpvridine ■ To a εolution a εolution of 5,7-dimethyl-2- ethylimidazopyridine (68.0 mg, 0.389 mmol) in dry DMF (1 mL) under N 2 at rt waε added 80% NaH in oil (17.5 mg, 1.5 equiv). When H 2 evolution ceaεed a εolution of the product of Step D (78.0 mg, 0.195 mmol) in dry DMF (0.5 mL) waε added via εyringe. After εtirring for 3 h the reaction mixture waε quenched with a εolution of εat'd NH4CI. The εolvent was removed in vacuo and the residue was dissolved in CH 2 C1 2 , dried over anhydrous MgSθ4, filtered and concentrated in vacuo. The residue was purified by flash chromato¬ graphy on a silica gel column eluted first with CHCl 3 /MeOH (25:1) then with CHCl 3 /MeOH/NΞ 4 OH (40:10:1) to afford the phoεphonate mono and dieεterε. The diester (7.8 mg) was obtained in 9% yield. Rf = 0.32 (20:1 CHCl 3 /Me0H). --E NMR (200 MHz, CDCI3, ppm): δ 1.27 (t, 3H), 2.48 (d, 3H), 2.57 (s, 3H), 2.62 (ε, 3H), 2.75 (q, 2H) , 3.69 (d, 3H), 3.79 (d, 3H), 5.33 (ε, 2H), 5.61 (d,lH), 6,72 (d, 2H), 6.87 (ε, IH), 6.98 (d, 2H), 7.19 (d, 3H), 7.52 (bm, IH). - 353 - The monoester (39.0 mg) waε obtained in 46% yield. Rf = 0.41 (40:10:1 CHCl 3 /Me0H/NH 0H). -■E NMR (300 MHz, CD3OD, ppm): δ 1.19 (t, 3H), 2.25 ( ε, 3H), 2.58 (ε, 3H), 2.61 (ε, 3H), 2.80 (q, 2H), 3.59 (d, 3H), 5.41 (ε, 2H), 5.55 (d,lH ) , 6,77 ( d, 2H ) , 6.95 (d, 2H), 7.00 (ε, IH), 7.03-7.18 (comp m, 3H), 7.51 (bm, IH). 10 15 20 25 - * 30

Claims: - 354 - WHAT IS CLAIMED IS: 1. A compound of Formula I wherein: 15 or a pharmaceutically acceptable salt thereof wherein: 20. R1 is: (a) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C -C6)-alkynyl each of which iε unεubstituted or εubεtituted with a εubstituent εelected from the group 5 consiεting of: i) aryl aε defined below in R 1 (b), ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, iv) OH, 0 v) NH 2 , vi) NH(C χ -C4)-alkyl, vii) N[(C 1 -C 4 )-alkyl)] 2 , viii) NHS0 2 R 2 , ix) CF 3 - 355 - x) C00R 2 , or xi) S0 2 NHR 2a ; and (b) aryl, wherein aryl iε defined as phenyl or naphthyl and is unsubεtituted, mono- or diεubεtituted with substituents selected from the group consiεting of: i) Br, Cl, F, I, ii) ( ^^alkyl, iii) (C 1 -C )-alkoxy, iv > N0 2 v) CF 3 vi) S0 2 NR 2a R 2a , vii) (C 1 -C 4 )-alkylthio, viii) hydroxy, ix) amino, x) (C 3 -C 7 )-cycloalkyl, xi) (C3-C-*Lo)-alkenyl; and (c) heteroaryl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety, which can contain one or two memberε selected from the group consisting of N, 0, S and wherein the heteroaryl iε unεubεtituted, mono- or diεubεtituted with εubstituentε εelected from the group conεiεting of: i) Br, Cl, F, I, ii) OH, iii) SH, iv) N0 2 , v) (C 1 -C )-alkyl, vi) (C 2 -C4)-alkenyl, vii) (C 2 -C 4 )-alkynyl, ix) CF 3 , or (d) perfluoro-(Ci~C4)-alkyl; and - 356 - when A^ and A$ are abεent, then -A-- * --A 2 -A3- ii R 22 (a) =C-G-C=, R 22 R 22 R 22 (d) =C-N-C= 23 (e) =N-G-N= R 2 I (f) =N-N-N= (g) =N- Ϋ-C 3 = 22 R 22 (h) =C-N-N= R ^ wherein _ repreεents a εingle bond in theεe definitions of A in structure I but, hereafter will repreεent a double bond. - 357 - , R 22 ( j ) -N=C-N-, R 2 3 p23 22 (k) -N-N=C-, R 22 (1) -S-C=CH-, R 22 (m) -CH=C-S-, E ,2-2 (n) -C=N-N-, R 2 3 > 22 (0) -G-C=N-, E ,2-2 (p) -N=C-G-, R 22 (q) -C=N-G-, R 22 (r) -G-N=C-, - 358 - R 22 R 23 I I (S) -C=C-N-, 22 R 22 ( V ) _G-C=C-, R 22 -N 3 (x) -N=N-, R 2 * R 24 \ / (y) -c—o-c-, o R 24 R 24 (z) -C—C-0-, u 0 R 24 R 24 (ba) -0-C-*-C-, 0 - 359 - R 24 R 24 \ / (bb) -C-0-C- , u 0 0 R 24 R 24 II (be ) -C-N- -C- , 23 >24 R 24 0 \ / II (bd ) -C- N-C- , I 23 when A 4 iε preεent and A- * * iε abεent, then -A 1 -A 2 -A3-A 4 - repreεentε: R 4 R 4 (be) -C=C—C=C-, 4 /. I /. R 4 R 4 (bf) -C=C—C=N-, A 4 R 4 R 4 (bg) -N=C—C=C-, R 4 R 4 R 4 (bh) -C=C—N=C-, 4 - 360 - i I (bi) -C=N—C=C-, R 4 (bj) -C=C—N-N-, R (bk) -N=N—C-C-, R 4 R* \ (bl) -C=N—N=C-, R* (bm) -N=C—C=N-, R' I (bn) -N=N-N=C-, R 4 (bo) -C=N-N=N-, R 4 I (bp) -N=N-C=N-, P 4 ? (bq) -N=C-N=N-, - 361 - R* R t I (bε) -C=N— C=N-, (bu) - C- , II 0 R • 0 I II (bv) -C=C— C-N- , i R 5 R (bw) -N-C-C-N-, 0 R R 3 (bx) -N-C-C-N-, 0 I II (by) -C=C-C-N-, 1 /. I c R 4 (bz) -C=C-N-C-, 1 »' R 4 0 - 362 - R *5 R* (ca) -N-C-C-C-, n R 3 10 (CC) _N-C-N=N-, it 0 0 (cd) -N-N-C-N-, 15 is 0 R 5 , n (ch) -C-N-N-C-, R 5 0 - 363 - *k 0 0 II II (ci) -C-N=N-C-, R 5a R 6a R 6a R 6a I I I I (cl) _ —C —C —C-, 6a R6a j ^6a 15 R 6a R 6a R 5 (cm) -C —C —C-N-, R 6a R 6a 0 - 364 - 0 R 6a R 6a R 5a |l I I I (cq) -C—C —C — -, R 6a R 6a when A 4 and A are present, then -A- ** --A 2 -A3-A 4 -AS- are: R 6 R 7 R 8 (cs) -N-C— C— D-C-, II II 0 0 0 R 7 R 8 R 6 11 N I (et) -C-D— C— C-N-, II 0 0 R 7 R 8 II \ / (cu) -C-N— C— C=N-, ■ R6 -i2a R 6 R 7 R 8 i \ / (cv) -N-C— C— C=N-, or 0 R 2a - 365 - ■ K B is: (a) a εingle bond, (b) -S(0) n (CH 2 ) ε -, or (c) -0-; and 5 n is 0 to 2; and s iε 0 to 5; and 10 D s (a) -0-, or (b) -N(R 6 )-; and G is: 15 (a) -0-, or (b) -S(0) n ; and T is -S-, -0- or -N(R 20 )-; and 20 R 2 is: (a) H, or (b) (C 1 -C 6 )-alkyl; and R 2a is: 25 ( a ) R2 > (b) CH 2 -aryl, or (c) aryl; and 30 R 4 groups are independently: (a) H, - 366 - - 367 - ■ H (p) -S0 2 NR 2a R 2a , (q) -N0 2 , (r) -NHS0 2 -(Cι-C4)-alkyl, or (ε) when R 4 groupε are on adjacent carbon atoms they may join to form a phenyl ring; and R5 is: (a) H, or (b) (C 1 -C 6 )-alkyl or (C 2 -C 6 )-alkenyl, optionally 10 substituted with: i) hydroxy, or 15 20 25 (b) (C 1 -C 6 )-alkyl εubεtituted with: i) C0 2 R 2 , ii) CONHR 2 , iii) C0N(R 2 ) 2 ; and 30 - 368 - nd R 8 are independently: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C£)-alkynyl unsubεtituted or substituted with a εubεtituent εelected from the group conεiεting of: i) hydroxy, ϋ) (C 1 -C 4 )-alkoxy, iii) (C 1 -C 4 )-alkylthio, iv) amino, vii) carboxy, viii) carboxamido, ix) C0 2 R 2a , x) 0C(0)R 2a , or xi) guanidino, (c) phenyl or wherein the phenyl group is unsubεtituted or εubεtituted with a member εelected from the group conεisting of: i) hydroxy, ii) halo, iii) (C 1 -C 4 )-alkyl, iv) (C 1 -C 4 )-alkoxy, (e) indolyl-(C 1 -C4)-alkyl; and - 369 - R 9 and R10 are independently: (a H, (b (Cι~C 6 )-alkyl, unsubstituted or subεtituted with (C 3 -C7)-cycloalkyl, (c (C 2 -C )-alkenyl, (d (C 2 -C 6 )-alkynyl, (e Cl, Br, F, I, (f (C 1 -C 6 )-alk03^, (g when R9 and R- ** -^ are on adjacent carbonε, they can be joined to form a phenyl ring, (h perfluoro-(Cι-C 6 )-alkyl, (i (C3-C )-cycloalkyl, unεubstituted or substituted with (C^-C^-alkyl, ( j aryl; and X is (a -0-, (b -S(0) n -, (c -NR 13 - (d -CH 2 0-, (e -CH 2 S(0) n , (f -CH 2 NR 13 -, (g -0CH 2 -, (h -NR 13 CH 2 -, (i -S(0) n CH 2 -, (j -CH 2 -, (k -(CH 2 ) 2 -, (1 single bond, or (m -CH=, wherein Y and R-- * - 2 are absent forming a -C=C- bridge to the carbon bearing 2 and ,11 and - 370 - Y is : (a) εingle bond, (b) -0-, (c) -S(0) n -, (d) -NR 13 -, or (e) -CH 2 -; and Except that X and Y are not defined in εuch a way that the carbon atom to which Z iε attached alεo εimultaneously iε bonded to two heteroatoms (0, N, S, SO, S0 2 ). R- ******* and R ** - 2 are independently: (a) H, (b) unεubεtituted or εubεtituted with: (i) aryl, or (ii) (C 3 -C 7 )-cycloalkyl, (c) aryl, unεubstituted or εubεtituted with 1 to 5 εubstitutents εelected from the group conεiεting of: i) Cl, Br, I, F, ii) (C 1 -C 6 )-alkyl, iii) [(C 1 -C 5 )-alkenyl]CH 2 -, iv) [(C 1 -C 5 )-alkynyl]CH 2 -, vi) (C 1 -C 5 )-alkylthio, and vii) -N0 2 , viii) -CF3, ix) -C0 2 R 2a , or x) -OH, - 371 - (d) aryl-(Cι-C )-alkyl, unsubstituted or εubεtituted with 1 to 5 εubεtitutentε εelected from the group consisting of: i) Cl, Br, I, F, ii) (C 1 -C 6 )-alkyl, iii) [(Ci-Cs)-alkenyl]CH 2 -, iv) [(C 1 -C 5 )-alkynyl]CH 2 -, v) (C1-C5)-alkoxy, or vi) (C- j -C5)-alkylthio, or vii) -N0 2 , x) -OH, (e) (C 3 -C7)-cycloalkyl; and ( 13 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, (d) aryl-(C 1 -C 6 )-alkyl-(C=0)-, (e) (C 1 -C 6 )-alkyl-(C=0)-, (f) [(C 2 -C 5 )-alkenyl]CH 2 -, (g) [(C 2 -C 5 )-alkynyl]CH 2 -, or (h) aryl-CH 2 -; and Z is: (a) -C0 2 H, (b) -C0 2 -(C 1 -C 6 )-alkyl, (c) -tetrazol-5-yl, (d) -C0-NH(tetrazol-5-yl) (e) -C0NH-S0 2 -aryl, - 372 - (f) -CONH-S0 2 -(C 1 -C 8 )-alkyl, wherein the alkyl group is unsubεtituted or substituted with a substituent selected from the group conεiεting of: -OH, -SH, -0(Cι-C4)-alkyl, 5 -S-(C 1 -C 4 )-alkyl, -CF 3 , Cl, Br, F, I, -N0 2 , -C0 2 H, -C0 2 -(Cι-C4)-alkyl, -NH 2 , -NH[(C 1 -C 4 )-alkyl], or -N[(C 1 -C )-alkyl] 2 , (g) -C0NH-S0 2 -perfluoro-(Cι-C4)-alkyl, (h) -CONH-S0 2 -heteroaryl, 10 (i) -C0NHS0 2 NR 2a R 2a , (j) -S0 2 NHC0-aryl, (k) -S0 2 NHCO-(C 1 -C 8 )-alkyl, wherein the alkyl group iε unεubstituted or εubεtituted with a εubεtituent selected from the group 15 consiεting of: -OH, -SH, -0(Cι~C4)-al yl, -S-(C 1 -C )-alkyl, -CF 3 , Cl, Br, F, I, -N0 2 , -C0 2 H, -C0 2 -(C 1 -C4)-alkyl, -NH 2 , -NH[(C 1 -C 4 )-alkyl], or -N[(C 1 -C 4 )-alkyl] 2 , (1) -S0 2 NHC0-perfluoro-(C 1 -C 4 )-alkyl, 2 0 . (m) -S0 2 NHC0-heteroaryl, (n) -S0 2 NHCONR 2a R 2a , (o) -P0(0H) 2 , (p) -P0(0R 2 ) 2 , or (q) -P0(0H)(0R 2 ); and 25 ,20 is: (a) H, (b) (C 1 -C 6 )-alkyl, (c) allyl, 0 (d) (C 3 -C 6 )-cycloalkyl (e) (C 1 -C 4 )-acyl, (f) benzyl, or (g) phenyl; and - 373 - R 21 is: (a) H, or (b) (Cι~C4)-alkyl, unsubstituted or subεtituted with: i) NH 2 , ii) NH[(C 1 -C 4 )-alkyl], iii) N[(C 1 -C 4 )-alkyl] 2 , iv) C0 2 H, v) C0 2 (C 1 -C 4 )-alkyl, vi) OH, vii) SO3H, or viii) S0 2 NH 2 ; and R 22 groupε are independently: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl, each of which iε unεubstituted or subεtituted with a εubstituent εelected from the group conεisting of: (C3-C7)-cycloalkyl, Cl, Br, I, F, -OH, -NH 2 , -NH[(C 1 -C 4 )-alkyl], -N[(C 1 -C )-alkyl] 2 , -NHS0 2 R 25 , -C0 2 R 25 , (C 1 -C 4 )-alkoxyl, (C 1 -C 4 )-alkylthio, (C 1 -C 4 )-acyl, or C(=0)NH 2 , (c) aryl, (d) εubstituted aryl in which the εubstituents are V or W, aε defined below, (e) aryl-(C 1 -C4)-alkyl, which can be subεtitut-≤d with V or as defined below, (f) Cl, Br, I, F, (g) hydroxyl, (h) amino, (i) NH[(C 1 -C 4 )-alkyl], - 374 - (j) N[(C 1 -C 4 )-alkyl] 2 , (k) (C 1 -C 6 )-alkoxy, (1) CF 3 , (m) C0 2 R 25 , (n) C(=0)N(R 25 ) 2 , (o) N(R 25 )-C(=0)R 25 , (p) (C1-C )-alkylsulfonyl, (q) (C 1 -C4)-alkylsulfinyl, or R 2 iε: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -Cg)-alkynyl each of which iε unεubstituted or εubεtituted with a εubεtituent εelected from the group conεisting of: (C3-C7)-cycloalkyl, Cl, Br, I, F, -OH, -NH 2 , -NH[(C 1 -C )-alkyl], -N[(C 1 -C 4 )-alkyl] 2 , -NHS0 2 R 25 , -C0 2 R 25 , (Cι~C4)-alkoxyl, (Cι-C4)-alkylthio, (d) -C0 2 R 25 , (e) aryl, which iε unεubεtituted or εubstituted with subεtituents V or W, (f) aryl-(Cι-C4)-alkyl, which iε unsubstituted or εubεtituted with V or W; and R24 roupε are independently: (a) H, (b) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl each of which iε unsubstituted or εubεtituted with a εubεtituent εelected from the group - 375 - consisting of: (C3-C )-cyclo l yl, Cl, Br, I, F, -OH, -NH 2 , -NH[(C 1 -C4)-alkyl], -N[(C 1 -C 4 )-alkyl] 2 , -NHS0 2 R 25 , -C0 2 R 25 , (C j -C4)-alkylthio, (c) aryl or aryl-(Ci~C )-alkyl which iε unεubstituted or substituted with V or W - 376 - 2. The compound of Claim 1 of structural formula : or a pharmaceutically acceptable salt thereof 3. The compound of Claim 1 of structural formula; or a pharmaceutically acceptable salt thereof - 377 - The compound of Claim 1 of structural formula: or a pharmaceutically acceptable salt thereof The compound of Claim 1 of εtructural formula: or a pharmaceutically acceptable εalt thereof. - 378 - 6. A compound which iε or a pharmaceutically acceptable εalt thereof, wherein: R 1 is: (a) (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C£)-alkynyl each of which iε unεubstituted or subεtituted with a εubεtituent εelected from the group conεisting of: i) aryl, ϋ) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, iv) OH, v) NH 2 , vi) NH(^-04)-alkyl, vii) N[(C 1 -C 4 )-alkyl)] 2 , viii) NHS0 2 R 2 , ix) CF 3 , x) C00R 2 , or xi) S0 2 NHR 2a ; and - 379 - (b) aryl, wherein aryl is defined as phenyl or naphthyl and is unsubstituted, mono- or disubεtituted with substituents selected from the group consisting of: i) Cl, Br, I, F, ii) (C 1 -C 4 )-alkyl, iv) N0 2 v) CF 3 vi) S0 2 NR 2a R 2a , vii) (Cι~C4)-alkylthio, viii) hydroxy, ix) amino, x) (C3-C7)-cycloalkyl, xi) (C3-Cιø)-alkenyl; and (c) heteroaryl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety, which can contain one or two members selected from the group consiεting of N, 0, S and wherein the heteroaryl iε unεubεtituted, mono- or diεubstituted with εubεtituents εelected from the group conεisting of: i) Cl, Br, I, F, ii) OH, iii) SH, iv) N0 2 , v) (C 1 -C 4 )-alkyl, vi) (C 2 -C4)-alkenyl, vii) (C 2 -C 4 )-alkynyl, viii) (C 1 -C4)-alkoxy, or ix) CF 3 , or (d) and - 380 - R 2a iε: H, (C^-C^)-alkyl, benzyl, or phenyl; and R 4 groupε are independently: (C 1 -C )-alkyl, (C 2 -C4)-alkenyl, (C 2 -C4)-alkynyl, (C3-C5)-cycloalkyl, C0 2 R 2a Br, Cl, F, I, -NR 2a R 2 a, S(0) n -(C 1 -C 4 )-alkyl, 0-(C 1 -C 4 )-alkyl, OH, CF 3 » CN, hydroxy-(C*L-C4)-alkyl, or phenyl, unεubstituted or εubεtituted with: (C!-C4)-alkyl, Br, Cl, F, I or, methoxy; and n is 0, 1 or 2, R9 and R^ are independently: H, (C χ -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, aryl, (C 2 -C 6 )-alkynyl, (C 1 -C 6 )-alkoxyl, Br, Cl, I, F or R 9 and R 10 join to form a phenyl ring and X is: (a) -0-, (b) -S(0) n -, - 381 - (C) -NR 13 - (d ) -CH 2 0- , (e ) -CH 2 S(0) n , (f ) -C^NR 13 - , (g ) -0CH 2 - , (h) -NR 13 CH 2 -, (i) -S(0) n CH 2 -, (j) -CH 2 -, (k) -(CH 2 ) 2 -, (1) εingle bond, or (m) -CH=, which is double bonded to the carbon bearing Z and R ******** ; and Z iε: (a) -C0 2 H, (b) -C0 2 -(C 1 -C 6 )-alkyl, (c) -tetrazol-5-yl, (d) -C0-NH(tetrazol-5-yl) (e) -CONH-S0 2 -aryl, (f) -CONH-S0 2 -(Cι-C β )-alkyl, wherein the alkyl group iε unεubεtituted or substituted with a εubεtituent εelected from the group conεisting of: -OH, -SH, -0(C 1 -C 4 )-alkyl, -S-(C 1 -C 4 )-alkyl, -CF 3 , Cl, Br, F, I, -N0 2 , -C0 2 H, -NH 2 , -C0 2 -(C 1 -C4)-alkyl, -NH[(C 1 -C 4 )-alkyl], or -N[(C 1 -C 4 )-alkyl] 2 , (g) -CONH-S0 2 -perfluoro-(C 1 -C 4 )-alkyl, (h) -CONH-S0 2 -heteroaryl, or (i) -C0NHS0 2 NR 2a R 2a ; and - 382 - t 11 is: aryl-CH 2 - or aryl, wherein aryl is defined aε phenyl or naphthyl, unsubstituted or subεtituted with 1 or 2 subεtituentε εelected from the group conεiεting of: Br, I, Cl, F, (C 1 -C4)-alkyl, (C 2 -C4)-alkenyl, (C 2 -C4)-alkynyl, (C 1 -C 4 )-alkoxyl, N0 2 , CF 3 , S0 2 NR 2a R2a f (C 1 -C )-alkylthio, hydroxyl, -NR 2a R 2a ; and (a) H, (b) (C 1 -C 6 )-alkyl, (c) aryl, wherein aryl iε unεubstituted or substituted with 1 or 2 εubεtituentε εelected from the group conεiεting of: Br, I, Cl, F, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, N0 2 , CF 3 , S0 2 NR 2a R 2a , (C 1 -C 4 )-alkylthio, hydroxy, -NR 2a R 2a , (d) aryl-(C 1 -C 6 )-alkyl-(C=0)-, or (e) (C 1 -C 6 )-alkyl-(C=0)-. - 383 - A compound which is or a pharmaceutically acceptable εalt thereof, wherein: R 1 iε: and cyclopropyl; and R 2a iε: H, (C 1 -C 6 )-alkyl, benzyl, or phenyl; and R 4 groups are independently: hydrogen, (C 1 -C4)-alkyl, -C0 2 -(Cι~C )-alkyl, CH 2 0H, C0 2 H, (C ] .-C )-alkoxy or NHCH 3 ; and R 9 and R 10 are: (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkenyl or (C x -C 6 )-alkynyl, (C 1 -C 4 )-alkoxyl, Cl, Br, I, F, (C3-Cg)-cycloalkyl, or aryl; and R 1 -*- is: aryl or aryl-CH 2 -, wherein the aryl is unsubεtituted or εubεtituted with 1 or 2 εubεtituents selected from the group consisting of: - 384 - Br, Cl, F, I, (C 1 -C )-alkyl, (C 1 -C4)-alkoxyl, N0 2 , CF 3 , (C 1 -C 4 )-alkylthio, OH, -NR 2a R 2a and X iε: 0, NR 13 , CH 2 , or -CH=, which iε double bonded to the carbon bearing Z and R *** - * - * -; and R 13 iε: H, (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkenyl, aryl; and Z is: C0 2 H, C0 2 -(Cι-C4)-alkyl, lH-tetrazol-5-yl, -C0NHS0 2 -aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted, mono- or disubstituted with εubεtituentε εelected from the group conεisting of: H, ' (C 1 -C4)-alkyl, (Cι-C4)-alkoxy, N0 2 , CF 3 , S0 2 NR 2a R 2a , (C 1 -C 4 )-alkylthio, hydroxy, amino, (C3~C7)-cycloalkyl, (C3-Cκ ) )-alkenyl, or -CONHS0 2 -heteroaryl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety, which can contain one or two members selected from the group consiεting of N, 0, S, andiε unεubstituted, mono- or disubεtituted with εubεtituents εelected from the group consiεting of: Br, Cl, F, I, OH, SH, N0 2 , (C 1 -C 4 )-alkyl, (C 2 -C )-alkenyl, (C 2 -C )-alkynyl, (C 1 -C 4 )-alkoxy, or CF 3 - 385 - 8. A compound of Claim 1 of structural formula : ■,4c or a pharmaceutically acceptable εalt thereof, wherein: R 1 iε: (C 1 -C 4 )-alkyl, R c is: hydrogen, methyl or ethyl; and R d is: R 4c , -C0 2 -(C 1 -C )-alkyl, CH 2 0H, C0 2 H, C0 2 CH 2 (C 1 -C4)-alkyl or NHCH3; and R 9 and R 10 are: (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkenyl or (C 1 -C 6 )-alkynyl, (C 1 -C 4 )-alkoxyl, Cl, Br, I, F, or phenyl; and X iε 0 or NR 13 ; and - 386 - R 11 iε: benzyl or phenyl, unsubεtituted or subεtituted with 1 to 5 εubεtituentε εelected from the group conεiεting of: Br, I, Cl, F, (C 1 -C 4 )-alkyl, C -C4-alkenyl, C -C4-alkynyl, (C 1 -C 4 )-alkoxyl, N0 2 , CF 3 , S0 2 NR 2a R 2a , (C 1 -C 4 )-alkylthio, hydroxyl, NR 2a R 2a , lH-tetrazol-5-yl. - 387 - A compound of Claim 1 of structural formula : ■>4c or a pharmaceutically acceptable εalt thereof wherein: R 1 iε: (C 1 -C 4 )-alkyl, R 4c is: hydrogen, methyl or ethyl; and R 4d is: R c , -C0 2 -(C 1 -C 4 )-alkyl, CH 2 0H, C0 2 H, R 9 and R 10 are: <C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkenyl or (C 1 -C 6 )-alkynyl, (C 1 -C 4 )-alkoxyl, Cl, Br, I, F, or phenyl; and - 388 - R ******* * iε: benzyl or phenyl, wherein phenyl iε unεubεtituted or substituted with 1 to 5 εubεtituentε εelected from the group conεisting of: Br, I, Cl, F, (C 1 -C 4 )-alkyl, C 2 -C4~alkenyl, C -C4-alkynyl, (C 1 -C 4 )-alkoxyl, N0 2 , CF 3 , S0 2 NR 2a R 2a , (C 1 -C 4 )-alkylthio, hydroxyl, -NR 2a R 2a Z iε: C0 2 H, C0 2 -(C 1 -C4)-alkyl, or lH-tetrazol-5-yl. - 389 - 10. A compound of Claim 1 of structural formula: 3 4c or a pharmaceutically acceptable εalt thereof, wherein: R 1 is: ( 1-C )-alkyl; and R 4c is: hydrogen, methyl or ethyl; and R is: R 4c , -C0 2 -(C 1 -C 4 )-alkyl, CH 2 0H, C0 2 H, (C 1 -C4)-alkyl or NHCH3; and R 9 and R 10 are: (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkenyl or (C 1 -C 6 )-alkynyl, Cl, Br, I, F, or phenyl; and - 390 - R**--- ** - is: benzyl or phenyl, unsubstituted or εubεtituted with 1 to 5 subεtituentε selected from the group consiεting of: Br, I, Cl, F, (C 1 -C 4 )-alkyl, C 2 -C4~alkenyl, C 2 -C4-alkynyl, (C!-C 4 )-alkoxy1, N0 2 , CF 3 , S0 2 NR 2a R 2a , hydroxyl, -NR 2a R 2a Z is: C0 2 H, C0 2 -(Cι~C4)-alkyl, or lH-tetrazol-5-yl. - 391 - 11. A compound which iε or a pharmaceutically acceptable εalt thereof, wherein: R 1 iε: (C 1 -C 4 )-alkyl, R^ C is: hydrogen, methyl or ethyl; and R 4d is: R 4c , -C0 2 -(C 1 -C 4 )-alkyl, CH 2 0H, C0 2 H, C0 2 CH 2 (C ] i-C4)-alkyl or NHCH3; and R 9 and R 10 are: (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkenyl or (C 1 -C 6 )-alkynyl, (C 1 -C 4 )-alkoxyl, Cl, Br, I, F, or phenyl; and - 392 - R-**--**- iε: benzyl or phenyl, wherein phenyl unεubεtituted or subεtituted with 1 to 5 εubεtituentε εelected from the group consisting of: Br, I, Cl, F, (C 1 -C 4 )-alkyl, C 2 -C4-alkenyl, C 2 -C4-alkynyl, (C ] ^)-alkoxy1, N0 2 , CF 3 , S0 2 NR 2a R 2a , (C 1 -C )-alkylthio, hydroxyl, -NR 2a R2a R 13 is: (C 1 -C 4 )-alkyl, (C 2 -C4)-alkenyl, or phenyl; and Z is: C0 2 H, C0 2 -(C 1 -C4)-alkyl, or lH-tetrazol-5-yl. - 393 - 12. The compound of Claim 1 wherein said compound or its pharmaceutically acceptable salt iε εelected from the group conεiεting of: 3-[4-(l-Carboxy-l-(2-methylphenyl))methoxyphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine; 3-[4-(l-Carboxy-l-(2-bromophenyl))methoxyphenyl]methyl -5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine; 3-[3-Chlor0-4-((1-carboxy-l-phenyl)methoxy)phenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine; 3-[4-(1-Carboxy-l-(3-methylnaphth-2-yl))methoxyphenyl] methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine; 3-[4-((1-Carboxy-l-ρhenyl)methoxy)-3-methylphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine; 3-[4-((1-Carboxy-l-(2-methylphenyl))methoxy)-3- chlorophenyl]methyl-5,7-d ~ imethyl-2-ethyl-3H-imidazo- [4,5-b]pyridine; 3-[4-((1-Carboxy-l-phenyl)methoxy)-3-propylphenyl]- methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]ρyridine; 3-[4-((1-Carboxy-l-(2-methylρhenyl))methoxy)-3-propyl¬ phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[ ,5-b]- pyridine; 3-[4-((l-Carboxy-l-(2-chlorophenyl))methoxy)-3-propyl- phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]- pyridine; - 394 - 3-[4-((l-Carboxy-l-(2,5-dibromo-3,4-dimethoxyphenyl))- methoxy)-3-propylphenyl]methyl-5,7-dimethyl-2-ethyl- 3H-imidazo[4,5-b]pyridine; 3-[4-((1-Carboxy-l-phenyl)methoxy)-3,5-dipropylphenyl] methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b3pyridine; 3_[4-N-(1-Carboxy-l-phenyl)methyl)-N-allylaminophenyl] methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine; 3-[4-(1-Carboxy-l-phenyl)methoxy-3-propylphenyl]methyl -5-carbomethoxy-2-ethyl-7-methyl-3H-imidazo[4,5-b]- pyridine; 3-[4-(l-Carboxy-?l-phenyl)methoxy-3-propylphenyl]methyl -5-carbobenzyloxy-2-ethyl-7-methyl-3H-imidazo[4,5-b]- pyridine; 5,7-Dimethyl-2-ethyl-3-[3-chloro-4-((1-(N-phenyl- εulfonyl)carboxamido)-l-phenyl)methoxyphenyl]methyl- 3H-imidazo[4,5-b]pyridine; 5,7-Dimethyl-2-ethyl-3-[3-ethyl-4-((1-(N-phenyl- εulfonyl)carboxamido)-l-phenyl)methoxyphenyl]methyl- 3H-imidazo[4,5-b]pyridine; 5,7-Dimethyl-2-ethyl-3-[3,5-dipropyl-4-((1-(N-phenyl- εulfonyl)carboxamido)-l-phenyl)methoxyphenyl]methyl- 3H-imidazo[4,5-b]pyridine. - 395 - 13. A procesε for the preparation of compound of Claim 1 compriεing a reaction between the alkali metal εalt of the heterocycle of I, with the εubεtituted phenyl where the εubstituents are as defined in Claim 1 and Q representε a leaving group, using a polar aprotic solvent or a polar protic solventε to yield the alkylation product - 396 - 14. A procesε for the preparation of an intermediate uεed in the εyntheεiε of the compound of claim 1 which compriεeε reacting the alkali metal εalt of the heterocycle with the substituted benzyl group of formula wherein the subεtituents are aε defined in Claim 1 and the Pg repreεents a εuitable protecting group to give R 1 the desired intermediate - 397 - 15. A procesε for the preparation of the compound of Claim 1 which comprises reacting the intermediate Pg with the appropriate method for deprotection, followed by treatment with a metal hydride to give the reactive alkali metal εalt which reactε with the intermediate Y-R' 2 - 398 - in a polar aprotic solvent where the subεtituentε are aε defined in Claim 1 and Q represents a leaving group to yield the deεired product. 16. A pharmaceutical compoεition useful in the treatment of hypertension which compriseε a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1. 17. The composition of Claim 16 which includes another antihypertenεive agent εelected from a diuretic, an angiotenεin converting enzyme inhibitor a calcium channel blocker and a β-blocker which are memberε εelected from the group consisting of: amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, - 399 - cryptenamine acetates and cryptenamine tannateε, deserpidine, diazoxide, guanethidine εulf te, hydralazine hydrochloride, hydrochlorothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, ra. plfia serpentina. reεcinnamine, reserpine, εodium nitropruεεide, spironolactone, timolol maleate, trichlormethiazide, trimethophan camεylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, foεinopril εodium, liεinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, difluniεal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, niεoldipine, nitrendipine, aε well aε admixtures and combinations thereof. 18. A method of treating hypertension which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of Claim 1. 19. An ophthalmological formulation for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertenεive amount of a compound of Claim 1. - 400 - 20. A method of treating ocular hypertenεion compriεing topical ocular adminiεtration to a patient in need of εuch treatment of an effective ocular antihypertenεive amount of a compound of Claim 1. 21. A method of treating cognitive dyεfunction, anxiety, or depresεion compriεing adminiεtering to a patient in need of εuch treatment, a therapeutically effective amount of a compound of Claim 1.

Inventors: DHANOA DALJIT S, FITCH KENNETH J, GREENLEE WILLIAM J, HANGAUER DAVID, PATCHETT ARTHUR A, RIVERO RALPH A, WALSH THOMAS, DHANOA, DALJIT, S., FITCH, KENNETH, J., GREENLEE, WILLIAM, J., HANGAUER, DAVID, PATCHETT, ARTHUR, A., RIVERO, RALPH, A., WALSH, THOMAS
Applicants: MERCK & CO INC, MERCK & CO., INC.
Application year: 1991
Main classification: A61K31
IPC codes: A61K31, A61P9, A61P25, A61P27, A61P43, C07D235, C07D239, C07D249, C07D401, C07D403, C07D405, C07D417, C07D471, C07D473, C07D487, C07D491, C07D495, C07D498, C07D513, C07F9