CA2075627A1 - Angiotensin ii antagonists incorporating a substituted benzyl element - Google Patents

Abstract

Substitued heterocycles attached through a methylene bridge to novel substituted phenyl derivatives of Formula (1) useful as angiotensin 11 antagonists.

Description

DEMANDES OU BREVE~S VOLUMINEUX

LA PRÉSENTE PART1E-DE CEI IE DEMANDE OU CE BREVET
COMPREND PLUS D'UN TOME.

CECI EST L,E TOME ~ DE 2 NOTE: Pour les tomes additionels, veuillez c~ntacter le Bureau canadien des brevets ,2 ~ 7 ~ 7 JUI\IIBO APPLICATIONS/PATENTS

THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE
THAN ONE VOLUME

THIS IS VOLUME L_ OF

NOTE: ~or additional volumes please c~ntact the Canadian Patent Office WO91/11~ PCT/USgl/~X~7 C~,gO~ q - V 3 TITI~ OF T~F. T~V~ ON
ANGIOTENSIN II ANTAGONISTS INCORPORATING A
SUBSTIlul~D BENZYL F.T .F.M~T

BACRGRO~ND OF T~ I NV~;~l I ON
The present application is a continuation-in-part of copending application Serial No. 479,786 filed on ~ebruary 13, 1990.
The Renin-angiotensin sy~tem (RAS) plays a central role in the regulation of normal blood pressure and seems to be critically in~olved in hypertension development and maintenance as well as congestive heart failure. Angiotensin II (A II), is an octapeptide hormone produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung. ~idney, and many other organs. It is the end product of the renin-angiotensin system (RAS) and is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes.

WO91/11~ PCT/US91/009~7 2a75~27 One of the possible modes of controlling the RAS is c angiotensin II receptor antagonism. Several peptide analogs of A II are ~nown to inhibit the effect of this hormone by competitively bloc~ing the receptors, 5 but their e~perimental and clinical applications have been limited by partial agonist activity and lack of oral absorption tM. Antonaccio. Cl in . ~Yp.
~y~ertens. A4, 27-46 (1982); D. ~. P. Streeten and G. H. Anderson, Jr. - ~ndbook of ~ypertension, 10 Clinical Pharmacolo~y of Antihy~erte~sive Dr--es, ed.
A. E. Doyle, Vol. ~, pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984].
Recently, several non-peptide compounds have been described as A II antagonists. Illustrative of 15 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. [Fur. J. Pharm. F.yp.
Therap, 157, 13-21 (1988)] and by P.C. Wong, ~ ~1-~J. Ph~rm. ~ 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 al~yl bridge to a substituted phenyl. European Patent Application 24S,637 discloses derivati~es of 4,5,6,7-tetrahydro-2~-imidazo~4,5-c~-pyridine-6-carboxylic acid and analogs thereof as antihypertensive agents.
None of the compounds disclosed within this application or in any US Patent, ~uropean Applications or literature publication are of the WO91/11~9 PCT/US91/oogs7 i

2 0 7 ~ 6 ~ 7 type containing su~stituted heterocycles bonded through an al~yl bridge to a novel ~ubstituted phenyl of the type disclosed herein. The imidazole-5-,6-, and 7-fused heterocycles ha~e been disclosed in 5 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; 375,6~5; 360,673; 375,217; and 386,328 and are hereby incorporated by reference.

- 8RIEF DESCRIPTION OF T~ V~N110N
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 acti~e ingredient and in combination with diuretics and other antihypertensive agents, including beta blockers, angiotensin converting enzyme inhibitors, calcium channel blockers or a combination thereof are disclo8ed and claimed.
~urther, methods of treating hypertension and congestive heart failure are described and claimed.

.

~ WO91/11999 PCT/USgl/00957 207~627 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 ~enile 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.

WO91/11~ PCT/US91/009S7 - .

207~6~7 D~TAITFn ~FSC~TPTTON OF T~ ~hvr;~llON
Thi~ invention relates to compounds of the general Formula I:

S ~ E-R' R9~1 o ~

, R~
~12 Rl is:
(a) (Cl-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of:
i) aryl as defined below in Rl(b), ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, 2s i~) 0~, v) NH2.
vi) N~(cl-c4)-al~yl~
~ii) N~(Cl-C4)-alkyl)]2, ~Ji i i ) NHS02R2, ix) CF3, x) COOR2, or xi) S02N~R2a; and ; WO91/11~ PCT/US91/009~7 -(b) aryl, wherein aryl i 8 defined as phenyl or naphthyl and is unsubstituted, mono- or disubstituted with ~ubstituents ~elected from the group consi~ting of:
5i) Cl, Br, I, F, ii) (Cl-C4)-alkyl~
iii ) (Cl-C4)-alko~cy, i'~) N02 v) CF3 10~i) S02NR2aR2a vii) (Cl-C4)-alkylthio, ~iii) hydroxy, ix) amino, x) (C3-C7)-cycloalkyl, 15xi) (C3-C10)-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, O, 20S and wherein the heteroaryl is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
i) Cl, ~r, I, F, ii) OH, iii) SH, iv) N0 v) (Cl-C4)-alkyl, vi ) (C2-C4)-al~enyl, 30~ii) (C2-C4)-alkynyl, viii) (Cl-C4)-al~oxy, or i~) CF3, or (d) perfluoro-(Cl-C4)-al~yl; and WO91/11999 PCT/US91/~ss7 ~ 2~75S~7 _Al-A2-A3-A4-A~

when A4 and A5 are absent, then -Al-A2-A3- is:

~22 (a) -C-G-C=, R,22 lo (b) =N-G-C=

(c) =C-G-N=

(d) =C-N-C=

(e) =N-G-N=

(f) =N-N-N=

(g) ~N-N-C=

(h) =C-N-N=

wherein ~ represents a single bond in these definitions of A in structure I but, hereafter will represent a double bond.

wogl/llggg 207~627 (i) -N-C=N-, (j) -N=C-N-, (k) -N-N=C-, (1) -S-C=CH-, 15(m) -CH=C-S-, R22 .
(n) -C=N-N-, (o) -G-C=N-, 25(p) -N=C-G-, (q) -C=N-G-, (r) -G-N=C-, WO 91/119~ ~ , ~ t ~ PCT/US91/00957 2075~27 (8) -C=C-N-, (t) -C=C-G-, (v) -G-C=C-.

(w) -N=N-N-, (x) -N-N=N-, (y ) --C--O--C--, ~ /
- (z) --C--C--O--, O

(ba) 0 r~ wO 9~ g~ 2 0 7 S 6 2 7 PCT/US91/~9~7 , .

- (bb) -C-O-C-, o (bc) -C-N-C-, R24 R24 o (bd) -C- N-C-, when A4 is present and A5 is absent, then _Al_A2_A3_A4_ represents:

(be) -C=C-C=C-, (bf) -C=C -C=N-, (bg) -N=C- C=C-, R
R4 ,R4 (bh) -C=C- N=C-, 2 0 7~ S2 7 R14 R~4 (bi ) -C=N--C-C-, R~
( b j ) -C=C--N=N-, ( bk ) -N=N C , 4 ( bl ) -C=N--N=C-, ( bm ) -N=C--C=N-, ( bn ) -N=N-N=C-, 2 5 ( bo ) -C=N-N=N-, ( bp ) -NsN-C=N-, ( bq ) -N=C-N=N-, Wo g~ g99 2 ~ 7 ~ 6 2 7 PCT/US91/~957 , .. = ~

(br) -N=C- N=C-, (bs) -C=N -C=N-, O O
(bt) -~C-N -C-N-, (bu) -N-C - N-C-, O O

R4 o (bv) -C=C- C-N-, (bw) -N-C-C=N-, o ,R4 R5 (~x) -N=C-C-N-, 2s 0 R4 o (by) -C=C-C-N-, ,R4 R5 (bz) -C=C-N-C-, R4 ol ~ 2075627 _ 13 -(ca~ -~-C-C=C-.

o R4 (cb) -~-N-C=C-, (cc)-N-C-N=N-, (cd) -N=N-C-N-, (ce) -C-N-N=N-, (cf)-Cl-N-C=N-, (cg)-N=C-N-C-, (ch)-C-N-N-C~-, ? i . wo 9l/llg99 2 0 7 5 6 2 7 PCI/US91/00957 .~ ' - .

O O
(ci) -C-N=N-C-, ( c j ) -N-C-C-N-, R6a R6a R6a R5a ( ck ) -C --C --C --N-, R6a R6a R6a R5a R6a R6a R6a - ( cl ) -N --C --C --C-, R6a R6a R6a R6a R6a R~
( cm ) -C --C --C-N-, R6a R6a 0 R6a R6a R5 ( cn ) -C --C --N-C-, ~.6a R6a b R6a o R6a ( c o ) -C --~-N --C-, R6a R5 R6a

3 o ( cp ) -C-C=C-N-, WO91/11999 PCT/US91/~957 2 Q 7~ 62 7 O R6a R6a R5a (cq) -C- C - C - N-, R6a R6a R6a R6a R5 R6a (cr) -C -C -N -C-, R6a R6a R6a when A4 and A5 are present, then -Al-A2-A3-A4-A~-are:

(cs) -N-C-C -D-C-, O O

(ct) -C-D--C--C-N-, O

(cu) -C-N -C -C=N-, ~6 '2a (c~) -N-C- C-C=N-, or O R2 a (cw) -C-N- C- C~2-T-; and ~ : ` ` ` 2 0 7 ~ 6 2 7 PCT/US91/00957 B is:
(a) a ~ingle bond, (b) -S(O)n(CR2)~-, or (c) -0-; and n is 0 to 2; and s is 0 to 5; and lo D is (a) -0-, or (b) -N(R6)-; and G is:
(a) -0-, or (b) ~S(O)n; and T is -S-, -0- or -N(R20)-; and R2 is:
~a) E, or (b) (Cl-C6)-alkyl; and R2a iE::
(a) R2, (b) C~2-aryl, or (c) aryl; and R4 ~roups are independently:
(a) ~, WO91/11~9 PCT/US91/~s~7 - 207~627 (b) (Cl-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6>-al~ynyl, each of which i~
unsubætituted or substituted with:
i) OH, ii) (Cl-C4)-alkoxy, iii) C02R2, iv) OCOR2, ~) CON~R2a ~i ) CON(R2a)2, ~ii) N(R2a)C(=O)R2 ~iii) N~2.
ix) (Cl-C4)-alkylamino, x) dit(Cl-C4)-alkyl]amino, xi ) -S-(Cl-C4)-alkyl, xii) aryl, xiii) heteroaryl, (c) Cl, Br, I, F, (d) CF3, (e) CO2R2a, (f) C(=O)N(R2a)2, or (g) -C(=O)-aryl, (h) (C3-C7)-cycloalkyl, ( i ) -oR24, ( j ) -S~ , 2s (k) -S(O)n~(Cl-C4)-alkyl, (1) -SO3~, (m) -NR2R21 (n) -NR2C(=o)R21 (O) -NR2CooR21 -WO91/11~9 PCT/USgl/009~7 207~627 `. ~:
.:

(P) -S02NR2aR2a ,.-`. (q) -N02, (r) -NHS02-(Cl-C4)-al~yl, or (s) when R4 groups are on adjacent carbon atoms ~5 - they may join to form a phenyl ring; and R5 is:
(a) X, or (b) (Cl-C6)-alkyl or (C2-C6)-alkenyl, optionally substituted with:
i) hydroxy, or ii) (Cl-C4)-alkoxy; and R5a is (a) R5, or (b) (Cl-C4)-acyl; and R6 is:
(a) ~, (b) (Cl-C6)-alkyl, or (c) (Cl-C6)-alkyl substituted with hydroxy;
and R6a is:
(a) R6, or (b) (Cl-C6)-alkyl substituted with:
i ) co2~2, i i.) CON~IR2, iii) CON(R2)2; and WO91/11~ PCT/US91/~ss7 : ; i` 2~7~627 R7 and R8 are independently:
(a) H, (b) (Cl-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl unsubstituted or ~ubstituted with a substituent selected from the group consisting of:
i) hydroxy, ii) (Cl-C4)-alkoxy, iii) (Cl-C4)-alkylthio, iv) amino, v) (Cl-C4)-alkylamino, vi~ di(Cl-C4)-alkylamino, vii) carboxy, viii) carboxamido, ix) C02R2a, x) OC(O)R2a, or xi) ~uanidino, (c) phenyl or phenyl-(Cl-C4)-alkyl, wherein the phenyl group is unsubstituted or substituted with a member selected from the group consisting of:
i) hydroxy, ii) Cl, Br, I, F, iii ) (Cl-C4)-alkyl, iv) (Cl-C4)-alkoxy, (d) imidazolyl-(Cl-C4)-alkyl, or (e) indolyl-(Cl-C4)-alkyl; and WO91/11~9 PCT/US91/OOgs7 ... . .

R9 and ~10 are independently:
(a) H, (b) (Cl-C6)-alkyl, unsubstituted or substituted with (C3-C7)-cycloalkyl, (c) (C2-C6)-alkenyl, (d) (C2-C6)-alkynyl, (e) Cl, Br, F, I, (f) (Cl-C6)-alko~y, (g) when R9 and R10 are on adjacent carbons, lo they can be joined to form a phenyl ring, (h) perfluoro-(Cl-C6)-alkyl, (i) (C3-C7)-cycloalkyl, unsubstituted or substituted with (Cl-C6)-alkyl, (j) aryl; and X is:
(a) -0-, (b) ~S(O)n~, (c) _NR13_ (d) -CH20-, (e) -CH2S(O)n~
(f) -CH2NR13 -, (g) -0CH2-, (h) -NR13CH2-, (i) ~S(O)nCH2-, (j ) -CH2-, (k) -(C~2)2-' (1) single bond, or (m) -C~=j wherein Y and R12 are absent forming a -C=C- bridge to the carbon bearing Z and Rll; and WO 91/11~ 2 ~ 7 5 ~ 2 7 PCT/US91/~957 Y is:
(a) single bond, (b) -o_, (c) ~S()n~.
(d) -NR13_, or (e) -CH2-; and Except that X ~nd Y are not defined in such a way that the carbon atom to which Z i6 attached also simultaneously is bonded to two heteroatoms (0, N, S, SO . SO2 ) Rll and R12 are independently:
(a) ~, (b) (Cl-C6)-alkyl, unsubstituted or ~ubstituted with a substituent selected from the group consisting of:
(i) aryl, or (ii) (C3-C7)-cycloalkyl, (c) aryl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of:
i) Cl, Br, I, F, ii ) (cl-c4)-alkyl, iii) ~(Cl-Cs)-alkenyl]C~2-, iv) ~ (Cl-C5 )-alkynyl]C}I2-, v) (Cl-C4)-alkoxy, vi) (Cl-C4)-alkylthio, ~i i ) -N02 ~
viii) -CF3.
ix) -C02R2a, or x ) --O~I, ~ WO 9~ 2 0 7 5 6 2 7 PCT/US91/009S7 (d) aryl-(Cl-C2)-alkyl. un6ubstituted or ~ubstituted with 1 to 5 sub6titutent6 selected from the group con~isting of:
i) Cl, ~r, I, F, ii) (Cl-C4)-alkyl, iii) ~(Cl-C5)-alkenyl]CH2-, iv) [(cl-c5)-alkynyl]cH
v) ( Cl-C4 )-alkoxy, vi) (Cl-C4)-alkylthio, vii) -N02, viii) -CF3, ix) -C02~2a, or x) -OH, or (e) (C3-C7)-cycloalkyl; and R13 is:
(a) H, (b) (Cl-C6)-alkyl, (c) aryl, (d) aryl-(Cl-C6)-alkyl-(C=O)-, (e) (Cl-C6)-alkyl-(C=O)-, (f) t(C2-Cs)-alkenyl~CH2-~(g) ~(C2-C5)-alkynyl]CH2-, or (h) aryl-CH2-; and Z i6:
(a) -CO2H, (b) -CO2-(Cl-C6)-,alkyl, (c) -tetrazol-5-yl, (d) -CO-NH(tetrazol-5-yl) (e) -CON~-S02-aryl, WO91/11~ PCT/US91/~s7 (f) -CONH-SO2-(Cl-Cg)-alkyl, wherein the alkyl group is un~ubstituted or substituted with a substituent selected from the group consi~ting of: -O~. -SH, -O(Cl-C4)-alkyl, -S-(Cl-C4)-al~yl, -CF3, Cl, Br, F, I, -NO2, -C02E- -C2-(Cl-C4)-alkyl, -N~2, -NHt(Cl-C4)-alkyl], or -Nt(Cl-C4)-alkyl]2, (g) -CON~-SO2-perfluoro-(Cl-C4)-alkyl, (h) -CONH-SO2-heteroaryl, (i~ -CON~S02NR2aR2a, ( j ) -S02NHCO-aryl, (k) -SO2NHCO-(Cl-Cg)-alkyl~ wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: -OH, -S~, -O(Cl-C4)-alkyl, -S-(Cl-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2, -C02H~ ~co2-(cl-c4)-alkyl~ -N~2, -NHt(Cl-C4)-alkyl], or -Nt(Cl-C4)-alkyl]2, (1) -S02NHCO-(Cl-C4)-perfluoroalkyl, (m) -S02N~CO-heteroaryl, (n) -SO2CONR2aR2a, (o) -PO(0~)2 ~
(p) -PO(OR2)2, or (q) -PO(OH)(OR2); and 2~
R20 is:
(a) ~.
(b) (Cl-C6)-alkyl, (c) allyl, (d) (C3-C6)-cycloalkyl, (e) (Cl-C4)-acyl, (f) benzyl, or (g) phenyl; and WO 91/11999 ') ~
V ~ J U ~ ~ PCI`/US91/00957 R21 iS:
(a) H, or (b) (Cl-C4)-alkyl, unsubstituted or sub~tituted with:
i) NR2, i i ) NH r ( cl-c4 ) -alkyl], iii) N~(Cl-C4)-alkyl]2, iv) C02~.
v) CO2(Cl-C4)-alkyl, ~i) OH, vii) SO3H, or viii) SO2NH2; and R ~roups are independently:
(a) H, (b) (Cl-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C3-C7)-cycloalkyl, Cl, Br, I, F, OH, -NH2, -N~t(Cl-C4)-alkyl~, -N[~Cl-C4)-alkyl~2, -NRSo2R25, -Co2R25, (Cl-C4)-alkoxyl, (Cl-C4)-alkylthio, (Cl-C4)-acyl, or C(=O)NH2, (c) aryl, (d) substituted aryl in which the substituents are V or W, as defined below, (e) aryl-(Cl-C4)-alkyl, which can be substituted with V or W as defined below, (f) Cl, Br, I, F, (g) hydroxyl, (h) amino, W091/11~9 PCT/US91/00957 ( i ) N~[ (Cl-C4)-alkyl], (j) N[(Cl-C4)-al~Yl]2 (k) (Cl-C6)-alkogy, (1) CF3, (m) Go2R25, (n) C(=o)N(R25)2, (o) N(R25)-C(=o)R25 (p) (Cl-C4)-alkylsulfonyl, (q) (Cl-C4)-alkylsulfinyl, or (r) (Cl-C4)-alkylthio; and R23 iS
(a) H, (b) (Cl-C6)-al~Yl. (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C3-C7)-cycloalkyl, Cl, Br, I, ~, OH, -NH2, -N~(Cl-C4)-alkyl], -Nt(Cl-C4)-alkyl]2. -N~So2R25, -Co2R25, (Cl-C4)-al~oxyl, (Cl-C4)-alkylthio, (Cl-C4)-acyl, or C(=O)NH2, (c) -C(=o)R25 (d) -Co2R25, 2s (e) aryl, which is unsubstituted or substituted with substituents V or W, (f) aryl-(Cl-C4)-alkyl. which is unsubstituted or substituted with V or W; and R24 groups are independently:
(a) H, (b) (Cl-C6)-alkyl. (C2-C6)-al~enyl or (C2-C6)-alkynyl. each of which i8 unsubstituted or su~stituted with a substituent selected from the group WO91/11~ PCT/US91/ooss7 207~62~
. .

consisting of: (C3-C7)-cycloalkyl, Cl, Br, I, F, 0~, -N~2. -N~[(Cl-C4)-alkyl~, -N[(Cl-C4)-alkyl]2, -N~So2R25, -Co2R25, (Cl-C4)-alkoxyl, (Cl-C4)-alkylthio, (Cl-C4)-acyl, or C(=O)N~2, (c) aryl or aryl-(Cl-C4)-alkyl which is unsubstituted or substituted with V or W

V and W are each independently selected from:
(a) ~, (b) (Cl-C5)-alkoxy, (c) (Cl-C5)-alkyl, (d) hydroxy, (e) -S(O)n(Cl-C5)-alkyl, lS (f) -CN, (g) -N02~
(h) _NR2R2a (i) ~(Cl-C5)-alkyl]-NR2R2a, ( j ) -C02R2a, (k) -CO(Cl-C5)-alkyl, (1) CF3, (m) I, ~r, Cl, F
(n) hydroxy-(Cl-C4)-alkyl-, (o) carboxy-(Cl-C4)-alkyl-, 2~ (p) -tetrazol-S-yl, (q) -N~-S02CF3, or (r) aryl; and R25 iS: .
(a) E, (b) (Cl-C6)-alkyl, (c) aryl, or (d) aryl-(Cl-Cs)-alkyl; and the pharmaceutically acceptable ~alts thereof, WO91~11999 PCT/US91/~9~7 ,. .:

Wherein a preferred embodiment is when:

R~
(a) (Cl-C6)-alkyl or (C2-C6)-alkenyl or (~2-C6)-alkynyl each of which i8 unsubstituted or substituted with a substituent selected from the group consisting of:
i) (Cl-C4)-alkylthio, ii ) (Cl-C4)-alkoxy, iii) CF3, iv) CF2-CF3, or v) (C3-C5)-cycloalkyl, (b) perfluoro-(Cl-C4)-alkyl, or - (c) (C3-C5)-cycloalkyl; and -Al-A2-A3-A4-A5- is:

when A4 and A5 are absent, then -Al-A2-A3- is:

(a) =C-G-C-, (b) =C-N-C=

wo 9~ g99 2 0 7 S 6 ~ ~ PCT/US91/~957 (c) =N-S-N=, wherein ~ represent~ a ~ingle bond in these definitions of -Al-A2-A3- in structure Ia but, hereafter will represent a double bond.

~23 (d) -N-C=N-, (e) -N=C-N-, ~23 ~22 (f) -N-N=C-, (g) -C=N-N-~23 (h) -G-C=N-(i) -N=C-G-(j) -~C=N-G-PCrIUS91100957 WO 91/llffl . .
. .
21)7S627 (k ) -G-N=C-. ~22 )C C G

G C C

(n ) -C--O-C-(o) --C--O--C--o ( p ) -C-~--C-R24 R24 o ( q ) --C--~--C--R

WO91/11999 2 0 ~ 5 6 2 7 PCT/USgl/U99S7 when A4 is present and A5 is absent, then -Al-A2-A3-A4- represents:

(r) -C=C- C=C~-, (s) -C=C- C=N-, (t) -C=C -~=C-, R14 ,R4 (u) -C=N-C=C-, ~4 R4 (~) -N=C-C=C-, (w) -IC=C -NCN-, (x ) -~ C=C-, WO91/11999 PCT/US91/009~7 207~627 `:~

(y) -N=C-N=C-, (z) -C=N-C=N-, (aa) R4 O O
(ab) (ac) -N-C-N-C-, (ad) -C=C- C-N-, l4 `5 ~R5 R~4 (ae) -N-C-C=N-, -WO91/11999 pcT/us9l/oo9s7 r !~ 2 0 7 5 6 27 :

(af) -C=C-N-C-, R4 o R6a R6a R6a R5a (ag)-C - C - C - N-, . R6a R6a R6a R6a R6a R5 lo (ah)-C - C - C-N-, R6a R6a 0 R6a R6a R5 (ai)-C - C - N-C-, R6a R6a 0 ,R6 R,8 (aj) -N-C-CH-D-C-, ll ll O O

(ak) -C-N-CH-C=N-, or R6 R2a (al)-C-D-CH-C-N-; and O O

B is:
(a) ~ingle bond, (b) -S-, or (c) -0-; and WO91/11 ffl PCT/US91/009~7 ~ - 207562~

113/VJC4~ - 33 -n is 0, 1, or 2; and D is ~a) -O-, or (b) -N(R6)-; and G is:
(a) -O-, or (b) ~S()n.

R2 is:
(a) H, or (b) (C1-C6)-alkyl; and R2a is:
(a) R2, (b) benzyl, or (c) phenyl; and R4 groups are independently:
(a) H, (b) (Cl-C6)-alkyl, which is unsubstituted or substituted with:
i) OH, ii) C02R2, iii) N~2.
iv) (Cl-C4)-alkylamino, . v) dit(Cl-C4)-alkyl]amino, (c) C1, Br, I, F, (d) CF3, (e) C02R2a.

. WO91/11~ PCTJUS91/009s7 : . , (f) C(=O)NR2aR2a (g) -C(=0)-aryl, (h) -oR24, (i) -S-(Cl-C4)-alkyl, (j) -Nt(cl-c4)-alkyl~
(k) -N~C(=O)(Cl-C4)-alkyl, (1) -N~COO(Cl-C4)-alkyl, (m) -S02N~(Cl-C4)-alkyl, (n) -N02, 1 0 ( O ) -NHS02CH3, (p) (C3-C7)-cycloalkyl, or (q) when R4 groups are on adjacent carbon atoms they may join to form a phenyl ring; and ~5 is:
(a) H, or (b) (Cl-C6)-alkyl, which i5 unsubstituted or substituted with: hydroxyl, or C02R2; and ~5a is (a) H, (b) (Cl-C4)-alkyl, or (c) (Cl-C4)-acyl; and R6 is:
(a) H, or (b) (Cl-C6)-alkyl; and R6a is:
(a) H, or (b) (Cl-C4)-alkyl; and WO91/11~ pcT/us9l/~ss7 .

R8 is:
(a) H, (b) (Cl-C6)-alkyl, (c) which is unsubstituted or substituted with a - 5 substituent selected from the group . consisting of:
i) hydroxy, iii) (Cl-C4)-alkylthio, iv) amino, lo vii) carboxyl, viii) carboxamido, ix) C02R2a, x) OC(O)R2a, or xi) guanidino, ~d) phenyl, (e) benzyl, (f) 4-hydroxybenzyl, (g) 4-imidazolylmethyl, or (h) 3-indolylmethyl; and R9 and R10 are independently:
~a) H, (b) (Cl-C6)-alkyl, unsubstituted or substituted with (C3-C7)cycloalkyl, (c) (C2-C6)-alkenyl, (d) (C2-C6)-alkynyl, (e) Cl, Br, F, I, (f) (Cl-C6)-al~oxy, or (g) when R9 and R10 are on adjacent carbons, they can be joined to form a phenyl ring, (h) perfluoro-(Cl-C6)-alkyl, (i) (C3-C7) cycloalkyl, which is unsubstituted - or ~ubstituted with (Cl-C6)-alkyl, or (j) aryl; and WO91/11~9 ~ PCT/US91/~9s7 6~

.'~

X is:
(a) -0-, (b) ~S()n~.
(c) _N~13_ (d) -C~2O-, (e) -C~2S(O)n.
(f) -CH2NR13 -, (~) --OC~2-, (h) -NR13C~2-, (i) -S(O)nCH2-( j ) _C~2_ , (~) -(C~2)2-~
(1) single bond, or (m) =(C~)-, wherein Y and R12 are absent formin~
a -C=C- bridge to the carbon bearing Z and Rll; and Y is:
(a) single bond, (b) _o_, ( c ) --C~2---(d) ~S(O)n~~ or (e) _NR13_; and E~cept that ~ and Y are DQ~ defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (O, N, S, SO . S02 ) Rll and R12 are independently:
(a) ~, (b) (Cl-C6)-alkyl, unsubstituted or substituted with:
i) aryl, or ii) (C3-C~)-cycloalkyl, WO91/11~ PCT/US91/~s~7 207S62~

(c) aryl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of:
i) Cl, Br, I, F, 5ii) (Cl-C4)-alkyl, i i i ), [ (Cl-C5 )-al~enyl]C~2-, iv) [(Cl-C5)-alkynyl]CH2-, v) (Cl-C4)-alko~y, or vi) (Cl-C4)-alkylthio. and (d) aryl-(Cl-C2)-al~yl, unsubstituted or æubstituted with 1 to 5 substitutents selected from the group consiæting of:
i) Cl, Br, I, ~, ii ) (Cl-C4)-alkyl, iii) t(Cl-c5)-alkenyl]c~2-~
iv) t(Cl-C5)-alkynyl]C~2-, ~) (Cl-C4)-alko~y, or ~i) (Cl-C4)-alkylthio, and (e) (C3-C7)-cycloalkyl; and R13 is:
(a) ~, (b) (Cl-C6)-alkyl, (c) aryl, (d) aryl-(Cl-C6~-alkyl-(C=0)-, or (e) (Cl-C6)-alkyl-(C=O)-; and z is:
(a) -C02~, (b) -CO2-(Cl-C6)-alkyl, (c) -tetrazol-5-yl, (d) -CO-NH(tetrazol-5-yl), (e) -CONH-502-aryl, WO 91/11~9 2 0~ 5 62~ PCT/US91/~Q9~7 (f) -CON~-SO2-(Cl-C4)-alkyl, (g) -CONH-SO2-perfluoro-(Cl-C4)-alkyl, (h) -CONH-S02-heteroaryl, wherein heteroaryl is defined as a 5 or 6 membered aromatic ring containing one or two heteroatoms selected from the group consisting of O, N, or S;
( i ) -CON~S02NR2aR2a, (j) -S02N~ICO-aryl, (k) -SO2N~CO-(Cl-C6)-alkyl, (1) -S02N~CO-(Cl-C4)-perfluoroal~cyl, (m) -S02N~CO-heteroaryl, wherein heteroaryl is defined as a 5 or 6 membered aromatic ring containing one or two heteroatoms Eelected from the group consisting of O, N, or S, (n) -S02NHCONR2aR2a, (o) -PO(0~)2 ~
(p) -PO(OR2)2, or (q) -PO(OH)(OR2); and R22 groups are independently:
(a) E, (b) (Cl-C6)-alkyl, (C2-C6)-al~enyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C3-C7)-cycloalkyl, Cl, Br, I, F, -0~, -NH[(Cl-C4)-alkyl]. -Nt(Cl-C4)-alkyl]2, -CO2R25, or C(=o)NHt(cl-c4)-alkyl)]~
(c) aryl or aryl-(Cl-C4)-alkyl, which is unsubstituted or substituted with a substituent selected from the group consistin~ of: H, Br, Cl, I, F, (cl-c4)-alkyl, hydroxy-(Cl-C4)-alkyl, (cl-c4j-al~oxy~ or Co2R25.

WO91/11~ PCT/US91/~gs7 113/VJC45 _ 39 _ (d) Cl, Br, I, ~, (e) amino, (f) N~[(Cl-C4)-alkyl], (g) Nt(Cl-C4)-alkYl]2~ -(h) (cl-c6)-alkoxy~
( i ) Co2R25, (j) C(=o)N(R25)2, or (k) (Cl-C4)-alkylthio; and R23 is:
(a) E, (b) (Cl-C6)-alkyl. which is unsubstituted or substituted with a substituent selected from the group consisting of: -OH, -N~2, -Nt(Cl-C4)-al~Yl~2~ or -Co2R25~
(c) aryl or aryl-(Cl-C4)-alkyl, which is unsubstituted or ~ubstituted with: Br, Cl, F, I, (Cl-C4)-alkyl, hydroxy-(Cl-C4)-alkyl, Co2R25, CoR25, or So2R25, R24 groups are independently:
(a) H, (b) (Cl-C6)-alkyl. which is unsubstituted or substituted with a substituent selected from 2s the group consisting of: Cl, Br, I, F, -Co2R25, hydroxy-(Cl-C4)-alkyl, or (Cl-C4)-acyl, or (c) aryl or aryl-(Cl-C4)-alkyl; and R25 is:
(a) H, (b) (Cl-C6)-alkyl, (c) aryl, or (d) aryl-(Cl-C5)-alkyl; and the pharmaceutically acceptable 5alt thereof.

WO 91/11999 Pcr/uS9l/~ngs7 `i 7~6~
,~ .

Wherein a more preferred embodiment of the in~ention is when:

~1 is:
(a) (Cl-C~)-alkyl (C2-C6)-alkenyl or . (C2-C6)-alkynyl, each of which is unsubstituted or ~ubstituted with a substituent selected from the group consisting of:
i ) (Cl-C4)-alkylthio, ii) (Cl-C4)-alkoxy, iii) C~3, iv) CF2CF3, or ~) (C3-C5)-cycloal~yl, or (b) perfluoro-(Cl-C4)-alkyl; and -Al-A2-A3-A4-A5- is:

when A4 and A5 are absent, then -Al-A2-A3- is:

(a) -N-C=N-, (b) -C=N-N-,, R23 (c) -G-C=N-(d) -N=C-&-~. WO91/11999 -~ PCT/US91/oogs7 !

20756~7 (e) -~=N-G-(f) -C=C-G-when A4 is present and A5 is absent, then -Al-A2-A3-A4- represents:

( g ) -C=C--C=C-, (h) -C=C- C=N-, (i) -C=N-C=N-, (j) -C=C- C-N-, R6a R6a R6a R5a (k) -C - C - C - N-, R6a R6a R6a WO91/11~9 PCT/USgl/~gs7 ~ 20756~ ~

When Al-A2-A3-A4-A~ are all present:

R6 R8 o (1)-N-C- C~-N-~-, or (m) R8 R6 -C-N - CX-C-N-; and B is a single bond; and G is -O-, or -S-; and R2 is:
(a) ~, (b) (Cl-C6)-alkyl; and R2a is:
(a) R2, (b) benzyl, or (c) phenyl; and R4 groups are independently:
(a) E, (b) (Cl-C6)-al~yl, which is unsubstituted or substituted with:
i) O~
i i ) C02R2a, iii) N~2~
iv) (Cl-C4)-al~ylamino.
v) dit(Cl-C4)-al~yl~amino, WO91/11999 PCT/US91/~957 ' ~

207362~

(c) Cl, Br, I, F, (d) CF3, (e) CO2R2a, (f) c(=o)NR2aR2a (g) (C3-C7)-cycloalkyl;
(h) -C(=O)-aryl, (i) -oR24, (j) -N[(Cl-c4)-alkyl]2~
(k) -NHC(=O)(Cl-C4)-alkyl, (1) -NHCO2(Cl-C4)-alkyl, (m) -SO2NH-(Cl-C4)-alkyl, (n) -S02NH-aryl, (o) -N02, ( p ) -NHS02CH3, R5 is:
(a) H, or (b) (Cl-C6)-alkyl, unsubstituted or substituted with: hydroxyl, or CO2R2; and R5a is (a) H, (b) (Cl-C4)-alkyl, or (c) (Cl-C4)-acyl; and R6 is:
(a) H, or (b) (Cl-C6)-alkyl; and R6a is:
(a) H, or (b) (Cl-C4)-alkyl; and .

~ WO 91/11999 2 0 7 5 6 27 Pcr~usgl/~q~s7 ~8 is:
(a) H, (b) (Cl-C6)-alkyl, which is unsubstituted or substituted with a ~ub~tituent selected from the group consi~ting of:
i) hydroxy, ii) (Cl-C4)-alkoxyl, iii) ~mino, iv) carboxyl, ~) carboxamido, vi ) C02R2a, vii) OC(O)R2a, or viii) guanidino, (c) phenyl, lS (d) benzyl, (e) 4-hydroxybenzyl, (f) 4-imidazolylmethyl, or (g) 3-indolylmethyl; and R9 and R10 are independently:
(a) H, (b) (Cl-C6)-alkyl, unsubstituted or substituted with (C3-C7)cycloalkyl, (c) (C2-C6)-alkenyl, (d) (C2-C6)-alkynyl, (e) Cl, Br, F, I, (f) (Cl-C6)-alkoxy, or (g) when R9 and R10 are on adjacent carbons, they can be joined to form an aryl ring, (h) perfluoro-(Cl-C6)-al~yl, (i) (C3-C7)-cycloalkyl, unsubstituted or su~stituted with (Cl-C6)-alkyl, or (j) aryL; and .~ WO91/11~9 PCT/US91/00957 2075~27 _ 45 -X is:
(a) -0-, (b) -S()n~~
(c) _NR13_ 5 (d) -C~20-, (e) ~CH2S(O)n, (f) -C~2NR13 -, (g) -OC~I2-, (h) -NR13CH2-, (i) -S(O)nC}~z-, ( j ) -CH2- , (k) -(C~2)2-~
(1) single bond, or (m) -C~=, wherein Y and R12 are absent forming a -C=C- bridge to the carbon bearing Z and Rll; and Y is:
(a) single bond, (b) -0_, ( c ) --C~2- ~
(d) ~S(O)n~, or (e) -NR13-; and Except that X and Y are nQ~ 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 . SO2 ) -Rll and R12 are independently: -(a) ~.
(b) (Cl-C6)-al~yl. unsubstituted or substituted with:
i) aryl, or ii) (C3-C7)-CYcloal~yl, WO91/11~9 7 PCT/US91/~gs7 2 0 ~ 5 6 2 . ~ , .

(c) aryl, (d) aryl-(Cl-C2)-al~yl, or (e) (C3-C7)-cycloalkyl; snd R13 i~
(a) ~, (b) (Cl-C6)-alkyl, (c) aryl, (d) aryl-(Cl-C6)-al~yl-(C=0)-, or lo (e) (Cl-C6)-alkyl-(C=0)-; and Z is:
(~) -C02~.
(b) -C02-(Cl-C6)-alkyl, (c) -tetrazol-5-yl, (d) -C0-N~(tetrazol-5-yl), (e) -CON~-502-aryl, (f) -CON~-S02-(Cl-C4)-alkyl, (g) -CON~-S02-perfluoro-(Cl-C4)-alkyl, (h) -CON~-S02-heteroaryl, where in heteroaryl i6 a ~ or 6 membered aromatic ring containing one or two heteroatoms selected from the group consi6ting of 0, N, or S, ( i ) -CON~S02NR2aR2a, (j) -S02N~CO-aryl, (k) -S02N~C0-(Cl-C4)-alkyl, (1) -S02N~CO-(Cl-C4)-perfluoroalkyl, (m) -S02N~CO-heteroaryl. where in heteroaryl is a 5 or 6 membered aromatic ring containing one or two heteroatoms 6elected from the group consi6ting of 0, N, or S, (n) -SO2N~coNR2a~2a (o) -PO(O~I)2 ~
(p) _PO(OR2)2, or (q) -Po(O~(OR2); and WO91/1l ffl . PCT/US91/oogs7 2~75627 R22 groups are independently:
(a) H, (b) (Cl-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-al~ynyl each of which is unsubstituted or substituted with a - substituent selected from the group consisting of: (C3-C7)-cycloalkyl, Cl, Br, I, F, -0~, -N~t(cl-c4)-alkyl]~
-Nt(cl-c4)-alkyl32~ -C02R or C(=O)N~t(Cl-C4)-alkyl)].
(c) aryl or aryl-(Cl-C4)-al~yl, which is unsubstituted or substituted with a substituent selected from the group consisting of: Br, Cl, I, F, (Cl-C4)-alkyl, hydroxy-(Cl-C4)-alkyl, (Cl-C4)-alkoxy, or Co2R25, (d) Cl, Br, I, F, (e) amino, (f) NH[(Cl-C4)-alkyl], (g) Nt(Cl-c4)-alkYl]2 (h) (Cl-C6)-alkoxy.
( i ) Co2R25, (j) C(=o)N(R25)2, or (k) (Cl-C4)-alkylthio; and R23 is:
(a) H, (b) (Cl-C6)-alkyl. which is unsubstituted or substituted with a substituent selected from the group consisting of: -0~, -N~2, -Nt(Cl-C4)-alkyl]2, or -Co2R25, WO91/ll ffl 2 0 7 S 6 2 7 PCr/US91/OO~S7 . .

(c) aryl or aryl-(Cl-C4)-alkyl, ~hich i~
unsubstituted or substituted with: Br, Cl, ~, I, (Cl-C4)-alkyl. hydroxy-(Cl-C4)-alkyl, Co2R25, CoR25, or So2R25, R~4 groups are independently:
(a) E, (b) (Cl-C6)-al~yl, which i8 unsubstituted or substituted with a ~ubstituent selected from lo the group consisting of: Cl, Br, I, F, -Co2R25, hydroxy-(Cl-C4)-alkyl, or (Cl-C4)-acyl, or (c) aryl or aryl-(Cl-C4)-al~yl; and R25 is:
(a) ~, (b) (Cl-C6)-alkyl, (c) aryl, or (d) aryl-(Cl-C5)-alkyl;
or a pharmaceutically acceptable salt thereof.

WO91~11~9 pcT/us9l/ooss7 , : .
207~S27 The al~yl substitutents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, isobutyl, neopentyl, isopentyl, etc.
The alkenyl and alkynyl substituents tenote al~yl groups as described above which are modified 80 that each contains a carbon to carbon double bond or triple bond, respectively, ~uch as vinyl, allyl and 2-butenyl.
Cycloal~yl tenotes rings composed of 3 to 8 methylene groups, each which may be substituted or unsubstituted with other hydrocarbon substituents, and include for e~ample cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohe~yl.
The alkoxy substituent represents an alkyl group as described above attached through an o~ygen 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, o~ygen, and sulfur, for example, pyridyl, thienyl, furyl, imidazolyl, and thiazolyl.

WO 91/11~9 2 0 7 5 6 2 7 PCT/US91/0~57 ! ~

- Compounds of the present in~ention illu~trative of - ~ubclasses of Formula I are:

5,5_F~S~n T~TDA7.oT~F~s:

2-~utyl-1-t4-(1-carboxy-1-phenyl)metho~yphenyl~methyl-1,4-dihydro-4-methylimidazot4,5-d]imidazole 1-t4-(1-Carboxy-l-phenyl)methoxyphenyl3methyl-1,4-dihydro-2-ethyl-4-methylimidazo[4.5-d]imidazole 1-t4-(1-Carboxy-1-(2-chlorophenyl))metho~yphenyl]-methyl-1,4-dihydro-2-ethyl-4-methylimidazot4,5-d]-imidazole .

l-t4-((1-Carboxy-1-(2-chlorophenyl))methoxy)-3-propyl-phenyl]methyl-1,4-dihydro-2-ethyl-4-methylimidazo-t4.5-d]imidazole l-t4-(1-Carboxy-1-(2-isopropylphenyl))methoxyphenyl]-methyl-1,4-dihydro-2-ethyl-4-methylimidazot4,5-d]-imidazole l-t4-(1-Carboxy-1-(2-trifluromethylphenyl))methoxy-phenyl]methyl-1,4-dihydro-2-ethyl-4-methylimidazo-t4.5-d]imidazole l-t4-((1-Carboxy-l-phenyl)methoxy)-3-propylphenyl]-methyl-1,4-dihydro-2-ethyl-4-methylimidazot4,5-d]-imidazole WO91/11~ pcT/us9l/~ss7 207~627 1-[4-(l-Carboxy-l-(l-naphthyl))metho~yphenyl]methyl-1,4-dihydro-2-ethyl-4-methylimidazot4.5-d~imidazole 1-[4-~-(1-Carboxy-1-(2-chlorophenyl))methylamino-phenyl3methyl-1,4-dihydro-2-ethyl-4-methylimidazo-[4,5-d]imid~zole l-t4-N-(l-Carboxy-1-(2-chlorophenyl))methyl-N-ethyl-aminophenyl]methyl-1.4-dihydro-2-ethyl-4-methyl-imidazot4,5-d]imidazole l-t4-(1-Carboxy-1-(2-chlorophenyl))methylthiophenyl~-methyl-1,4-dihydro-2-ethyl-4-methylimidazo[4,5-d]-imidazole l-t4-(1-Carboxy-l-phenyl)methoxyphenyl]methyl-1,4-dihydro-5-hydroxymethyl-4-methyl-2-propyl-imidazo-t4.5-d]imidazole 2-Butyl-l-t4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-1,4-dihydro-4-ethyl-5-methylimidazot4,5-d]imidazole 2-Butyl-l-t4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-1,6-dihydro-6-methylimidazo~4,5-d]imitazole Z-butyl-1-[4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-l~-thieno[3,4-d]imidazole l-t4-(1-CarboXy-l-phenyl)methoxg-phenyl~methyl-2-propyl-lE-furo[3,4-d]imidazole 2-.~utyl-1-[4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-

4-methyl-1~-thieno[3,4-d]imidazole WO91/11~ PCT/US91/oogs7 .. ; , _ -~- 2075627 ---. ~ .

l-t4-(1-Carboxy-l-phenyl)methoxyphenyl]methyl-4-ethyl-- 2-propyl-lR-thieno~3.4-d~imidazOle-~,5-diogide 2-Butyl-1-[4-(1-carboxy-1-phenyl)methoxyphenyl~methyl-1,5-dihydro-5-methylpyrrolot3,4-d]imidazole 2-Butyl-1-[4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-1,5-dihydro-4,5-dimethylpyrrolo[3,4-d]imidazole 2-Butyl-1-[4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-1,5-dihydro-4-ethyl-5-methylSul~onylpyrrolot3,4-d~-imidazole 3-t4-(1-Carboxy-l-phenyl)methoxyphenyl]methyl-6-methyl

-5-hydroxymethyl-2-propyl-3R-thienot2.3-d~imidazole 2-Rutyl-5-carboxy-3-t4-(1-carboxy-1-phenyl)methoxy-phenyl]methyl-6-methyl-3H-thienot2,3-d]imidazole 2-Butyl-5-carbomethoxy-3-[4~ carboxy-1-phenyl)-methoxyphenyl3methyl-6-methyl-3R-thienot2,3-d]-imidazole 5-Carbomethoxy-3-t4-(1-carboxy-1-phenyl)methoxyphenyl`~
methyl-2-ethyl-6-methyl-3R-thienot2,3-d]imidazole 5-Carbomethoxy-3-[4-(1-carboxy-1-(2-chlorophenyl))-methoxyphenyl~methyl-2-ethyl-6-methyl-3R-thieno-~2,3-d]imidazole 5-Carbomethoxy-3-[4-(1-carboxy-1-(2-isopropylphenyl))-methoxyphenyl3methyl-2-ethyl-6-methyl-3E-thieno-t2.3-d]imidazole WO91/11~9 PCT/US91/oogs7 207562~

5-Carbomethoxy-3-~4~ carboxy-1-(1-naphthyl))-methoxyphenyl~methyl-2-ethyl-6-methyl-3~-thieno-t2.3-d~imidazole 5-Carbomethoxy-3-t4-(1-carboxy-1-(2-methoxyphenyl))-methoxyphenyl]methyl-2-ethyl-6-methyl-3~-thieno-[2,3-d]imidazole 5-Carbomethoxy-3-t4-(1-carboxy-1-(2-methoxyphenyl))-lo methylthiophenyl]methyl-2-ethyl-6-methyl-3~-thieno-t2.3-d]imidazole 5-Carbomethoxy-3-[4-N-(l-carboxy-1-(2-metho~yphenyl))-methylaminophenyl]methyl-2-ethyl-6-methyl-3~-thieno-lS t2.3-d]imidazole

6-[4-(1-carboxy-l-phenyl)methoxyphenyl~methyl-1,6-dihydro-1.3-dimethyl-5-propylimidazot4.5-c~pyrazole 5-Butyl-6-t4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-2-hydroxymethyl-6~-imidazo[4,5-d]thiazole 5-Butyl-6-t4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-2-phenyl-6~-imidazot4,5-d~thiazole 5-Butyl-6-[4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-2-(2-chloro)phenyl-6~-imidazot4,5-d]thiazole 6-t4-(1-Carboxy-l-phenyl)metho~yphenyl]methyl-5-ethyl-2-phenyl-6~-imidazo~4,5-d]thiazole WO91/11~9 PCT/US91/00957 ,t. , _ .
2075627 `~

6-t4-(1-Carboxy-l-phenyl)methoxyphenyl]methyl-2-(2-`- chloro)phenyl-5-ethyl-6H-imidazot4.5-d~thiazole 6-[4-(1-Carboxy-l-phenyl)methoxyphenyl]methyl-2-(2-chloro)phenyl-5-ethyl-6H-imidazot4,5-d]oxazole 6-[4-(1-Carboxy-l-phenyl)methoxyphenyl]methyl-3-methyl -5-butyl-6H-imidazot4,5-d]isothiazole 6-t4-(1-Carboxy-l-phenyl)metho~yphenyl]methyl-5-ethyl-3-methyl-6~-imidazo[4,5-d~isothiazole 6-[4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl3-methyl-5-ethyl-3-methyl-6H-imidazo[4.5-d]i60thiazole 6-[4-(1-Carboxy-1-(2-ethylphenyl))methoxyphenyl]methyl -5-ethyl-3-methyl-6H-imidazot4.5-d]isothiazole 6-t4-(1-Carboxy-1-(2-trifluromethylphenyl))methoxyphen yl]methyl-5-ethyl-3-methyl-6H-imidazo[4,5-d]-isothiazole 6-t4-(1-Carboxy-1-(2-nitrophenyl))methoxyphenyl]methyl -5-ethyl-3-methyl-6H-imidazot4,5-d~isothiazole 6-t4-N-(l-Carbo~y-1-(2-chlorophenyl))methylaminophenyl ]methyl-5-ethyl-3-methyl-6~-imidazot4~5-d]isothiazole 6-t4-(1-Carbo~Y-1-(2-chlorophenyl))methylthiophenyl]-methyl-5-ethyl-3-methyl-6H-imidazo[4~5-d]isothiazole WO91/11~ PCT/US91/~957 2D7562~

6-t4-(1-Carboxy-1-(2-chlorophenyl))methylsulfonyl-phenyl]methyl-5-ethyl-3-methyl-6~-imidazot4,5-d]-isothiazole 6-t4-(1-Carboxy-l-(l-naphthyl))metho~yphenyl3methyl-5-ethyl-3-methyl-6E-imidazo[4,5-d]isothiazole 6-[4-(1-Carboxy-l-phenyl)metho~yphenyl]methyl-3,5-diethyl-6H-imidazot4,5-d]isothiazole 2-Butyl-1,4-dihydro-4-methyl-1-[4-(1-(tetrazol-5-yl)-l-phenyl)methoxyphenyl]methylimidazo[4,5-d]imidazole 1,4-Dihydro-2-ethyl-4-methyl-1-t4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl]methylimidazot4,5-d]imidazole 1,4-Dihydro-2-ethyl-4-methyl-1-t4-(1-(tetrazol-5-yl)-1-(2-chloro)phenyl)methoxyphenyl]methylimidazot4,5-d]-imidazole 1,4-Dihydro-2-ethyl-4-methyl-1-[4-(1-(tetrazol-5-yl)-1-(2-isopropyl)phenyl)methoxyphenyl]methylimidazo-t4,5-d]imidazole 1,4-Dihydro-2-ethyl-4-methyl-1-t4-(1-(tetrazol-5-yl)-1-(2-trifluromethyl)phenyl)methoxyphenyl]methyl-imidazot4,5-d]imidazole 1,4-Dihydro-2-ethyl-4-methyl-1-t4-(1-(tetrazol-5-yl)-1-(1-naphthyl))methoxyphenyl]methylimidazo[4,5-d]-q imidazole WO91/11~9 PCT/US91/oogs7 A ~' 2 0 7 5 6 ' ~ ,I,,. ., ~ ~ ;, 1,4-Dihydro-2-ethyl-4-methyl-1-[4-N-(l-(tetrazol-5-yl)-l-(2-chlorophenyl))methylaminophenyl]methyl-- imidazo[4,5-d~imidazole 1,4-Dihydro-2-ethyl-4-methyl-1-t4-N-(l-(tetrazol-5-yl)-l-(2-chloro)phenyl)methyl-N-ethylaminophenyl]-methylimidazo[4,5-d]imidazole 1,4-Dihydro-2-ethyl-4-methyl-1-t4-(1-(tetrazol-5-yl)-lo 1-(2-chlorophenyl))methylthiophenyl]methylimidazo-t4,5-d]imidazole 1,4-Dihydro-5-hydroxymethyl-4-methyl-2-propyl-1-t4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl]methylimidazo-t4~5-d]imidazole 2-Butyl-1,4-dihydro-4-ethyl-5-methyl-1-t4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl~methylimidazo-t4.5-d]imidazole 2-Butyl-1,6-dihydro-6-methyl-1-t4-(1-(tetrazol-5-yl)-l-phenyl)methoxyphenyl~methylimidazo[4,5-d]imidazole 2-Butyl-l-t4-(l-(tetrazol-5-yl)-1-phenyl)methoxy-phenyl]methyl-lH-thienot3,4-d]imidazole 2-Propyl-1-[4-(1-(tetrazol-5-yl)-1-phenyl)methoxy-phenyl]methyl-lH-furot3,4-d]imidazole 2-Butyl-4-methyl-1-t4-(1-(tetrazol-5-yl)-1-phenyl)-methoxyphenyl]methyl-lH-thienot3.4-d]imidazole WO91/11~ - PCT/USgl/009~7 ~`- ` 207~627 4-Ethyl-2-propyl-l-t4-(l-(tetraZol-5-yl)-l-phen - metho~yphenyl]methyl-lH-thieno[3,4-d~imidazole-5,5-dioxide 5 2-Butyl-1,5-dihydro-5-methyl-1-t4-(1-(tetrazol-5-yl)-l-phenyl)methoxyphenyl]~ethylpyrrolot3,4-d]imidazole 2-Butyl-1,5-dihydro-4,5-dimethyl-1-t4-(1-(tetrazol-5-yl)-l-phenyl)methoxyphenyl~methylpyrrolo[3,4-d]-10 imidazole 2-Butyl-1,5-dihydro-4-ethyl-5-methylsulfonyl-1-[4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl]methylpyrrolo-~3,4-d]imidazole 5-~ydroxymethyl-6-methyl-2-propyl-3-t4-(1-(tetrazol-5-yl)-l-phenyl)methoxyphenyl]methyl-3H-thieno~2,3-d]-imidazole 2-Butyl-5-carboxy-6-methyl-3-[4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl]methyl-3H-thieno[2,3-d]imidazole 2-Butyl-5-carbomethoxy-6-methyl-3-t4-(1-(tetrazol-5-yl)-l-phenyl)methoxyphenyl]methyl-3H-thienot2,3-d]-2s imidazole 5-Carbomethoxy-2-ethyl-6-methyl-3-[4-(1-(tetrazol-5-yl)-l-phenyl)methoxYphenyl~methyl-3H-thieno~2,3-d~-imidazole 5-carbomethoxy-2-ethyl-6-methyl-3-t4-(l-(tetrazol-5 yl)-1-(2-chloro)phenyl)methoxyphenyl]methyl-3H-thieno~2,3-d]imidazole WO 91/11~ 2 0 7 5 6 2 7 PCT/US91/ ~ 7 5-Carbomethoxy-2-ethyl-6-methyl-3-[4-(1-(tetrazol-5-yl)-1-(2-isopropylphenyl))methoxyphenyl3methyl-3H-thienot2,3-d]imidazole 5-Carbomethoxy-2-ethyl-6-methyl-3-t4-(1-(tetrazol-5-yl)-1-(1-naphthyl))methoxyphenyl]methyl-3~-thieno-t2.3-d]imidazole 5-Carbomethoxy-2-ethyl-6-methyl-3-t4-(1-(tetrazol-5-lo yl)-1-(2-methoxyphenyl))methoxyphenyl]methyl-3~-thienot2,3-d]imidazole 5-Carbomethoxy-2-ethyl-6-methyl-3-[4-(1-(tetrazol-5-yl)-1-(2-methoxyphenyl~)methylthiophenyl]methyl-3H-thienot2,3-d]imidazole 5-Carbomethoxy-2-ethyl-6-methyl-3-t4-N-(l-(tetrazol-5-yl)-l-(2-methoxyphenyl))methylaminophenyl]methyl-3H-thienot2,3-d]imidazole 1,6-dihydro-1,3-dimethyl-5-propyl-6-t4-(l-(tetrazol-5-yl)-l-phenyl)methoxyphenyl]methyl-imidazot4,5-c]-pyrazole 5-Butyl-2-hydroxymethyl-6-t4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl]methyl-6~-imidazot4~5-d]thiazole 5-Butyl-2-phenyl-6-t4-(1-(tetrazol-5-yl)-1-phenyl)-methoxyphenyl]methyl-6~-imidazot4~5-d3thiazole 5-Butyl-2-(2-chloro)phenyl-6-t4-(1-(tetrazol-5-yl)-l-phenyl)methoxyphenyl]methyl-6~-imidazot4,5-d]~hiazole ,' '; ' ~
207~27 5-Ethyl-2-phenyl-6-[4-(1-(tetrazol-5-yl)-1-phenyl~-methoxyphenyl~methyl-6~-imidazo~4.5-d]thiazole 2-(2-Chloro)phenyl-5-ethyl-6-[4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl]methyl-6H-imidazot4,5-d]thiazole 2-(2-Chloro)phenyl-5-ethyl-6-t4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl]methyl-6H-imidazo[4,5-d]oxazole 3-Methyl-5-butyl-6-~4-(1-(tetrazol-5-yl)-1-phenyl)-methoxyphenyl]methyl-6H-imidazot4,5-d~isothiazole 5-Ethyl-3-methyl-6-t4-(1-(tetrazol-5-yl)-1-phenyl)-methoxyphenyl]methyl-6H-imidazot4,5-d]isothiazole 5-Ethyl-3-methyl-6-t4-(1-(tetrazol-5-yl)-1-(2-chloro-phenyl))methoxyphenyl]methyl-6H-imidazot4.5-d]-isothiazole 5-Ethyl-3-methyl-6-t4-(1-(tetrazol-5-yl)-1-(2-ethyl-phenyl))methoxyphenyl]methyl-6H-imidazot4,5-d]-isothiazole 5-Ethyl-3-methyl-6-t4-(1-(tetrazol-5-yl)-1-(2-trifluoromethylphenyl))methoxyphenyl]methyl-6~-imidazot4,5-d]isothiazole - 5-Ethyl-3-methyl-6-t4-(1-(tetrazol-5-yl)-1-(2-nitrophenyl))methOXYPhenyl]methyl-6~I-imidazo-t4.5-d]isothiazole WO 91/11999 Pcr/us9l/oo 207~627 ~`

5-Ethyl-3-methyl-6-t4-N-(l-(tetrazol-5-yl)-1-(2-chlorophenyl))methylsminOphenYl]methyl-6~-imidazo-[4,5-d]isothiazole - ~ S-Ethyl-3-methyl-6-t4-(1-(tetrazol-5-yl)-1-(2-chloro- phenyl))methylthiophenyl]methyl-6~-imidazo[4,5-d]-isothiazole ~-Ethyl-3-methyl-6-t4-(1-(tetrazol-5-yl)-1-(2-chloro-phenyl))methylsulfonylphenyl~methyl-6H-imidazot4,~-d~-isothiazole 5-~thyl-3-methyl-6-[4-(1-(tetrazol-5-yl)-1-(1-naphthyl)methoxyphenyl]methyl-6~-imidazo~4,5-d]-lS isothiazole 3,5-Diethyl-6-~4-(1-(tetrazol-5-yl)-1-phenyl)methoxy-phenyl]methyl-6~-imidazo[4,5-d]isothiazole 2-Butyl-l-t4-(l-((N-phenylsulfonyl)carboxamido)-l-phenyl)methoxyphenyl]methyl-1,4-dihydro-4-methyl-imidazot4,5-d]imidazole 2-Butyl-l-t4-(1-((N-methylsulfonyl)carboxamido)-l-phenyl)methoxyphenyl~methyl-1.4-dihydro-4-methyl-imidazo[4,~-d]imidazole 2-Butyl-1-~4-(1-((N-trifluoromethylsulfonyl)-carboxamido)-l-phenyl)methoxyphenyl~methyl-l,4-3~ dihydro-4-methylimidazo[4.5-d]imidazole WO91/11~ . PCT/US91/00957 2-Butyl-l-t4-(1-((N-phenyl~ulfonyl)carboxamido)-l-phenyl)methoxyphenyl~methyl-1,5-dihydro-5-methyl-pyrrolo~3,4-d]imidazole 2-Butyl-l-t4-(1-((N-trifluoromethylsulfonyl)-carboxamido)-l-phenyl)methoxyphenyl]methyl-1,5-dihydro-5-methylpyrrolo~3,4-d]imidazole 2-(2-Chloro)phenyl-5-ethyl-6-[4-(1-((N-i~opropyl-sulfonyl)carboxamido)-l-phenyl)methoxyphenyl]methyl-6H-imidazo~4,5-d]oxazole BF.~TMTn~0l.~S:

2-~utyl-1-[4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-benzimidazole 2-Butyl-1-[4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-

7-methylbenzimidazole l-t4-(1-Carboxy-l-phenyl)methoxyphenyl]methyl-7-methyl -2-propylbenzimidazole 1-[4-(1-Carboxy-l-phenyl)methoxyphenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole 1-[4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl]-methyl-5,7-dimethyl-2-ethylbenzimidazole 1-[4-(l-Carboxy-l-(2-methylphenyl))methoxyphenyl]_ methyl-5,7-dimethyl-2-ethylbenzimidazole WO9lJ11~ 2 0 7 5 6 2 7 PCT/USsl/onss7 1-[4-(1-Carboxy-l-(2.6-dichlorophenyl))methoxyphenyl]-methyl-5,7-dimethyl-2-ethylbenzimidazole l-t4-(1-Carboxy-1-(2-nitrophenyl))methoxyphenyl]-methyl-5,7-dimethyl-2-ethylbenzimidazole l-t4-(l-Carboxy-1-(2-trifluromethylphenyl))methoxy-phenyl~methyl-5,7-dimethyl-2-ethylbenzimidazole 1o 1-[4-(1-Carboxy-1-(2-ethoxyphenyl))methoxyphenyl]-methyl-5,7-dimethyl-2-ethylbenzimidazole 1-[4-(1-Carboxy-l-(l-naphthyl))methoxyphenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole 1-[4-(1-Carboxy-1-(2.6-dimethylphenyl))methoxyphenyl]-methyl-5,7-dimethyl-2-ethylbenzimidazole 1-[4-(N-(l-Carboxy-1-(2-chlorophenyl))methyl)amino-phenyl3methyl-5.7-dimethyl-2-ethylbenzimidazole 1-[4-(N-(l-Carboxy-1-(2-chlorophenyl))methyl-N-methyl)aminophenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole l-t4-(N-(l-carboxy-l-(2-chlorophenyl))methyl-N-acetyl) aminophenyl]methyl-5.7-dimethyl-2-ethylbenzimidazole l-t4-(1-Carboxy-1-(2-chlorophenyl))methylthiophenyl]-methyl-5,7-dimethyl-2-ethylbenzimidazole WO91/11~ PCT/US91/009S7 20~627 l-t4-(1-Carboxy-1-(2-chlorophenyl))methylsulfinyl-phenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole 1-~4-(1-Carboxy-1-(2-chlorophenyl))methyl~ulfonyl-phenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole 1-~4-(1-Carboxy-1-(2-chlorophenyl))metho~y-3-methyl-phenyl3methyl-5,7-dimethyl-2-ethylbenzimidazole l-t4-(1-Carboxy-1-(2-chlorophenyl))methoxy-3-ethyl-phenyl]methyl-5,7-dimethyl-2-ethylbenzimidazole 1-~4-(1-Carboxy-1-(2-chlorophenyl))methoxy-3-propyl-phenyl~methyl-5,7-dimethyl-2-ethylbenzimidazole l-t4-(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))metho~yphenyl3-methyl-2-ethyl-S-hydroxymethyl-7-methylbenzimidazole 5-Carboxy-l-t4-(1-carbo~y-1-(2-chlorophenyl))metho~y-phenyl]methyl-2-ethyl-7-methylbenzimidazole 5-Carbo~ethoxy-1-[4-(1-carboxy-1-(2-chlorophenyl))-methoxyphenyl3methyl-2-ethyl-7-methylbenzimidazole WO 91/11~9 2 0 7 5 6 2 7 PCT/US91/00957 l-t4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl]-methyl-2,5-diethyl-7-methylbenzimidazole l-t4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl3-methyl-2,5;7-triethylbenzimidazole 1-[4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl]-methyl-2-ethyl-4,5,7-trimethylbenzimidazole 1-t4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl~-methyl-5,7-dimethyl-2-ethyl-4-hydroxybenzimidazole 5,7-Dimethyl-2-ethyl-1-t4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))methoxyphenyl]methylbenzimidazole 5,7-Dimethyl-2-ethyl-1-t4-(1-(tetrazol-5-yl)-1-(2-methylphenyl))methoxyphenyl]methylbenzimidazole 5,7-Dimethyl-2-ethyl-1-t4-(1-(tetrazol-5-yl)-1-- 20 (2-ethoxyphenyl))methoxyphenyl~methylbenzimidazole 5,7-Dimethyl-2-ethyl-1- r 4-(1-(tetrazol-5-yl)-1-(2-trifluoromethylphenyl))methoxy-3-methoxyphenyl]-methylbenzimidazole 5,7-Dimethyl-~-ethyl-l-t4-N-(l-(tetrazol-5-yl)-1-(2-chlorophenyl))methylaminophenyl]methylbenzimidazole 5,7-Dimethyl-2-ethyl-1-t4-N-(l-(tetrazol-5-yl)-1-(2-chlorophenyl))methyl-N-methylaminophenyl~methyl-benzimidazole WO91/11~9 PCT/US91/009~7 2 0 7 ~ 6 2 7 5,7-Dimethyl-2-ethyl-1-[4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))methylthiophenyl]methylbenzimidazole 5,7-Dimethyl-2-ethyl-1-t4-(l-(tetrazol-5-yl)-1-(2-chlorophenyl)~methylsulfinylphenyl]methyl-benzimidazole 5,7-Dimethyl-2-ethyl-1-t4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))methylsulfonylphenyl]methyl-benzimidazole 2-Ethyl-5-hydroxymethyl-7-methyl-1-[4-(1-(tetrazol-5-yl)-l-(2-chlorophenyl))methoxyphenyl~methyl-benzimidazole 5-Carboxy-7-methyl-2-ethyl-1-[4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))methoxyphenyl]methylbenzimidazole 5-Carbomethoxy-2-ethyl-7-methyl-1-t4-(l-(tetrazol-5-yl)-1-(2-chlorophenyl))methoxyphenyl~methyl-benzimidazole 2,5-Diethyl-7-methyl-1-[4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))methoxyphenyl]methylbenzimidazole 1-[4-(1-(Tetrazol-5-yl)-1-(2-chlorophenyl))methoxy-phenyl~methyl-2.5.7-triethylbenzimidazole 2-Ethyl-1-[4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))-methoxyphenyl~methyl-4,5.7-trimethylbenzimidazole WO91/11~ PCT/US91/009s7 5,7-Dimethyl-2-ethyl-4-hydroxy-1-[4-tl-(tetrazol-5-yl) -1-(2-chlorophenyl))methoxyphenyl]methylbenzimidazole 5,7-Dimethyl-2-ethyl-1-r4-(1-(N-Phenyl~ulfonyl)-carboxamido-1-(2-chlorophenyl))metho~yphenyl]methyl-benzimidazole 5,7-Dimethyl-2-ethyl-1-~4-(1-(~-trifluoromethyl-sulfonyl)carboxamido-l-(2-chlorophenyl))methoxyphenyl]
methylbenzimidazole 5,7-Dimethyl-2-ethyl-1-[4-(1-(N-methylsulfonyl)-carboxamido-l-(2-chlorophenyl))methoxyphenyl]methyl-benzimidazole TMID~0PY~TDT~F5 2-Butyl-1-[4-(1-carboxy-1-phenyl)methoxyphenyl~methyl-7-methyl-3H-imidazo[4,5-b]pyridine 3-t4-(1-Carboxy-l-phenyl)methoxyphenyl~methyl-7-methyl -2-propyl-3H-imidazo[4,5-b]pyridine 3-t4-(1-Carboxy-l-phenyl)methoxyphenyl~methyl-5,7-dimethyl-2-ethyl-3~-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-1-(2-chlorophenyl)~methoxyphenyl]-methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b~pyridine WO91/11~ PCT/US91/~gs7 v~ ~ 2a75~27 3-~4-(1-Carboxy-1-(3-chlorophenyl))methoxyphenyl3-methyl-7-methyl-2-propyl-3H-imidazot4,5-b]pyridine 3-[4-(1-Carboxy-1-(2,6-dichlorophenyl))metho yphenyl]-methyl-7-methyl-2-propyl-3H-imidazo~4,5-b3pyridine 3-t4-(1-Carboxy-1-(4-chlorophenyl))methoxyphenyl~-methyl-7-methyl-2-propyl-3H-imidazot4,5-b]pyridine 10 3-t4-(1-Carboxy-1-(2-bro~ophenyl))methoxyphenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b]pyridine 3-[4-(1-Carboxy-1-(2-methylphenyl))methoxyphenyl]-methyl-7-methyl-2-propyl-3~-imidazot4,5-b]pyridine 3-t4~ Carboxy-1-(2-methylphenyl))methoxyphenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b]pyridine 3-t4-(1-Carboxy-1-(2-methoxyphenyl))metho~yphenyl]-20 methyl-7-methyl-2-propyl-3~-imidazot4,5-b~pyridine 3-t4-(1-Carboxy-1-(2-methoxyphenyl))methoxyphenyl]-methyl-5,7-dimethyl-2-ethyl-3~-imidazot4,5-b]pyridine 2s 3-t4-(1-Carboxy-1-(2-etho~yphenyl))methoxyphenyl]-methyl-7-methyl-2-propyl-3H-imidazo~4,5-b]pyridine 3-[4-(1-Carboxy-l-(2-ethoxyphenyl))methoxyphenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b]pyridine 3-[4-(1-Carboxy-1-(2-(1-hexyloxy)phenyl))methoxy-phenyl]methyl-7-methyl-2-propyl-3H-imidazo-[4.5-b]pyridine WO 91/11999 . ; PCI/US91/OQ,n. 'i7 ~ : i 2 07 ~ 6 2~

3-~4-(1-Carboxy-1-(2-(1-he~yloxy)phenyl))methoxy-phenyl]methyl-5 ! 7-dimethyl-2-ethyl-3~-imidazo-[4.5-b]pyridine -3-[4-(l-Carboxy-1-(2~6-dichlorophenyl))meth phenyl~methyl-5,7-dimethyl-2-ethyl-3~-imidazo-[4,5-b]pyridine 3-~4-(1-Carboxy-1-(2-nitrophenyl))methoxyphenyl3-methyl-7-methyl-2-propyl-3H-imidazo~4,5-b]pyridine 3-[4-(1-Carboxy-1-(2-nitrophenyl))methoxyphenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b3pyridine 3-t4-(1-Carboxy)-1-(2-carboxyphenyl)methoxyphenyl3-methyl-7-methyl-2-propyl-3~-imidazot4,5-b]pyridine 3-[4-(1-Carboxy)-1-(2-carboxyphenyl)methoxyphenyl]-methyl-5,7-dimethyl-2-ethyl-3~-imidazot4,5-b]pyridine 3-t4-(1-Carboxy-1-(2-trifluoromethylphenyl))metho~y-phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazot4,5-b]-pyridine 3-t4-(1-Carboxy-l-phenyl)methoxy-3-chlorophenyl]methyl -7-methyl-2-propyl-3~-imidazot4,5-b]pyridine 3-[4-(1-Carboxy-l-phenyl)methoxy-3-chlorophenyl]methyl -5,7-dimethyl-2-ethyl-3~-imidazot4,5-b~pyridine 3-~4-((1-Carboxy-l-phenyl)methoxy)-2-chlorophenyl3-methyl-5~7-dimethyl-2-ethyl-3~-imidazot4~5-b]pyridine WO91/11~ PCT/US91/00957 . .
2~5627 3-t4-(1-Carboxy-1-(2-chlorophenyl))methoxy-3-chloro-phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo-t4.5-b]pyridine 3-t3-Benzoyl-4-~(1-carboxy-1-phenyl)methoxy)phenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b]pyridine 3-t3-AcetYl-4-((l-carbo~y-l-phenyl)methoxy)phenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b~pyridine 3-[4-((1-Carboxy-l-phenyl)methoxy)-3-methoxyphenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b]pyridine 3-[4-((1-Carboxy-l-phenyl)methoxy)-3-ethoxyphenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b]pyridine 3-t3-tert-Butyl-4-((1-carboxy-1-phenyl)methoxy)phenyl]
methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b]pyridine 3-t4-((1-Carboxy-l-phenyl)methoxy)-3-methylphenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b]pyridine 3-t4-((1-Carboxy-1-(2-methylphenyl))methoxy)-3-chloro-phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo-t4.5-b]pyridine 3-t4-((1-Carboxy-l-phenyl)methoxy)-3.5-dichlorophenyl~
methyl-5,7-dimethyl-2-ethyl-3H-imidazot4.5-b]pyridine 30 3-t4-(1-Carbo~y-1-(2-Chlorophenyl))metho~y-3,5-dichlorophenyl~methyl-5,7-dimethyl-2-ethyl-3H-imidazo~4,5-b]pyridine WO 91/11999 Pcr/ussl/nnss7 3-t4-((1-Carboxy-l-phenyl)methoxy)-3-chloro-5-methoxy-phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo~4,5-~]-pyridine 3-t4-((1-Carboxy-l-phenyl)methoxy)-3-(prop-2-enyl)-phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazo[4,5-b]-pyridine 3-[4-((1-Carboxy-l-phenyl)methoxy)-3-propylphenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b]pyridine 3-t4-((1-Carboxy-1-(2-methylphenyl))methoxy)-3-propyl-phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b]-pyridine 3-[4-((1-Carboxy-1-(2-chlorophenyl))methoxy)-3-propyl-phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b]-pyridine 20- 3-t4-((l-Carboxy-1-(4-chlorophenyl))methoxy)-3-propyl-phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b]-pyridine 3-t4-((1-Carboxy-1-(2-methoxyphenyl))methoxy)-3-propyl phenyl3methyl-5,7-dimethyl-2-ethyl-3~-imidazo[4,5-b]-pyridine 3-t4-((l-Carboxy-1-(2,5-dibromo-3,4-dimetho~yphenyl))-methoxy)-3-propylphenyl3methyl-5.7-dimethyl-2-ethyl-3H-imidazot4,5-b]pyridine PCT/US91/009~7 3-[4-((1-Carboxy-1-(3,4-dimethoxyphenyl))methoxy)-3-propylphenyl]methyl-5.7-dimethyl-2-ethyl-3~-imidazo-[4,5-b~pyridine 3-{4-(1-Carboxy-l-phenyl)methoxy-3-propylphenyl~-methyl-5-carbomethoy -2-ethyl-7-methyl-3E-imidazo-[4,5-b]pyridine 3-[4-(1-Carboxy-l-phenyl)methoxy-3-propylphenyl3-methyl-5-carboxy-~-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-3~-imidazo-t4.5-b]pyridine 3-[4-((1-Carboxy-l-phenyl)methoxy)-3-(1-methyl-cyclohex-l-yl)phenyl]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-3~-imidazo[4,5-b]pyridine 3-[4-((1-Carboxy-1-(2-methoxyphenyl))methoxy)-3,5-2s dipropylphenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazo[
4,5-b]pyridine 3-[4-((1-Carboxy-1-(2.5-dibromo-3,4-dimethoxyphenyl))-methoxy)-3.5-dipropylphenyl]methyl-5.7-dimethyl-2-ethyl-3~-imidazo[4,5-b]pyridine " WO 91/11999 2 0 7 5 6 2 7 Pcr/ usg 1 /Or ~Q9~;7 -3-[4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl]-methyl-2-ethyl-5-hydroxymethyl-7-methyl-3H-imidazo-t4.5-b]pyridine 5-Carboxy-3-t4-(1-carbo~y-1-(2-chlorophenyl))methoxy-phenyl]methyl-2-ethyl-7 methyl-3~-imidazot4,5-b]-pyridine 5-Carbomethoxy-3-t4-(1-carboxy-1-(2-chlorophenyl~)-1o methoxyphenyl]methyl-2-ethyl-7-methyl-3~-imidazo-t4.5-b]pyridine 5-Carbomethoxy-3-t4-(1-carboxy-1-(2-chlorophenyl))-methoxyphenyl]methyl-2-ethyl-7-trifluromethyl-3H-imida zot4~5-b]pyridine 3-t4-(1-Carboxy-l-cyclohexyl)methoxyphenyl]methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-l-propyl)methoxyphenyl]methyl-7-methyl-2-propyl-3H-imidazot4,5-b]pyridine 3-t4-((1-Carboxy-1-(3-phenyl)propyloxy)phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazot4,5-b]pyridine 3-t4-((1-Carboxy-1-(2-phenyl)ethoxy)phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazot4.5-b]pyridine 3-[4-(1-carboxy-1-phenoxy)methylphenyl]methyl-7-methyl-2-propyl-3~-imidazo[4,5-b]pyridine WO91/ll ffl PCT/US91/009~7 - 2~75627 - (z)-3-t(4-((2-Carboxy-2-phenyl)ethylenyl)phenyl)-methyl]-7-methyl-2-propyl-3H-imidazot4,5-b]pyridine 3-t(4-((2-Carboxy-2-phenyl)ethyl)phenyl)methyl3-7-methyl-2-propyl-3~-imidazo[4,5-b]pyridine 3-[4-(1-Carboxy-l-methyl-l-phenyl)methoxyphenyl]-methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine 3-t4-(1-Carboxy-l-(naphth-l-yl))methoxyphenyl]methyl-7-methyl-2-propyl-3~-imidazot4,5-b]pyridine 3-~4-(1-Carboxy-1-(3-methylnaphth-2-yl))methoxy-phenyl]methyl-7-methyl-2-propyl-3~-imidazo[4,5-b]-15 pyridine 3-t4-N-(l-Carboxy-l-phenyl)methyl)-N-methylamino-phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazo-t4,5-b]pyridine 3-[4-N-(l-Carboxy-l-phenyl)methyl)-N-ethylaminophenyl]
methyl-5,7-dimethyl-2-ethyl-3H-imidazot4.5-b]pyridine 3-[4-N-(l-Carboxy-l-phenyl)methyl)-N-propylamino-phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazo-t4,5-b]pyridine 3-t4-N-(l-Carboxy-l-phenyl)methyl)aminophenyl]methyl-5,7-dimethyl-2-ethY1-3~-imidaZot4~5-b]pyridine 3-t4-N-(l-Carboxy-l-phenyl)methyl)-N-allylaminophenyl]
methyl-5~7-dimethyl-2-ethyl-3~-imidazot4~5-b]pyridine WO91/11~ PCT/USgl/00957 207 S 627 ~-:
.

3-[4-N-(l-Carboxy-l-phenyl)methyl)-N-i~o-butylamino-phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazo-[4,5-b]pyridine 3-[4-N-(l-Carboxy-l-phenyl)methyl)-N-cyclopropyl-methylaminophenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-b]pyridine 3-[4-N-(l-Carbogy-l-phenyl)methyl)-N-sec-butylamino-lo phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazo-[4,5-b]pyridine 3-~4-N-(l-Carboxy-l-phenyl)methyl)-N-iso-propylamino-phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazo~4,5-b]-pyridine 3-[4-N-(l-(Tetrazol-5-yl)-1-phenyl)methyl)-N-methyl-aminophenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo-[4,5-b]pyridine 2-Butyl-7-methyl-1-[4-(1-(tetrazol-5-yl)-1-phenyl)-methoxyphenyl]methyl-3H-imidazo[4.5-b]pyridine 7-Methyl-2-propyl-3-[4-(1-(~etrazol-5-yl)-1-phenyl)-methoxyphenyl3methyl-3H-imidazot4.5-b~pyridine 7-Methyl-2-propyl-3-[4-(1-(tetraZol-5-yl)-1-(2-chloro-phenyl)methoxyphenyl3methyl-3H-imidazo[4.5-b3pyridine 7-Methyl-2-propyl-3-[4-(2-phenyl-2-(tetrazol-5-yl)-ethyl~phenyl~methyl-3H-imidazo[ 4 . 5-b] pyr i d ine WO91/11~ PCT/US91/00957 207S62~

5,7-Dimethyl-2-ethyl-3-[4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl]methyl-3~-imidazot4,5-b]pyridine 5,7-Dimethyl-2-ethyl-3-[4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))methoxyphenyl]methyl-3~-imidazot4,5-b]-pyridine 5,7-Dimethyl-2-ethyl-3-t4-(1-(tetrazol-5-yl)-1-(2-methylphenyl))methoxyphenyl]methyl-3E-imidazot4,5-b]-10 pyridine 5,7-Dimethyl-2-ethyl-3-t4-(1-(tetrazol-5-yl)-1-(2-etho~yphenyl))methoxyphenyl]methyl-3~-imidazo-[4,5-b]pyridine ~,7-Dimethyl-2-ethyl-3-t4-(1-(tetrazol-5-yl)-1-(2,6-dichlorophenyl))methoxyphenyl3methyl-3~-imidazo-t4.5-b]pyridine 20 5,7-Dimethyl-2-ethyl-3-t4-(1-(tetrazol-5-yl)-1-(2-nitrophenyl))methoxyphenyl]methyl-3H-imidazo-t4,5-b]pyridine 5,7-Dimethyl-2-ethyl-3-t4-(1-(tetrazol-5-yl)-1-(2-trifluoromethylphenyl))metho~yphenyl]methyl-3~-imidazot4,5-b]pyridine 5,7-Dimethyl-2-ethYl-3-t4-(1-(tetraZol-5-yl)-1-(2-chlorophenyl))methoxy-3-chlorophenyl]methyl-3~-imidazot4,5-b]pyridine WO91/11~9 PCT/US91/O~gs7 : - ~

5,7-Dimethyl-2-ethyl-3-t4-(1-(tetrazOl-5-yl)-1-(2-chlorophenyl))metho~y-3.5-dichlorophenyl~methyl-3H-imidazo[4,5-b]pyridine 2-~thyl-5-hydro~ymethyl-7-methyl-3-t4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))metho~yphenyl]methyl-3H-imidazot4,5-b]pyridine 5-Carbo2y-2-ethyl-7-methyl-3-t4-(l-(tetrazol-5-yl)-l-1o (2-chlorophenyl))methoxyphenyl]methyl-3H-imidazo-t4.5-b]pyridine 5-Carbmethoxy-2-ethyl-7-methyl-3-t4-(1-(tetrazol-5-yl) -1-(2-chlorophenyl))methoxyphenyl~methyl-3H-imidazo-t4~5-b]pyridine 5-Carbmethoxy-2-ethyl-3-t4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))metho2yphenyl]methyl-7-trifluromethyl-3H-imidazot4,5-b]pyridine 5,7-Dimethyl-2-ethyl-3-t4-(1-((N-phenylsulfonyl)-carboxamido)-1-(2-chloro)phenyl)methoxyphenyl]methyl_ 3H-imidazot4,5-b]pyridine 5,7-Dimethyl-2-ethyl-3-t4-(1-((N-methylsulfonyl)-carbo~amido)-1-(2-Chloro)phenyl)metho2yphenyl]methyl-3H-imidazo~4,5-b]pyridine 5,7-Dimethyl-2-ethyl-3-[4-(1-((N-trifluoromethyl-sulfonyl)carboxamido)-l-(2-chloro)phenyl)meth phenyl]methyl-3H-imidazot4,5-b]pyridine WO91/11~9 PCT/US91/009~7 2075S2~

3-[4-(l-(~ydroxymetho~ypho~phoryl)-l-(2-methylphenyl)) methoxyphenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazo-t4,5-b]pyridine p~T~FS:

9-[4-(1-Carboxy-l-phenyl)methoxyphenyl~methyl-6-methyl-8-propylpurine 9-t4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl3-methyl-6-methyl-8-propylpurine 4,6-Dimethyl-8-ethyl-9-[4-(1-carboxy-1-~2-chloro-phenyl))methoxyphenyl3methylpurine 9-t4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl]-methyl-8-ethyl-6-methylpurine 9-t4-(1-Carboxy-1-(2-chlorophenyl))methoxy-3-propyl-phenyl]methyl-8-ethyl-6-methylpurine 9-~4-(1-Carboxy-l-phenyl)methoxy-3-propylphenyl]-methyl-8-ethyl-6-methylpurine 9-t4-(l-Carboxy-l-(2-chlorophenyl))methoxyphenyl3-methyl-4-dimethylamino-8-ethyl-6-methylpurine 9-t4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl]-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 . WO91/11~ PCT/US91/~Q957 9-t4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl]-methyl-4,8-diethyl-6-methylpurine 9-r4-(1-Carboethoxy-1-(2-chlorophenyl))methoy phenyl]- methyl-4,8-diethyl-6-methylpurine 9-~4-(1-Carboxy-1-(2-chlorophenyl))metho~yphenyl]-methyl-4,8-diethyl-6-trifluoromethylpurine 10 9-t4-(l-carboxy-l-(2-trifluoromethylphenyl))meth phenyl~methyl-8-ethyl-6-methyl-4-methylaminopurine 6-Methyl-8-propyl-9-t4-(l-(tetrazol-5-yl)-1-phenyl)-methoxyphenyl]methylpurine 6-Methyl-8-propyl-9-t4-(1-(tetrazol-5-yl)-1-(2-chloro-phenyl))methoxyphenyl]methylpurine 4,6-Dimethyl-8-ethyl-9-t4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))metho~yphenyl]methylpurine

8-Ethyl-6-methyl-9-t4-(1-(tetrazol-5-yl)-1-(2-chloro-phenyl))methoxyphenyl]methylpurine 4-DimethylaminO-8-ethyl-6-methyl-9-t4-(1-(tetrazol-5-yl)-l-(2-chlorophenyl))methoxyphenyl~methylpurine 8-Ethyl-6-methyl-4-(morpholin-4-yl)-9-t4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))metho~yphenyl]methylpurine 8-Ethyl-6-methyl-4-methylamino-9-t4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))methoxyphenyl]methylpurine WO91/11~ PCT/US91/~gs7 4,8-Diethyl-6-methyl-9-t4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))metho~yphenyl3methylpurine 4,8-Diethyl-6-methyl-9-t4-(l-(tetrazol-5-yl)-1-(2-S chlorophenyl))methoxyphenyl]methylpurine 4,8-Diethyl-9-t4-(1-(tetrazol-5-yl)-1-(2-chloro-phenyl))methoxyphenyl3methyl-6-trifluoromethylpurine 8-Ethyl-6-methyl-4-methylamino-9-t4-(1-(tetrazol-5-yl)-1-(2-trifluoromethylphenyl))methoxyphenyl]methyl-purine 4,6-Dimethyl-8-ethyl-9-~4-(1-(N-phenylsulfonyl)-carboxamido-1-(2-chlorophenyl))metho~yphenyl]-methylpurine 4,6-Dimethyl-8-ethyl-9-~4-(1-(N-methylsulfonyl~-carboxamido-1-(2-chlorophenyl))methoxyphenyl~methyl-purine 4,6-Dimethyl-8-ethyl-9-[4-(1-(N-trifluoromethyl-sulfonyl)carboxamido-l-(2-chlorophenyl))methoxy-phenyl]methylpurine 4,6-Dimethyl-8-ethyl-9-t4-(1-(N-acetyl)sulfonamido-l-(2-chlorophenyl))methoxyphenyl]methylpurine 4,6-Dimethyl-8-ethyl-9-t4-(1-(N-benzoyl)sulfonamido-l-(2-chlorophenyl))methoxyphenyl]methylpurine WO91/11~ PCT/US91/~gs7 2 0 ~ 5 6 2 ~ ~ ?

4,6-Dimethyl-8-ethyl-9-t4-(1-(N-pyrimidin-2-yl)-6ulfonamido-1-(2-chlorophenyl))methoxyphenyl]methyl-purine - 5 5~7-FusT~n TMTD~OT.T.S

2-Butyl-1-[4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-1,4,6,7-tetrahydroimidazot4,5-e]tl,4]diazepine-5,8-dione 2-Butyl-l-t4-(1-carboxy-1-(2-chlorophenyl))methoxy-phenyl]methyl-1,4,6,7-tetrahydroimidazot4,5-e]~1,4]-diazepine-5,8-dione 2-Butyl-l-t4-((1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-1,4,6,7-tetrahydroimidazot4,5-e]tl,4]-diazepine-5,8-dione 2-Butyl-l-t4-((1-carboxy-1-(2-chlorophenyl))methox)-3-propylyphenyl]methyl-1,4,6,7-tetrahydroimidazot4,5-e ]tl.4]diazepine-5.8-dione WO91/11~9 PCT/US91/00957 ~ ~ ", 2075S~7 RAT. I~ )S ~OR ~ RATTON OF cn~ Jr.~s OF
G~F:~AT. ~'-Ol~-u I ~ T
The methods described in P~T T AND PA~T TI
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 seadily applicable for the preparation of certain antagonists of Formula I.
It should be recognized that antagonists of Formula I consist of a heterocyclic component designated above by formula I and a substituted benzyl substitutent which i6 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 P~T T below.
Then the heterocycle is alkylated at a nitrogen atom with a substituted benzyl halide or pseudohalide gi~ing an alkylated heterocycle. In the Schemes below, this alkylating agent is often designated as "Ar-CH2Q where Q is a halide (-Cl,Br,I) or pseudohalide (-OMs, OTs, OTf). In some cases, WO91/11~ PCT/US91/~ss7 207 5 62~

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 desired product. In some cases, the alkylation step produces a fully-assembled antagonist of Formula I, e~cept 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-C~2Q"), but here the alkylation step is followed by subsequent steps which are required to assemble the substituted benzyl element of the antagonist of Formula I. The alkylation steps and subsequent steps used to prepare antagonists of Formula I, are described in P~T TI below.

2- In another approach to antagonists of Formula I, a substituted benzyl element is introduced at the beginning of, or during the preparation of the heterocyclic element. Routes of this type are illustrated in Part II below. In most caseæ where this general approach is used, the substituted benzyl component which is introduced during the synthesis 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 TI, this substituted benzyl component is designated as "-C~2Ar," and is usually introduced by an alkylation step with a WO91/11~ PCT/US91/00957 207~627 - substituted benzyl halide or pseudohalide designated ArC~2-Q (where Q i~, for e~ample, Cl, Br, I, ~, OTs, or OMs). Substituted benzyl halides or pseudohalites which are useful in the preparation of al~ylated heterocycles described in PA~T T 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 ~tandard methods of lo organic synthesis. Subseguent steps which may be required to complete the synthesis of antagonists of Formula I are desribed in P~T TT below.
The compounds of this invention maybe resolved using techniques ~nown in the art. The diastereomeric salts or esters of the enantiomer~ are separated and the desired compound is the more active stereoisomer. The compounds of this invention, their pharmaceutically acceptable ~alts and their prodrug forms are included within the ~cope of this invention.

9 ~ 0~ 5 6 27 Pcr/US9l/oo9~7 Tabl e CH2Br CHzBr CH2Br (~ ~CH3 OCH2Ph OCH2Ph OCH2Ph CH2Br CH2Br CH2Br Cl ~ Cl J~C1 ~H3 OCH2Ph OCH2Ph OCH2Ph CH2Br CH2Br CH2Br CN CO2CH3 CH20TBD~;
CH2Br CH2Br CH20Ts [~
S CH2 Ph N2 CH2 OTBD~;

WO91/11~9 PCT/US91/00957 .

2~7562~

Abbreviations used in the schemes and examples are listed in Table 3.

T~ble 3 s Re~ents NBS N-bromosuccinimide AIBN Azo(bis) isobutyronitrile

10 DDQ Dichlorodicyanoquinone Ac20 acetic anhydride TEA triethylamine DMAP 4-dimethylaminopyridine PPh3 triphenylphosphine lS TFA trifluroacetic acid TMS-Cl trimethylsilyl chloride Im imidazole AcSK potassium thioacetate p-TsOH p-toluenesulfonic acid 20 FMOC-Cl 9-Fluorenylmethyloxycarbonyl chloride Solvents:

25 DMF dimethylformamide HOAc (AcO~) acetic acid EtOAc (EtAc) ethyl acetate ~ex hexane T~F tetrahydrofuran 30 DMSO dimethylsulfoxide MeOH methanol iPrO~ isopropanol WO91/11~ PCT/USsl/~ss7 ~ 20~6~7 Others:

rt room temperature TBDMS t-butyldimethyl~ilyl 5 OTf OS02CF3 . Ph phenyl FAB-MS Fast atom bombardment mass ~pectroscopy NOE Nuclear Overhauser Effect 10 SiO2 ~ilica gel trityl triphenylmethyl Bn benzyl PART I: Preparation of the heterocycles ~hown in Formula A. Preparation of the imidazo-5,6-and 7-membered fused heterocycles The preparations of the imidazo-S-, 6-, 7-membered heterocycles are described in the Schemes below. There are ~everal routes which have been used to prepare these 8ystems. The first route involve6, 2~ in the final ~teps, the closure of the imidazole ring. In other ca6e6 it ha6 been advantageou~ to do the imidazole ring closure early in the ~ynthe~is and generate the fused 5-, 6-, or 7- membered ring in the final steps.

WO91/11~9 PCT/US91/ooss7 ! ~' : 1 2 0 7 5 S 2 7 ~MTD~0-5~ n F~SF:n ~TF~OCYC~-~S

A~ r \ ~ B-R
`A3 ~
CH2 Ar The compounds of Formula I, wherein -Al-A2-A3- represents a 3 ~tom seguence defined by (a) - (dd) in the Detailed Description of the Invention to generate the imidazo-5-fused 6ystem, 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 synthesis that the functionality present on the heterocycle and other parts of the structure 8hould be consi6tent with the chemical transformation6 proposed.
Depending upon the reactions and techniques employed, 25 - thi~ may involve changing the order of sy~thetic steps, the use of required protecting groups followed by deprotection. and, depending upon the particular imidazo-fused 5-mem~ered heterocycle being formed, the use of different strategie6 may be employed regarding the cyclization 6teps and the particular starting material utilized.

WO91/11~9 PCT/US91/00957 - 2075~:27 The ~tarting material~ for preparing the compound~ of this invention are dependent upon the nature of the heterocycle being formed. In many caser the heterocycles can be prepared either from a ~uitably functionalized 5-membcred heterocycle by a ring closure ~tep which gives an imida20 fused bicyclic ring system (see Reaction Schemes I-l to I-4) or by starting with a suitably functionalized substituted imidazole and ring closing to give an imidazo-fused 5-membered rin~ 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 material~.
lS One approach (Reaction Scheme I-l) start~
with monocyclic derivatives bearing vicinal carbon-bound nitro and amino functions, such as 2 which are often readily a~ailable, or can be prepared from the mono nitro deri~atives 2 by reaction with hydro~ylamine. Compounts ~ may be reduced by any one of several methods, including catalytic hydrogenation or reaction with SnC12 to give the diamino deri~ative 3. Such deri~atives are often unstable and can be ring-closed to the imidazo fused heterocycle 4 (E=
single bond) by reaction with ~n appropriate carbogylic acid, nitrile, imidate ester, thioimidate ester, amidine, or orthoformate, either neat, or in a - solvent sppropriate and compatible with the starting materials and reagent8, ruch as polyphosphoric acid, ethanol, methanol, hydrocarbon 801~entr and with a catalytic amount of acid if required.

WO91/11~ pcTlus9l/~9s7 Another pos6ible approach, not ~hown in Reaction Scheme I-l, to compounds having the general 6tructure 4 (B= single bond) from 3 involve6 the reaction of ~ with an appropriate altehyde in the presence of an osidizing agent such as CuII, nitrobenzene, or dicyanodichloroguinone (DDQ) to give heterocycles such as 4.
Ring closure of the vicinal diamino heterocycles 3, to give deri~atives 6uch as ~ can be lo effected by treatment with reagent6 such as CS2, CSC12, COC12j N~2CON~2, alkyl chloroformate6, dialkyl carbonates, or potassium cyanate in the presence of bases ~uch as ~0~ or K2CO3. Another potential route to S (B= O) involves the use of a vicinal amino carboxylate such as ~ or ~ which can be converted to ~ via a Curtius or ~ofmann rearrangement on suitable derivatives of ~a/~ such as scyl azites, hydroxyamides or N-haloamide6. The bicyclic derivatives ~ can be alkylated under the appropriate conditions with al~yl halides, alkyl mesylates, alkyl tosylates, trialkyloxonium 6alt6 or with diazomethane to afford compounds of type 4 (B= O or S).
Another approach to 4 (~= single bond) which has been used for example when Al-A2-A3- together are -N=C(C~3)-N(C~3)- 6tart6 from ~ and utilize6 acylation of the amino function with an acyl chloride or anhydride to give the nitro amido compound 7.

WO 91/11999 PCI/US91/009~7 207~627 .

~CTTON St~$~MF. T-1 H2N~ 2CXAl or NXA' 2 HO2C H2NA~ Hofr~nn 3 6a ~b rrent H 5 CSC12 ~
ot he r R' - Q
~ reagent H2NXA3 H NXA3 ~ NXA3 1 5 ¦ R1 B- COC1 /~i d or ~
o H XC)A2 [ H~ O H X)A2 , Na~
R1-~C-N A R1-B-C-N
2 ArCi~2 , ~NXAl 2 ArC~ DH ,~XOA~ [ H~ ~COA~ R
H A ~ Ar~N A or ot~er H ~ r-ag~nt lo tl --- __ Q = a rultable l-avlng group ruoh or Cl. 9r. I. I~ yl or O-to~y WO91/11~ pcT/us9l/~ss7 2075~27 Reduction of the nitro group leads to ~ and this can be ring closed to g via cyclodehydration, by heating and/or acid catalysis.
The imidazo fused heterocycle g can then be - 5 al~ylated with ArC~2-Q (where Q is a suitable leaving group such as Cl, Br, I, O-mesyl, or O-tosyl) in one of several ways. One way is initially to form the alkali metal salt of 4 by using M~ (where M is Li, Na or ~) in anhydrous dimethylformamide (DMF) or by treating 4 with a-metal alkoxide such as sodium or potassium methoxide, etho~ide 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 4 in an anhydrous aprotic solvent such as DMF, dimethylsul-foxide (DMSO) or tetrahydrofuran (T~F) and reacting it with the al~ylating agent ArC~2-Q (preparation of ArC~2-Q is described hereinbelow) at 20-C to reflux temperature of the solvent for 1 to 24 hours.
If the substituents on the heterocyclic ring system result in an unsymmetrical heterocycle, then the alkylation may produce a mixture of regioisomers.
These regioisomers pOSseSs distinct physico-chemical and biological properties and in most cases can be separated and purified using conv-ntional separation techniques such as chromatography and/or crystallization. In those ca8es where the separation of regiosomers is difficult by conventional methods, the mi~ture can be transformed into suitable derivatives that are more amen~ble to the usual separation methods. The identification of the indi~idual regioi80mer8 can be made u~ing Nuclear WO 91/11999 2 ~ ~ 5 6 ~ 7 PCT/USsl/009s7 Overhauser Effect (NOE) NMR methods, 13C NMR methods (e.g. vicinal 13C-l~ coupling constant6) or by single crystal ~-ray crystallography.
It should be noted that the relative amounts of the regioisomers formed in the al~ylation reaction can be influenced by several factors including the nature of the base used (while the al~ali metal salt of the hete~ocycle is generally used, the regioisomeric ratio can be altered in some instances lo by using the heterocycle in the presence of a weaker base such as triethylamine, diisopropylethylamine, potassium carbonate or sodium bicarbonate) and the nature of the solvent used in the reaction.
An alternative approach, also shown in Reaction Scheme I-l, starts with the mono nitro derivative 9. This can be reacted with a substituted hydroxylamine bearing the ArCH2 side chain, to give lQ Reduction of the nitro function gives the vicinal substituted tiamine 11 which can be ring closed in the usual fashion. This allows for regioselective introduction of the Ar-C~2 side chain into the bicyclic system.
Another approach to the compounds of this invention is shown in Reaction Scheme I-2. In this instance, a monoamino heterocycle such a6 1~ can be acylated under 8tandard condition6 to give the amido derivative 1~. Thi8 amido compound can be reduced with LiA1~4 in a anhydrou6 801~ent 8uch as '1~ or WO91/11~ PCT/US91/oogs7 .
20756~7 Et20 to the al~ylamino derivative 4 which can then be nitro~ated with isoamyl nitrite to give 1~- Such al~ylamino nitroso derivatives particularly, for example, when Al-A2-A3- together are -C(C~3)~N-N(CH3)-, undergo cyclodehytration when heated in pyridine to give the imidazo fused bicyclic heterocycle 4. The conversion of g to 1 can be carried out as described in Reaction Scheme I-l.
Alternatively, it should be possible to al~ylate 1 prior to ring closure to give the bis-N-al~ylated derivative 1~ which can then be ~ubjected to cyclodehydration in hot pyridine to give the blocked 1- Separation of any regioisomer~ that may be formed can be effected by using conventional chromatographic methods.
An alternative approach to the synthesi~ of 1~ might utilize al~ylation of the monoal~ylated side-chain 14 with ArCH2-Q. This would provide the bi~-N-alkylated derivative 11 which can be nitrosated with isoamyl nitrite to give 1~-An additional approach to the compounts ofthis invention i6 shown in Reaction Scheme I-3. In thi~ approach the starting material is a vicinal bromo nitro heterocycle 1~ which is reacted with an appropriate mono al~ylamine to give 12- Ring clo~ure can be effectet u8ing MeO~/NaO~ with heating to give the N-o~ide derivative 2Q which can be reduced with either triethylpho8phine. TiC12 or Si2C16 to give the imidazo-fuset bicyclic heterocycle 4. This can be converted to 1 in the u8ual fashion as described above in Reaction Scheme I-l.

Wo g~ g~ 2 0 7 ~ PCT/US91/00957 -94_ Alternatively, 1~ can be reacted with the appropriate dialkylamine to give 21 (which can also be prepared by alkylation of 12 with ArC~2-Q under the appropriate conditions). Ring closure of 21 in a fashion similar to that described above in the conversion of 12 to ~Q is followed by reduction and separation of the products to give 1.
Another approach to compounds of the Formula 1 (particularly where -Al-A2-A3- together are -C(R7a)=C(R7b)-S-) is shown in Reaction Scheme I-4.
In these instances, the starting material is the substituted heterocycle 23 which can be alkylated with ArC~2-Q to gi~e 2~. Treatment with hydrazine/nitrous acid and a refluxing alcohol (HORl) gives rise to ~ ~ia a Curtius rearrangement of the intermediate acyl azide. The cyclization of 2~ can be accomplished with polyphosphoric acid or other acidic catalyst to provide 1--9S~- 2a7aS27 y~F~cTI 01~ S C~FMF T--2 X A2 X~ A2 H 1 ~ONO ON
R - CH2- N, R' - CH2- N A
H H \ pyridine 1. NaH/D~ 1. NaH/DMF
2. ArCH2-Q 2. ArCH2-Q

HXA~ 2 ~f NXA' 2 -<NX ) R - CH2- N R1 _ CH2- N A3 H A3 2 0 CH2Ar CH2Ar 16 \ / 4 / 1 . Na H /DM~
1. pyridin6. ~ 2. ArCH2-Q

N Al R~ 3A2 CH~Ar WO 91/11999 PCr/US91/00957 207~627 - ~F~CTTON S~MF T_3 XOA ~XAA N~oH R ~NXdAA or ; R--\ R- - CI~
C~2Ar ~ ~D~ 2. ArCH2-Q
0 \ 12. Ar-~-Q

CH~r ~ICH,Ar CH,A
Zl Z2 WO91/ll ffl ~ PCT/US91/009s7 ' 2l17~;S27 Re~ctio~ S ch ~m e I-4 CH302C _~ CH302C _}~
~ 21. N~H~D~ 1O~A2 . N2H4, ~ 2. ArCH2-Q ~1 02CN~--A
H 1 3 . ~ HOR
CH2 Ar H
R OzC ~ o ` 2 ~ ~ O ~ 2 CH2Ar C H2 Ar - 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 i6 shoWn below in Table 4.

WO 91/11~9 2 0 7 5 6 2 7 PCT/US91/~957 - ; ~;. , , -St ruct ure Nane ~ef erence H__N 5-an~no-1- J. Che~ Soc., H ~ethyl- 2028 (1948) H2N~-N ln~dazole CH
H~_N~ 5-a~lno- Can. J. Re~., H2N~N in~dazole 19~3 296 (1941) H
N 5-an~no-1.2- J. Che~ Soc, ~CH3 di~ethyl- 164S (1954) H2N N in~dazole H2N~_N 4-an~no-5- J. Het. Che~
~ ~CH3 nltro-1,2- 6, 53 (1969) N02 I dim3t hyl-CH3 in~dazole NO2~ - ~ 5-an~no-4- Ibid.
~ ~CH3 4-nitro-1,2-H2N I dinet hyl-lnidazole H~ 5-an~no-1,3- US. Patent ~ ,N dimethyl- 3,646,059 H2N N, pyrazole 5-an~no-3- Ibld.
Il ,N net hyl-H2N Nl pyrazole Ph J. Gen. Chem H2N~ 4,5-diamino- (USSR) 32.
Ll ,N 1 -'nethyl- 1898 (1962) - N 3 - phe nyl -CH3 pyrazole SUBSTITUTE SHEET

WO 91/11999 PCI'/US91/00957 ,. ; - ~, - 99 ~ 2~75627 TAE~LE 4 ~ cont ) .

StructurQ Nar~ Reference CH3 3-nitro-1, 5_ J. Gen. Chem ~,N-CH3 di~Tet hyl~ SR) 50, ~N pyrazole 21 06 ( 1 980) H2N ~ 3, 4-dla~no- Ibid.
l_ ,N-CH3 1 . 5 - di m3 t hyl -H2N--N pyrazole 2 CH3 4-nitro-1, 3- J. GerL Chorn N~ dirrethyl- ( U~SR) 50, H pyrazole 2106 (1980) ~3 5-arr~no-3- J. Het. Chem, ¦1 `,N rrethyl- 10, 181 (1973) H2N~ oxazole H2N CH3 4, 5-dlamLno- J. Het. Chem, ~,N 3-n~thyl- 10, 181 (1973) H2N is oxazole H 4- ~ut yr - Eur. J. Med.
~H amido- Chem 14 105 C3H2CONH--N t hiazole ( 1 979) 02N~S 5-nitro-2- J. Org. Chem, CH3 rrethyl- 33 2545 (1968) H --N t hiazole H S 4- nit ro- Ibid.
3 XN>CH3 2 - ne t hyl -NOz SUBSTITUTE SHEET

WO 91/11999 PCI~/US91/00957 TABLE 4 ( cont ) .

Structure Nar~e Re~erence HzN 4-a~noi~o-J. Chem Soc., J~N thlazole 306 (1959) H

CH3 4-arTiLno- Ibld.
H2 N~ 3 - iTe t hyl -~--S i5 ot hiazole CH3 5-amLno- Ibid.
~N 3 - r~e t hyl -~ is ot hiazole H2N ~
lS O2N~ 4-nitro- Ibid.

H2N isothiazole 2 ~, N 3, 4-dialTino- Liebigs Ann.
1- ~S2 1, 2, 5-thia- Cheln 4. 337 H2N' N diazole 1, 1- (1988) N

H2N\~ 4, 5-dla~no- IZV. Akad. Nauk H N~N' 1 H- 1 - ~enzyl- SSRR, Ser Khim ~3 1, 2, 3-triazole 11- 2633 (19 H2N~3 2, 3-dian~no- Arch, Pharm H2N~S thlophene (Wbinheim), 314, 567 ( 1 981 ) SUB~ 111 lJT~ SHEEr WO 91/11999 PCI`/US91/00957 2075~27 -lOOA-TABLE 4 (cont).

Structure Nar~ ReFerence - H2N~ ~ 1-benzyl-3. 4- Liebeigs P~nrL
J~N-CH2~ dia~no - 2 H- Chen~ 18 3 , 142 4 o pyrrol-2-one ( 1978) N-CH~h~ 4. 5-diamLno-3_ Japanese Patent H2N~ ( \=/ [ (phenylnethyl- 53/109527 ~co ene) arr~no~ - 2H-H2N^N pyrrol-2-one H2N~ 2, 3-diarriLno- Chem ~er., ¦I NH ~aleimLde 116, 2591 H2~ ( 1983) H2 N~
I_,S 3, 4-dialT~no- ~3ull Soc.
H2N~ thiophene Chem Fr., 5-6, pt. 2, 1 53 ( 1 983) H2NrN 3, 4-dia~no- J. Het. Chem, H2NJ--N 1, Z, 5-thia- 13, 13 (1976) diazole SUBSTITUTE SHEEr WO91/11~ PCT/US91/009~7 - 2075S27 -~---101-- .

In certain ca~es due to the nature of the heterocycle being prepared and to the availability of starting materials, it may be advantageous to prepare ~ome of the compounds of this invention from a ~uitably functionalized imidazole ring by ring closing to give compounds of Formula 1. Some ~pecific examples ~re shown in Reaction Schemes I-5 to I-7. Thus, Reaction Scheme 6 shows an approach to the preparation of the ~ubstituted regioisomers of lE- and 3~- thienot2,3-~imidazoles. The substituted imidazole ~ can be readily al~ylated in the fa6hion described earlier by using Na~ in DMF, followed by treatment of the anion ~o formed with the al~ylating agent ArC~2-Q to give a separable mixture of the regioisomers ~1~ and 21~. These can be independently converted to ~etones 2~ and ~, respectively, ~ia oxidation with a suitable oxidizing agent ~uch as MnO2 to the aldehyde, followed by reaction with an appropriate ~rignard reagent to give the ~econdary alcohol which is further oxidized with ~nO2 to ~, k.
These isomers can then be independently converted to the corresponding thienot2,3-~]imidazoles ~2 by treatment with a thioglycolic acid ester and the appropriate al~oxide in the appropriate reflu~ing alcohol (i.e., ~ gives the 3~-thieno-t2,3-~]imidazole ~2~ and 2~ gives the lE-thieno-[2,3-~]imidazole regioisomer 29b). Saponification of 2~ gives the carbo~ylic acid 33a~. Other conversions possible with the ?9A.b regioisomers include WO91/11~ pcT/us9l/~ss7 207~S27 reduction with LiA1~4 to the alcohol 30~.b, saponification followed by tecarbo~ylation to give 31~.b, and conver~ion of the al~yl carbo~ylate to a ~etone uith an al~yl lithium reagent to give ~?A.b.
In addition, the intermediate 2~ can be utilized as a precursor to the 1,6-dihydro-imitazo-t4,5-~3pyrazole, series by cyclization with a ~ubstituted hydrazine deri~ative, to give ~4a.
Similarly, ~ can be converted to the lo imidazot4,5-~]pyrazole 1,4-dihydro sesie~ 34b.

WO 91/11999 PCI'/US91/00957 ~F.~CTI ON S t~MF. T - 5 R' ~ . R~ + R' --<N3~;
2. ArC~z-Q I~~
C~2 Ar C ~2 Ar 26 27b 27a -- 1. MnO2 2 R22~ r 1 0 / 1 . MnOz N / 2 R22-~7E3r R'-<~ / 3. MnO2 Ar ~ 2 2Bb N C-R2 R --<l~
J
Ar 2Ba Pcr/us9l/oo9s7 CTTON S(~FMF T-5 CON ' T

2Bo ~ R' ~;C~,~R~, Ar J R~
N~O~
~DR~ 34 R~J R~

N~0!1 ~C

30~
/ \ LlOH H~O
~,~ 1. R~Ll \~F, ~0 R~2-2 0 F' ~<~ R' ~,p~ F' ~4~ CC~i3 31~ 0 Ar J

Slrrll-rly 2~b c~n b cont~ rt-d ~ nto t~
r-glol-sn-riC 29b 30b, 31 b 32b, 33b nd 3~b ~ h-log-n ( Cl, ar F, I) Ip~ yl, ~u~tltut--d lkyl ryl or rub~tltut-d oryl R~J = alkyl or ub~ t ~t ut d al kyl R2J ~ olkyl or ~tltut~d olkyl WO 91/11~ 2 0 7 5 6 2 7 PCT/US91/~9s7 .

Similarly, 2~ can be converted into the regioisomeric 22~, 30b, 31b, ~Zb, ~, and Ra - halogen (Cl, Br, F, I) R22a - ~, alkyl, substituted alkyl, aryl or substituted aryl R23 = al~yl or substituted al~yl.
R25 _ alkyl or substituted alkyl.

A similar cyclization using hydro~ylamine can be used to give the 6~-imidazor4,5-d]isoxazole ~eries (starting from ~) or the 4~-imidazot4,5-d]-isoxazole series (starting from 2~
Preparation of the lactone derivatives 36A.b can probably be accomplished from the regioisomers 35a.b as shown in Reaction Scheme I-6. These tertiary alcohol 6tarting materials can be obtained from respective ketones such as 28a.b (6ee Reaction Scheme I-5) by reaction with an appropriate Grignard reagent, followed by protection of the alcohol with t-butyldimethylsilylchloride. Thus, lithiation of 35A.b can be carried out with ~-BuLi and the lithio derivative reacted with methyl chloroformate. The intermediate 60 formed can be treated with acid to remove the ~-butyldimethylsilyl protecting group snd to effect cyclization to the lactone. Deblocking can be effected as described earlier in Reaction Scheme 1.
A possible route to the substituted 1,5-dihydropyrrolo~3,4-~]imidazole 41 is shown in Reaction Scheme I-7. Thus, the functionalized WO 91/11999 PCI/US91/009s~

imidazole ~7 (or its regioisomer) prepared as describet in European Patent Application 2~3,310 can be treated with tosyl chloride in pyridine to give the 0-tosylate which can then be converted to the aminomethyl derivatlve ~ia a Gabriel synthe~is (displacement of tosylate with potassium phthalimide, followed by de-phthaloylation with hydrazine). This intermediate can be bloc~ed by treatment with 1,2-bis(chlorotimethylsilyl)ethane to give the intermediate 38. Lithiation and sub~equent formylation i8 accomplished by treatment with butyllithium and DMF to give the intermediate,~
which can cyclize under acid cataly~is to the pyrrolot3,4-~]imidazole derivative 40. Compound 40 then treated with an alkyl, acyl or ~ulphonyl halide to block the pyrrole ring nitrogen.
Deblocking with acid under the conditions described earlier gives rise to the required 41.
With regard to the preparation of derivatives containing the furot2~3-~]imidazole heterocycle (i.e., compounds of Formula 1 where Al-A2-A3- to~ether are -C(R22)~C(R22)-0- and -0-C(R22)zC(R22~-) these can be prepared by alkylation of the appropriate furo~2~3-~]imidazole tprepared as described in Chem.
Pap., 40, 675(1986)] using the general procedures shown in Reaction Scheme I-l for the conver~ion of 4 to 1-WO 91/11999 2 d 7 5 6 2 7 PCT/US91/00957 RZ4b R22 R24bM3E~r N~- S i- C~ cH3) - 2. T~DMS-Cl, Br in~dazole J
Ar 35a 1. tBuLi R1 ~/ ~ C
2. ClCO2CH3 N
3. H~ J O
4. deblock ~r 36a 1 R24bMg~r N ~ Br CH /CH3 - 2. TBDM5-Cl. N ~ -S1-C(CH3)3 inidazole J I RZ2~ -Ar Ra4b 35b 1. tBuLi N
2. ClCO2CH3 R 4 3- ~ J R
4. deblbck Ar 36b SUB~ ~ JTE SHEE~

W O 91/11999 ' ~ PC~r/US91/U0957 -107A- 2~75~27 R24a = aryl, substituted aryl, alkyl or substituted alkyl Ar = subs. phenyl Ar* = deprotected Ar TBDMS = t-butyldimethylsilyl.

SU~ JTE SHEEl-WO 91/11999 2 0 7 5 ~ 2 7 PCI`/US91/00957 . . ~

-- 108 _ RI:ACTION S(~ I-7 1 . Tos yl chloride/
pyridine \/
,~zOH O~ R~ ]

Ar O , Ar 3 . Nz H~

4 . S i S i ` kt 3 N
Cl Cl 1 . BULi /DMF ~ N~\NH2 . N--\CHO

N~ ,. ba s e Ar J 2 R23 Q Ar R23 = alkyl, acyl, or alkyls ulphonyl.

SUBSTITUTE S~IEET

WO91/11~9 PCT/US91/Oogs7 -lO9-RF:~l'IITDA7:0~ FS

A2-A ~ N
H

(Formula I, wherein A5 is a single bond and -Al-A2-A3-A4- is as defined by (r) above) The compounds of Formula I wherein (-Al-A2-A3-A4-) is a 4-atom sequence as defined in the General Description of the inYention 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 s~illed in the art of organic synthesi6 that the functionality present on the benzimidazole and other parts of the structure should be consi6tent with the chemical transformations proposed. Depending upon the reactions and techniques employed, this may involYe changing the order of Bynthetic step~, use of required W091/11~9 . 2 0 7 S ~ ~ 7 PCT/US91/00957 --110- , protecting groups followed by deprotection, and acti~ation of the benzylic po~ition of the alkylating - agent~ used to enable alkylation at the nitrogen on . the imidazole part of benzimidazoles.

I3F~CT~ON SC~t~: T--8 R b ~ -Rl . B"

(Q = I, ~r, OMs, OT~) R3b R3~ R3b R3C

R'~ R~
R~b CH2~ ~-b CH2Ar 3a 3b 2 0 7 ~ S 2 7 ..

As shown in Reaction Scheme I-8, compounds of Formula (~ can be prepared by carrying out direct al~ylation of al~ali-metal 8alt of benzimidazole (1) (preparation of benzimidazole6 are described in Reaction Schemes I-9 to I-12) using appropriately protected benzyl halide, tosylate (OTs) or mesylate (OMs) derivatives (2). The salt is prepared preferably u~ing M~ (where M is lithium, sodium or potassium) in anhydrous dimethylformamide (DMF), or ~Y treating it with metal alko~ide such as sodium or potassium methoxide, ethoxide or t-buto~ide in an appropriate alcohol such a~ methanol, ethanol or t-butanol as the solvent. The al~ylation is generally carried-out by di~solving the metal salt of benzimidazole in a dipolar aprotic ~olvent such a~
DMF or dimethylsulfoxide (DMSO) and reacting it with the al~ylating agent at 20C to reflux temperature of the ~olvent for 1-24 hour~.
If substituents on the benzene ring result in an unsymmetrical benzimidazole, the al~ylation may produce a mi~ture of two regioisomers a~ products, which may be represented by formulas ~ and ~.
These regioisomers possess distinct physico-chemical and biological properties and in most cases can be ~eparated and purified by using conventional separation techniques ~uch as chromatography (flash column chromatograPhy, medium-pressure liquid chromatography. high pre8sure liquid chromatography (~PLC) and/or crystallization- In thoRe cases where separation of regioi~omers i6 difficult by conventional techniques, the mi~ture can be transformed into suitable derivatives that can be WO 91/11~ 2 0 7 ~ 6 ~ 7 PCT/US91/009~7 separated by usual separation methods. The structural assignments of the isomers can be made using proton NMR, Nuclear Overhauser Effect (NOE) e~periments or X-ray crystallography.

w ~ v ~ zl;~;

~ K 3 D la ~;
15 ~ ~ 8,~ ~

c \
~: v \
O
r~
~" \ };

~ o~ rl ~p~ a D

SUBSTITUTE SHEE~

WO91/11~ PCT/US91/~ss7 .
207~62~

The starting benzimidazoles can be readily prepared by any of the standart procetures described in the literature tP. N. Preston, Ch~mistry of ~eterocyclic Co~Donnds, Vol. 40, part I, pp. 1-286 (1981) and references cited therein]. Se~eral alternative routes to obtain benzimidazoles are outlined in Reaction Scheme I-9. The most widely used starting material, o-phenylenediamines (11). can be readily prepared from the corresponding o-nitro-I0 aniline (lQ) using standard reducti~e procedures suchas metal-acid reduction or catalytic reduction. The substituted or un~ubstituted 11 can then be treated with an appropriate imidate hydrochloride (1~) to form corresponding benzimidazoles (l~).
Alternatively, the reaction of carboxylic acids (1~) with o-phenylenediamines in the pre~ence of polyphosphoric acid (PPA) is also effective in producing benzimidazoles (1~). Benzimidazoles (ll) can also be prepared from o-phenylenediamines and aldehyde (1~) using cupric salt as an oxidant ~R.
Weidenhagen, Ch~m. Per., ~, 2263 (1936)].

` - 20~627 WO 91/11999 - - ~ PCI/US91100957 R~;ACTION SCHEME I-lO

R4~ R3b ~1 (R= H, 0~ Cl) (R1= aryl, heteroaryl) R3 b R3~
R4~ -~ +R1 _ C- NH- COOEt o r ~2 Et OH
4b 20 R

R3b R3a 2 5 R4~-~

SUBST~TUTE St1EET

WO 91/11999 ; - 2 0 7 5 6 ~ 7 pcr/US91/009~7 ~, . .

REACTION ~CHEME I-10 cont ' d [~ }

S, 170, 1 Oh R4 H

. 30 SUBSTITUTE SHEET

wo 9~ 2 0 7 5 6 2 7 - PCT/US91/~957 Although some benzimidazoles having aryl and heteroaryl groups at the 2 po~ition can be prepared using the methods described in Reaction Scheme I-9, Reaction Scheme I-10 outlines methods which are more ~uitable for the cynthesis of this class of compounds. N'-aryl-N-hydroxyamidines (l~; R=O~) are cyclized under mild conditions using benzene-sulfonyl chloride in pyridine or triethyl~mine to give 12 in good yield ~M. W. Partridge and E. A.
Turner, J. Chem. Soc., 2086 (1958)]. Parent amidines (1~; R=~) ;an also be oxidized with ~odium hypochlorite under basic conditions to form 12 ~V. J.
Grenda, R. E. Jones, G. Gal and M. Sletzinger, ~.
- Or~. Chem., ~Q, 259, (1965)].
l~ Alternatively, a~ ~hown in Reaction Scheme I-10, o-phenylenediamines (ll) can be reacted with N-ethoxycarbonylthioamides (2Q) to give 2-substituted benzimidazoles (21) in excellent yields. This method avoids the use of acidic catalysts. The reagents (~Q) are easily obtained in one ~tep from etho~y-carbonyl isothiocyanate and 6imple aromatic or heterocyclic compounds or al~ylmagnesium halides ~B.
~eorge and E. P. Papadopoulos., J. Or~. Chem ., ~1 .
3233(1976); E. P. Papadopoulos., J. Or~. Chem., gl, 962(1976)]. ~eterocyclic compounds containing reactive methyl groups (e.g., 2-picoline) can also be reacted with o-phenylenediamines in the presence of sulfur at elevated temperatures to give 2-heteroaryl benzimidazoles (~

wo 9l/llg99 2 ~ 7 ~ ~ ~ 7 PCI/US91/009~7 , REACTION SC~IEME I-l 1 3~
~' R3~ H

R4 ~ z 4 R4~CNH

(W and Y= Cl, NH2 or N~N P~13 R3~ R3b R3b~ o ~ R'-O~Na~ ~Cl 27 ( Rl = C~ -C,5 alkyl) 26 ~ + CS~ ~ R~.~SH

R3~
R3 b ~CN~)~ Rl SUBSTITUTE SHEET

WO 91/11~ 2 0 7 5 6 2 7 PCT/US91/0~9s7 , ~ ...
-As outlined in Reaction Scheme I-ll, benzimidazole~ containin~ 2-al~osy and thioalkyl substituent6 (27 and 22) can be prepared from the corresponding benzimidazolone~ (2~) or benzimidazol-ethione~ (2~). Benzimidazolone~ are conve~iently prepared from o-phenylenediamines and pho~gene or urea t~. Hofmann, ~Imidazole and its Deri~ati~e~, Part 1," Wiley-Interscience, New ~or~, 1953, pp.
285-291]. Carbonate e~ters, diethylpyrocarbonate, lo N,N-carbonyldiimidazole and N,N-diethylcarbamyl chloride may al~o be used in this reaction. The reaction of phosgene i~ apparently facilitated by the use of N,N'-bis-trimethylsilYl (TMS) deri~ati~e (2~) instead of the parent diamine tL. Bir~hofer, H. P.
guhlthau, and A. Ritter, Chem. Ber., 2~. 2810 (1960)].

WO 91/11999 ` PCI/US91/009~7 2~7~627 R3a R3 b ~,~NHz PPA
R4~ J~ + Cl-(CH2)n-COOH

R3 b ~$~N R1 S ~ Na R4b H Cl R3~
( n= 1 - 3 R3 b ~_N
R1= alkyl, alkyl- R4~ ~--N> (~n aryl and alkyl- R4b H S--het eroaryl) /RlQ

R4 ~ / (Q = I ~r, O~i, OT~) R4b H

SUBSTITUTE SHEET

.!, 'WO 9 ~ 999 2 ~ 7 5 6 2 ;7 Pcr/ us g 1/00957 :

.

As described in Reaction Scheme I-12, 2-al~ylthioal~yl substituted benzimidazole~ (~1) can be prepared from the reaction of RS-M (where M is sodium, potassium or lithium) with 2-chloroal~yl benzimidazoleE (~Q). 2-Chloroal~yl benzimidazoles (~Q) can ~e conveniently prepared from the diamines and the chloroal~yl carboxylic acid~ using PPA tW.
~nobloch, Ch~m Ber., 21. 2557 (1958)].
Alternatively, compound ~1 can also be prepared f~om the readily available 2-thioal~yl derivative (~) tE.
S. Milner, S. Snyder, and M. M. Joullie, J. Ch~m.
~, 4151 (1964)].

TMT DAZ0- 6-FusFT) ~TF~OCYC~ F S

A2,A ~ N
~A4 CH2Ar (FORMULA I, wherein A5 i~ a ~ingle bond and -Al-A2-A3-A4- is a 4-atom sequence as defined in the Detailed Description of the Invention) WO91/11~ PCT/US91/00957 , , ~ -120-The compounds of ~ormula I, wherein -Al-A2-A3-A4- are defined by (a~) to (bw) in the Detailed De~cription of the invention can be ~ynthesized using the reactions and technique6 5 de~cribed herein below. The reaction~ are performed in a solvent appropriate to the reagent~ and materials employed and suitable for the transformation being effected. It i~ under~tood ~y those s~illet in the art of organic synthesis that the functionality lO present on the heterocycie and in the reactants being employed should be consistent with the chemic`al transformations being conducted. Depending upon the reactions and techniques employed, optimal yields may require changing the order of ~ynthetic ~teps or use 15 f protecting groups followed by deprotection.
As shown in Reaction Scheme 1, compounds of ~ormula I can be prepared by carrying-out direct alkylation of al~ali-metal salts of heterocycles (1) (preparation of heterocycles are described in 20 Reaction Schemes 3-6) using appropriately protected benzyl halide, tosylate (OTs) or mesylate (OMs) derivatives (~). The salt is prepared preferably using M~ (where M is lithium, ~odium or potassium) in anhydrous dimethylformamide (DMF), or by treating it 25 with a metal al~oxide ~uch as ~odium or pota~sium methoxide. etho~ide or t-buto~ide in an appropriate alcohol such as methanol, ethanol or t-butanol as the solvent. The al~ylation is generally carried-out by di~sol~ing the metal salt of the heterocycle in a 30 dipolar aprotic sol~ent such as DM~ or dimethylsulfO~ide (DMSO) and reacting it with the alkylating agent at 20'C to reflux temperature of the ~ol~ent for 1-24 hour~.

-WO 91/11~ 2 0 7 S 6 2 7 PCT/US91/00957 If ~ubstitucnts and/or the heteroatom positions in the si~ membered ring are not symmetrically di~posed, the al~ylation on the imidazole nitrogen(s) generally produces a mi~ture of two regioisomers as product~ arising from Nl and N3 al~ylation. These regioisomers I and Ia posses6 distinct physico-chemical and biological propcrties and in most cases can be separated and purified by using conventional separation techniques ~uch as chromatography (flash column chromatography, medium-pressure liquid chromatography, high performance liquid chromatography) and/or crystallization. In those cases where separation of regioisomers is difficult by c~n~entional techniques, the mixture can be transformed into ~uitable derivati~es that can be separated by the above separation methods. The structural assignments of the isomers can be made using Nuclear Overhauser ~ffect (NOE), 1~-l3c coupled NMR e~periments or ~-ray ~rystallography.
When there is potential for alkylation of the 6-membered heterocyclic ring, this can be a~oided 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 tJ.A. Montgomery and J.A. Secri~t III in "Comprehensi~e Eeterocyclic Chemistry,~l Vol. 5, A.R.
Katritsky and C.W. Rees Eds., Pergamon Press 1984; pp 567-597 and 631-656 and references cited therein].
As shown in Reaction Scheme I-13, the most widely used starting materials are si~ member heterocyclic ~icinal diamines (9). Fused imidazoles (lO) can be - - - - - - - - - - - -WO91/11~9 pcT/us9l/~9s7 , 2075~27 prepared by condensation of (9) with an appropriate - carboxylic acid, nitrile, imidate ester, or orthoester, either neat, or in a sol~ent appropriate and compatible uith the starting material~ and reagents, such as polyphosphoric acid, ethanol, methanol, hydrocarbon solvent~, and with a catalytic amount of acid if required. Oxidation of an imine formed by reaction of diamine (9) with an appropriate aldehyde using oxitants such as Cu (II), nitrobenzene, lo or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) also affords heterocycles (lQ)- Aminoamides (11. W =
H) or diamides (11, W R6CO) can be converted to - fused imidazole~ (lQ) by heating neat, or at an elevated temperature in a solvent such as ~ylene under acidic or neutral conditions.
- Ealogenation of the imidazot4,5-b~pyridine rin~ at the 6-position can be accomplished using Br2, or N-bromosucCinimide. ~alogenation of the 7-position can be accomplished by reaction of the corresponding imidazopyridine-4-oxide (prepared by reaction of the imidazopyridine with peracids such a~ m-chloroperben-zoic acid) with POC13. When the 7-position i~
substituted other than hydrogen halogenation at the 5-position of the 4(N)-oxide precursor occurs on treatment with POC13. Chlorides may be substituted by bromides or iodides by treatment with either ~Br or ~I, respecti~ely, in a sol~ent ~uch as EOAc.

WO91/11~ pcT/us9l/oo9s7 2075627 ~-2-Al~yl-imidazot4,5-b]pyridines can be ~ubstituted at the 5, 6, or 7 po~itions by di~place-ment of a halogen at that po~ition by nucleophile~
~uch as cyanide (followed by hydrolysis to obtain carbo~ylic acids), amine~, copper alkosides, trial~yl-phosphite~, and thiolate~. Also, sub6titution of the halogens, in particular bromides or iotide~, can be - accompli~hed by reaction with a coupling partner ~uch as alkylzinc or arylzinc halide~, or monoalkylaryl-phosphonites in the pre~ence of an appropriate metal catalyst ~uch as nickel, palladium, ruthenium, or platinum. In cases where the di~placement of a halogen is luggish or otherwi~e complicated due to - an acidic proton, the imidazopyridine may be protected at the 1, 3, or 4 positions by benzyl or other arylmethyl groups.
7-Methyl-2-propylimidazot4,5-b]pyridine-5-carbo~ylic acid or the 2-ethyl analog i~ prepared from 7-methyl-2-propylimidazot4,5-b]pyridine or the 2-ethyl analog by treatment with m-chloro-peroxybenzoic acid to obtain the N-oxide which i~
then treated with POC13 to gi~e 5-chloro-7-methyl-2-propylimidaZO-t4,5-b]pyridine or 2-ethyl analog . The chloride i8 then e2changed for a bromide by seaction of 5-chloro-7-methyl-2-propylimidazot4,5-b]Pyridine or the 2-ethyl analog with B r in acetic acid. The re~ulting 5-bromo-7-methyl-2-propylimidazot4~5-b]- pyridine or 2-ethyl analog is treated with Na~ in DMF followed by benzyl bromide to o~tain 3-benzyl-5-bromo_ 7-methyl-2-propylimitaZOt4.5-b]Pyridine or it~
corre~ponding 2-ethyl analog which is in turn treated .

WO91/11~9 PCT/US91/00957 2 0 7 ~ 6 ~ 7 with CuCN in hot pyridine to obtain 3-benzyl-5-cyano-7-methyl-2-propylimidazot4,5-b]pysidine or the corresponding 2-ethyl analog. The cyano compound is hydrolyzed to 3-benzyl-7-methyl-2-propylimldazo-~4,~-b]pyridine-~-carbo~ylic acid or the corresponding 2-ethyl analog by treatment with E2S04-H20. Thi~ acid i8 e~terified by reaction with MeOH-~Cl. The benzyl group is removet by hydrogenation at 1 atm. in MeO~-ECl solution using Pd(0~)2 as catalyst. This compound can be alkylated as described earlier and the product methyl ester is converted to the carboxylic acid by treatment with hydroxide.
As ~hown in Reaction Scheme I-14, methods of ~reparing heterocycles of types 1~ and 1~ involve treatment of diamines (9) with reagents such as urea, phosgene, potassium cyanate, al~yl chloroformates, dialkylcarbonates, or carbon di~ulfide in the presence of bases such as potassium hydroxide or potassium car~onate. Amino acid5 14 or 1~ can be converted to 1~ via Curtius or ~offman rearrangement of suitable derivatives such 8S acyl azides, hydroxy-amides, or N-haloamides. ~icyclic compounds of type (16, E = ~ulfur or o~ygen) are formed fsom 1~ ~y reaction under neutral or ba~ic conditions with al~yl halides, alkyl mesylates, al~yl tosylates, trial~yl-oxonium ~alts, or with an appropriate diazoal~ane.
Compounds of type (16; B - o~y~en or sulfur) are prepared by di~placement reactions u~ing alkogides or alkyl mecaptides with chloro intermediate~ a~
indicated.

WO 91/11~ 2 0 7 5 6 2 7 PCT/US9l/~S7 Diamines of type 2 can be prepared by a wide variety of methods such as hydroly8is of bis-amides or amino amides, reduction of dinitro or aminonitro or hydrazino or azido groups, displacement of heteroaromatic halites or al~osy or thio or al~ylthio or hydroxy or al~yl sulfonyl groups with ammonia or amines, or rearrangement of ~cyl azides or amides or acids (Curtius, Eoffman, or Schmidt rearrangements).
[A.S. Tomcufcik, L.~. Star~er in "~eterocyclic Compounds, Pyridine and it's Deri~atives~' Pt 3, ~.
Klingsberg Ed., Wiley Interscience, 1962, pp S9-62, and references cited therein; T. Na~agome in "~eterocyclic Compounds, Pyridazines" Vol. 28, R.N.
Castle, ~d., Wiley Interscience, 1973, pp 597-601, lS and references cited therein; "Heterocyclic Compounds, The Pyrimidines" Vol. 1~, D.J. Brown Ed., Wiley Interscience 1985, pp 299-325; F, Schipper, and A.R. Day J ~m Che~. Soc. (1952) 74, 350;
"Comprehensive ~eterocyclic Chemistry," Vol. 5, A.R.
2D Katritsky and C.W. Rees Eds., Pergamon Press 1984; pp 567-S97 and 631-656 and references cited therein].
In cases wherein heterocycles of type lQ or 1~ are not easily prepared from their corresponding diamines, or when these diamines cannot be prepared then alternati~e routes invol~ing fusion of the six member heterocycle onto an 8ppropriately substituted imidazole, are used. Two of these routes are illustrated in Reaction Scheme I-15. ~or example, imidazo[4,S-d]~1,2,33triazines (18) are preferentially prepared ~y treatment of amino carboxamido imidazoles (11) with sodium nitrite in ~queous acid. Precursor imidazoles (17) are prepared WO91/11~ PCT/US91/009~7 .,, ~,-~736~7 ~:

~y tegradation of an appropriately su~stituted ~anthine or by condensation of an appropriate imidate ester uith aminocyanoacetamide. Imidazo~4,5-b3-pyridazines (2Q) can be prepared from imitazodi-carbo~ylate esters (1~) by treatment with hydrazine.
Oxidation of (~Q) gives pyridazinediones (21)- The oxygen(s) in (~Q) or (21) can be con~erted to other functionalities such as halides or thiones, which are themsel~es precursors for the synthesis of more lo ela~orate systems ["Comprehensi~e Eeterocyclic Chemistry," Vol. 5, A.R. Katritsky and C.W. Rees Eds., Pergamon Press 1984; pp 567-597 and 631-656 and references cited therein].

2~

WO 91/11999 Pcr/uss~ s7 2 ~ 7 ~ 6 2 7 cTToN SL~ MF T_l~

H2 ~ ~A2 Rl C02 H~PPA ,~ R~
H2N ",A A~t~rn~te M~thod~ N A~'A3 X I heat~lnort rolvent R~
Rl C0~7H A~A or ne~t ~ ~,A3

11 H 10 AltGrn~t-~ r~genes ~nd re~ction condltlons:
Rl - CN, PPA
R~ - C- C oC2 Hs) . C2~sH
N~r ~1 2 0 Rl C( OCH3 ) 3, t ol ue ne, H~
RlCHO. C2~0~L CU(OCH3)2 ~. WO 91/11999 PCI/US91/00957 ~FP~CT~ON S~ T_14 XA 13CS?/~ H~3~ Al g H 12 2 XA ~A2 Cl 2 C= O~ e ~ `A2 H2N 4 ( NH2) 2C O, He~t ~ ~

X13cr X ;l3 1) 5O~l2~ N~N3. HO~ A

12 or 13 ~ R1Q N3~A~,A

12K~C13 Cl~ A3 R OH or ' 16 WO 91/11999 2 {) 7 S ~ 2 7 PCI`/US91/01"'~7 . .

CTION St~MF: T_l 5 II,N~)--8-R Nl ~
~,N~,O-BCl N
ll H

~ 7 C~OC~ E~ Rl o o ¦ DDQ

R
o H

As ~hown in Reaction Scheme I-16 amino imidazole esters and amides are ~ersatile intermediates for the preparation of purines. This scheme 81so illustrates the synthesis of the 6-membered hetçrocyclic ring after the alkylating agent 2 has been reacted with a suitably substituted imidazole to afford ~ os 24.

WO91~11~9 PCT/USgl/009~7 ~^ ~
207~;S27 ~CTION S~F.MF. I-16 ~-N=C-O ~

z2 23 R~- NH- CONH~

O O
1S ~c-oNH2 ~ ~ ~NH
R'-~ ~ ~ R'-~
NH2 R~-C(Oc2~)3 J
ArJ AC20 or D~F, Ar 24 ~ 25 The preparation of reduced forms of hetero-cycles can be achieved by catalytic reduction, or by synthesis from a suitable imidazole precursor. ~or example. hi~tidine ant derivatives thereof react with formaldehyde to afford partially ~aturated imidazo(4!5-c) pyridines [cf. Neuberger, A. Biochem, J., (1944), ~8, 309].

WO 91/11999 PCI/US91/00~57 2~75627 i ~ `

IMTD~7:o-7-~sFM~RF~T~ FIJSF:n ~ 0CYCIF:S

- A2-Al A'3 r ~
S A'~_A~ --N
C~2 X

R~ ~z y Compounds of FORMULA I, wherein -Al-A2-A3-A4-A5-represents a 5-atom sequence as defined in the Detailed Description of the Invention are prepared as described below in Schemes I-17 to I-23.

S~M~ I-17 R'-B ~ - N H ~-A

(7) ArJ (l ) ~ WO91/11999 PCT/US91/00957 2~75627 The imidazoles (7) reguired in al~ylation Scheme I-17 can be prepared by a number of methods well ~nown in the literature including those de~cribed in EP0 publication 253,310. A useful method of generating compound (7) wherein A* and A**
are NH2 and COM~R6 or Co2R7 i8 illustrated ln Scheme I-18.

wo 9~ g99 - 2 0 7 5 6 2 ~ PCI/US91/0~457 Sch~me T_l 8 C--N

R C-N HClH R'-C-OEt CONH, '~J~H2 C-N H

l 0 C2 Et N--~H2 R'~
N--\
I CO2Et R~ NH, . Et O~l R1 ~/ 3~
N

CONHR~

- W091/11999 PCT/US91/~ss7 2075~2~

-134_ The 6ynthesis of intermediate (l) wherein A*
i6 N~R6 and A** is CON~R6 or C02R7 (R7- ethyl) and B
is a single bond can be accomplished by the al~ylation of the cyanoamidine (13) with a benzylic halide or pseudohalide repre6ented a~ "ArC~2-Q" where Q is a leaving group as outlined in Scheme I-l9.

WO 91/119g9 2 0 7 5 6 2 7 Pcr/US9~ 7 Sch~me T_1 9 NH N-C_N
R' - C- OEt + NH2C- N Et OH, R' - C- OEt N-C=N
12 + NH2CH2CO2Et ~ R'-C

N-C-N
1 3 t ArCH2Q _ R'-C~CH2CO2Et CH2Ar ~ WO91/11~9 l ~ PCT/US91/00957 20756~7 Sch~me T-l9 tCont'd) ~2 NH2 /~ R~NH2 N~IH,/~O,Et ~ R'~ON~
DMF C~Ar c~2 R~ I N--( N~ H/DMF ~Oz Et CH2 ~

Cyanoamidine (13) is prepared according to the methods described by Edenhofer, ~ . Chim ~ , 58, 2192(1975).
Al~ylation of cyanoamidine 1~ may require an alkylating reagent which incorporates functional groups. In ~uch cases, protecting groups may be required for these functional groups during the al~ylation step. For egample, a carbosyl group can be conviently protected a6 a t-butyl ester and a tetrazole group as an N-trityl derivative. The al~ylated cyanomidine (14) is purified by silica gel chromatography as is the ring-closed product (15).
Conver~ion of (15) to amide (16) is accomplished by heating the ester with R6N~2 in an inert solvent such as ethanol. Compound (15) can be al~ylated on the amino moiety using a small e~cess of Rl-I in DMF in the presence of Na~.

WO 91~11999 2 0 7 5 S ~ 7 PCr/US91/Qn~57 Compounds of Formula (7) wherein A* and A**
are either Cl and C~20~ or C~2OE and Cl respectively are also useful intermediates, and their preparations are described in ~P0 publication 253,310. The primary alcohol (C~20~) moiety in their al~ylation products (18) can be o~idized directly to the corresponding -C02C~3 ester groups using MnO2 in the presence of NaCN and acetic acid in methanol as illustrated in Scheme I-20.

Sche~e T-20 Cl Cl S~ ~hO2. N~CN ~
R'~ OH HDA~, MEOR, B/~ 2C~3 ~H2 Ar CH2 Ar 1~ 19 - C}~OH CO~CH3 R'-~ hO2. ~CN, R' ~3~1 C~ Ar~)A~ H CH2 Ar 2~ 21 2S Compounds (19) and (21) from Scheme I-20 can be further converted to thiol compounds as illustrated by the methodology of Scheme I-21.
Scheme I-21 also illustrates an alternate route to amino compounds (22) which involves azide displacement of Cl followed by hydrogenation.

~ WO91/11~9 ~ ~ PCT/US91/00957 i 20 ~5S2 7 Sch~me CO2cH3 R C~CH~
R1 ~C 1 )CH,C_SH. N(Et~
-B ~ 2)~aOCH3 ~OH R'_B~;H
CH2 Ar CH2 Ar N~( 1 ?N~N3, DMF ~
~ N~C1 2)H2, Pd/C ,~2 CH2 Ar CH2 Ar Formation of the products (I) wherein the fused ring A represented by Al-A2-A3-A4-A5 contains D
= NR6 is carried out from intermediates (1) wherein A* and A** are (M~R6, COM~R6) or (C0N~K6, NHR6) 2~ re~pectively by treatin~ (1) in DMF with Q-C(o)-C(R7)(R8)-Q in the pre~ence of a tertiary amine such as triethylamine. Q i5 a lea~ing group which preferably is a halo group. When A* or A** is Co2R7 and R7 = E then Y in the resultant products i~
oxygen. The transformations illu5trated in Scheme I-22 with intermediate (16) are analogous to transformatiOnS which can be employed to synthesize similarly ~ubstituted benzodiazepine~.

WO 91/11999 2 0 ~ ~ 6 2 7 PCI~US91/~4~57 Sch~me ~ 2 Cl-C-C~R )~-Cl R~
c02CH3 R~ ~ / ~7 1 5 /~( 1 ) Cbz - N- C~ R7 ~ ( R8 ) _ COOH /~
R1 ~--~32 DCC ~ R1 _ B~
CH2 Ar 2 ~ HE r /H0Ac J H
3)~ Ar 25 Scheme ~-22 also pro~ides an alternate route to generate products (I) wherein ~ is NR6. In this sequence N-protected amino acids are used to acylate intermediate (1) wherein A* or A** is NR6, by employing either an acyl halide, or a standard carboxyl acti~ating reagent such a~ dicyclohexyl-carbodimide (DCC) or (benzotriazol-l-yl)o~ytri~-(dimethylamino) phosphonium hexafluorophosphate (~OP). The N-protecting group of the amino acid ~uch as the carbobenzyloxy (Cbz), t-buto~ycarbonyl (t-ROC) or the fluorenylethylmetho2ylo~ycarbonyl (FMOC) group ~ WO91/11~9 PCT/US91/009~7 2075~7 .

is removed according to standard peptide synthetic conditions. The final ring forming ctep is made by heating this intermetiate in an alcoholic solvent or by ~aponifying the imidazole Co2R7 group to yield a carbo~ylic acid which iB treated with a carboxyl activating reagent such as DCC or polyphosphoric acid.
Following the methodology of the above described transformation of Scheme I-22, if A* and A** are S~ and Co2R7, as illustrated by intermediate lo (23), and the ring forming reagent is ~NR6C(R7)(R8)C~2Cl, it is possible to form products of formula (I) wherein the Al-A2-A3-A4-A5 element is -CON(R6)-C(R7)(R8)-C~2S
-SC~2C(R7)(R8)-N(R6)-Co--CoN(R6)-C(R14)(Rl5)-CH2S--SCII2C (R14 ) (R15 )-N(R16 )CO-The preparation of products of Formula I, wherein _Al_A2_A3_A4_A5 is -coN(R6)-c(R7)(R8)-c(R9)=
N- is carried out in Scheme I-23. The final ring closure, which involves a dehydration to yield an amine, can be assisted by heating in the presence of molecular sieves and acetic acid in an inert solvent such as dioxane. or by employing polyphosphoric acid 2~ as the dehydrating agent.

WO 91/11999 PCr/US91/00957 2~7S~27 ^

., Sche-ne T_?3 CO2C~
l )o~, F~ Chlorido 4~ 2)H2~C-CR )(R~)CCoEt)2-R7 ArJ 22 3)Plp~rldlne o R7 R~
I I \ / o I ,~,-C- NH- C ~ ~N~/~

R' - B~N~2 ~ R' -CH2Ar ~ 27 WO91/11~ PCT/US91/00957 20756~7 PART II: Preparation of Qubstituted benzyl derivatives of the general Formula I.
Preparation of compounds of Formula I starting from the heterocycles or benzyl-sub~tituted heterocycles described in Part I i8 illustrated in the following schemes and descriptions.

The synthesis of Angiotensin II Antagonists incorporating a substituted benzyl group as shown in Formula I may be accomplished 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 R9, R10, Rll, R12, g, Y and Z as shown in Formula I. Alternatively, compounds with structures according to Formula I may also be synthesized in stages from a benzyl-substituted heterocycle which contains the substituents R9, R10 and X, followed by reaction with an intermediate 20 - (such as a substituted alpha-bromophenylacetic ester) which introduces the substituents at Rll, R12 and Z.
Examples of this latter methodology in which a benzyl-substituted heterocyclic intermediate is prepared first, and then elaborated to afford 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:

WO91/11~9 PCT/US91/~ss7 ,.

207~627 _ 143 --Al-A2-A3-A4- = -C~=C~-C~=C~-, B= a single bond, Rl=
butyl, R9, R10 and Rll are ~ 0, Y- a ~ingle bond~
Z= C02~ and R12= phenyl appear~ in Scheme II-l and in Example 1 of the experimental section. Deprotonation of 2-butylbenzimidazole with strong bases such as sodium hydride or potassium tert-buto~ide in DMF for a period of 1-24 hours at temperatures of 20-lOO-C, followed by al~ylation with 4-benzylo~ybenzyl chloride affords the protected ether 2. The benzyl lo ether is ne~t removed by hydrogenolysis using hydrogen and an appropriate catalyst ~uch a~ Pd/C, Pd(0~)2/C or Pt/C which affords the intermediate phenol 3. The phenolic proton is then abstracted, and the phenolate is al~ylated with methyl 2-bromophenylacetate to furnish ester 4. Finally, the ester is hydrolyzed and the free acid 5 is obtained.

WO 91/11999 Pcr/us9l/oo9~7 :

,~ 2Q7S6~7 SC~MF II-l ~ ~ ~ D~ ~ ~' ~nO Cl r~nO'13J n-\~"~t~H. DM~ \~3 J3~ 3 ~CO~ oJ3J

OH, M~ OH \~
2) }~

~CO~ H

The synthesis of compound 10 of Formula I
wherein: -Al-A2-A3-A4- = -C(CH3)=C~-C~=N-, B= a single bond Rl= n-propyl, R9, R10 and Rll are E, X=
O, Y= a single bond, Z= C02~ and R12= phenyl is presented in Scheme II-2 and in Example 2 of the experimental section. Deprotonation of 7-methyl-2-WO91/11~ pcT/us9l/oo9s7 20756~7 propylimidazo[4,5-~]pyridine (6) with sodium hydride in DMF, followed by treatment with 4-benzyloxybenzyl chloride gives compound 7. The benzyl ether is removed by hydrogenolysis to give the phenol 8, which is then deprotonated with potassium hydride and 18-crown-6 in DMF and al~ylated with methyl 2-bromophenylacetate to give the ester 9. Basic hydrolysis of 9 gives the free acid 10. Al~ylation of the phenol 8 with substituted 2-bromophenylacetic lo esters, followed by ester hydrolysis leads to compounds of Formula I where R12 is a substituted phenyl ~roup such as those shown in Examples 6 (R12=
2,6-dichlorophenyl), 7 (Rl2= 2-nitrophenyl), 8 (R12=
cyclohexyl), 9 (R12= n-propyl), and lO (R12=
o-carboxyphenyl) in the experimental section.

WO91/11999 PCT/US91/~9~7 .
. " ; 207562~

S t~ MF`. T T--2 ~nO ~~
~' ~ ' 15 ~,J~ ¢~co,l~ ,0~ 9 ~CO,~

1~ ~O~ or~
2) Kl ~C0,31 The synthesi 6 of compound 15 of Formula I
wherein: -Al-A2-A3-A4- = -C(CH3)=C~-C(C~3)=N-, B= a single bond, Rl= ethyl, R9, R10 and Rll are ~, X= 0, Y= a sin~le bond, Z= C02~ and R12= 2-methylphenyl is shown in Scheme II-3 and in Eæample 24 of the WO91/11~ PCT/US91/~s~7 experimental section. Deprotonation of 5,7-dimethyl-2-ethylimidazot4,5-~]pyridine (11) with a strong base such as sodium hydride in DMF, followed by treatment with 4-benzyloxybenzyl chlorite produces the ether 12. The benzyl ether is removed by hydrogenolysis to give the phenol 13, which is then deprotonated with potassium hydride and 18-crown-6 in DME and alkylated with methyl 2-bromo-2'-methylphenyl-acetate to give the ester 14. Alkaline hydrolysis of lo 14 gives the free acid 15. Reaction of the phenol 13 with other substituted alpha-bromophenylacetic esters followed by alkaline hydrolysis leads to additional derivatives in this heterocycle series, such as Examples 25 (R12= 2-chlorophenyl), 26 (R12=
2-bromophenyl) and 40 (R12= 2-phenylethyl) in the experimental section.

WO 91/11999 PCI/US91/00957 ~;
....

- 148 - 2073~7 ~1BnO ~ o~C~3 ~CH3 H~, Pd~C ~J
~OH J~J 13 HO

2 0 ~H DME ~[3J 1 4 cro~n-6 0 ~CO

N~CH3 1 ) NaO~ ~30H ,¢~J 1 5 2) HCl O
~CO2H
~C~

&lJB~ 11~ lJTE S~EEr WO91/11~9 PCT/US91/~9~7 benzaldehydes (18) with trimethylsilyl cyanide affords the trimethylsilyl-cyanohydrins 19.
Treatment of 19 with acidic ethanol produces the hydroxy esters ~0, and subsequent reaction with carbon tetrabromide and triphenylphosphine provides the substituted 2-bromophenylacetic esters 17.

SC~F.MF. TI-4 R R ~r ~02H 1 ) SOCl~ r2 ~

1 5 SC~F.~E II-5 o~s ~fHD ~SlCN. ~CN ~N }~Cl. EtOH
2 0 1 ~-cro~-6 1~ 19 OH R
2 ~ ~02Et PPh3. C~r~ Et WO91/11~ PCT/US91/00957 2075~27 The synthesis 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 lea~ing group, and with all of the appropriate substituents ~9 R10 Rll ~12, ~, y and Z in place. Thi~
approach which i6 generally preferred when either R9 or R10 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-cresol (21) with strong bases such as potassium hydride or potassium tert-butoxide in DM and alkylation with methyl 2-bromo-2-phenylacetate gives the ether 22.
Bromination of 22 at the benzylic methyl group with N-bromosuccinimide gi~es 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 subsequent ester hydrolysis provides the acid 24.

- 151- 207~627 S C~IEME I I - 6 ~3~CH3 1 8 - cr o~- 6 ~l~cH3 HO ~CO2~ ~CO2M~

J~r NBS, AI BN o Na H,DMF
CC14 reflux ~COzMe C~l 1 ) NaOH, ~OH, \ <,N~

2 ) HC1 N~CH3 0~
~CO2H

SUE~ 111 ~JTE SHEEr WO 91/11~ 2 0 7 ~ 6 2 7 PCT/US91/~57 -15lA-A strategy similar to that of Scheme II-6 is applied when substitution at Rll 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 lo 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.

2s SUBSTITUTE SHEET

-152- 207~27 ~,CH3 LiN( S1~33) 2~ f H3 CH3I H3C ~
~COzl~ ~CO2~

H3C NaH, D~

CCl~. r~Flux [3~Co~ ~3 2 0 N~
1~ NaOH, ~OH ~ J
2 ) HCl H3C

SaJBSTITUTE SHEET

WO91/11~ PCT/US91/O~gs7 20756~7 ~

The synthesis of compound 32 of Formula I
wherein: -Al-A2-A3-A4- = -C(CH3)=C~-C(CH3)=N-, B= a single bond, Rl= ethyl, R9, R10 and Rll are ~, X= 0, Y= CH2, Z= C02H and R12= 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 lo 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.

SlJBSTITUT~ SHEET

WO 91/119g9 PCI/US91/00957 -153- 207362~

., ~H 1 ) Br CH2co2cH3 ~OT8D~
,~J K2CO3, acet one ~
HO 2) t-~u~2SlCl I 29 28 DM~P, CH2Cl2 CO2~

~--OT~D~S
1 ) KN(Si~3)z 13~,~J 1 ) n-~u~NF, T~

2) PhCH2~3r 2~ 2) C~3r4, PPh3 CH2Cl2 ~r CH3 N$~ 1 ) NaH, DMF

1 ) NaOH, ~OH ~3~CH3 2 5 [3~`co2 H

SUBSTITUTE SHE~Er WO 91/11~ 2 0 7 5 ~ 2 7 PCT/US91/ ~ 7 Scheme II-9 illustrates the preparation of an antagonist of Formula I wherein: -Al-A2-A3-A4-=
-C(CH3)=CE-CH=N-, B= a single bond, Rl= propyl, R9, R10 and Rll are ~, g is a single bond, Y= 0, Z= C02~
and, R12= 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 DME, 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.

8UBS ~ JTE SHEEl-. .
... .
-154- 2a75~2~

S (~F.M~. I I - 9 .

HO~C~ 1 ) SOCla, Br~ ~eozc~fH3 33 2~ ~OH Br 34 Phe no 1 f ~CH3 KH, DMF ~ozc~l NE~ IBN
1 8-crown-6 ~O CCl~ rcflux ~1 35 ~3r NaX DMF
~02C~ CH3 ~ 3 5 ~NJ~;3 6 H

25N~ 1 ) NaOX ~5eOH N~
~o c~3J 2) HCl Ho2C~3J38 ~ 37 [~f SUBS~ITUTE SHEET

WO 91/11~ 2 0 ~ 5 6 2 7 PCT/US91/~957 Schemes II-10 and II-ll illustrate the preparation of analogs where -Al-A2-A3-A4- =
-C(C~3)=C~-C~ , B= a single bond, Rl= n-propyl, R9 and R10 are ~, Y= a single bond, R12 is phenyl, Z=
C02~ and X is either methyne or methylene. A
Reformatsky reaction is first employed to prepare methyl 3-hydro~y-3-(4-methylphenyl)-2-phenyl-propanoate (39) from the starting materials shown in Scheme II-10. When heated in the presence of p-toluenesulfonic acid in benzene 39 i8 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 lS hydrolysis of 42 affords the product 43, in which X
is a methyne group (Rll is absent) doubly bonded to the carbon atom bearing substituents R12 and Z as shown in Scheme II-ll and in Example 11. Catalytic hydrogenation of 43 gives the derivati~e 44 where X
is a methylene group and Rll is a hydrogen atom (Scheme II-ll; Example 12 in the e~perimental section).

WO 91/11999 PCI~US91/00957 S t~F.MF. T I--~ O

S E~n' H,cJ~f ~ 39 p- n OH ~~ N ~r ~ t 1 ~ CCl4. r~ x SC~MF II-ll c~3 CH3 H ~
6 0~ Z

N~O~ ~aOH ~1 H2, Pd- C
2 5 ~3J Et OAc ,13J

~CO~H 43 ~H

WO91/11999 `. 20~ 5 6~ PCT/USsl/OQ9~7 The synthesi~ of compound 47 of Formula I
which has the same substituents a~ compound 10 (Scheme II-2) with the exception that Z is a tetrazol-5-yl group, is illustrated in Scheme II-12.
Exposure of ester 9 to excess ammonia in methanol produces the corresponding amide which is then dehydrated with phosphorous oxychloride and triethylamine to give the nitrile 45. Reaction of the nitrile 45 with trimethylstannyl azide in lo refluxing toluene provides the tetrazole derivative 46.

S~MF II-12 CH, CH3 1 ) N~33, ~OH ~3 2 0 J3J 2) POCl~, Et ,N J3J

0~0~a 9 E~N 45 1) ~,SnN3 ~
tolu n- r-rlu~
2 ) ~Ac ,13J

~ `r WO 91/11~99 2 0 7 5 6 2 7 Pc~/us9l/00957 Scheme II-13 illustrates the preparation of a tetrazole analog (52) similar to structure 46 wherein Rl2 is a 2-chlorophenyl group. In this synthesis, the ester 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 II-13 (Example 15).
lS

SUB~ 111 ~JTE SHEET' wo 91~11999 ` 2 0 7 ~ 6 2 ~ PCI`/US91/0(~957 SC~FME II-13 ~f NH3, I~OH ,~f H~

~CO2~3 H~~248 POCl~. Et~N oJ~f NE3S, AIBN, ~N CCl4, re~lux o~f ~ 6 ~ ~33 o~lJ t oluene re~ lux J3J 52 ~ 2) ~P.c Cl SUBSTITUTE ~HEE r WO 91/11~9 2 0 7 ~ ~ 2 7 PCT/US91/00957 The preparation of a deriYati~e of ~ormula I analogous to tetrazole 47 (Scheme II-12) which haæ
a methylene group for the ~ substituent, is shown in Scheme II-15 and in E~ample 16 of the e~perimental section. In this synthesis, phenylacetonitrile is deprotonated with lithium bis(trimethyl~ilyl)amide and then al~ylated with the tert-butyldimethylsilyl-ether of p-hydroxymethylbenzyl bromide (preparation of bromide S3 i8 shown in Scheme II-14 and Example 16 lo f the e~perimental section) to yield nitrile 54.
The silylether group in compound 54 is directly converted to the bromide 55 with carbon tetra~romide, triphenylphosphine and acetone in dichloromethane (Mattes, ~.; Benezra, C. Tetrahedron Lett., 1987, 1697). Alkylation of the sodium salt of heterocycle 6 with bromide 5~, followed by reaction of 56 with trimethylstannyl azide in refluxing toluene yields the tetrazole ~7.

S~F~E II-14 Br~[~ 2H E3H3, T~ }~r [~OH

t - 9uMe2S iCI. DM~P 9r ~BD~
i-PrEt2N. CH2C12 WO 91/11~ 2 0 7 5 6 2 7 PCT/US91/~957 .

S ~ T - ~ 5 1 ) LIN~Sl~)~ THF ~BD~;

r~ . CEir, E~ S3 ~CN C~Cl~. el~tone 5q 10 ~ ~36 DMF ,13J

~ ~N

1 ) ~SnN3CH~
toul~ne r~flux, ~J~
2) ~Ac ~

,~J 57 2 0 ~

Scheme II-16 illustrates the preparation of a derivative of ~ormul-a I where -Al-A2-A3-A4- =
2~ -C(CH3)=CH-C(CH3)=N-. Rl is ethyl, B i8 a sin~le bond, R9, R10 and Rll are ~, X= 0, I= a ~inEle bond, R12 is 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. ~romination of the hydro~yl group of 59 with carbon tetrabromide and triphenylphoSphine in dichloromethane gi~es bromide 60. Deprotonation of p-hytroxybenzyl alcohol with ~ WO91/11~9 PCT/US91/~9~7 2a75s27 sodium hydride in DME followed by addition of bromide 60 affords intermediate 61. A second bromination reaction (CBr4, PPh3, C~2C12) converts alcohol 61 to the bromide 62 which is then used to alkylate a heterocyclic compound described in Part I. Scheme II-16 illustrates the case where the anion of heterocycle 11 is reacted with bromide 62 to give upon workup, the phosphonate mono-ester 63 (Example 67). Phosphonic acid 64 may be obtained by treatment lo Of ester 63 with trimethylsilyl bromide.

SC~MF. II-16 OH ~r ~ (~0)2POH ~OMa)2 PPH3. C~r~ ~O~le)2 CH3 H3 C}32Cl, H3 5~ 59 60 2 0HO~OH ,~f PPH3 . C~r ~ o~

(~PO( ~) 2 CH2Cl2 [3~PCI( O~k) 2 25~ ~cH~ O ~slrr O
3 ~POC O~S ) OH ~PO~ OH) 2 WO 9l/llg99 2 0 7 5 S 2 7 pcr/us9l/on4~7 The ~ynthesis of a derivative of Formula I
where Z is an acyl-~ulfonamide group is illu~trated in Scheme II-17. Alkylation of the anion deri~ed from heterocycle 11 with bromide 6~ (synthesis described in Example 28 of the experimental ~ection) and alkaline hydrolysis of the resulting e~ter (66) affords the acid 67 (Example 29). Reaction of acid 67 with 1,1'-carbonyldiimidazole in T~F at elevated temperatures gives an acylimidazolide which may be reacted with a ~ulfonamide (benzenesulfonamide in this example) and DBU in THF to provide the target compound (68) where Z is the acyl-sulfonamide group.

SC~E~F II-17 - 05 ~CO,~

c~ C~33 2s ~ ~ ~ ~
N~OH Cl~J 1~ CD~. ~XF Cl_~J N~CH3 o~J o7 2~ P~-90,N~,. DE~o,~J o~

~HN` -'[3 ~ WO91/11~9 PCT/USgl/~9~7 2a75~27 Precursors for the synthesis of AII
Antagonists incorporating a 8Ubstituted benzyl element wherein either substituents R9 or R10 are non-hydrogen include substituted p-cresols (Scheme II-6), 4-hydroxybenzyl alcohols, 4-hydroxybenz-aldehydes, 4-hydroxybenzoic acids and their esters as shown in Schemes II-18-20.
Commercially available benzyl alcohols such as 3-chloro-4-hydroxy-5-methoxybenzyl alcohol may be lo selectively alkylated by alpha-bromophenylacetic esters when they are refluxed together in the presence of bases such as anhydrous potassium carbonate, giving 2-phenoxyesters like 69 shown in Scheme II-18. Conversion of the benzyl alcohol group in 69 to a bromide (CBr4, PPh3, CH2C12) affords an alkylating agent (70). A heterocyclic compound from Part I (11) is then alkylated with bromide 70;
hydrolysis of the intermediate ester affords 71, the product of Example 37 in the experimental section.
Alternati~ely, a heterocyclic compound from Part I
may be directly coupled with benzyl alcohols like 69 using Mitsunobu reaction conditions (diethyl azodicarboxylate, PPh3, THF). Again, hydrolysis of the resulting ester completes the synthesis.

WO 9 1 / 1 1 999 2 0 7 5 6 2 7 Pcr/ us 9 1 /0~95 7 '~

S ~F~ 18 Cl~H acet ~ne, he-~t ~ [3~o2Me ~CO

Cl~r PPh ~, CBr ~ O
CH2Cl2 ~co2~

\~ 1 )N~ DMF N OH ~H3 11 Cl`~fb ~J

~CO, ~b ~ ~

Scheme II-19 illustrates the use of commercially available 3-ethoxy-4-hydro~ybenzaldehyde (72~ to prepare an AII Antagonist of ~ormula I
bearing a 3-ethoxy group (R9) on the substituted benzyl element- Alkylation of the phenolic group of 72 with methyl 2-bromophenylacetate gives the WO91/119~ pcT/us9l/~9s7 2075~2~

aldehyde 73 which is then reduced to a benzyl alcohol with sodium borohydride in methanol or ethanol. The alcohol i5 con~erted to the bromide 74, and the ~ynthesis of product 75 (Example 34) is completed as pre~iously described.

S~ E II-l9 c,~o~f ~c~tone, raf lux C~f 72 ~02~'b [~C02~

C2H~~ r H~. EtOH, J~l 2 ~ PPh~, C~r ,~
CH2Cl2 ~C27 q 2 5 \~N~ 1 ? N~ DMF NrOH \~H~
H CE~3 2)c H ~ I~OH C~3J
(3~co, Me ~C2 H

W091/11~9 ; - 2 0 7 S 6 ~ 7 PCT/US91/~957 . ', Substituted 4-hydroxybenzoic esters are also convenient precursor6 for the synthesis of the ~ubstituted benzyl element defined in AII Antagonists of Formula I. In this approach, the phenolic hydroxyl group is usually first protected with a suitable protecting group, the ester is then reduced to a hydro~ymethyl group, and deprotection affords a 4-hydroxybenzyl alcohol deri~ative. Scheme II-20 illustrates the preparation of derivati~e 80 usin~
this sequence starting from methyl 3,5-dichloro-4-hydroxybenzoate (76). Silylation of phenol 76 followed in turn by lithium aluminum hydride reduction of the ester and silylether deprotection affords 3,5-dichloro-4-hydroxybenzyl alcohol (77).
Phenol 77 was then selectively alkylated with methyl 2-bromophenylacetate, and the synthesis of derivative 80 (Example 38) was completed using the previously described methods.

WO91/11~9 PCT/USgl/~ss7 ~ .

S C~MF. T I--2 0 1 ) t-~,Bl~l Cl ~co,Cl~f~
Cl ~fO~DM~P, CH~Cl~ ~f c-tor~ . r-l-ux 0~
~J 2) L~
Tl ~) ~4N~. ~ 77 ~ 7e PP~ ~-$~ \~H~ Cl ~)~ 1~ N~' D~F
79 2) N~O}i. 1~0~ 0~
~O~H 00 A variety of 2-substituted phenols are selectively carbo~ylated when refluxed with carbon tetrachloride, 50Z agueous sodium hydroxide and powdered copper (European Patent Application 2 #193,8~3, 10-Sept-86) to afford the corresponding 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 AII Antagonist from a readily available 2-substituted phenol. This strategy is illustrated for the preparation of derivative 84 shown in Scheme II-21. Carboxylation of 2-ethylphenol provides 3-ethyl-4-hydro~ybenzoic acid (81). Acid 81 is then esterified, silylated, 3 reduced and desilylated to give the 3-ethyl-4-WO 91/11999 2 0 7 ~ 6 2 7 PCT/US91/~9~7 hydroxybenzyl alcohol 82. Alcohol 82 may then be used to complete the synthesis of AII Antagonist 84 shown in Scheme II-21 using the previously discussed methodology.

C~ 3 CCl, Cu 2Hs~CO~H
heat 81 1 ) 2~0~ H2SO"
2) t-~3uMQ2SlCl C2H~ ~bH
DM~P. CH2Cl2, 3) LlAlH4 THF HD
1 S 4) n- E~u"NF. THF

1 ) ~3r ~O~Q
~ K2CO3, ~r acetone, reflu,x 2) PPh3. CBr"
CH2Cl~ ~ 2MQ
~ 83 CH3 CH~
\ <~

2) NaOH, M~OH O
[3~Co2H 84 ~;UB~ ~ JTE SHEEr WO91/11~9 ~ - PCT/US9lt~9~7 2 ~ 73 6 2 7 The Claisen rearrangement of phenyl-allylethers offer~ another useful technigue for the introduction of alkyl ~ubstitutents (R9 or RlO) at the meta position of the substituted benzyl element. In Scheme II-22, Claisen rearrangement at 185-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, such as imidazopyridine 11, followed by silylether removal gives intermediates related to 88. Alkylation of 88 with methyl 2-bromophenylacetate followed by alkaline hydrolysis gives a derivative of ~ormula I (89) wherein R9 is a meta-allyl group (Example 42). ~ydrogenation of intermediate 88 followed by the same sequence provides derivative 90 where R9 is the meta-propyl group as shown in Scheme II-22 and described in Example 43 of the experimental section.

~ WO 9~ 2 0 7 5 6 2 7 PCT/US91/00957 St~.~F. T I -~ 2 q ~ Cl 5,~J~ 18~C, ~DM1~P. CB~C1 O ~Cl D2) L~Al~, ~F 5~8 es W~ c}~ci, 87 C~, CH, ) N~ Dt~ ~3J ~B
Z) n-E~u~NF, THF ~X~
C~ C~

--~3J~ 9 or ~3J

0~CO~H ~0~ H

The Claisen rearrangement strategy for the introduction of a meta-alkyl ~ubstituent onto the substituted benzyl element of an AII Antagonist of ~ormula I may be exercised twice when it is desired that both R9 and R10 be meta-alkyl substituents.
Thus, allyl phenol 86 may be con~erted to its O-allylether and subjected to a second Claisen rearrangement to provide the phenol (91) shown in Scheme II-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 Mitsunobu reaction of the benzyl alcohol 92 with a heterocyle (11) described in Part WO91/11999 - PCT/US91/~gs7 2~75G27 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 R9 and R10 are meta-propyl groups as shown in Scheme II-23 and Example 52.

SUBSTITUTE SHEE~

` `- 2 0 7 5 6 2 7 PCr/US91/009~7 SC~EME II-23 ~CO2~ ~ Br, K2CO3 acetone, reflux~
.~ ~ Cl 86 2) 1 85C, ~l ) t - Bu~2sicl ~ DM~P, CH2Cl2 HO~' 2 ) H2, Rh/C, Et OH
91 3) LiAlH4, THF

3~H
TBD~O l' 2s SUB~;TITUTE SHEEr WO 91/11999 PCI/US91/009~7 -- 20~ a 627 SCHEM~ 23 cont ' d ~ CH3 2 ) n- Bu4NF, T~ 9 3 H~ ~

~o Br CH3 ~C2 ~ N~CH3 acetone, reflux ~
2) NaO~ ~OH O~J g4 2 0 ~ o~2 H

SUBSTITUTE SHEEl WO9l/llW9 2 0 7 ~ 6 2 7 PCTIUS91/00957 The synthesis of compounds of Formula I
wherein: -Al-A2-A3-A4- = -C(CH3)=CH-C(CH3)=N-, B= a single bond Rl= ethyl, R~, R10 and Rll are H, Y= a single bond, Z= C02H R12= phenyl, and X= NR, are presented in the following two Schemes. To access these analogs, a heterocycle (ie. ~1) defined in Part I is alkylated with p-nitrobenzyl bromide to yield nitro compounds such as 95 in Scheme II-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).

SUB~ I 11 IJTE SHEEr SCHE~ 4 CH3 1 ) N~ ~. Dl~ r \~H3 H 2) ~3 ~2N

H2~ Pd/C \~q 1 ) Na~, DMF
~:H3 2 ) 9r ,~ 96 ~CO~Me }~N

\~N~ ~H3 ,13J 2*10H J3J 9 9 [3~co,~ [3~o,H

SUB~ ~ JTE SHE~

wo 9~ ~g 2 0 7 ~ 6 2 7 PCT/US91/~957 The preparation of AII Antagonists of Formula I similar to 98 in Scheme II-24 but having X=
NR may be accomplished by methodology shown in Scheme II-25. The substituted aniline (96) presented abo~e, is readily con~erted to the N-tert-butylcarbamate (~OC) 99. Carbamates such as 99 may be deprotonated at the amide nitrogen atom when reacted with bases such as sodium hydride in DMF, and then reacted with an alkyl halide. Subsequent treatment of the lo intermediate with trifluoroacetic acid remove~ the ~OC group providing the mono-al~ylated aniline derivative 100. The aniline nitrogen in 100 may be deprotonated again with sodium hydride in DMF and alkylated a second time with a substituted lS alpha-bromoester to provide esters such as 101.
Alternatively~ the order of introduction of the substituents on the nitrogen atom may be re~er~ed.
Intermediate 97 (Scheme II-24) may also be deprotonated by strong base~ such as lithium bis(trimethylsilyl)amide in THF and then reacted with an alkyl halide to yield similar products (101).
~ster 101 prepared by either synthetic route, is then hydrolyzed to afford the targeted AII Antagonists (102) of Formula I where ~= NR.

WO 91/11999 PCI~/US91/009s7 - 2075~27 N~CH3BOC20, ~[3J Et 3N, CH2Cl2, \ <~N~ 1 ) Na~ D~
N~CH3 ~3r ¦~IJ 99 2) CF3C02H.
BOC~N~ CH2Clz SUBSTITUTE SHEET

WO 9~ 9g9 2 0 7 5 6 2 7 PCI/US91/~00957 SC~MF II-25 cont ' d CH3 13r ~H3 ~CO2~$ CH3 100 NaH, DMF \ \~N~H3 H ~J 101 N~H3 ~~
J3' 2 ) ~ E3r H~ 97 ~~ NaOH, MaOH

N~H3 ~O~ H

SUBSTITUTE SHEEl W091/11~9 ~ PCT/US91/~957 2~75~27 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 salts, alkali metal salts li~e sodium and potassium salts, al~aline earth metal salts li~e the calcium and magnesium salts, salts with organic bases; e.g., dicyclohexylamine salt6, N-methyl-D-glucamine, salt6 with amino acids like arginine, lysine, and the like. Also, ~alts with lo organic and inorganic acids may be prepared; e.g., ~Cl, HBr, ~2S04, H3P04, methane-sulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic.
The non-toxic, physiologically, acceptable salts are preferred, although other salts are also useful;
e.g., in isolating or purifying the product.
The salts 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 in which the salt is insoluble, or in a sol~ent such as water which is then removed in ~acuo or by freeze-drying or by exchanging the cations of anexisting salt for another cation on a suitable ion exchange resin.
Angiotensin II (AII) is a powerful arterial vasoconstrictor, and it exerts its action by interacting with specific receptors present on cell membranes. The compounds described in the present invention act as competitive antagonists of AII at the receptors. In order to identify AII antagoni~ts and determine their efficacy in vitro, the following ~wo ligand-receptor binding assays were established.

WO 91/11~ 2 0 7 5 6 2 7 PCT/US91/00957 ~eceptor binding assay using rabbit aortae membrane pre~ration Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) were su6pended in 5 mM
Tris-0.25M Sucrose, p~ 7.4 buffer (50 mL) homogenized, and then centrifuged. The mi~ture was filtered through a cheesecloth and the supernatant was centrifuged for 30 minutes at 20,000 rpm at 4-C. The pellet thus obtained was resuspended in 30 mL of 50 mM Tris-5 mM
MgC12 ~uffer containing 0.2% Bovine Serum Albumin and 0.2 mg/mL ~acitracin and the suspension was used for 100 assay tubes. Samples tested for screening were done in duplicate. To the membrane preparation (0.25 mL) there was added 125I-SarlIle8-angiotensin II [obtained from New England Nuclear]
(10 mL; 20,000 cpm) with or without the test sample and the mi~ture was incubated at 37C for 90 minutes. The mixture was then diluted with ice-cold 50 mM Tris-0.9% NaCl, pH 7.4 (4 mL) and filtered through a glass 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 (ICsO) of potential AII
antagonist which gives 50% displacement of the total specifically bound 125I-SarlIle8-angiotensin II was presented as a measure of the efficacy of such compounds as AII antagonists WO91/11~ PCT/US91/00957 Receptor assay using Bovine adrenal cortex preparAtion Bovine adrenal cortex was selected as the source of AII receptor. Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended in Tris ECl (50 mM), pH 7.7 buffer and homogenized. The homogenate was centrifuged at 20,000 rpm for 15 minutes. Supernatant was discarded and pellets resuspended in buffer tNa2~P04 (10 mM)-NaCl (120 mM)-disodium EDTA (5 mM) containing phenylmethane sulfonyl fluoride (PMSF)(0.1 mM)]. (For screening of compounds, generally duplicates of tubes are used).
To the membrane preparation (O.5 mL) there was added 3H-angiotensin II (50 mM) (10 mL) with or without the test sample and the mi~ture was incubated at 37-C for l hour. The mixture was then diluted with Tris buffer (4 mL) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in scintillation cocktail (lO mL) and counted for radioactivity using Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC50) of potential AII antagonist which gives 50%
displacement of the total specifically bound 3H-angiotensin II was presented as a measure of the efficacy of such compounds as AII antagonists.
The potential antihypertensive effects 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) were anesthetized with methohexital (Brevital; 50 mg/~g i.p.) and the trachea was cannulated with PE

wo 9l/ll~g 2 ~ ~ 5 6 ~ ~ PCT/US91/00957 205 tubing. A stainles6 ~teel 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 ~arvard Rodent Ventilator (rate - 60 ~trokes per minute, ~olume -1.1 cc per 100 grams body weight). The right carotid artery was ligated, both left and right ~agal ner~es were cut, and the left carotid artery was cannulated with PE 50 tubing for drug administration, and body temperature was maintained at 37C by a thermostati-cally controlled heatin~ pad which received input from a rectal temperature probe. Atropine (1 mg/kg i.v.) was then administered, and 15 minutes later propranolol (1 mg/kg i.v.). Thirty minutes later angiotensin II or other agonists were administered intravenously at 30 minute intervals and the increase in the diastolic blood pressure was recorded before and after drug or vehicle administration.
Using the methodology described above, representative compounds of the invention were evaluated and found to exhibit an activity of at least IC50 ~ ~0 mM thereby demonstrating and confirming the utility of the compounds of the invention as effective AII antagonists.
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 hyperaldosteronism, primary and secondary pulmonary hyperaldosteronism, primary and ~econdary pulmonary hypertension, renal failure and renal WO91/11~ PCT/US91/~gs7 vascular hypertension, and in the management of vascular disorders such as migraine or Raynaud 1 8 disease. The application of the compounds of this invention for these and similar disorders will be apparent to those skilled in the art.
The compounds of this invention are also useful to treat elevated intraocular pressure and can be administered to patients in need of such treatment with typical pharmaceutical formulations ~uch as lo tablets, capsules, injectables, as well as topical ocular formulations in the form of solutions, ointments, inserts, gels and the like.
Pharmaceutical formulations prepared to treat intraocular pressure would typically contain about 0.1% to 1~% by weight, and preferably 0.5% to 2.0% by weight of a compound of this invention.
In the management of hypertension and the clinical conditions noted above, the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administra-tion, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. The compounds of this invention can be administered to 2s 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 factors which those s~illed in ~ WO 91/11~ 2 0 7 5 S ~ 7 PCT/US91/00957 the art will recognize, the do~age range will generally be about 1 to 1000 mg per patient per day which can be administered in single or multiple doses. 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 thi~ 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 this invention can be given in combination with such compounds as amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, ~uanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydro-chloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan camsylate, benzthiazide, guinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, diflunisal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine. nitrendipine, and the like, as well as admixtureS and combinations thereof.

WO91/11~9 PCT/US91/~s~7 Typically, the individual daily dosages for the~e combination~ can range from about one-fifth of the minimally recommended clinical dosages to the ma~imum recommended levels for the entities when they are given singly.
To illustrate these combinations, one of the angiotensin 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 (6~-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 thiæ invention (0.5-250 mg) or hydrochlorothiazide (15-200 mg) and nifedipine (5-60 mg) plus an angiotensin II antagonist of this invention (0.5-250 mg) are effective combinations to control blood pressure 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 disease, weight of patient, ~pecial diets and other factors.

wo 9~ 9 `2 0~ ~ G ~ PCT/US91/~957 Typically, these combinations can be formulated into pharmaceutical compositions as discussed below.
About 1 to 100 mg of compound or mixture of compounds of Formula I or a physiologically acceptable salt is compounded with a physiologically acceptable ~ehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical o practice The amount of active substance in these composltlons 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 as gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage 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 physical form of the tosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or eli~ir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

WO91/11~ PCT/US91/~9~7 ~7~i627 Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or su6pending the active substance in a vehicle such a6 water for injection, a naturally occuring vegetable oil li~e se6ame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preserYatives, antioxidants and the like can be incorporated as required.
The compounds of this invention are also useful to treat elevated intraocular pressure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, capsules, injectables, as well as topical ocular formulations in the form of solutions, ointments, inserts, gels and the like. Pharmaceutical formulations prepared to treat intraocular pressure would typically contain about 0.1% to 15% by weight, and preferably 0.5% to 2.0% by weight of a compound f 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 ~econdary hyperaldosteronism, primary and secondary pulmonary hypertension. renal failure such as diabetic nephropathy. glomerulonephritis, scleroderma, and the like, renal vascu~ar hypertension, left ventricular dysfunction, diabetic retinopathy, and in the management of ~ascular disorders 6uch as migraine or Raynaud's di8ease- The application of the WO91/11~ PCT/US91/OOs~7 .' 2~7562~

-184_ compounds of this invention for these and similar disorders will be apparent to those skilled in the art.
The useful central nervous system (CNS) activities of the compounds of this invention are demonstrated and exemplified by the ensuing assays.

COGNIllv~; F~NCTTON A~SAY

The efficacy of these compounds to enhance cognitive function can be demonstrated in a rat passive a~oidance assay in which cholinomimetics such as physostigmine and nootropic agents are ~nown to be active. In this assay, rats are trained to inhibit their natural tendency to enter dark areas. The test apparatus used consists of two chambers, one of which is brightly illuminated and the other i5 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 shoc~ to the feet. The test animals are pretreated with 0.2 mg/~g of the muscarinic antagonist scopolamine which disrupts learning or are treated with scopolamine and the compound which is to be tested for possible reversal of the scopolamine effect. Twenty-four hours later, the rats are returned to the illuminated chamber.
Upon return to the illuminated chamber, normal young rats who have been subjected to this training and who have been treated only with control vehicle take longer to re-enter the dark chamber than test animals who have been exposed to the apparatus but who ~Aave WO91/11~ PCT/USgl/~ss7 - 2~75~27 not received a shoc~. Rats treated with scopolamine before training do not ~how this hesitation when tested 24 hours later. ~fficacious test compounds can overcome the disruptive effect on learning which scopolamine produces. Typically, compounds of this invention should be efficacious in this passive avoidance assay in the dose range of from about 0.1 mg/kg to about 100 mg/kg.

~N~TOI.YTIC ASSAY

The anxiolytic activity of the invention compounds can be demonstrated in a conditioned emotional response (CER) assay. Diazepam is a clinically useful anxiolytic which is active in this assay. In the CER protocol, male Sprsgue-Dawley rats (250-350 g) are trained to press a lever on a variable interval (VI) 60 second schedule for food reinforcement in a standard operant chamber over weekly (five days per week) training sessions. All animals then receive daily 20 minute conditioning sessions, each session partitioned into alternating 5 minute light (L) and 2 minute dark (D) periods in a fixed LlDlL2D2L3 sequence. During both periods (L or D), pressing a lever delivers food pellets on a VI 60 second schedule: in the dark (D), lever presses 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 (C~R).

~------~~~~ WO91/11~9 2 07 s~7 PCT/US91/0095 Drug te~ting in this paradigm i6 carried out under e~tinction conditions. During e~tinction, animals learn that responding for food in the dar~ iæ
no longer punished by shock. Therefore, response rates gradually increase in the dar~ periods and animals treated with an anxiolytic drug ~how a more rapid increase in response rate than vehicle treated animals. Compounds of this in~ention should be efficacious in this test procedure in the range of from about 0.1 mgtkg to about 100 mgt~g.

D~P~SSION ASSAY

The antidepressant activity of the compounds f this invention can be demonstrated in a tail suspension test using mice. A clinically useful antidepressant which serves as a positive control in this assay is desipramine. The method is based on the observations that a mouse 5uspended by the tail shows alternate periods of agitation and immobility and that antidepressants modify the balance between these two forms of behavior in favor of agitation.
Periods of immobility in a 5 minute test period are recorded using a keypad linked to a microcomputer which allows the experimenter to assign 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 test procedure in the ran~e of from about 0.1 mglkg to about 100 mg/kg.

WO91/11~9 PCT/US91/~ss7 S~T~OP~RF~IA ASSAY

The antidopaminergic activity of the compounds of this invention can be demonstrated in an apomorphine-induced stereotypy model. A cli~ically useful antipsychotic drug that i8 used as a positive control in this assay is haloperidol. The assay method is based upon the observation that stimulation of the dopaminergic system in rats produces stereo-typed motor behavior. There is a strong correlationbetween the effectiveness of clas~ical neuroleptic drugs to block apomorphine-induced stereotypy and to prevent schizophrenic symptoms. Stereotyped behavior induced by apomorphine, with and without pretreatment with test compounds, is recorded using a keypad linked to a microcomputer. Compounds of the inven-tion should be efficacious in this assay in the range of from about 0.1 mg/kg to about 100 mg/kg.
In the treatment of the clinical conditions noted above, the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspen-~ions for parenteral or intramuscular administration, and the like. The compounds of thi5 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 ~everity of disease, the patient~s weight, special diets then being followed by a patient, concurrent medication. and other factors WO91/11~9 PCT/US91/~957 20~562~ ~ ~

which those skilled in the art will recognize, the dosage range will generally be about 5 to 6000 mg.
per patient per day which can be administered in single 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 acetylcholinesterase inhibitors such as heptylphysostigmine and tetrahydroacridine (THA; tacrine), muscarinic agonists such as oxotremorine, inhibitors of angiotensin-converting enzyme such as octylramipril, captopril, ceranapril, enalapril, lisinopril, fosinopril and zofenopril, centrally-acting calcium channel blockers such as nimodipine, and nootropic agents such as piracetam.
In order to achieve optimal anxiolytic activity, the compounds of this invention may be combined with other anxiolytic agents such as alprazolam, lorazepam, diazepam, and busipirone.
In order, to achieve optimal antidepressant activity, combinations of the compounds of this invention with other antidepressants are of use.
These include tricyclic antidepressants such as nortriptyline, amitryptyline and trazodone, and monoamine oxidase inhibitors such as tranylcypromine.
In order to obtain maximal antipsychotic activity, the compounds of this invention may be combined with other antipsychotic agents ~uch as promethazine, fluphenazine and haIoperidol.

WO91/11~9 PCT/US91/oogs7 : 2075627 The following examples illustrate the preparation of the compounds of ~ormula I and their incorporation into pharmaceutical compositions and as such are not to be considered as limiting the invention set forth in the claims appended hereto.

F.~A~ple 1 2-Butyl-1-[4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-10 benzimidazole Step A: Preparation of 1-(4-benzyloxyphenyl)-methyl-2-~utylbenzimidazole A suspension of 1.50 g (8.62 mmol) of 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 eg) was added to the reaction mixture. After stirring overnight, the reaction mixture was concentrated in vacuo and the residue was chromatographed on a medium pressure liquid chromatograph eluted with 30%
ethyl acetate/hexane to yield 3.08 g (96%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ O.9-1.0 (t, 3H), 1.35 (m, 2H), 1.75-1-9 (m, 2H), 2-8-2.9 (t, 2~), 5.0 (s, 2H), 6.85-6.95 (d, 2H), 6.95-7.05 (d, 2H), 7.15-7.45 (m, 8~),7.75-7.80 (d, lH).
FAB-MS: m/e 371 (M+H).

WO 91/11999 PCr/US91/OOg57 -; 207562~

Step B: Preparation of 2-butyl-1-(4-hydroxyphenyl~-~ethylbenzi~idazole A solution of the pr~duct of Step A (1.00 g, 2.70 mmol) dissolved in 20 mL of MeO~, wa~ added 0.100 g of a lOZ PdlC catalyst and the reaction mixture was ~tirred under an ~2 atmosphere (1 atm) for 6.5 hours. The reaction mixture was filtered through MgS04 and the filtrate concentrated ~n v~cuo to yield 0.628 g (83%) of the title compound.
1~ NMR (300 MHz, CD30D, ppm): ~ 0.9-1.0 (t, 3~), 1.35-1.50 (m, 2~), 1.65-1.8 (m, 2~), 2.9-3.0 (t, 2~), 5.4 (s,2H),6.7-6.8 (d, 2H), 6.9-7.0 (d, 2~), 7.25-7.35 (m, 2H), 7.4-7.5 (m, lH), 7.6-7.7 (m, lH;
FAB-MS: m/e 281 (M+H).

Step C: Preparation of 2-butyl-l-t4-(l-carbometh l-phenyl)methoxyphenyll~ethylbe~zimidazole To a solution of the product of Step B (100 mg, O.357 mmol) in DMF (1 mL) was added Na~ (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) was added and the reaction mixture was stirred for 60 hours. The reaction mixture was quenched with saturated ammonium chloride solution and the organic layer was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and then brine.
The organic layer was dried (MgS04), filtered and concentrated in ~acuo and the residue was purified on a silica gel flash chromatography column (120 x 40 mm) eluted with 50% ethyl acetatelhexane to yield 26 mg (17%) of the title compound.

- - - - - - - - - -WO91/11~ PCT/US91/00957 ` .: ~. ;
20~627 lH NMR (300 MHz, CDC13, ppm): ~ O.9-1.0 (t, 3E), 1.35-1.50 (m, 2H), 1.65-1.75 (m, 2H), 2.75-2.85 (t, 2H), 3.7 (s, 3H), 5.25 (s, 2H), 5.6 (~, lE), 6.8-6.9 (d, 28), 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-1-~4-(1-carboxy-1-~henyl)methoxyphenyll~et~ylbenzimidazole To a solution of the product of Step C (25 mg, 0.058 mmol) in 2.0 mL of MeOH was added 1 N ~OH
(0.5 mL). The reaction mixture was stirred for 1 hour and then concentrated ~n vacuo. The residue was dissolved in water, acidified to pH 4 with 1 N HCl, and the resulting precipitate was extracted into chloroform. The organic extracts were dried (MgS04), filtered and evaporated in vacuo, and then precipitated from HCl/EtOAc to yield 7.1 mg (30~/~) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ O.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 (s, lH), 6.85-7.00 (m, 4~), 7.2-7.4 (m, 6H), 7.65-7.75 (m, 2H), 7.75-7.85 (m, lH).
FAB-MS: m/e 415 (M+H).

WO91/11~ PCT/US91/009~7 ., . , ~ .
207~627 F~A~Dle ~

3-~4-(1-carboxy-l-phenyl)methoxyphenyl]methyl-7-methy~ ropyl-3~-imid~zor4~5-blpyridi~e S
Ste~ A: Preparation of 2,3-diamino-4-picoline (cf.
Lappin, G. R.; Slezak, F. B. J. Am. Chem.
Soc.. l950. 7Z. 2806-7~
To a ~lurry of 2-amino-4-methyl-3-nitropyri-dine (10.0 g, 65.3 mmol) in 350 mL of 95% EtOH was added 500 mg of a 10% Pd/C catalyst. The mixture was stirred under a H2 atmosphere (1 atm) for 36 hours.
~iltration and evaporation gave 8.05 g of a black solid which was used directly in the next step.

Step B: Preparation of 7-methyl-2-propylimidazo t4,5-b]pyridine (cf. Lappin, G. R.; Slezak, F. ~. J. Am. Chem. Soc.. ~950. 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 polyphosphoric acid (50 g) was heated to 100C
with stirring for 3 hours, and monitored by tlc of N~40H neutralized aliquots. Basification (NH40H), extraction (CH2C12, 4 ~ 50 mL), drying (K2C03), purification (by filtering through 100 g silica gel, EtOAc elution), and concentration gave 10.0 g (87%) of the title compound as an amorphous tan solid which was judged pure by lH NMR and tlc: mp 110-112C
(without recrystallization).
l~ NMR (300 M~z, CDC13, ppm): ~ 8.13 (d, lH, J=5 Hz), 7.01 (d, lH, J=5 Hz), 3.01 (t, 2H, J=7.8 Hz), 2.67 (s, 3~), 2.07-1.93 (m, 2H), 1.06 (t, 3~, J=7.5 ~z).

WO91/11~9 - pcT/ussl/~ss7 207~627 Step C: Preparation of 3-(4-benzyloxyphenyl)methyl-7-methyl-2-~ropYl-3R-imidazor4~5-blpyridine A suspension of 7-methyl-2-propylimidazo-t4,5-b~pyridine (1.00 g, 5.71 mmol) and NaH (189 mg, 1.1 eq) in DME (25 mL) was stirred for 1 hour and then cooled to 0-C. 4-Benzylo~ybenzyl chloride (1.46 g; 1.1 eg) was then added and the ice bath removed.
The reaction mixture was stirred for 2.5 hours and was then concentrated LB vacuo. The re~idue was 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.
H NMR (300 MHz, CDC13, ppm): ~ O.9-105 (m, 3H), 1.7-1.85 (m, 2H), 2.65-2.85 (m, 5H), S.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, lH).

Step D: Preparation of 3-(4-hydroæyphenyl)methyl-7-methyl-2-pro~yl-3H-imid~zor4.5-blpyridine 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 catalyst and was stirred under a H2 atmosphere (1 atm) for 7 hours. The reaction miæture was then filtered through magnesium sulfate and the filtrate was concentrated ~n ~acuo to yield 0.372 g (82%) of the title compound.
lH NMR (300 M~z, CD30D, ppm): ~ O.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, 2~), 7.0-7.1 (d, 2H), 7.2-7.5 (d, lH), 8.25-8.3 (d, lH).

WO 91/11~9 ~ Q 7 ~ 6 27 PCT/US91/00957 Step F: Preparation of 3-t4-(1-carbomethoxY-l-phenyl)-metho~yphenyl]methyl-7-methyl-2-propyl-3~ idAzor4.5-blpyridine To a 6uspension of K~ (45 mg, 1.1 eg) in DME
(0.5 mL) was added the product of Step D (100 mg, 0.365 mmol) followed by 18-crown-6 (20 mg, 0.2 eg).
After stirring the reaction mixture for 0.5 hour until the foaming subsided, a solution of methyl 2-bromophenylacetate (81 mg, 1.O eg) in DME (0.5 mL) was added and the reaction mixture was stirred 2 hours and was then concentrated in vacuo. The residue was purified on a silica gel flash chromato-graphy column (120 x 20 mm) eluted with 50% ethyl acetate/hexane to yield 67 mg (44%) of the title COmpound 1~ NMR (300 M~z, CDC13, ppm): ~ O.9-1.0 (t, 3H) 1.65-1.80 (m, 2~), 2.65 (s, 3H), 2.7-2.8 (t, 2~), 3.7 (s, 3H), 5.4 (s, 2~), 5.6 (s, lH), 6.8-6.9 (d, 2~), 6.95-7.1 (m, 3H), 7.35-7.45 (m, 3H), 7.5-7.6 (m, 2H), 8-2 (d, lH) Ste~ F: Preparation of 3-~4-(1-carbomethoxy-1-phenyl)methoxyphenyl]methyl-7-methyl-2-propyl-3~-imidazor4.5-blpyridine To a solution of the product of Step E (21 mg, 0.0490 mmol) in MeO~ (1 mL) was added lN NaO~ (1 mL). The reaction mixture was stirred for 1.5 hours, and was then concentrated in ~acuo. The residue was partitioned between brine and T~F. The organic layer was separated from the aqueous layer, dried (MgS04), filtered, and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column.

WO91/11~ ~ PCT/US91/009~7 (15 x 130 mm) eluted first with 20% methanol/ethyl acetate, and later with 50% methanoltethyl acetate.
The product fractions were concentrated Ln ~cuo, redissolved in ethyl acetate and filtered to yield 16 mg (76~Z) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ O.8-0.9 (t, 3~), 1.5-1.7 (m, 2~), 2.2-2.3 (m, 5H), 5.1 (s, 1~), 5.25 (s, 2H), 6.6-6.6 (d, 2~), 6.7-6.8 (d, 2~), 6.9-7.0 (m, 4H), 7.15-7.25 (m, 2H), 8.1 (d, 1~).
FAB-MS: m/e 438 (M+H).

F~A~le 3 3-t4-(1-Carboxy-1-(4-chlorophenyl)methoxyphenyl]-methyl-7-methyl-2-~ropyl-3~-imidazor4.5-bl~yridine Step A: Preparation of methyl 2-bromo-2-(4-chloro-phenyl)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 o~er 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, as an exotherm and violent bubbling resulted. The reaction mixture was then concentrated ~n 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 5Z Na~S03, dried (MgS04), filtered, and concentrated ~n ~acuo.
The residue was purified on a silica gel flash WO 91/11~ 2 0 7 5 6 2 7 PCT/US91/~957 chromatography column (170 x 45 mm) eluted with 15%
ethyl acetate/hexane to yield 2.89 g (37%) of the title compound.
1~ NMR (300 MHz, CDC13, ppm): ~ 3.8 (s, 3E), 5.35 (s, lH), 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 ~: Preparation of methyl 2-(4-methylphenoxy)-4-chlorophenylacetate To a O~C suspension of ~ (530 mg, 1.0 eq) in DME (10 mL) was quickly added p-cresol (500 mg, 4.63 mmol), and the reaction mixture was stirred at room temperature. After stirring 10 minutes hydrogen evolution had subsided, 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 stirred 2.5 hours and was then concentrated in v~cuo. The residue 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.
lH NMR (300 M~z, CDC13, ppm): ~ 2.3 (5, 3H), 3.75 (s, 3H), 5.6 (s, lH), 6.8-6.9 (d, 2H), 6.9-7.1 (d, 2~), 7.3-7.4 (d, 2~), 7.5-7.6 (d, 2H).
~I-MS: m/e 290, 292 (Ml, 3:1 ratio).
2s Step C: Preparation of methyl 2-(4-bromomethyl-~henoxy)-4-chlorophenylacetate A solution of the product of Step B (200 mg, 0.690 mmol), NB5 (117 mg, 0.95 eq) and AIBN (10 mg, catalytic amount) in CC14 (5 mL) was heated at reflux for 2 hours and then cooled and concentrated in vacuo.
The residue was purified on a silica gel flash WO91/11~9 PCT/US91/~957 2~75~27 chromatography column (30 x 130 mm) eluted with 5%
ethyl acetate/hexane to yield 128 mg (50%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 3.75 (s, 3H), 4.5 (s, 2~), 5.6 (s, 1~), 6.8-6.9 (d, 2H), 7.25-7.35 (d, 2~), 7.35-7.45 (d, 2H), 7.5-7.6 (d, 2~).

Ste~ D: Preparation of l-t4-(1-carbomethoxy-1-(4-chlorophenyl))methoxyphenyl]methyl-7-methyl-2-propyl-3H-imidazor4.5-blpyridine To a suspension of NaH (4.3 mg, 1.0 eq) in DMF (1 mL) was added 7-methyl-2-propylimidazot4~5-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 added. The reaction mixture was stirred for 2 hours and then concentrated L~ 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.
lH NMR (300 M~z, CDC13, ppm): ~ O.9-1.0 (t, 3H), 1.65-1.8 (m, 2H), 2.65 (s, 3~), 2.7-2.8 (t, 2H), 3.7 (s, 3H), 5.4 (s, 2H), 5.55 (s, lH), 6.8-6.9 (d, 2~), 7.0-7.1 (m, 3~), 7.3-7.4 (d, 2H), 7.4~-7.5 (d, 2H), 8.2 (d, lH).
2~ FAB-MS: m/e 464, 466 (M~l, 3:1 ratio).

Step E: Preparation of 1-[4-(1-carbo~y-1_(4_ chlorophenyl))metho~yphenyl]methyl-7-methyl-2-~ropyl-3H-imidazor4.5-blpyridine To a solution of product from Step D (16 mg, 0.035 mmol) in MeOH (1 mL) was added lN NaOH (1 mL).
The reaction mixture was stirred 10 minutes, and then WO 91/11~ 2 0 ~ ~ 6 2 7 PCT/US91/00957 "

concentrated Ln vAcl~o. Water was added to the residue and the mixture was acidified to pH 2 with 1 N ~Cl. The aqueous layer was then extracted 3 times with chloroform, the combined organic layers were dried (MgS04), filtered and concentrated ~n ~cuo to yield 12 mg (70Z) of the titled product.
H NMR (300 M~z, CDC13, ppm): ~ O.75-0.85 (t, 3H), 1.55-1.7 (m, 2H), 2.65 (s, 3H), 2.9-3.0 (t, 2~), 5.4 (s, 2H), 5.55 (s, lH), 6.85-6.95 (d, 2H), 7.05-7.1 lo (d, 2H), 7.15 (d, lH) 7.3-7.4 (d, 2H), 7.5-7.6 (d, 2H), 8.3 (d, lH).
FAB-MS: m/e 450, 452 (M+l, 3:1 ratio).

~ le 4 3-r4-(1-Carboxy-1-(2-chlorophenyl))methoxyphenyl]-methyl-7-methyl-2-~ropyl-3H-imidazor4.5-b~pyridine Step A: Preparation of methyl 2-bromo-(2'-chloro)-phenylacetate Commercially available 2-chlorophenylacetic acid (5.00 g, 29.3 mmol) was converted to 2.13 g (28%) of the title compound in a procedure ~imilar to that described in Step A of Example 3.
lH NMR (300 M~z, CDC13, ppm): ~ 3.8 (s, 3~), 5.95 (s, lH), 7.25-7.45 (m, 3H), 7.7-7.8 (m, 1~).

Step B: Preparation of methyl 2-(2-chlorophenyl)-2-(4-methylpheno~y)acetate The product of Step A (1.22 g, 4.63 mmol) was used to alkylate p-cresol (0.5 g, 4.63 mmol) using the procedure described in Step ~ of Example 3, and afforded 1.03 g (77%) of the title compound.

WO91/11~9 PCT/US91/~957 - 207~627 H NMR: (300 MHz, CDC13, ppm): ~ 2.25 (~, 3H), 3.8 (~, 3H), 6.12 (~, lE), 6.85 (d, 2H), 7.05 (d, 2H), 7.28-7.35 (m, 2H), 7.40-7.45 (m, lH), 7.63-7.70 (m, lH).
EI-MS: m/e 290, 292 (M+).

Ste~ C: Preparation of methyl 2-(4-bromomethylphen-oxy)-2-(2-chloro~he~yl)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 (73Z) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 3.8 (s, 3H), 4.5 (s, 2H), 6.15 (s, lH), 6.85-6.95 (d, 2H), 7.25-7.35 (m, 4H); 7.4-7.5 (m, lH), 7.6-7.7 (m, lR).
~I-MS: m/e 368, 370, 372 (M+l, 10:13:3 ratio).

Step D: Preparation Of 3-t4-(1-carbomethoxY-l-(2-chlorophenyl))methoxyphenyl]methyl-7-methyl-2-propyl-3~-imidazor4.5-bl~yridine 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 (E~ample 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.
H NMR (300 M~z, CDC13, ppm): ~ O.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, lH), 6.8-6.9 (d, 2H), 7.0-7.1 (m, 3H), 7.25-7.35 (m, 2H), 7.35-7.45 (m, lH), 7.55-7.65 (m, lH), 8.2 (d, lH).
~AB-MS: m/e 464, 466 (M+l, 3:1 r~tio).

WO9l/ll~9 æo~ ~ 627 PCT/US9l/~957 Step F: PreparatiOn of 3-t4-(l-carboxy-l-(2-chlor phenyl))metho~yphenyl]methyl-7-methyl-2-~ropyl-3H-imidazor4.5-bl~yridine The product of Step D (O.040 g, O.086 mmol) was dissolved in 1.0 mL of methanol and 1.0 mL of 1 N
NaOH was added. The hydrolysis was complete in 5 minutes, and the solution was then concentrated in VACUO. The residue was chromatographed on silica gel (130 ~ 20 mm) eluted with ethyl acetate/hexane/
acetic acid (19:5:1) to afford 33 mg (85Z) of the title compound.
1~ NMR (300 MHz, CD30D, ppm): ~ 0.85-0.95 (t, 3H), 1.55-1.75 (m, 2H), 2.65 (s, 3H), 2.8-2.9 (t, 2H), 5.5 (s, 2H), 6.05 (s, 1~, 6.85-6.95 (d, 2~), 7.05-7.20 (m, 3H), 7.25-7.35 (m, 2H), 7.35-7.45 (m, 1~), 7.55-7.65 (m lH). 8.2 (d, 1~).
FAB-MS: m/e 450,452 (M~l).

E~ample 5 3-[4-(1-Carboxy-1-(3-chlorophenyl))methoxyphenyl]-methyl-7-methyl-2-propyl-3~-imidazor4.5-blpyridine 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.
1~ NMR (300 MHz, CDC13, ppm): ~ 3.80 (s, 3~) 5.30 (s, lH) 7.25-7.60 (m, 4H).

WO91/11~9 PCT/US91/~957 2~7~;627 Step B: Preparation of 3-t4-(1-carbomethoxy-1-(3-chlorophenyl))methoxyphenyl~methyl-7-methyl-2-propy]-3~-imid~zor4.~-b~pyridine To a solution of 0.150 g (0.54 mmol) of the product of Step D of Example 2 dis~olved in 1.0 mL of DMF was added 61 mg of RH, and 0.141 g of 18-crown-6.
The reaction was stirred under an N2 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 was stirred an additional 30 minutes, then partitioned between water and ethyl acetate. The organic layer was washed with water, dried (MgS04), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted first with 30Z ethyl acetate/hexane then with 50% ethyl acetate/hexane to afford 0.087 g (35%) of the title compound.
H NMR (300 MHz, CDC13, ppm): ~ O.90-1.00 (t, 3H), 1.65-1.85 (m, 2H), 2.65 (s, 3H), 2.70-2.85 (t, 2H), 3.75 (s, 3H), 5.45 (s, 2H), 5.55 (s, lH), 6.80-6.90 (d, 2H), 7.00-7.10 (m, 3H), 7.25-7.35 (m, 2H), 7.30-7.35 (m, lH), 7.55 (br s, 1~), 8.15-8.25 (d, lH).

Step C: Preparation of 3-t4-(1-carboxy-1-(3-chloro-phenyl))methoxyphenyl~methyl-7-methyl-2-propyl-3~-imidazot4.5-bl~yridine To a ~olution 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 for 2 hours at room temperature. The reaction mixture was concentrated in vacuo and applied to a .:, WO 91/11999 silica gel flash chromatography column eluted with CHC13/MeO~/~OAc (100:3:1) to afford 0.049 g (58%) of the title compound.
lH NMR (300 MHz, CD30D, ppm): ~ 0.90-1.00 (t, 3H), 1.60-1.75 (m, 2~), 2.65 (s, 3~), 2.80-2.90 (t, 2~), 5.50 (s, 2~), 5.70 (s, l~), 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, lH), 7.55 (br s, 1~), 8.15-8.25 (d, lH).
~AB-MS: m/e 450,452 (M+l).

~mple 6 3-[4-(1-carboxy-1-(2,6-dichlorophenyl))methoxyphenyl3-methyl-7-methyl-2-~ro~yl-3E-imidazor4.5-blpyridine Step A: Preparation of methyl 2-bromo-2',6'-dichloro-phenylacetate Commercially available 2,6-dichlorophenyl-acetic acid (5.00 g, 24.4 mmol) was converted to 2.60 g (35%) of the title compound in a procedure similar to that described in Step A of Example 3.
H NMR (300 MHz, CDC13, ppm): ~ 3.80 (6, 3H), 6.70 (s, 1~), 7.20-7.30 (m, lH), 7.35-7.40 (d, 2H).

Step B: Preparation of 3-t4-(l-carbomethoxy-l-(2~6 dichlorophenyl))methoxyphenyl]methyl-7-methyl-2-propyl-3E-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-WO91/11~9 PCT/US91/~957 ~ ` 207~627 tion on a silica gel flash chromatography column eluted with 40% ethyl acetate/hexane afforded 0.085 g (48X) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ O.90-1.00 (t, 3H), 1.60-1.80 (m, 2E), 2.65 (s, 3~), 2.70-2.80 (t, 2~), 3.80 (s, 3~), 5.40 (s, 2~), 6.40 (s, 1~), 6.60-6.65 (d, lH), 6.85-6.90 (d, lH), 6.90-7.05 (m, 5~), 7.15-7.35 (m, 2~), 8.15-8.35 (d, lH).

Step C: Preparation Of 3-t4-(1-carboxy-1-(2,6-dichlorophenyl))methoxyphenyl]methyl-7-methyl-2-propyl-3~-imidazor4.5-b~pyridine To a solution of 0.085 g (0.17 mmol) of the product of Step ~ dissolved in 1.0 mL of methanol was added 1.0 mL of 1 N NaOH and the reaction was stirred for 3 hours at room temperature. The reaction mixture was concentrated in vacuo and applied to a silica gel flash chromatography column eluted with CHC13/MeOH/NH40H (80:15:1) to afford 0.070 g (84%) of the title compound.
H NMR (300 M~z, CD30D, ppm): ~ O.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, lH), 6.95-7.10 (m, 2H), 7.30-7.40 (d, 2H), 8.20 (d, lH).
FAB-MS: m/e 484 (M+l).

Example 7 3-t4-(1-carboxy-1-(2-nitrophenyl))methoxyphenyl3-methyl-7-methYl-2-~ropyl-3~-imidazor4.5-bl~yridine Step A: PreparatiOn of methyl 2'-nitrophenylacetate To a flask charged with 5 mL of methanol was introduced a fine stream of hydrogen chloride gas WO 91/11~ 2 0 7 5 6 2 7 PCT/US91/~957 until the solution was saturated. The hydrogen chloride was 6topped, and 0.50 g (2.7 mmol) of 2'-nitrophenylacetic acid was added and the reaction mixture was stirred for 1.5 hours. The reaction mixture was then partitioned between ethyl acetate and water, the organic layer was washed with saturated NaHC03, brine, dried (MgS04), filtered and evaporated to afford 0.529 g (98%) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ 3.75 (~, 3H), 4.05 (s, 2H), 7.25-7.30 (d, lH), 7.45-7.55 (m, lH), 7.55-7.65 (m, lH), 8.20-8.25 (d, lH).
FAB-MS: m/e 196 (M+l).
5 Step B: Preparation of methyl 2-bromo-2'-nitrophenyl-acetate To a solution of the product of Step A
dissolved 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 was then cooled and evaporated and the residual oil was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate.
Evaporation of the purified fractions afforded 0.335 2s g (50~/) of the title compound.
1~ NMR (300 MHz, CDC13, ppm): ~ 3.80 (s, 3H), 6.10 (s, lH), 7.50-7.60 (m, lH), 7.70-7.80 (m, lH), 8.00-8.10 (m, 2H).

WO91/11~ PCT/US91/00957 207~627 Step C: Preparation Of 3-t4-(1-carbomethoxy-1-(2-nitrophenyl))methoxyphenyl]methyl-7-methyl-2-propylimidazo r 4.5-blpyridine A solution of 0.364 g (1.30 mmol) of 3-(4-hydroxyphenyl)methyl-7-methyl-2-propyl-3~-imidazo ~4,5-b]pyridine (Step D, Example 2) dissolved i~ 5 mL
of DMF was deprotonated (O.163 g ~H, 0.376 g 18-crown-6) and alkylated with 0.355 g (1.30 mmol) of the product of the previous step similarly 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 (48Z) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ O.95-1.05 (t, 3H), 1.70-1.80 (m, 3H), 2.65 (s, 3H), 2.70-2.80 (t, 2~), 3.75 (s, 3H), 5.40 (s, 2H), 6.65 (s, 1~), 6.85-6.95 (d, 2H), 7.00-7.10 (m,3H), 7.50-7.55 (t, 1~), 7.60-7.65 (t, lH), 7.80-7.85 (d, lH), 8.05-8.10 (d, lH), 8.20-8.25 (d, lH).

Step D: Preparation of 3-[4-(1-carboxy-1-(2-nitro-phenyl))methoxyphenyl]methyl-7-methyl-2-propyl-3H-imidazor4.5-blpyridine Hydrolysis of 0.030 g (0.063 mmol) of the ester prepared in the previous ~tep was performed in a manner similar to that described in Example 2, Step F. Purification on a silica gel flash chromatography column eluted with CHC13/MeOH/~OAc (100:3:1) afforded 0.023 g (74%) of the title compound.
lH NMR (300 M~z, CD30D, ppm): ~ O.90-1.00 (t, 3H), 1.60-1.75 (m, 2H), 2.65 (s, 3H), 2.80-2.90 (t, 2H), WO91/11~9 ~7S~ pCT/US9l/009~7 ~.50 (~, 2H), 6.45-6.60 (~r s, lH), 6.90-7.00 (d, 2H), 7.05-7.15 (d, 2H), 7.15-7.20 (d, 2H), 7.50-7.60 (t, lH), 7.60-7.70 (t, lH), 7.75-7.80 (t, lH), 8.00-8.05 (d, lH), 8.20-8.25 (d, lH).
FAB-MS: m/e 461 (M+l).

F.~n~le 8 3-[4-(1-Carboxy-l-cyclohexyl)methoxyphenyl~methyl-7-~ethyl-2-propyl-3~-imidAzor4.5-blpyridine Step A: Preparation of 3-[4-(1-carbomethoxy-1-cyclo-hexyl)methoxyphenyl]methyl-7-methyl-2-propyl-3~-imidazor4.5-blpyridine A solution of 0.200 g (0.71 mmol) of 3-(4-hydroxyphenyl)methyl-7-methyl-2-propyl-3H-imidazo t4,5-b3pyridine (Step D, Example 2) dissolved in 0.5 mL of DMF was deprotonated (82 mg ~H, 0.188 ~
18-crown-6) and al~ylated with 0.184 g (0.78 mmol) of 2~ commercially available methyl 2-bromo-2-cyclohexyl-acetate similarly 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 2s Cmpound.
lH NMR (300 M~z, CDC13, ppm): ~ 0.97 (t, J=8 Hz, 3H), 1.10-1.90 (m, 13H), 2.66 (s, 3H), 2.78 (t, J=8 ~z, 2~), 3.70 (F, 3H), 4.31 (d, J=6 ~z, lH), 5.40 (s, 2H), 6.77 (d, J=10 Hz, 2H), 7.02-7.10 (m, 3H), 8.10 (d, J=6 ~z, 1~).

WO91/11~ PCT/US91/~s~7 207~i~2~

Step B: Preparation of 3-t4-(l-carbo2y-l-cyclohexyl) methoxyphenyl~methyl-7-methyl-2-propyl-3~-imidazor4.5-blpyridine ~ydrolysis of 0.029 g (0.066 mmol) of the ester prepared in Step A was performed in a manner similar to that described in Example 2, Step F.
Purification on a silica gel flash chromatography column eluted with CHC13/MeOH/~OAc (100:3:1) afforded 0.017 g (61%) of the title compound.
1~ NMR (300 M~z, CD30D, ppm): ~ 0.95 (t, J=8 ~z, 3H), 1.10-1.90 (m, 13~), 2.65 (s, 3~), 2.85 (t, J=8 Hz, 2H), 4.38 (d, J=6 ~z, 1~), 5.48 (s, 2H), 6.84 (d, J=10 Hz, 2H), 7.06 (d, J=10 Hz, 2H), 7.15 (d, J-6 Hz, lH), 8.20 (d, J=6 Hz, lH).
FAB-MS: m/e 422 (M+l).

F~ple 9 3-t4-(l-carboxy-l-propyl)methoxyphenyl]methyl-7 methyl-2-~ropyl-3~-imidazor4.5-blpyridine Step A: Preparation of 3-t4-(1-carbomethoxy-1-propy})methoxyphenyl]methyl-7-methyl-2-p~opyl-3~-imidazor4.5-blpyridine To a suspension of ~ (22 mg, 1.1 eq) in 0.25 mL of DMF under N2 was added 0.050 g (0.18 mmol) of the product of Step D in Example 2, and the reaction mixture was stirred for 15 minutes. When the K~ had dissolved, 18-crown-6 (10 mg, 0.2 eq) was added, followed by ethyl 2-~romopentanoate (30 uL, l.0 eq). After 5 minutes, tlc showed that the ~romide had disappeared~ ~ut that some of the starting `- WO 91/11999 PCT/US91/~957 207~i 62~ ~

phenolic intermediate remained. The reaction mixture was quenched with saturated ~mmonium chlor~de and concentrated in vacuo. The residue was chromato-graphed on silica gel (120 x 20 mm) eluted with 30%
ethyl acetate/hexane. The product was isolated in a 19Z yield (14 mg).
1~ NMR (300 MHz, CDC13 ppm): ~ O.9-1.0 (m, 6~), 1.15-1.25 (t, 3H), 1.4-1.6 (m, 2H), 1.7-2.0 (m, 4H), 2.65 (s, 3H), 2.7-2.8 (t, 2H), 4.1-4.2 (m, 2H), 4.5-4.6 (m, lH), 5.4 (s, 2~), 6.7-6.8 (d, 2H), 7.0-7.1 (m, 3H), 8.2 (d, lH).
FAB-MS: m/e 410 (M+l).

Ste~ B: Preparation of 3-~4-(1-carboxy-1-propyl)-methoxyphenyl~methyl-7-methyl-2-propyl-3~-i~idazor4.5-blpyridine To a solution of 21 mg (0.049 mmol) of the product of Step ~ dissolved in 1 mL of ethanol was added 0.25 m~ of 1 N NaOH. The reaction mixture was stirred overnight, after which time tlc indicated the consumption of the starting material. The reaction mixture was neutralized with 1 N HCl and concentrated La 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 times to remove residual acetic acid.
Drying in ~acuo afforded 13 mg (93Z) of the title CmpOund~

WO91/11~ PCT/US91/~9S7 H NMR (300 MHz, CD30D, ppm): ~ 0.9-1.0 (m, 6H), 1.4-1.6 (m, 2H), 1.6-1.8 (m, 2~), 1.8-1.9 (m, 2H), 2.65 (s, 3H), 2.8-2.9 (t, 2H), 4.5-4.6 (t, lH), 5.5 (s, 2H), 6.8-6.9 (d, 2H), 7.0-7.1 (d, 2H), 7.15 (d, lH), 8-2 (d, lH).
FAB-MS: m/e 382 (M+l).

~ 1e 10 1o 3-[4-(1-Carboxy)-1-(2-carboxyphenyl)methoxyphenyl]-methyl-7-methyl-2-propyl-3H-imidazor4~5-blpyridine Step A: Pre~aration of dimethyl homo~hthal~te To homophthalic acid (500 mg, 2.78 mmol) cooled to O-C was added a saturated solution of HC1/CH30H (20 mL). The solution was gradually warmed to room temperature and stirred ~or 3 days. The reaction was concentrated in vacuo, the residue was partitioned between ethyl acetate and water, and the organic layer washed with saturated NaHC03 and brine. The organic layer was concentrated n vacuo, then redissol~ed in ethyl acetate, dried (MgS04), filtered and evaporated to afford 0.470 g (81%) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ 3.7 (s, 3H), 3.9 (s, 3H), 4.0 (s, 2H), 7.2-7.2 (m, lH), 7.25-7.35 (m, lH), 7 45-7.55 (m, lH), 8.0-8.1 (m, lH).
EI-MS: m/e 208 (M+).

Step B: Preparation of methyl 2-bromo-(2'-carbo-metho~y)phenyl~cetate To a solution of the product of Step A (464mg, 223 mmol) in 10 mL CC14 were added NBS (377 mg, W091/ll ffl PCT/US91/~gs7 0.95 eq) and a catalytic amount of AIBN. The reaction mixture was refluxed overnight, and then concentrated in vac~o. The residue was chromatogra-phed on silica gel (140 x 40 mm) eluted with 8% ethyl acetate/hexane. The product was isolated in a 65%
yield (398 mg).
1~ NMR (300 MHz, CDC13, ppm): ~ 3.8 (s, 3~), 3.9 (s, 3~), 6.6 (s, 1~), 7.35-7.45 (t, lH), 7.55-7.65 (t, 1~), 7.8-7.9 (d, lH), 7.95-8.0 (d, 1~).

Step C: Preparation of 3-t4-(1-carbomethoxy-1-(2-carbomethoxyphenyl))methoxyphenyl]methyl-7-~ethyl-2-propyl-3~-imidazor4.5-bl~yridine To a suspension of KH (22 mg, 1.1 eq) in 250 uL DMF under N2 was added 50 mg (0.178 mmol) of 3-(4-hydroxyphenyl)methyl-7-methyl-2-propyl-3~-imidazot4,5-b]pyridine (Example 2, Step D), and the reaction mixture was stirred for 1 hour. To this solution were added 18-crown-6 (47 mg, 1.1 eq) and 20 - the product of Step ~ (56 mg, 1.1 eq). The reaction mixture was stirred at room temperature overnight.
The reaction mixture was then guenched with saturated ammonium chloride and concentrated ~n vacuo. The residue was partitioned between ethyl acetate and water, the organic layer extracted with saturated NaHC03 and concentrated in ~acuo. The product was purified on a silica gel flash chromatography column (130 x 20 mm) eluted with 40Z ethyl acetate/hexane to afford 33 mg (38%) of the title compound.

WO91/11~ PCT/USgl/~ss7 - ~''"' 207~627 lH NMR (300 M~z, CDC13, ppm): ~ O.9-1.0 (t, 3~), 1.65-1.8 (m, 2H), 2.65 (s, 3H), 2.7-2.8 (t, 2H), 3.7 (s, 3H), 3.9 (s, 3~), 5.2 (s, 2H), 6.8-6.95 (m, 3H), 7.0-7.1 (m, 3H), 7.35-7.45 (m, lH), 7.45-7.55 (m, lH), 7.7 (m, lH), 7.9-8.0 (m, lH), 8.2 (d, lH).
~AB-MS: m/e 488 (M+l).

Step D: Preparation of 3-t4-(1-carboxY)-1-(2-carbo~yphenyl)methoxyphenyl]methyl-7-methyl-2-~ropyl-3~-imidazor4.5-b~pyridine To a methanol solution (1.5 mL) of the product of Step C (33 mg, 0.068 mmol) wa~ added 1.5 mL of 1 N NaOH. The reaction mixture was ~tirred at room temperature for 4.5 hours, and was then neutralized with 1 N ~Cl and concentrated in vacuo.
The residue was chromatographed on silica gel (120 x 20 mm) eluted with CHC13/MeOH/HOAc (100:10:2) to afford 32 mg (94%) of the title compound.
lH NMR (300 MHz, CD30D, ppm): ~ O.85-0.95 (t, 3H), 1.5-1.7 (m, 2H), 2.6 (s, 3H), 2.7-2.8 (t, 2~), 5.35 (s, 2H), 6.3 (s, lH), 6.8-7.0 (m, 4~), 7.05-7.30 (m, 3H), 7.55-7.7 (m, 2H), 8.15 (d, 2H).

~rA~ le 11 (z)-3-t(4-((2-Carboxy-2-phenyl)ethenyl)phenyl)-methyll-7-methyl-2-pro~Yl-3H-imidazor4~5-bl~yridine Step A: Preparation of methyl 3-hydroxy-3-(4-meth phenyl)-2-phenylpropionate To a solution of methyl 2-bromophenylacetate (4?3 mg; 2.065 mmol) and 4-methylbenzaldehyde (188 WO91/11~9 PCT/USgl/~ss7 20~5~27 ~

mg, 1.57 mmol) in dry THF (5 mL) under N2 was added powdered zinc (201 mg, 3.09 mmol). After ~tirring at reflux for 10 min, a few crystals of iodine were added. The mixture was refluxed under N2 for 4 hours, then allowed to stand at room temperature overnight. The next day the mixture was diluted in Et20 and 1 N HCl was added. The biphasic mixture was stirred until the zinc had completely dissolved in the aqueous layer. The organic layer was separated, lo washed with brine, dried (MgS04), filtered, and concentrated in VACUO. The residue which contained two diastereomers (Rf=0.22, 0.17 in 15%
EtOAc/hexane), was purified on a ~ilica gel flash chromatography column eluted with 15X ethyl acetate/hexane. A total of 283 mg (67%) of both diastereomers was isolated. The 300 MHz lH NMR
spectra of each diastereomer was consistent with its structure.

Step B: Preparation of methyl (Z)-3-(4-methylphenyl)-- 2-ghenyl~ropenoate To a solution of a mixture of the diastereo-isomers from Step A (34 mg, 0.126 mmol) in dry benzene (3 mL) was added a few crystals of p-TsO~ and the mixture was heated to reflux. After several minutes tlc analysis indicated complete reaction. The mi~ture was diluted with Et20, washed with saturated NaHC03, brine, dried (MgS04), filtered and concentrated in vacuo to provide 31 mg (98/c) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ Z.27 (s, 3H), 3.79 (s, 3H), 6.92 (g, 4~), 7.25 (m, 2H), 7.40 (m, 3H), 7.82 (s, 1~).

WO91/11~9 PCT/US91/~957 Ste~ C: Preparation of methyl (Z)-3-(4-bromomethyl-phenyl)-2-~heny~propeno~te To a solution of the product of Step B (31 mg, 0.123 mmol) in dry CC14 (1 mL~ under N2 were added NBS (20 mg, 0.9 eq) and a catalytic amount of AIBN. The mixture was stirred at reflux under N2 for 1.5 hours. The mixture was cooled to room tempera-ture, diluted with Et2O and filtered to remove the precipitated succinimide. The filtrate was concen-trated in vacuo and the residue was purified on asilica gel flash chromatography column eluted with 15:1 hexane/EtOAc to afford 27.4 mg (67%) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ 3.80 (s, 3H), 4.49 (s, 2H), 7.02 (d, 2H), 7.18 (d, 2~), 7.24 (d, 1~), 7.39 (m, 4~), 7.82 (s, 1~).

Step D: Preparation of (Z)-3-~(4-(2-carbomethoxy-2-phenylethen-l-yl)phenyl)methyl]-7-methyl-2-propyl-3~-imidazor4.5-blpyridine To a solution of 30 mg (0.171 mmol) of 2-propyl-7-methylimidazO[4,5-b]pyridine (Example 2, Step D) dissolved in 1 mL of dry DME was added 11 mg of a 60% oil dispersion of Na~ (1.5 eq) and the reaction mixture was stirred under an N2 atmosphere.
After stirring at room temperature for 30 minutes the product from Step C (27.4 mg, 0.082 mmol) dissolved in 0.5 mL DMF was added ~ia syringe. The reaction mixture was quenched with saturated N~4Cl solution, and the solvent was removed under in vacuo. The residue was dissolved in EtOAc and washed with E2O
and brine. The organic layer was dried (MgSO4), WO 91/11999 Pcr/us9l/oo9s7 - 2~7~627 filtered, and concentrated ~n ~cuo. The residue was purified on a silica gel flash chromatography column eluted with 50% ethyl acetate/hexane to provide 13.2 mg (38%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ O.9S (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, lH), 7.19 (dd, lH), 7.32 (m, 3H), 7.79 (s, lH), 8.16 (d, lH).

Step ~: Preparation of (Z)-3-t(4-((2-carboxy-2-phenyl)ethen-l-yl)phenyl)methyl]-7-methyl-2-propyl-3H-imidazor4.5-blpyridine To a solution of the product of Step D (13.2 mg, 0.031 mmol) in MeOH (1 mL) was added 1 N NaOH
1~ (0.138 mL, 4.5 eq). After stirring overnight the mixture was quenched with 0.5 mL of acetic acid and concentrated in ~acuo. The product was purified on a silica gel flash chromatography column eluted with he~ane/EtOAc/HOAc (75:50:1) to afford 10.8 m~ (85-/.) of the title compound.
H NMR (300 M~z, CD30D, ppm): ~ O.91 (t, 3H), 1.63 (q, 2H), 2.62 (s, 3H), 2.79 (t, 2H), 5.47 (s, 2H), 6.87 (d, 2H), 6.96 (d, 2H), 7.12 (m, 3H), 7.31 (m, 3H), 7.79 (s, lH), 8.12 (d, lH).

F.~ple 12 3-[(4-((2-Carboxy-2-phenyl)ethyl)phenyl)methyl]-7-methyl-2-propyl-3H-imidazor4.~-blpyridine WO91/ll ffl PCT/US91/00957 2075(i27 Ste~ A: Preparation of 3-[(4-((2-carbo~y-2-phenyl)-ethylphenyl)methyl]-7-methyl-2-propyl-3~-imidazor4.5-blpyridine To a ~olution of 2.2 mg (0.0054 ~ol) of the product of Step E of Example ll 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 stirred for 1 hour. The catalyst was removed by filtering the mixture through a pad of celite, and the filtrate was concentrated Ln ~acuo to provide 1.3 mg (59%) of the title compound.
H NMR (300 MHz, CDC13, ppm): ~ O.87 (t, 3H), 1.63 (q, 2~), 2.62 (s, 3~), 2.67 (t, 2H), 5.30 (5, 2H), 6.80 (s, 4~), 6.92 (d, lH), 7.01 (m, SH), 8.12 (d, lH).

F~ple 13 3-[4-(1-carboxy-1-methyl-1-phenyl)methoxyphenyl3-methyl-7-methyl-2-~ro~yl-3~-imidazor4~5-bl~yridine Step A: Preparation of methyl 2-(4-methylphenoxy)-~henylacetate To a cooled (0C) suspension of ~ (2.12 g, 1.0 eq) in DMF (30 mL) was added a solution of p-cresol (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 dissolved in 10 mL of DME. The reaction mixture was stirred 45 minutes, then partitioned between ethyl acetate and water. The organic layer was washed with WO91/11~ PCT/US91/009~7 207562~

water, brine, dried (MgS04~, filtered and evaporated ~n vacuo. The re~idue was purified on a silica gel flash chromatography column (150 x 40 mm) eluted with 5% ethyl acetate/hexane to yield 2.63 g (58%) of the title compound.
lH NMR (300 M~z. CDC13): ~ 2.3 (s, 3H), 3.75 (s, 3H), 5.6 (s, lH), 6.8-6.9 (d, 2H~, 7.0-7.1 (d, 2E), 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 solution of the product of Step A (50 mg, O.195 mmol) in 500 uL of T~F was cooled to -78OC. A
solution of lithium bis(trimethylsilyl)amide (195 uL, 1.O M in THF) was added and the reaction was stirred for 15 minutes. Methyl iodide (12 uL, 1.0 eg) was added and the cooling bath remo~ed. After 8 minutes, the reaction mixture was quenched with saturated N~4Cl 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.
2~ lH NMR ~300 MHz, CDC13, ppm): ~ 1.9 (s, 3H), 2.3 (s, 3H), 3.75 (s, 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).
~AB-MS: m/e 271 (M+l).
0 Step C: Preparation of methyl 2-(4-bromomethyl-phenoxy~-2-phenylpropanoate A solution of the product of Step B (26 mg.
~ 0.096 mmol) NBS (16 mg, 0-95 eq) and AIBN (2 mg, WO91/11~ PCT/US91/~9~7 207~1~2~

catalytic amount) in CC14 (2 mL) was heated to reflux for 1 hour and then concentrated Ln v~cllo. The residue was purified on a silica gel fla~h chromato-graphy column (125 x 20 mm) eluted with 5% ethyl acetate/hexane to yield 21 mg (62%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 1.9 (s, 3~), 3.75 (s, 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).

Step D: Preparation of 1-[4-(1-carbomethoxy-1-methyl-l-phenyl)methoxyphenyl]methyl-7-methyl-2-~ro~yl-3~-imidazor4.5-bl~yridine To a suspension of NaH (2.0 mg, 1 eq) in DM~
(0.25 mL) was added lO mg (l.0 eq) of 7-methyl-2-propylimidazot4,5-b]pyridine (Example 2, Step B), and the reaction mixture was stirred 15 minutes. Next, a solution of the product of Step C (20 mg, 0.057 mmol) in DMF (0.5 mL) was added. After stirring 1.5 hours, the reaction mixture was concentrated ~n ~acuo. The residue was purified on a silica gel flash chromato-graphy column (140 x 15 mm) eluted with 50% ethyl acetate/hexane to yield 12 mg (48/o) of the titled product.
lH NMR (300 M~z, CDC13, ppm): ~ O.9-1.0 (t, 3H), 1.65-1.8 (m, 2H), 1.85 (s, 3H), 2.7 (s, 3H), 2.75-2.85 (t, 2H), 3.7 (s, 3H), 7.55-7.65 (m, 2H),8.2 (d lH).
EAB-MS: m/e 444 (M+l).

WO 91/11~ 2 0 ~ 5 6 2 7 PCT/US91/~957 Step F: Preparation Of 3-t4-(1-carbo~Y-l-methyl-l-phenyl)methoxyphenyl]methyl-7-methyl-2-propyl-3~-imidazor4.5-blpyridine To a solution of the product of Step D (12 mg, O.027 mmol) in MeOH (2 mL) was added 2 mL of a 1 N NaOH solution. The reaction mi~ture was stirred for 45 minutes, and was then concentrated Ln ~Acuo.
The residue was taken up in water and acidified to pH
2 with 1 N HCl. Next, the agueous layer was diluted with water and extracted 3 times with chloroform.
The combined organic layers were dried (MgS04), filtered, and concentrated ~n vacuo to yield 8.3 mg (70%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 0.9-1.0 (t, 3H), 1.7-1.85 (m, 2H), 1.8 (s, 3H), 2.8 (s, 3~), 3.1-3.2 (t, 2H), 5.5 (s, 2~), 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, 1~).
FAB-MS: m/e 450, 452 (M+l, 3:1 ratio).

~A~yle 14 7-Methyl-2-propyl-3-[4-(1-(tetrazol-5-yl)-1-phenyl)-methoxy~henyllmethyl-3H-imidazor4.5-blpyridine ~ Step A: Preparation of 3-[4-(1-carboxamido-1-phenyl)-methoxyphenyl3methyl-7-methyl-2-propyl-3H-imidazor4.5-blpvridine A solution of the product of Example 2, Step E (125 mg, 0.291 mmol) in MeOH (10 mL) was cooled to 0C and ammonia was bubbled through the mixture for 1.5 hours. The flask was stoppered and stirred for 6 hours, during which time the product precipitated.

WO91/11~ PCT/US91/~gs7 207562~

The reaction mixture was concentrated Ln ~acuo to yield 105 mg (88Z) of product (Rf=0.50 5% methanol/
ethyl acetate) which was used in the next step without further purification.
lH NMR (300 MHz, CDC13, ppm): ~ O.9-1.0 (t, 3~), 1.7-1.8 (m, 2H), 2.65 (5, 3H), 2.7-2.8 (t, 2~), 5.4 (s, 2H), 5.45 (s, lH), 5.5-5.6 (s, lH), 6.55-6.65 (s, lH), 6.8-6.9 (d, 2H~, 7.0-7.1 (m, 3H), 7.3-7.4 (m, 3~), 7.45-7.55 (m, 2H), 8.2 (d, lH).

Step B: Preparation of 3-[4-(1-cyano-1-phenyl)-methoxyphenyl]methyl-7-methyl-2-propyl-3H-imidazor4.5-blpyridine To a 0C suspension of the product of Step A
(83 mg, 0.20 mmol) in phosphorous oxychloride (0.51 mL, 27 eq) was added Et3N (61 uL, 2.2 eg) 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.
Next, the reaction mixture was concentrated in vacuo, and the residue was partltioned 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 was separated and concentrated in ~acuo to yield 59 mg (74%) of crude product (Rf=0.35 in 50Z ethyl acetate/hexane), which was used in the next step without purification.

PCT/US91/~957 2075~7 `-`

Step C: Preparation of 7-methyl-2-propyl-3-~4_(1_ (tetrazol-5-yl)methoxyphenyl]methyl-3~-imidazo-r4.5-b~pyridine To a solution of the product of Step B (29 mg, 0.073 mmol) di~sloved in 0.5 mL of toluene was added 15 mg (1.2 eq) of Me3SnN3 and the reaction mixture was refluxed for 22 hours. An additional 15 mg (1.2 eq) of ~e3SnN3 was then added, and the refluxing continued for another hour. The reaction mixture was then poured into ethyl acetate/ether and washed with saturated N~4Cl and brine. The organic layer was separated and concentrated Ln ~cuo. The residue 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.
lH NMR (300 MHz, CD30D, ppm~: ~ 0.9-1.0 (t, 3~), 1.6-1.7 ~m, 2H), 2.65 (s, 3H), 2.8-2.9 (t, 2H), 5.5 (s, 2H), 6.8 (s, 1~), 6.95-7.1 (m, 5H), 7.1-7.2 (d, lH), 7.3-7.4 (m, 2~), 7.45-7.55 (m, 2H), 8.2 (d, lH).
~AB-MS: m/e 440 (M+l).

F~Ample 15 7-Methyl-2-propyl-3-t4-(1-(tetrazol-5-yl)-1-(2-chloro-phenyl~metho~yphenyllmethyl-3H-imidazor4 5-blpyridine Step A: Preparation of 2-(4-methylpheno~y)-2-(2-chlorophenyl)acetamide To a solution of 0.700 g (2.41 mmol) of methyl 2-(2-chlorophenyl)-2-(4-methylpheno~y)acetate (Example 4, Step ~) in 10 mL of methanol, ~tirred at WO91/11~ PCT/US91/~957 20~5627 0C (ice-bath) was added anhydrous NH3 for 45 minutes.
The reaction mixture wa~ warmed to room temperature and stirred o~ernight. The reaction mixture was then concentrated Ln v~c--o and afforded O.658 g (99%) of title compound.
lH NMR (300 M~z, CD30D, ppm): ~ 2.25 (s, 3H), 6.0 (s, lH), 6.8-6.9(d, 2H), 7.0-7.1 (d, 2H), 7.25-7.35 (m, 2H), 7.4-7.5 (m, lH), 7.55-7.6 (m, lH) FAB-MS: m/e 276, 278 (M+l, 3:1 ratio).

Step ~: Preparation of 2-(4-methylphenoxy)-2-(2~-chlorophenyl)aceto~itrile The product of Step A (0.650 g, 2.36 mmol) was added to phosphorous oxychloride (5.95 mL, 27 eq) at 0C followed ~y slow 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 H20. The crude product was concentrated ~a vacuo and purified on a silica gel flash chromato-graphy column (140 x 30 mm) eluted with 2% ethylacetate/hexane to afford 0.555 g (9lZ) of the title compound.
H NMR (300 M~z, CD30D, ppm): ~ 2.35 (s, 3H), 6.15 (s, lH), 6.95-7.05 (d, 2H), 7.1-7.2 (d, 2H), 7.4-7.6 (m, 3H), 7.8-7.9 (m, lH).
~I-MS: m/e 257,259 (M+, 3:1 ratio).

WO 91/11~ ~ 07 ~ 6~ PCT/US91/00957 Step C: Preparation of 2-(4-bromomethylphenoxy)-2_ (2-chlorophe~yl)~cetonitrile To a CC14 solution (5 mL) of the product (0.200 g) of Step B was added NBS (0.132 g, 0.95 eq) and a catalytic amount of AIBN. The reaction mi~ture was refluxed overnight. TLC indicated clean conver-sion to product, and the reaction mixture was cooled to room temperature and concentrated ~n VACUO. The crude product was purified on a ~ilica gel flash chromatography column (120 x 30 mm) eluted with 5%
ethyl acetate in hexane to afford 0.178 g (72%) of the title compound.
lH NMR (300 M~z, CDCl3 ppm): ~ 4.5 (s, 2H), 6.2 (s, 1~), 7.0S-7.15 (d, 2H), 7.35-7.55 (m, 5H), 7.8-7.9 (m, lH).

Step D: Preparation of 3-[4-(l-cyano-1-(2-chloro-phenyl)methoxyphenyl~methyl-7-methyl-2-~ropyl-3~-imidazor4.5-blpyridine To a DMF suspension (0.5 mL) of NaH (7.5 mg, 0.252 mmol) under N2 was 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 ~tirred at room temperature for 1.5 hours. To the resulting sodium salt was added the product of Step C (84 mg, 1.1 eq) and the reaction mixture was stirred for 5 hours.
The reaction mixture was then guenched with saturated NH4Cl and concentrated in vacuo The crude product was purified on a silica gel flash chromatography column (130 x 20 mm) eluted with 30% ethyl acetate/hexane to afford 24 mg (24%) of the title compound.

WO91/11~ PCT/US91/~957 2 0 1~ 6 2 7 H NMR (300 MHz, CDC13, ppm): d 0.9-1.0 (t, 3H), 1.7-1.85 (m, 2H), 2.7 (s, 3H), 2.75-2.85 (t, 2H), 5.45 (8, 2H), 6.15 (6, lH), 6.95-7.05 (m, 3H), 7.1-7.2 (d, 2H), 7.35-7.5 (m, 3H), 7.75-7.85 (m, lH), 8-2 (d, lH).
FAB-MS: m/e 431 (M+l).

Step E: Preparation of 7-methyl-2-propyl-3-t4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl)methoxy-phenyllmethyl-3~-imidazor4.5-blpyridine To a toluene solution (1 mL) of the product of Step D (24 mg, 0.056 mmol) was added trimethyl-stannyl azide (14 mg, 1.2 eq) and the mixture was refluxed for 48 hours. The reaction mi~ture was then concentrated in vacuo and purified on a silica gel flash chromatography column (130 x 15 mm) eluted with CHC13/MeOH/HOAc (100:3:1) to afford 13 mg (50%) of the title compound.
lH NMR (300 MHz, CD30D, ppm): ~ 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, 2~), 6.9-7.0 (d, 2H), 7.05-7.2 (m, 4H), 7.3-7.5 (m, 3H), 7.55-7.65 (m, lH), 8.2 (d, lH).
~AB-MS: m/e 474, 476 (M~l).

2~ le 16 7-Methyl-2-propyl-3-t4-(2-phenyl-2-(tetrazol-5-yl)-ethyl~phenyllmethyl-3H-imidazor4.5-blpyridine WO91/11~9 PCT/US91/~ss7 2~)75627 - -Step A: Prepar~tio~ of 4-(bromo~ethyl)benzyl Alcoh A suspension of 4-bromomethylbenzoic acid (5.04 g, 23.3 mmol) in TEF (30 mL) was cooled to 0-C
and treated with borane/TEF (35 mmol). The ice bath was removed and the mixture was allowed to warm to room temperature and stirred for 1.5 hours. The excess borane was quenched first with MeOH, then with water. The reaction mixture was then concentrated in vacuo and redis~olved in ethyl acetate. The ethyl acetate layer was washed with 5% HCl, water, NaHCO3, brine, dried (MgSO4), filtered, and evaporated in vacuo to afford 4.44 g (94~Z) of the titled product.
H NMR: (300 MHz, CDC13,ppm): d 7.38 (q, 4H), 4.70 (s, 2H), 4.51 (s, 2H).
FAB MS: m/e 202 (M+l).

Step B: Preparation of 4-(bromomethyl)-1-(tert-butyl-dimethylsilylo~ymet~yl)benzene To a solution of the product of Step A (4.44 g. 22.1 mmol) in CH2C12 were added N,N-diisopropyl-ethylamine (1.2 eq.), 4-dimethylaminopyridine (0.1 eq), and tert-butyldimethylsilyl chloride (1.2 eq).
The reaction mixture was stirred for 1.5 hours at room temperature, then concentrated Ln v~cuo. The 2~ residue was dissolved in ethyl acetate and washed with water, brine, dried (MgSO4), filtered, and concentrated La vacuo. The residue was chromatogra-phed on silica gel eluted with 2.5Cb ethyl acetate/
hexane to afford 5.0 g (71 %) of the titled product.
lH NMR (300 MHz, CDC13, ppm): ~ 7.34 (q, 4H), 4.74 (s, 2H), 4.59 (s, 2H), 0.95 (s, 9H), 0.11 (s, 6H).

-WO91/11~ PCT/US91/~9~7 2075~27 Ste~ C: Preparation of 3-~4-(tert-butyldimethyl-silyloxymethy~henyll-2-~henyl~ropanonitrile A solution of phenylacetonitrile (1.5 mL, 12.7 mmol) in T~F (40 mL) containing EMPA (11 mL, 63.4 mmol) was cooled to -78-C and treated with 16 mL
(16 mmol) of a 1.0 M TEF solution of lithium bis(trimeth-ylsilyl)amide dropwise while the temperature was maintained at -78C. The reaction was stirred at -780C for 1.5 hours, and a solution of the product of Step B (2.00 g, 6.34 mmol) in THF (8 mL) was added dropwise with the temperature maintained below -70cC.
The reaction temperature uas maintained below -68C
for 3 hours. The reaction was quenched ~t this temperature by addition of 1 N NaHS04. After warming to room temperature, the mixture was partitioned between EtOAc and water, and the combined organic layers were washed with water, ~aturated NaRC03, brine, dried (MgS04), filtered, then concentrated in vacuo. The residue was chromatographed on a silica gel flash chromatography column eluted with 5%
ethyl acetate/he~ane to afford 1.5 g (67%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 7.40-7.30 (m, 3H), 7.30-7.22 (m, 4H), 7.10 (d, 2~), 4.73 (s, 2~), 3.98 (t, lH), 3,23-3.08 (m, 2H), 0.94 (s, 9H), 0.10 (s, 6~).
~AB MS: m/e 294 (M+ less tert-Bu).

WO91/11~ PCT/US91/~957 207~627 Step D: Preparation of 3-t4-(bromomethYl)phenyl]-?-phenylpro~no~itrile To a cooled ~0C) colution of 1.5 g ( 4.27 mmol) of the product of Step C dissolved in 20 mL of acetonitrile, was added 2.12 g (6.4 mmol) of carbon tetrabromide, and 1.68 ~ (6.40 mmol) of triphenyl-phosphine. The reaction mixture was ~tirred 30 minutes at 0C, 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 e~aporated in ~acuo. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 0.~75 g (4~%) of the title Compound.
lH NMR (300 M~z, CDC13, ppm): ~ 7.48-7.10 (m, ~H), 4.50 (s, 2H), 4.00 (t, lH), 3.26-3.10 (m, 2H).
FAB MS: m/e 299, 301 (M+l).

Step F: Preparation of 3-~4-(2-cyano-2-phenylethyl)-phenyl~methyl-7-methyl-2-propyl-3~-imida~o r4.5-blpyridine To a solution of 7-methyl-2-propylimidazo t4,5-b]pyridine (106 mg, 0.61 mmol) in DMF (3 mL) was added NaH (0.91 mmol). The suspension was stirred 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 mi~ture was stirred for 2 hours at room temperature, quenched with water, and then concentrated in vacuo. The residue was partitioned ~etween water and EtOAc, and WO91/11~ PCT/US91/009~7 .

20756~7 the combined organic layer~ were washed with brine, dried (R2C03), filtered, and evaporated Ln vAcuo.
The residue was chromatographed on a silica gel flash chromatography column eluted with 50% ethyl acetate/
hexane to afford 46 mg (19%) of the title compound.
1~ NMR (300 M~z, CD30D, ppm): ~ con~istent 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-3~-imidazor4.5-blpyridine 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 was refluxed for 24 hours. The reaction mixture was concentrated ~B vacuo. The residue was dissolved in T~F and treated with 12 N
~Cl (5 drops) for 5 minutes at room temperature. The miæture was concentrated ~n vacuo and purified on a silica gel flash chromato~raphy column eluted with C~C13/MeO~/NH40H (80:20:2) to afford 19.6 mg (38%) of the title compound.
1~ NMR (300 M~z, CD30D, ppm): ~ 8.18 (d, lH), 7.28-7.12 (m, 6~), 7.05 (d, 2H), 6.93 (d, 2H), 5.48 (s, 2H), 4.58 (t, lH), 3.59-3.49 (m, 1~), 3.38-3.30 (m, 1~), 2.78 (t, 2~), 2.65 (s, 3~), 1.68-1.52 (m, 2H), 0.89 (t, 3~).
FAB MS: m/e 438 (M+l).

WO91~ PCT/US91/~gs7 20756~

F.~A~ple 17 3-~4-(l-carbo2y-l-phenoxy)methylphenyl]methyl-7-~ethyl-~-propyl-3~-imidazor4.5-blpyridine Step A: Preparation of methyl 2-bromo-4'-methyl-phenylacetate 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 overni~ht (17 hours). The reaction mixture was cooled to room temperature and 34 mL of methanol was added slowly.
The reaction mixture was concentrated ~n ~acuo 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.
lH NMR (300 M~z, CDC13, ppm): d 2.35 (s, 3~), 3.8 (s, 3H), 5.35 (s, 1~), 7.1-7.2 (d, 2E), 7.4-7.5 (d, 2H).
FAB-MS: m/e 243, 241 (M+l, 1:1 ratio).

Step B: Preparation of methyl 2-pheno2y-2-(4-methyl-phenyl)acetate To a suspension of ~H (244 mg, 2.13 mmol) in 2 mL of DM~ at room temperature under N2 was added a DMF solution (1 mL) of phenol (200 mg, 2.13 mmol).
When the KH had completely dissolved, the reaction mi2ture was cooled to 0C. A DMF solution (1 mL) of the product of Step A (517 mg, 2.13 mmol) was then added by syringe- After the addition was complete, - - - - - - - - - - -WO91/11~9 PCT/US91/~957 207~627 . .

the reaction mixture was allowed to warm to room temperature, and was then stirred for 2 hours. The reaction mixture was quenched with saturated N~4Cl and concentrated ~n ~cuo. The residue was purified on a silica gel flash chromatography column (130 x 40 mm) eluted with 5X ethyl acetate/hexane to afford 0.126 g (23%) of the title compound.
H NMR (300 MHz, CDC13, ppm): ~ 2.35 (s, 3H), 3.75 (s, 3H), 5.65 (s, lH), 6.9-7.0 (m, 3H), 7.1-7.3 (m, lo 4H), 7.4-7.5 (d, 2H).
EI-MS: m/e 256 (M+).

Step C. Preparation of methyl 2-phenoxy-2-(4-bromo-methylphenyl)acetate To a CC14 solution (1 mL) of the product of Step B (126 mg, 0.495 mmol) was added N-bromosuccin-imide (44 mg, 246 mmol) and a catalytic amount of AIBN. The solution was refluxed for 30 minutes and then concentrated Ln vacuo. The residue was purified on a silica gel flash chromatography column (150 x 30 mm) eluted with 5% ethyl acetate/hexane to afford 27 mg (33%) of the title compound.
lH NMR (300 M~z, CDC13 ppm): ~ 3.75 (s, 3~), 4.5 (s, 2H), 5.65 (s, lH), 6.9-7.0 (m, 3H), 7.25-7.35 (m, 2~), 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-(1-carbomethoxy-1-phenoxy)methylphenyl]methyl-7-methyl-2-propyl-3H-imidazor4.5-blpyridine To a DMF suspension (0.1 mL) of NaH (2.4 mg;
0.081 mmol) under N2 was added 1.0 eq. of 7-methyl-2-WO91/11~ PCT/US91/~gs7 - 207~627 propylimidazo~4,5-b]pyridine (14 mg). After 15 minutes, the Na~ 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. Th~ crude product was chromatographed on silica gel (140 x 20 mm) eluted first with 300 mL of 30% ethyl acetate/hexane, then with 50% ethyl acetate/hexane to afford 5.2 mg (15%) of the titled compound.
lH NMR (300 MHz, CDC13, ppm): ~ O.9-1.0 (t, 3H), 1.65-1.85 (m, 2~), 2.7 (5, 3H), 2.75-2.85 (t, 2~), 3.7 (s, 3~), 5.5 (s, 2H), 5.65 (s, 1~), 6.9-7.1 (m, 4~), 7.1-7.2 (m, 2H), 7.2-7.3 (m, 2~), 7.5 (d, 2~), 8-2 (d, lH).

Step E: Preparation of 3-t4-(1-carboxy-1-phenoxy)-methylphenyl3methyl-7-methyl-2-propyl-3~-imidazo-r4.5-blpyridine To a methanol solution (50 uL) of the product of F.xample 9, Step D (5.2 mg, O.012 mmol) was added 1 N NaO~ (12.1 uL, 1.0 eq). The hydrolysis was complete after stirring for 4 days. The reaction mixture was chromatographed on silica 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.
H NMR (300 MHz, CD30D, ppm): ~ O.9-1.0 (t, 3E), 1.6-1.8 (m, 2~), 2.65 (s, 3H), 2.8-2.9 (t, 2H), 5.4 (s, 1~), 5.6 (s, 2~), 6.8-7.0 (m, 3~), 7.1-7.3 (m, 5H), 7.55-7.65 (d, 2H), 8.2 (d, 1~).
FAB-MS: m/e 416 (M+l).

WO91/11~9 PCT/US91/~9~7 207~627 F~ le 18 3-[4-(1-Carboxy-1-(2-methylphenyl))metho~yphenyl]-methyl-7-methyl-2-propyl-3~-imidazor4.5-bl~yridine General procedure for the synthesis of 2-bromophenyl-acetic esters from benzaldehydes (Steps A-C):

Step A: Preparation of 2-trimethylsilylo~y-2-(2-methyl~henyl~acetonitrile To a solution of 1.00 g (8.33 mmol) of 2-methylbenzaldehyde dissolved in 20 mL of dichloro-methane was added 1.33 mL (10.0 mmol) trimethylsilyl-cyanide, 1-2 mg of potassium cyanide, 1-2 mg of 18-crown-6, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted into diethyl ether, washed with 5%
NaHC03, brine, dried (MgS04), filtered and evaporated.
The residual oil was used directly in the next step.

Step B: Preparation of ethyl 2-hydroxy-2-(2-methyl-~henyl)acetate To a stirred 0C (ice-water bath) solution of 1.83 g (8.35 mmol) of the product of Step A
dissolved in 10 mL of ethanol was introduced a slow stream of anhydrous hydrogen chloride gas. After 5 minutes the hydrogen chloride was turned off and the reaction mixture was stoppered and stirred at room temperature 14 hours. The reaction was then poured into ice-water and extracted into chloroform. The chloroform solution was filtered through a 60 mL

WO91/11~ PCT/USgl/~9~7 ,,. ~ ..

20~5~æ7 sintered funnel filled with silica gel and the silica gel was wa~hed with additional chloroform. The combined filtrate was evaporated ~n VACUO to afford 0.437 g (27%) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ 1.15-1.25 (t, 3~), 2.40 (s, 3~), 3.35-3.45 (d, lH), 4.05-4.30 (m, 2H), 5.30-5.35 (d, 1~), 7.05-7.20 (m, 4~).

Step C: Preparation of ethyl 2-bromo-2-(2-methyl-~henyl)acetate To a cooled (0C) solution of 0.425 g (2.19 mmol) of the product of Step B dissolved in 10 mL of dichloromethane was added 0.717 g (2.74 mmol) of triphenylphosphine 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 Ln V~CUQ and the residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetatelhexane to afford 0.373 g (66~/c) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ 1.20-1.30 (t, 3~), 2.40 (s, 3~), 4.15-4.30 (m, 2H), 5.60 (s, 1~), 7.10-7.25 (m, 3~), 7.55-7.65 (m, 1~).

WO91/11~ PCT/US91/~957 2~75~27 General procedure for the al~ylation of i~idazo~4,5-b]
pyridi~es with 2-~romophenylacetic esters:

Step D: Preparation of 3-[4-(1-carbomethoy )-1-(2-methylphenyl)methoxyphenyl~methyl-7-methyl-2-progyl-3~-imid~zor4.5-bl~yridi~e To a suspension of 37 mg (0.32 mmol) of a 35% oil dispersion of potassium hydride in 0.5 mL of DMF was added 0.090 g (0.32 mmol) of 3-(4-hydroxy-phenyl)methyl-7-methyl-2-propyl-3H-imidazot4,5-b]
pyridine (Example 2, Step D) and the reaction was stirred under an N2 atmosphere. After stirring for 15 minutes, 0.085 g of 18-crown-6 was added followed by addition of a solution of 0.090 g (0.35 mmol) of the product of Step C dissolved in 0.75 mL of DMF.
The reaction mi~ture was stirred for 4 hours, then concentrated in ~acuo. The residue was purified on a silica gel flash chromatography column eluted with 40% ethyl acetate/hexane to afford 0.099 g (68%) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ O.90-1.00 (t, 3E), 1.15-1.25 (t, 3H), 1.65-1.80 (m, 2E), 2.45 (s, 3~), 2.65 (s, 3H) 2.70-2.80 (t, 2H), 4.05-4.25 (m, 2H), 5.35 (s, 2~), 5.75 (s, 1~), 6.75-6.85 (d, 2~), 2s 6.95-7.05 (m, 3~), 7.10-7.25 (m, 3~), 7.45-7.55 (m, 1~), 8.15-8.20 (d, 1~).
~AB-MS: m/e 458 (M+l).

WO9l~ll ffl 2 0 ~ 5 1~ 2 7 Pcr/usgl/oo9s7 General procedure for ester hydrolysis:

Step F: Preparation of 3-t4-(1-carbo~Y)-1-(2-methyl-phenyl)methoxyphenyl~methyl-7-methyl-2-propyl-3~-imidAzor4.5-blpyridi~e To a solution of 0.097 g (0.21 mmol) of the product of Step D dissolved in 3 mL of ethanol was added 1 mL of a 1 N NaOH solution. The reaction mixture was stirred at room temperature for 1.5 hours, neutralized to pH 7 with 1 N ECl and then concentrated Ln ~acuo. The residue was purified on a silica gel flash chromatography column eluted with C~C13tMeOH/NH40R (80:15:1) to afford 0.076 g (84Z) of the title compound.
lH MMR (300 M~z, CDC13, ppm): ~ O.90-1.00 (t, 3~), 1.65-1.75 (m, 2H), 2.50 (s, 3H), 2.70 (s, 3H), 2.85-2.95 (t, 2~), 5.50 (s, 2~), 5.85 (s, 1~), 6.85-6.95 (d, 2H), 7.05-7:15 (d, 2H), 7.15-7.25 (m, 4H), 7.45-7.55 (d, lR), 8.20-8.25 (d, 1~).
FAB-MS: m/e 430 (M~l).

Fx~le 19 3-[4-(1-Carboxy-1-(2-ethoxyphenyl))methoxyphenyl]-methyl-7-methyl-2-~ropyl-3R-i~idazor4.5-blpyridine Step A: Preparation of ethyl 2-bromo-2-(2-ethoxy-phenyl~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 WO 91/119g9 PCI/US91/009s7 207562~

2-etho~ybenzaldehyde was converted to 0.291 g (1.01 mmol) of the title compound in 15% overall yield.
H MMR (300 MHz, CDC13, 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, lH), 6.80-6.85 (d, lE), 6.90-7.00 (t, lH), 7.00-7.30 (t, lH), 7.55-7.65 (d, lH).

Step B: Preparation of 3-t4-(l-carbomethoxy)-1-(2-ethoxyphenyl)metho~yphenyl]methyl-7-methyl-2-~ropyl-3~-imidazor4.5-blpyridine 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-imidazot4,5-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.
H NMR (300 M~z, CDC13, ppm): ~ O.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 ts, 3H), 2.70-2.80 (t, 2H), 4.00-4.25 (m, 4H), 5.35 (s, 2H), 6.05 (s, lH), 6.80-7.05 (m, 6H), 7.20-7.30 (m, 2H), 7.40-7.50 (d, lH), 8.15-8.20 (d, lH).

2s Step C: Preparation of 3-t4-(1-carbo~Y)-1-(2-ethoxy-phenyl)methoxyphenyl]methyl-7-methyl-2-propyl-3H-imidazor4.5-blpyridine Using the general procedure for ester hydrolysis described in Step E of Example 19, 0.107 g (0.22 mmol) of the product of Step ~ was converted to 0.087 g (86%) of the title compound.

WO91/11~9 PCT/US91/009~7 20756~

lH NMR (300 M~z, CD30D, ppm): ~ O.90-1.00 (t, 3H), 1.35-1.45 (t, 3H), 1.50-1.65 (m, 2~), 2.70 (s, 3H), 2.80-2.90 (t, 2H), 4.05-4.20 (m, 2H), 5.50 (~, 2H), 6.05 (~, lH), 6.90-7.05 (m, 3H), 7.05-7.10 (m, 3H), 7.15-7.20 (d, lH), 7.25-7.35 (t, lH), 7.45-7.50 (d, lH), 8.20-8.25 (d, 1~).
FAB-MS: m/e 460 (M+l).

F.~ ple 20 3-[4-(1-Carboxy-1-(2-(1-hexyloxy)phenyl))methoxy-phenyl]methyl-7-methyl-2-propyl-3H-imidazot4,5-b]
pyr~dlne Step A: Preparation of ethyl 2-bromo-2-(2-(1-hexyloxy)phenyl)acetate Using the general procedure for the synthesis of 2-bromophenylacetic esters from benzaldehydes (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 llZ overall yield.
lH NMR (300 MHz, CDC13, ppm): ~ O.85-0.95 (t, 3~), 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, 1~), 6.80-6.85 (d, lH), 6.90-7.00 (t, 3H), 7.20-7.30 (t, lH), 7.55-7.65 (d, lH).

Step B: Preparation of 3-t4-(1-carbomethoxy)-l-(2-(1-hexyloxy)phenyl)methoxyphenyl]methyl-7-methYl-2-propyl-3~-imidazor4~5-blpyridine WO91~ PCT/USgl/~957 2075~7 Using the general procedure for the alkylation reaction described in Step D of E~ample 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 (71Z) of the title compound.
lH NMR (300 MHz, CDC13, ppm): d 0.80-0.90 (t, 3~), 0.90-1.00 (t, 3H), 1.15-1.50 (m, 9H), 1.65-1.80 (m, lo 4H), 2.65 (s, 3~), 2.70-2.80 (t, 2H), 3.95-4.05 (t, 2E), 4.05-4.25 (m, 2H), 5.35 (s, 2~), 6.05 (s, 1~), 6.80-7.05 (m, 6H), 7.20-7.30 (m, 2~), 7.40-7.45 (d, lH), 8.15-8.20 (d, lH).

Step C: Preparation of 3-[4-(1-carboxy)-1-(2-(1-hexyloxy)phenyl)methoxyphenyl3methyl-7-methyl-2-~ropyl-~-imidazor4.5-bl~yridine Using the general procedure for ester hydrolysis described in Step E of Example 19, 0.090 g (0.17 mmolj of the product of Step B was converted to 0.072 g (85%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 0.80-0.90 (t, 3H), 0.90-1.00 (t, 3H), 1.20-1.35 (m, 4~, 1.50-1.60 (m, 2H), 1.60-1.85 (m, 2H), 2.65 (s, 3~), 2.80-2.90 (t, 2s 2H), 3.95-4.05 (m, 2~), 5.50 (s, 2H), 6.05 (s, 1~), 6.90-7.05 (m, 4~), 7.05-7.15 (d, 2H), 7.15-7.20 (d, 1~), 7.25-7.35 (t, lH), 7.40-7.45 (d, lH), 8.20-8.25 (d, 1~).
FAB-MS: m/e 516 (M+l).

wo 9~ ~g ~ ~ 7 ~ 6 2 ~ PCT/US91/00957 F.~A~le 21 3-t4-(1-Carboxy-1-(2-methoxyphenyl))methoxyphenyl3-methyl-7-methyl-2-pro~yl-3~-imidazor4~5-b~pyridine S

Ste~ A: Preparation of ethyl 2-bromo-2-(2-methoxy-~henyl)acetate Using the general procedure for the synthesisof 2-bromophenylacetic esters 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.
lH MMR (300 MHz, CDCl3, ppm): ~ 1.20-1.30 (t, 3H), 3.85 (s, 3H), 4.15-4.30 (m, 28), 5.85 (c, lH), 6.80-6.90 (d, lH), 6.90-7.00 (t, lH), 7.25-7.35 (t, lH), 7.55-7.65 (d, lH).

Step B: Preparation of 3-[4-(1-carbomethoxy)-1-(2-methoxyphenyl)methoxyphenyl3methyl-7-methyl-2-propyl-3~ idazor4.5-blpyridine Using the general procedure for the alkylation reaction described in Step D of E~ample 18, 0.090 g (0.32 mmol) of 3-(4-hydroxyphenyl)methyl-7-methyl-2-propyl-3H-imidazot4,5-b]pyridine (Example 2, Step D) was alkylated with 0.096 g (0.35 mmol) of the product of Step A, to afford 0.126 g (83Z) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ O.90-1.00 (t, 3H), 1.15-1.25 (m, 3H), 1.65-1.80 (m, 2H), 2.65 (s, 3H), 2.70-2.80 (t, 2H), 4.05-4.25 (m, 2H), 5.35 (s, 2H), 6.05 (s, lH), 6.80-7.05 (m, 7H), 7.25-7.35 (m, lH), 7.45-7.50 (d, lH), 8.15-8.20 (d, lH~.
FAB-MS: m/e 474 (M+l).

WO91/11~ PCT/US91/~ss7 Step C: Preparation of 3-~4-(1-carboxy)-1-(2-methoxy_ phenyl)methoxyphenyl]methyl-7-methyl-2-pro~yl-3~-imid~zor4.5-bl~yridi~e Using the general procedure for ester hydrolysis descri~ed in Step F of Example 19, 0.123 g (0.26 mmol) of the product of Step B was converted to 0.095 g (82%) of the title compound.
lH NMR (300 M~z, CD30D, ppm): ~ 0.90-1.00 (t, 3H), 1.60-1.80 (m, 2H), 2.60 (s, 3~), 2.80-2.90 (t, 2~), lo 3-90 (s, 3H), 5.50 (s, 2H), 6.00 (s, lH), 5.90-7.15 (m, 6H), 7.15-7.20 (d, lH), 7.20-7.25 (t, lH), 7.45-7.55 (d, lH), 8.20-8.25 (d, lH).
FAB-MS: m/e 446 (M+l).

~ ple 22 3-~4-(1-Carboxy-l-(naphth-l-yl))methoxyphenyl~methyl-7-methyl-2-propyl-3~-imidazor4.5-blpyridine Step A: Preparation of ethyl 2-bromo-2-(naphth-1-yl)aceta~e Using the ~eneral procedure for the synthesis of 2-bromophenylacetic esters from benzaldehydes (Steps A-C, Example 18), 1.00 g (6.40 mmol) of l-naph-thaldehyde was converted to 0.694 ~ (2.69 mmol) ofthe title compound in 37% overall yield.
lH MMR (300 M~z, CDC13, ppm) ~ 1.20-1.30 (t, 3H), 4.15-4.3S ~m, 2~), 6-15 (~, lH), 7.40-7.65 (m, 3H), 7.75-7.9S (m, 3~), 8.05-8.15 (d, 1~).
EI-MS: m/e 292, 294 (M+, 1:1 ratio).

` WO91/11~9 PCT/USgl/00957 ~0~2~ -~

Step B: Preparation of 3-t4-(1-carbometho~y-1-(naphth-l-yl)~methoxyphenyl]methyl-7-methyl-2-~ropyl-3~-imidazot4.5-blpyridine Using the general procedure for the al~yla-tion reaction described in Step D of Egample 18, 0.090 g (0.32 mmol) of 3-(4-hydroxyphenyl)methyl-7-methyl-2-propyl-3H-imidazot4,5-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 CmPound.
lH NMR (300 MHz, CDC13, ppm) ~ O.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, 2~), 4.05-4.25 (m, 2H), 5.35 (s, 2H), 6.20 (s, lH), 6.80-6.90 (d, 2H), 6.95-7.05 (m, 3H), 7.40-7.60 (m, 3H), 7.65-7.75 (d, lH), 7.80-7.90 (m, 2H), 8.15-8.20 (d, 2H), 8.20-8.30 (d, lH).
FAB-MS: m/e 494 (M+l).

Step C: Preparation of 3-[4-(1-carboxy-l-(naphth-1-yl))methoxyphenyl]methyl-7-methyl-2-propyl-3H-imidazor4.5-bl~yridine Using the general procedure for ester hydrolysis described in Step E of Example 19, 0.125 g (0.25 mmol) of the product of Step B was cOnverted to 0.108 g (91%) of the title compound.
lH NMR (300 MHz, CD30D, ppm): ~ 0.90-1.00 (t, 3H), 1.50-1.75 (m, 2H), 2.70 (~, 3H), 2.80-2.90 (t, 2~), 6.50 (s, 2H), 6.20 (s, lH), 6.95-7.05 (d, 2H), 7.05-7.15 (d, 2H), 7.15-7.20 (d, lH), 7.45-7.55 (m, 3H), 7.80-7.95 (m, 2H), 8.15-8.25 (d, lH), 8.35-8.45 (d, lH).
FAB-MS: m/e 466 (M~l).

WO91/11~ - PCT/US91/~9S7 207~627 T~ple ~3 3-[4-(1-Carboxy-1-(3-methylnaphth-2-yl))methoxy-phenyl]methyl-7-methyl-2-propyl-3~-imidazot4,5-b]
pyridi~e Step A: Preparation of ethyl 2-bromo-2-(3-methyl-naphth-2-yl)acetate Using the general procedure for the synthesis Of 2-bromophenylacetic esters 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.
1~ NMR (300 M~z, CDC13, ppm): ~ 1.20-1.30 (t, 3~), 2.55 (s, 3H), 4.20-4.40 (m, 2~), 5.60 (s, lH), 7.40-7.50 (m, 2H), 7.65 (s, 1~), 7.70-7.75 (d, 2H), 7.75-7.85 (d, 1~), 8.10 (s, 1~).
EI-MS: m/e 306, 308 (M+, 1:1 ratio).

Step B: Preparation of 3-t4-(1-carbomethoxy-1-(3-methylnaphth-2-yl))methoxyphenyl]methyl-7-methyl-2-propyl-3H-imidazor4.5-bl~yridine Using the general procedure for the 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/O) of the title compound.

WO91/11~9 Z O ~ 5 6 2 7 PCT/US91/~9s7 1~ NMR (300 M~z, CDC13, ppm): ~ O.85-0.95 (t, 3E), 1.15-1.25 (m, 2H), 1.65-1.75 (m, 2H), 2.60 (~, 3H), 2.65 (s, 3H), 2.70-2.80 (t, 2H), 4.05-4.30 (m, 2H), 5.40 (s, 2H), 5.85 (s, lH), 6.80-6.90 (d, 2H), 6.95-7.05 (m, 3H), 7.35-7.45 (m, 2H), 7.65 (8, lH), 7.70-7.80 (m, 2H), 8.00 (s, lH), 8.15-8.20 (d, lH).
FAB-MS: m/e 508 (M+l).

Step C: Preparation of 3-[4-(1-carboxy-1-(3-1o methylnaphth-2-yl))methoxyphenyl]methyl-7-methyl-2-propyl-3H-imidazor4 5-bl~yridine Using the general procedure for ester hydrolysis described in Step F of Example 19, 0.090 g ~0.32 mmol) of the product of Step B was converted to 0.121 g (75/O) of the title compound.
H NMR (300 MHz, CD30D, ppm): ~ 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, lH), 6.95-7.05 (d, 2H), 7.05-7.15 (d, 2H), 7.35-7.50 (m, 2H), 7.65 (s, lH), 7.75-7.85 (t, 2H), 8.00 (s, lH), 8.15-8.25 (d, lH).
~AB-MS: m/e F.~A~P1 e 24 3-[4-(1-Carboxy-1-(2-methylphenyl))methoxyphenyl]-methyl-5.7-dimethyl-2-ethYl-3~-imid_ZOr4.5-blpyridine WO91/11~ PCT/US91/00957 207~27 Step A: Preparation of 2-nitramino-4,6-dimethyl-~yridine 2-Amino-4,6-dimethylpyridine (10.0 g, 81.8 mmol) was added portion-wise to 65 mL of ~2S04 (conc.
d=1.84) which was stirred (mechanical) at 0C. After complete addition, the mixture was warmed to room temperature until the mixture became homogeneous.
The solution was then cooled to -10C and a pre-cooled (0C) mixture of conc EN03 (11.5 mL, d = 1.40) and H2S04 (8.2 mL, d = 1.84) was added at such a rate as not to raise the internal reaction temperature above -9C. Ten minutes after the addition was complete this cooled (-10C) mixture was poured onto 400 g of crushed ice. The resulting slurry was neutralized by the addition of conc N~40H (to p~ 5.5) while cooling (ice bath). The solid was isolated by filtration, and dried at room temperature to give 13.3 g of the title compound as a white solid.

Step B: Preparation of 2-amino-3-nitro-4,6-dimethyl-pyridine To 75 mL of stirred conc H2S04 cooled to -5C (ice-salt bath) was added 4,6-dimethyl-2-nitraminopyridine (13.2 g, 79 mmol) portion-wise at such a rate as to maintain the internal temperature below -3C. The mixture was warmed to O-C until homogeneous (30 minutes) at which time tlc (SiO2, 1:1 EtOAc/hexanes on a N~40H neutralized aliquot) indicated that the rearrangement was complete. The mixture was poured onto 400 g of crushed ice and the pH was adjusted to 5.5 by the addition of conc WO91/11~ PCT/USgl/00957 20~562~

NH40H. The resulting yellow slurry was cooled to 0C, filtered, washed with cold water (50 mL), and dried at room temperature to gi~e 10.32 g of a mixture of the title compound and the 5-nitro isomer in a 55:45 ratio (determined by 1~ N~R). Thi8 mixture was used directly in the next step.

Ste~ C: Preparation of 5,7-dimethyl-2-ethylimidazo r4~5-bl~yridine 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) was added 10 % Pd/C (2.4 g). The reaction vessel was evacuated then purged with ~2 at 1 atm. and stirred 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 solid. To 5.40 g (39.4 mmol) of this mixture was added propionic acid (B.80 mL, 118 mmol) followed by polyphosphoric acid (100 mL). This stirred mixture was heated to 90C for 3 h then to 100C for 1 hour. The inside walls of the flask were scraped with a spatula to assist dissolution of the solids. After the reaction was complete, the warm mixture was poured onto 300 g of ice and the mixture was made basic with N~40H. The migture was egtracted (4 x 50 mL CH2C12), dried (K2C03) and concentrated to give a mixture of the title compound and 4,6-dimethyl-2,5-bis(propionamido)pyridine. Purification (SiO2, 5% MeO~/ EtOAc) gave 1.66 g of the title compound as the ~lower eluting component.

WO91/11~ PCT/US91/009s7 207~627 H NMR (CD30D, 300 MHz, ppm): ~ 6.95 (~, lH), 2.92 (q, J=7.8 Hz, 2H), 2.54 (apparent s, 6H), 1.40 (t, J=7.8 Hz, 3H).

steP D: Preparation of 3-(4-(benzyloxy)phenyl)-methyl-5,7-dimethyl-2-ethyl-3~-imidazo r4.5-blpyridine To a suspension of 0.503 g (12.5 mmol) of a 60% oil dispersion of sodium hydride in 20 mL of DM~
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 additional 4 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgS04), filtered and evaporated. The residual oil was purified on a silica gel flash 20- chromatography column eluted with 30% ethyl acetate/hexane to afford 3.33 g (79%) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ 1.20-1.30 (t, 3H), 2.55 (s, 3H), 2.60 (s, 3H), 2.70-2.80 (m, 2~), 5.00 (s, 2H), 5.35 (s, 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).

WO91/11~ PCT/US91/00957 ~ .~
~o756~

Step ~.: Preparation of 5,7-dimethyl-2-ethyl-3-(4 hydro~yphenyl)methyl-3H-imidazo~4,~-b]
~yridine A ~olution of 1.40 g (3.77 mmol) of the product of Step D di~solved in 38 mL of methanol was placed in a Parr hydrogenation flas~ and 0.140 g of 10% Pd/C catalyst was added. The reaction mixture was placed in a Parr apparatus and roc~ed under a hydrogen atmosphere (32 psig) for 2 hours. The reaction mixture was then filtered through a plug of ~ilica gel eluted with 20Z methanol/chloroform to remo~e the catalyst. Evaporation of the filtrate and drying in vacuo afforded 0.650 g (61%) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ 1.20-1.30 (t, 3~), 3.64 (s, 3H), 3.66 (s, 3H), 2.85-2.95 (m, 2~), 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-(1-carboethoxy-1-(2-methylphenyl)metho~yphenyl]methyl-5,7-dimetbyl-2-ethyl-3H-imidazor4.5-blpyridine To a ~uspension 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 N2 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) dissolved in 1 mL DME were added and the reaction was then stirred an additional 15 minutes. The reaction WO91/11~ PCT/US91/009~7 207~627 mi~ture was then partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried (MgS04), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 40% ethyl acetate/hexane to afford 0.338 g (79%) of the title compound.
H NMR (300 MHz, CDC13, ppm): ~ 1.10-1.20 (t, 3H), 1.20-1.30 (t, 3H), 2.45 (s, 3H), 2.55 (s, 3H), 2.60 lo (s, 3~), 2.70-2.80 (m, 2H), 4.05-4.25 (m, 2H), 5.35 (s, 2H), 5.70 (s, lH), 6.75-6.85 (d, 2H), 6.88 (s, lH), 6.95-7.05 (d, 2H) 7.15-7.25 (m, 3H), 7.45-7.55 (d, lH).
FAB-MS: m/e 458 (M+l).

Step G: Preparation of 3-t4-(1-carbo~Y-1-(2-methyl-phenyl)methoxyphenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazor4.5-blpyridine Using the general procedure for ester hydrolysis described in Step E of Example 19, 0.060 g (0.13 mmol) of the product of Step ~ was converted to 0.054 g (96%) of the title compound.
lH NMR (300 M~z, CD30D, ppm): ~ 1.20-1.30 (t, 3H), 2.50 (s, 3H), 2.60 (s, 3H), 2.65 (s, 3H), 2.85-2.95 2s (m, 2H), 5.50 (s, 2H), 5.85 (s, lH), 6.90-7.00 (d, 2H), 7.05-7.15 (m, 3H), 7.15-7.25 (m, 3H), 7.50-7.55 (d, lH).
~AB-~S: m/e 430 (M+l).

WO91/11~9 PCT~US91/~ss7 -.

2~7~2 -24~-~ ple ~5 3-[4-(1-Carboxy-1-(2-chlorophenyl))metho~yphenyl]-~ethyl-5.7-dimethy~-2-ethyl-3~ idazor4.5-bl~yridi~e Step A: Preparation of 3-r4-(1-carboetho~y-1-(2-chlorophenyl)methoxyphenyl]methyl-5,7-dimet~yl-2-ethyl-3R-imidazor4.5-blpyridine 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-3~-imidazot4,5-b]
pyridine (Example 24, Step E) was al~ylated with 0.052 g (0.20 mmol) of methyl 2-bromo-(21-chloro)-phenylacetate (Example 4, Step A) to afford 0.053 g (64%) of the title compound.

Step B: Preparation of 3-~4-(1-carboxy-1-(2-chloro-phenyl)methoxyphenyl~methyl-5,7-dimethyl-2-ethyl-3~-imidazor4.5-blpyridine Using the general procedure for ester 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 (78Z) of the title compound.
lH NMR (300 M~z, CD30D, ppm): ~ 1.20-1.30 (t, 3H), 2.60 (s, 3E), 2.63 (s, 3H), 2.85-2.95 (m, 2~), 5.50 (s, 2H), 6.05 (s, lH), 6.90-7.00 (d, 2H), 7.05-7.15 (m, 3H), 7.30-7.40 (m, 2R), 7.40-7.50 (m, lR), 7.60-7.65 (m, 1~).
~AB-MS: m/e 450, 452 (M+l, 3:1 ratio).

WO91/11~ PCT/US91/~9~7 ~ ple 26 3-~4-(1-Carboxy-1-(2-bromophenyl))methoxyphenyl]-methyl-5,7-dimet ~1-2-etl~yl-3~-imid~zor4.5-blpyridirle s Ste~ A: Preparation of methyl 2-bromo-2-(2-~romo-~henyl~cetate Commercially available 2-bromophenylacetic acid (5.00 g, 23.3 mmol) was converted to 4.89 g 10 (68%) of the title compound in a procedure similar to that described in Step A of Example 3.
1~ NMR (300 MHz, CDC13, ppm): ~ 3.80 (s, 3H), 5.90 (s, lH), 7.15-7.20 (t, lH), 7.20-7.25 (t, lH), 7.50-7.55 (d, lH), 7.70-7.75 (d, lH).
FAB-MS: m/e 306 ~ 308 ~ 310 (M+l, 1:2:1 ratio).

Step B: Preparation of 3-[4-(1-carbomethoxy-1-(2-bromophenyl)methoxyphenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazor4.5-blpyridine 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-imidazot4,5-b]
pyridine (Example 24, Step E) was alkylated with 0.060 g (0.20 mmol) of the product of Step A to afford 0.077 g (85Z) of the title compound.
lH NMR (300 MHz ~ CDC13, ppm): ~ 1.20-1. 30 (t, 3~) ~
2.55 (s, 3H), 2.60 (s, 3H), 2.65-2.75 (m, 2H), 3.75 (s, 3H), 5.35 (s, 2H), 6.05 (s, lH), 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~ 1 ratio).

WO 91/11~9 2 ~ 7 5 6 2 7 PCT/US91/~957 Ste~ C: Preparation of 3-t4-(1-carboxY-1-(2-bromophenyl)methoxyphenyl]methyl-5,7-dimethyl-2-ethyl-~-imidazor4.5-bl~yridine Using the general procedure for e~ter hydrolysis described in Step E of E~ample 19, 0.077 g (0.15 mmol) of the product of Step B was converted to 0.065 g (86%) of the title compound.
1~ NMR (300 MHz, CD30D, ppm): ~ 1.20-1.30 (t, 3~), 2.64 (s, 3H), 2.66 (s, 3H), 2.85-2.95 (m, 2H), 5.50 lo (s, 2~), 5.95 (s, 1~), 6.90-7.00 (d, 2~), 7.05-7.15 (m, 3H), 7.20-7.30 (t, lH), 7.30-7.40 (t, lH), 7.60-7.70 (m, 2H).
~AB-MS: m/e 494, 496 (M+l, 1:1 ratio).

F~ple 27 3-t4-(1-Carboxy-l-phenyl)methoxyphenyl]methyl-5,7-dimethyl-2-ethyl-3~I-imidazor4.S-blpyridine Step A: Preparation of methyl 2-(4-bromomethyl-phenoxy)-2-~henylacetate To a solution of 0.710 g (2.77 mmol) of methyl 2-(4-methylphenogy)phenylacetate (Step A of Example 13) dissolved in 10 mL of CC14, was added 0-494 g (2.77 mmol) of N-bromosuccinimide, and 25 mg of AIBN (catalytic amount). The mi~ture wa~ stirred and heated to reflux for 4 hours, then cooled to room temperature and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column (25 ~ 170 mm) eluted with 5% ethyl acetate/
hexane to afford 0.509 g (5~/.) of the title compound.

WO91/11~9 PCT/US91/009~7 20~5627 lH NMR (300 M~z, CDC13, ppm): ~ 3.75 (s, 3H), 4.5 (s, 2H), 5.65 (s, lH), 6.9-7.0 (d, 2H), 7.3-7.35 (d, 2~), 7.35-7.5 (m, 3H), 7.5-7.6 (d, 2~).
EI-MS: mte 334, 336 (M+, 1:1 ratio).

Step ~: Preparation of 3-~4-(1-carbomethoxy-1-phenyl)methoxyphenyl]methyl-5,7-dimethyl-2-ethyl-3R-i~idazor4.5-bl~yridine To a suspen~ion 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 t4,5-b]pyridine (Example 24, Step C) and the mixture was stirred at room temperature under an N2 atmosphere. After 15 minutes, a solution of 0.105 g (0.32 mmol) of the product of Step A dissolved in 1 mL of DMF was added and the reaction was stirred an additional 75 minutes. The mixture was then concentrated in vacuo and purified on a silica gel flash chromatography column eluted with 50% ethyl acetate/hexane to afford 0.068 g (55%) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ 1.20-1.30 (t, 3H), 2.55 (s, 3H), 2.60 (s, 3H), 2.70-2.80 (m, 2H), 3.70 (s, 3H), 5.35 (s, 2H), 5.55 (s, lH), 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+l).

Step C: Preparation of 3-t4-(1-carboxY-l-Phenyl)-methoxyphenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazor4.5-blpyridine WO 91/11999 PCI'/US91/009s7 .. -. 2o~62~ ,.

Using the general procedure for ester hydrolysis described in Step E of Egample l9, 0.065 g (0.15 mmol) of the product of Step B was converted to O . 044 g (70%) of the title compound~
lH NMR (300 MHz, CD30D, ppm): ~ 1.20-1.30 (t, 3~, 3.60 (s, 3H), 3.65 (s, 3H), 2.85-2.95 (m, 2~), 5.50 (s, 2H), 5.65 (8, lH), 6.90-7.00 (d, 2~), 7.05-7.15 (m, 3~), 7.35-7.45 (m, 3~), 7.55-7.65 (m, ZH).
FAB-MS: m/e 416 (M+l).

~ le 28 3-t3-Chloro-4-((1-carboxy-1-phenyl)methoxy)phenyl]-~ethyl-7-methyl-2-~ropyl-3H-imidazor4.5-bl~yridi~e Step A: Preparation of methyl 2-(2-chloro-4-methyl-pheno~y~-2-phenylacetate To a suspension of 0.282 g (7.04 mmol) of a 60% oil dispersion of sodium hydride in DME was added 1.00 g (7.04 mmol) of 2-chloro-4-methylphenol and the mixture was stirred under an N2 atmosphere at room temperature. After 10 minutes, a solution of 1.94 g (8.45 mmol) of methyl 2-bromophenylacetate dissolved in 10 mL of DM~ was added and the reaction was stirred an additional 1.5 hours. The reaction was then diluted into ethyl acetate, uashed with water, dried (MgS04), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 4% ethyl acetate/hexane to afford 1.70 g (83%) of the title compound.

WO 91/11999 PCI~/USsl/ooss7 1~ NMR (300 MEz, CDC13, ppm): ~ 2.20 (s; 3E), 3.70 (~, 3~), 5.60 (~ ), 6.70-6.80 (d, 1~), 6.85-6.95 (d, 1~), 7.20 (br s, lH), 7.20-7.30 (m, 3H), 7.~5-7.65 (m, 2~).
EI-MS: m/e 290 (M+).

Step ~: Preparation of methyl 2-(2-chloro-4-bromo-methylpheno~y)-2-~henylacetate To a solution of 1.70 g (5.86 mmol) of the product from Step A dissolved in 20 mL of CC14 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 hours, 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 10Z ethyl acetate/hexane to afford 0.730 g (34%) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ 3.70 (s, 3~), 4.40 (s, 2H), 5.65 (s, lH), 6.75-6.85 (d, 1~), 7.10-7.20 (d, lH), 7.30-7.45 (m, 4~), 7.55-7.65 (m, 2~).
FAB-MS: m/e 369 (M+l).

Step C: Preparation of 3-~3-chloro-4-((1-carbo-methoxy-l-phenyl)methoxy)phenyl]methyl-7-methyl-2-~ro~yl-3H-imidazor4.5-bl~yridine 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.

WO 91/11999 2 0 7 5 6 2 ~ Pcr/usgl/oog57 lH NMR (300 M~z, CDC13, ppm): ~ 0.90-1.00 (t, 3H), 1.65-1.80 (m, 2H), 2.65 (s, 3H), 2.65-2.80 (t, 2H), 3.70 (s, 3H), 5.35 (s, 2H), 5.60 (8, lH), 6.70-6.75 (d, lH), 6.85-6.95 (d, lH), 7.00-7.05 (d, 1~), 7.20 (br s, lH), 7.30-7.45 (m, 3H), 7.50-7.60 (m, 2R), 8.15-8.20 (d, lH).
FAB-MS: m/e 464 (M+l).

Step D: Preparation of 3-t3-chloro-4-((1-carboxy-1-phenyl)methoxy)phenyl]methyl-7-methyl-2-~ro~yl-3~ idazor4.5-blpyridine Using the general procedure for ester hydrolysis 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.
lH NMR (300 MHz, CD30D, ppm): ~ 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, lH), 6.95-7.10 (m, 2H), 7.15-7.20 (d, lH), 7.25 (br s, 1~), 7.35-7.45 (m, 3H), 7.60-7.70 (m, 2H), 8.20-8.25 (d, lH).
FAB-MS: m/e 450 (M+l).

T.~A~le 29 2s 3-[3-Chloro-4-((1-carboxy-1-phenyl)methoxy)phenyl]-methyl-5.7-dimethYl-2-ethYl-3~-imidazor4.5-blpyridi~e Step A: Preparation of 3-~3-chloro-4-((1-carbo-metho~y-l-phenyl)methoxy)phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazor4.5-bl~yridine WO 91/11999 PCI~/US91/009s7 The product of Example 28, Step B (0.127 g, 0.34 mmol) was used to al~ylate 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 0.080 g (61%) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ 1.20-1.30 (t, 3~), 2.55 (s, 3H), 2.60 (s, 3H), 2.65-2.80 (m, 2H), 3.70 (s, 3H), 5.35 (s, 2~), 5.60 (s, 1~), 6.80-6.85 (d, lH), 6.85-6.95 (m, 2H), 7.20-7.25 (d, lH), 7.30-7.45 (m, 3~), 7.50-7.60 (m, 2H).
FAB-MS: m/e 464 (M+l).

Step B: Preparation of 3-t3-chloro-4-((1-carbo~y-1-phenyl)metho~y)phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazor4.5-blpyridine Using the general procedure for ester hydrolysis described in Step ~ of Example 19, 0.080 g (0.17 mmol) of the product of Step A was converted to 0.047 g (60%) of the title compound.
lH NMR (300 MHz, CD30D, ppm): ~ 1.25-1.35 (t, 3H), 2.60 (s, 3H), 2.65 (s, 3H), 2.85-2.95 (m, 2H), 5.50 (s, 2~), 5.75 (s, lH), 6.95-7.10 (m, 3H), 7.25 (s, lH), 7.35-7.45 (m, 3H), 7.60-7.70 (m, 2H).
FAB-MS: m/e 450 (M+l).

WO 91/11~9 ~ 07 5 6 ~7 PCT/US91/~957 , ~ ple 30 3-t3-Benzoyl-4-((l-carboxy-l-phenyl)methoxy)phenyl]-metl~,yl-5 . 7-dimet~url-2-etl~yl-3~ nidAzor4 . 5-bl~yridi~e Step A: Preparation of methyl 2-(2-benzoyl-4-methyl-~heno~y)-2-phe~ylAcet~te To a solution of 1.00 g ~4.72 mmol) of 2-hydroxy-5-methylbenzophenone and 1.19 g (5.19 mmol) f methyl 2-bromophenylacetate in 10 mL of acetone was added 1.30 g (9.44 mmol) of ~2C03 and the mixture was stirred and refluxed for 14 hours. The mi~ture was cooled, filtered and evaporated Ln v~cuo and the residue was purified on a silica gel flash chromato-graphy column eluted with 5/. ehtyl acetate/hexane toafford 0.320 g (19%) of the title compound.
1~ NMR (300 MHz, CDC13, ppm): ~ 2.30 (s, 3H), 3.60 (s, 3~), 5.50 (s, 1~), 6.65-6.75 (d, lE), 6.90-7.00 (d, 2H), 7.10-7.25 (m, 4~), 7.30 (s, 1~), 7.40-7 50 (m, 2H), 7.50-7.55 (m, lH), 7.80-7.90 (m, 2H).
FAB-MS: m/e 361 (M+l).

Step B: Preparation of methyl 2-(2-benzoyl-4-bromo-methylphenoxy)-2-phenylacetate To a solution of 0.314 g (0.87 mmol) of the product of Step A dissolved in 10 mL of CC14 was added 0.155 g (0.87 mmol) of N-bromosuccinimide and 15 mg (catalytic amount) of AIBN. The mixture was stirred at reflux for 7 hours, then cooled filtered and evaporated ~s vacuo. The residue was purified on a silica gel flash chromatography column eluted with WOgl/ll~9 PCT/US91/009~7 207562~

15% ethyl acetate/hexane to afford 0.136 g (36%) of the title compound.
H NMR (300 MHz, CDC13, ppm): ~ 3.65 (s, 3H), 4.50 (s, 2E), 5.55 (s, lE), 6.75-6.85 (d, 1~) 6.90-7.00 (d, 2H), 7.10-7.25 (m, 4~), 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-((1-carbo-methoxy-1-phenyl)methoxy)phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazor4.5-blpyridine 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-ethylimidazot4,5-b]pyridine (Example 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.
lH NMR (300 MHz, CDC13, ppm): ~ 1.20-1.30 (t, 3~), 2.50 (s, 3H), 2.55 (s, 3H), 2.65-2.80 (m, 2H), 3.80 (s, 3~), 5.30 (s, 3H), 6.80-7.30 (m, 14~).
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-2-ethyl-3R-i~idazor4.5-bl~yridine Using the generzl procedure for ester hydrolysis described in Step E of Example 19, 0.060 g (0.11 mmol) of the product of Step C was converted to 0.031 g (53%) of the title compound.
lH NMR (300 M~z, CD30D, ppm): ~ 1.20-1.30 (t, 3H), 2.55 (s, 3~), 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).

WO 91/11~ 2 0 ~ 5 ~ 2 7 PCT/US91/~957 ~ le 31 3-t3-Acetyl-4-((1-carboxy-1-phenyl)methoxy)phenyl]-methyl-5~7-di~ethyl-2-et~yl-3~-imid~zsr4~5-blpyridine Step A: Preparation of methyl 2-(2-acetyl-4-methyl-~heno1~y~-2-~henylAcetAte Using the ~2CO3/acetone conditions for phenol alkylation described in`Step A of Example 30, 1.00 g (6.67 mmol) of 2'-hydroxy-5l-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~ NMR (400 MHz, CDC13, ppm): ~ 2.25 (s, 3H), 2.70 (s, 3~), 3.70 (s, 3H), 5.70 (d, 1~), 6.65-6.75 (d, lH), 7.10-7.20 (d, lH), 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 CC14 was added 0.821 g (4.61 mmol) of N-bromosuccinimide and 20 mg (catalytic amount) of AIBN. The mixture was stirred at reflux for 3.5 hours, then cooled, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 15% ethyl acetate/hexane to afford 0.431 g (27%) yield of the title compound.

-WO91/11~9 ~ PCT/US91/~957 207~S27 H NMR (400 M~z, CDCl3, ppm): ~ 2.75 (s, 3H), 3.75 (s, 3H), 4.45 (s, 2H), 5.70 (~, lH), 6.75-6.80 (d, 2H), 7.35-7.45 (m, 4H), 7.50-7.60 (m, 2H), 7.75 (s, lH).

Step C: Preparation of 3-t3-acetYl-4-((1-carbo-methoxy-l-phenyl)methoxy)phenyl]methyl-5,7-di~et~yl-2-et~yl-3H-imidazor4.5-bl~yridine The product of Step B (0.119 g, 0.31 mmol) was used to al~ylate 0.050 g (0.28 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b]pyridine (E~ample 24, Step C) according to the procedure described for Step B of Example 27, which after purification afforded 0.040 g (30%) of the title compound.
lH NMR (400 M~z, CDC13, ppm): ~ 1.20 (s, 3H), 1.20-1.30 (t, 3H), 2.55 (s, 3~), 2.60 (s, 3H), 2.70-2.80 (m, 2H), 3.75 (s, 3~), 5.35 (s, 3H), 6.85 (s, lH), 6.95-7.00 (d, lH), 7.05-7.10 (s, lH), 7.15 (s, lH), 7.20-7.30 (m, 3H), 7.50-7.55 (m, 2H).
FAB-MS: m/e 472 (M+l).

Step D- Preparation of 3-~3-acetyl-4-((1-carbo~y-1-phenyl)methoxy)phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazor4.5-blpyridine Using the general procedure for ester hydrolysis described in Step E of Example 19, 0.038 g (0.08 mmol) of the product of Step C was converted to 0.016 g (43%) of the title compound.
lH NMR (400 MHz, CD30D, ppm): ~ 1.15 (s, 3~), 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 (s, lH), 7.10 (s, lH), 7.25-7.35 (m, 3H), 7.60-7.70 (m, 2H).
FAB-MS: m/e 458 (M+l).

WO 91/11999 2 ~ ~ ~ 5 2 7 Pcr/usgl/009s7 ~Am~le 32 3-~4-(tl-carboxy-l-phenyl)methoxy)-3-metho~yphenyl]-~ethyl-5.7-dimethyl-2-ethyl-3~ id~zor4.5-bl~yridine Step A: Preparation of methyl 2-(4-hydroxymethyl-2-~etho~ypheno~y)-2-~henylAcet~te Using the ~2C03/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 (25%) of the title compound.
1~ NMR (300 MHz, CDC13, ppm): ~ 1.20-1.30 (t, 1~), 3-70 (s, 3~), 3.85 (s, 3~), 4.60 (d, 2E), 5.65 (s, 1~), 6.75-6.85 (m, 2H), 6.95 (s, lH), 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-methoxyphenoxy)-2-phenylacetate To a cooled (0C) solution of 0.490 g (1.62 mmol) of the product of Step A dissol~ed in 8 mL of CH2C12 was added 0.673 g (2.03 mmol) of carbon tetrabromide and 0.531 g (2.03 mmol) of triphenyl-phosphine. The reaction mixture was ~tirred for 1.5 hours and was allowed to slowly warm to room temper-ature. The reaction mixture was then concentrated in vacuo, and purified on a silica gel flash chromato-graphy column eluted with 15% ethyl acetate/hexane toafford 0.478 g (81%) of the title compound.

WO91/11~9 PCT/US91/~957 , H MMR (300 MHz, CDC13, ppm): ~ 3.75 (s, 3R), 3.85 (s, 3H), 4.40 (8, 2H), 5.60 (s, lH), 6.75-6.85 (m, 2H), 6.90 (s, lH), 7.30-7.40 (m, 3H), 7.50-7.60 (m, 2H).

Ste~ C: Preparation of 3-~4-((1-carbometho~y-1-phenyl)methoxy)-3-metho~yphenyl~methyl-5,7-di~ethyl-2-ethyl-3H-imidAzor4.5-b~pyridine The product of Step B (0.115 g, 0.31 mmol) was used to alkylate 0.050 g (0.28 mmol) of 5,7-dimethyl-2-ethylimidazot4,5-b]pyridine (Example 24, Step C) according to the procedure described for Step of Example 27, which after purification afforded 0.084 g (64%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 1.20-1.30 (t, 3H), 2.55 (s, 3H), 2.60 (s, 3E), 2.70-2.80 (m, 2H), 3.70 (s, 3H), 3.75 (s, 3H), 5.35 (s, 2H), 5.55 (s, lH), 6.50-6.60 (d, lH), 6.70-6.75 (d, lH), 6.80 (s, lH), 6.85 (s, lH), 7.30-7.40 (m, 3E), 7.45-7.55 (m, 2H).
FAB-MS: m/e 460 (M+l).

Step D: Preparation of 3-t4-((1-carbo~Y-l-phenyl)-methoxy)-3-methoxyphenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazor4.5-blpyridine Using the general procedure for ester hydrolysis described in Step E of Example 19, 0.080 g (O.17 mmol) of the product of Step C was converted to 0.064 g (82%) of the title compound.
1~ NMR (300 MHz, CD30D, ppm): ~ 1.20-1.30 (t, 3H), 2.60 (s, 3~), 2.62 (s, 3H), 2.85-2.95 (m, 2~), 3.80 (s, 3H), 5.50 (s, 3H), 6.50-6.60 (d, lH), 6.80-6.90 (d, lH), 6-95 (s, lH), 7.05 (s, lH), 7.30-7.40 (m, 3H), 7.55-7.65 (m, 2H).
FAB-MS: m/e 446 (M+l).

-WO 91/11~9 2 07 ~ 62~ PCT/US91/~9S7 F.~ le 33 3-r3-tert-Butyl-4-((1-carboxy-1-phenyl)methoxy)-phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]
~yridine Step A: Preparation of methyl 2-(2-tert-butyl-4-methylpheno~y)-2-~henylacetate To a suspension of 1.05 g (9.15 mmol) of a 35% oil dispersion of RH in 15 mL of DMF was added 1.50 g (9.15 mmol) of 2-tert-butyl-4-methylphenol and the mixture was stirred under N2 at room temperature.
After 10 minutes, 2.41 g (91.5 mmol) of 18-crown-6 and then a solution of 2.30 g (10.1 mmol) of methyl 2-bromophenylacetate dissolved in 10 mL of DMF were added. THe reaction mi~ture was stirred 17 hours, then partitioned between ethyl acetate and water.
The organic layer was separated, washed with water, dried (MES04), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 0.750 g (26%) of the title compound.
H NMR (300 MHz, CDC13, ppm): ~ 1.43 (s, 9~), 2.24 (s, 3~), 3.68 (s, 3H), 5.64 (s, lH), 6.56 (d, J=10 Hz, lH), 6.86 (dd, J=2, 10 Hz, lH), 7.12 (d, J=2 ~z, lH), 7.30-7.44 (m, 3H), 7.54-7.62 (m, 2H).

Step B: Preparation of methyl 2-(2-tert-butyl-4-bromomethylphenoxy)-2-~henylacetate 30To a solution of 0.494 g (1.58 mmol) of the product of Step A dissolved in 10 mL of CC14 was WO91/11~ PCT/US91/~9~7 , 207562~

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 hours. The reaction was cooled, filtered and evaporated ~n vacuo. The residue was purified on a ~ilica gel flash chromato-graphy column eluted with 3% ethyl acetate/hegane to afford 0.134 g (22Z) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ 1.44 (æ, 3~), 3.70 (s, 3~), 4.45 (s, 2~), 5.64 (s, lH), 6.70 (d, J=10 Hz, lH), 7.12 (dd, J=2, 10 Hz, lH), 7.22 (d, J=2 Hz, 1~), 7.32-7.42 (m, 3~), 7.53-7.60 (m, 2H).

Step C: Preparation of 3-~3-tert-butyl-4-((1-carbo-methoxy-l-phenyl)methoxy)phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazor4.5-bl~yridine 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-b3pyridine (Example 24, Step C) according to the procedure described for Step ~ of Example 27, which after purification afforded 0.088 g (62~/o) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ 1.20-1.3~ (t, 3~), 1.40 (s, 9~), 2.55 (s, 3H), 2.60 (s, 3E), 2.75-2.85 (m, 2~), 3.65 (s, 3~), 5.30 (s, 2H), 5.60 (s, 1~), 6.45-6.55 (d, lH), 6.70-6.80 (d, 1~), 6~85 (br s, lH), 7.25-7.40 ~m, 4H), 7.50-7.55 (m, 2H).
~AB-MS: m/e 486 (M+l).

Step D~ Preparation of 3-[3-tert-butyl-4-((1-carboxy-1-phenyl)methoxy)phenyl3methyl-5,7-dimethyl-2-ethy~-3H-imidazor4.~-blpyridine WO91/11~ PCT/US91/Oo9s7 20756~7 ~ :`

Using the general procedure for ester hydrolysis described in Step E of Example 19, 0.080 g (O.16 mmol) of the product of Step C was converted to 0.056 g (73%) of the title compound.
lH NMR (300 M~z, CD30D, ppm): ~ 1.25-1.35 (t, 3~), 1.40 (s, 9H), 2.63 (s, 3H), 2.65 (8, 3H), 2.85-2.95 (m, 2H), 5.50 (s, 2H), 5.65 (s, lH), 6.75-6.85 (d, lH), 6.90-6.95 (d, lH), 7.05 (s, 1~), 7.30 (s, lH), 7.35-7.45 (m, 3H), 7.60-7.70 (m, 2H).
EAB-MS: m/e 472 (M+l).

F~ple 34 3-t4-((1-carboxy-1-phenyl)metho~y)-3-ethoxyphenyl]-methyl-5.7-dimethyl-2-ethyl-3H-imidazor4.5-blpyridine Step A- Preparation of methyl 2-(2-ethoxy-4-formyl-phenoxy)phenylacetate Using the K2C03/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.
2~ lH NMR (300 ~z, CDC13, ppm): ~ 1.40-1.50 (t, 3H), 3.85 (s, 3~), 4.10-4.20 (m, 2H), 5.75 (s, lH), 6.95 (s, lH), 7.20-7.35 (m, 5H), 7.50-7.60 (m, 2H), 9.85 (s, lH).
FAB-MS: m/e 315 (M+l).

-WO91/11~9 PCT/US91/00957 - - 2075~27 Step B: Preparation of methyl 2-(2-ethoxy-4-hydroxy-met}~ heno~ h enyl ~ c et at e A stirred solution of 1.74 g (5.54 mmol) of the product of Step A dissolved in 22 mL of methanol was 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 was washed with water, brine, dried (M~S04), filtered and evaporated n vacuo. The residue was purified on a silica gel flash chromatography column eluted with 30/O ethyl acetate/hexane to afford 1.15 g (66%) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ 1.20-1.30 (t, 1~), 1.35-1.45 (t, 2H), 3.70 (s, 3H), 4.05-4.15 (m, 2H), 4.60 (s, 2H), 5.65 (s, 1~), 6.75-6.80 (d, lH), 6.85-6.95 (m, 2H), 7.30-7.40 (m, 3H), 7.50-7.60 (m, 2~).
~AB-MS: m/e 317 (M+l).

Step C: Preparation of methyl 2-(4-bromomethyl-2-ethoxy~heno2y)phenylacetate To a stirred and cooled (~C) solution of 1.15 g (3.64 mmol) of the product of Step B dissolved in 18 mL of CH2C12 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 mi~ture was then evaporated in ~acuo and purified on a silica gel flash chromato-graphy column eluted with 15% ethyl acetate/hexane to afford 1.21 g (88%) of the title compound.

WO91/11~9 PCT/USgl/oogs7 ., 207~627 lH NM~ (300 M~z, CDC13, ppm): ~ 1.3S-1.45 (t, 3~), 3.75 (8, 3~), 4.05-4.15 ~m, 2~), 4.40 (~, 2~), 5.65 (s, 1~), 6.80-6.90 (m, 2~), 6.9S (s, 1~), 7.35-7.4S
(m, 3H), 7.50-7.60 (m, 2H).
FAB-MS: m/e 378, 380 (M~l).

Ste~ D: Preparation of 3-t4-((1-carbomethoxy-1-phenyl)methoxy~-3-ethoxyphenyl]methyl-5,7-~imethyl-2-ethyl-3H-imidazor4.5-blpyridine 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 ~ of Example 27, which after purification afforded lS 0.084 g ~62Z) of the title compound.
lH NMR (400 M~z, CDC13, ppm): ~ 1.20-1.30 (t, 3~), 1.30-1.40 (t, 3H), 2.55 (s, 3E), 2.60 (s, 3H), 2.70-2.80 (m, 2H), 3.70 (s, 3H), 3.90-4.00 (m, 2~), 5.30 (s, 2H), 5.60 (s, 1~), 6.50-6.55 (d, 1~), 6.75-6.80 (m, 2H), 6.85 (s, 1~), 7.30-7.40 (m, 3~), 7.50-7.55 (m, 2H).
FAB-MS: m/e 474 (M+l).

Step E: Preparation of 3-t4-((l-carboxy-l-phenyl)-methoxy)-3-ethoxyphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazor4.5-blpyridine Using the general procedure for ester hydrolysis described in Step E of E~ample 19, 0.080 g (0.17 mmol) of the product of Step D was con~erted to 0.069 g (88Z) of the title compound.

WO91/11~9 PCT/US91/oogs7 1~ NMR (400 M~z, CD30D, ppm): ~ 1.20-1.30 (t, 3~), 1.30-1.40 (t, 3~), 2.55 (s, 3H), 2.60 (8, 3H), 2.80-2.90 (m, 2H), 3.95-4.05 (m, 2~), 5.45 (s, 2H), 5.50 (s, lE), 6.50-6.55 (d, lH), 6.80-6.85 (m, 2~, S 7.25-7.35 (m, 3H), 7.50-7.55 (m, 2~).

F~ e 35 3-[4-((l-Carboxy-l-phenyl)metho~y)-3-methylphenyl~-methyl-5.7-dimethyl-2-ethyl-3~-imidazor4.5-blpyridine Step A: Preparation of methyl 2-(4-formyl-2-methyl-phenoxy)phenylacetate Using the ~2C03tacetone conditions for phenol alkylation described in Step A of Example 30, O.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.
1~ NMR (400 M~z, CDC13, ppm): ~ 2.40 (s, 3~), 3.70 (s, 3H), 5.70 (s, lH), 6.80 (d, 1~), 7.35-7.45 (m, 3~), 7.55-7.60 (m, 2~), 7.65 (d, lH), 7.70 (s, 1~), 9.85 (s, 1~).
FAB-MS: m/e 285 (M+l).

Step B: Preparation of methyl 2-(4-hydroxymethyl-2-methylphenoxy~phe~ylacetate A stirred solution of 1.00 g (3.52 mmol) of the product of Step A dissolved in 14 mL of methanol was treated with 0.067 g (1.8 mmol) of sodium borohydride at room temperature. After 15 minutes WO91/11~ PCT/US91/00957 - 2o~627 the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid, and the organic layer was separated. The product was washed with water, brine, dried (MgS04), filtered and evaporated in vacuo. The residue was purified on a ~ilica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 0.660 g (66%) of the title compound.
lH NMR (400 M~z, CDC13, ppm): ~ 2.10 (s, lH), 2.35 lo ~s, 3H), 3.70 (s, 3H), 4.55 (s, 2H), 5.65 (s, lH), 6.70 (d, lH), 7.05 (d, lH), 7.15 (s, lH), 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-methylphenoxy)phenylacetate To a stirred and cooled (0CC) solution of 0.660 g (2.31 mmol) of the product of Step B dissolved in 12 mL of CH2C12 was added 0.957 g (2.89 mmol) of carbon tetrabromide and 0.756 g (2.89 mmol) of triphenylphosphine. After the addition the reaction mixture was allowed to warm to room temperature and was stirred overnight. The mixture was then evaporated in vacuo and purified on a silica gel flash chromatography column eluted with 15% ethyl acetate/hexane to afford 0.704 g (87%) of the title compou~d.
1~ NMR (400 MHz, CDC13, ppm): ~ 2.30 (s, 3H), 3.70 (s, 3H), 4.45 (s, 2H), 5.60 (s, lH), 6.65 (d, lH), 7.10 (d, lH), 7.20 (s, lH), 7.35-7.45 (m, 3H), 7.55-7.60 (m, 2H).
FAB-MS: m/e 269 (M~l).

WO91/11~ PCT/USgl/oogs7 2075~27 Step D: Preparation of 3-[4-((1-carbomethoxy_l_ phenyl)methoxy)-3-methylphenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazor4.5-bl~yridine The product of Step C (0.110 g, 0.31 mmol) was used to al~ylate 0.050 g (0.28 mmol) of 5,7-dimethyl-2-ethylimidazot4,5-b]pyridine (Example 24, Step C) according to the procedure described for Step B of Example 27, which after purification afforded 0.041 g (33%) of the title compound.
lH NMR (400 MHz, CDC13, ppm): ~ 1.20-1.30 (t, 3~), 2.25 (s, 3H), 2.55 (s, 3H), 2.60 (s, 3H), 2.70-2.80 (m, 2H), 3.65 (s, 3H), 5.35 (s, 2H), 5.55 (s, lH), 6.60 (d, lH), 6.80 (d, lH), 6.85 (s, 1~), 6.95 (s, lH), 7.30-7.40 (m, 3H), 7.50-7.55 (m, 2H).
FAB-MS: m/e 444 (M+l).

Step ~: Preparation of 3-[4-((1-carbo~y-1-phenyl)-methoxy)-3-methylphenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazor4.5-~lpyridine Using the general procedure for ester hydrolysis described in Step E of E~ample 19, 0.040 g (0.09 mmol) of the product of Step D was converted to 0.023 g (60%) of the title compound.
lH NMR (400 MHz, CD30D, ppm): ~ 1.15-1.25 (t, 3H), 2,25 (s, 3H), 2.58 (s, 3H), 2.60 (s, 3H), 2.80-2.90 (m, 2H), 5.45 (s, 2H), 5.60 (s, lH), 6.75 (d, lH), 6.85 (d, lH), 6.95 (s, lH), 7.05 (s, lH), 7.30-7.40 (m, 3H~, 7.55-7.65 (m, 2H).
FAB-MS: m/e 430 (M+l).

WO91/11~9 PCT/US91/~s~7 ` 20~562~

F.~AnU 1e 36 3-[4-((1-Carbo~y-1-(2-methylphenyl))methoxy)-3-chloro-phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]-pyridine Step A: Preparation of methyl 4-tert-butyldimethyl-silylo~y-3-chlorobenzoate To a solution of 5.00 g (26.8 mmol) of methyl 3-chloro-4-hydro~ybenzoate dissolved in 40 mL of CH2C12 was added 6.55 g (53.6 mmol) of 4-dimethyl-aminopyridine, 4.85 g (32.2 mmol) of tert-butyl-dimethylchlorosilane and the mi~ture was stirred at room temperature for 3.5 hours. The reaction mi~ture was filtered, diluted with ethyl acetate, washed with 0.1 N ~Cl, saturated NaHC03, and brine. The product layer was then dried (MgS04), filtered and evaporated in vacuo to afford 8.05 g (100Z) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ 0.25 (s, 6H), 1.00 (s, 9H), 3.85 (s, 3H), 6.85 (d, lH), 7.80 (d, lH), 8.05 (s, lH).
FAB-MS: m/e 301, 303 (M+l).

Step B: PreparatiOn of 4-tert-butyldimethylsilyloxy-3-chlorobenzyl alcohol To a stirred and cooled (0C) solution of 8.00 g (26.7 mmol) of the product of Step A dissolved in 50 mL of anhydrous THF was added 53.3 mL (53.3 mmol) of a 1 M solution of lithium aluminum hydride in THF. After the addition was complete the reaction WO91/11~9 PCT/US91/oogs7 .; :

mixture was allowed to warm to room temperature and stirred 2 hours. The stirred reaction was 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 was then filtered and concentrated ~n vacuo. The residue was dissolved in ethyl acetate, washed with 1 N HCl, sturated NaHC03, dried (MgS04), and evaporated ~n vacuo to afford 4.0 g (53~/c) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ O.20 (s, 6H), 1.00 (s, 9H), 1.80 (br s, lH), 4.55 (s, 2H), 6.85 (d, lH), 7.10 (d, lH), 7.35 (s, lH).
FAB-MS: m/e-255, 257 (M+l).

Step C: Preparation of 4-tert-butyldimethylsilyl-o~y-3-chlorobe~zyl bromide To a stirred and cooled (0C) solution of 4.00 g (14.1 mmol) of the product of Step ~ dissolved in 70 mL of CH2C12 was added 5.84 g (17.6 mmol) of carbon tetrabromide and 4.61 g (17.6 mmol) of triphenylphosphine. After the addition the reaction mixture was allowed to warm to room temperature and was stirred 3 hours. The mi~ture was then evaporated in vacuo and purified on a silica gel flash chromato-2s graphy column eluted with 2Z ethyl acetate/hexane toafford 4.50 g (92%) of the title compound.
H NMR (300 M~z. CDC13, ppm): ~ O.20 (s, 6H), 1.00 (s, 9H), 4.40 (s, 2H), 6.80 (d, lH), 7.15 (d, lH), 7.35 (s, lH).

WO91/11~ 20~ ~æ~ PCT/US91/~957 Step D: Preparation of 3-(4-tert-butyltimethyl-~ilyloxy-3-chlorophenyl)methyl-5,7-dimethyl-?-et~yl-3~-imid~zor4.5-bl~yridine The product of Step C (1.79 g, 5.15 mmol) was used to al~ylate 0.750 g (4.29 mmol) of 5,7-dimethyl-2-ethylimidazo[4,5-b~pyridine (Example 24, Step C) according to the procedure described for Step of Example 27, which after purification afforded 0.294 g (15%) of the title compound.
lH NMR (300 MXz, CDC13, ppm): ~ O.20 (s, 6H), 1.00 (s, 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, lH), 7.85-7.90 (m, 2H), 7.15 (s, lH).
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 r4.5-blpyridine To a solution of 0.294 g (0.661 mmol) of the product of Step D dissolved in 4 mL of THF was added 0.69 mL (0.69 mmol) of a 1.0 M solution of tetra-n-butylammonium fluoride in l~, and the reaction mixture was stirred 2 hours at room temperature. The reaction was then concentrated in vacuo and purified by filtration through a silica gel pad eluted with chloroform. Evaporation of the filtrate and drying L~ vacuo afforded 0.188 g (87%) of the title compound.
lH NMR (300 MHz, CD30D, ppm): ~ 1.25-1.35 (t, 3H), 2.65 (s, 3H), 2.67 (s, 3H), 2.85-2.95 (m, 2H), 5.45 (s, 2H), 6.90 (d, lH), 6.95 (d, lH), 7.05 (~, lE), 7.15 (~, lH).
FAB-MS: m/e 316, 318 (M+l).

WO91/11~ PCT/US91/~9~7 2075~27 Ste~ F: Preparation of 3-[4-((1-carbomethoxy-1-(2-methylphenyl))metho~y)-3-chlorophenyl~methyl-5,7-dimethyl-2-ethyl-3~-imidazo~4,5-b~
~yridi~e To a suspension of 7 mg of a 60% oil disper-sion of sodium hydride in 0.75 mL of DMF was added O.050 g (0.16 mmol) of the product of Step E and the reaction mi~ture was stirred 10 minutes under an N2 atmosphere. A solution of methyl 2-bromo-2'-methyl-lo phenylacetate (prepared from 2'-methylphenylacetic acid via a Hell-Volhard-Zelins~y reaction similar to Step A of Example 17) dissolved in O.75 mL of DMF was then added and the reaction was stirred for 2 hour~
at room temperature. The reaction mixture was then partitioned between ethyl acetate and water, the organic layer was separated, dried (MgS04), filtered and e~aporated. The residue was purified on a silica gel flash chromatography column eluted with EtOAc/
hexane/CHC13 (50:40:10) to afford 0.070 g (92%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 1.25-1.35 (t, 3H), 2.45 (s, 3H), 2.60 (s, 3H), 3.65 (s, 3H), 2.75-2.85 (m, 2H), 3.70 (s, 3H), 5.35 (s, 2H), 5.60 (s, lH), 6.75 (d, lH), 6.85-6.95 (m, 2H), 7.15-7.40 (m, 4H), 7.55-7.65 (m, lH).
FAB-MS: m/e 478, 480 (M~l, 3:1 ratio).

WO91/11~ PCT/USgl/~9~7 297~i27 Ste~ G: Preparation of 3-t4~ -carboxy-l-(2-meth phenyl))methoxy)-3-chlorophenyl]methyl-5,7-di~ethyl-2-et~yl-3~-imidAzor4.5-bl~yridi~e Using the general procedure for ester hydrolysis described in Step E of E~ample 19, 0.040 g (0.15 mmol) of the product of Step F was con~erted to 0.066 g (97%) of the title compound.
lH NMR (300 MHz, CD30D, ppm): d 1.25-1.35 (t, 3H), 2.50 (s, 3H), 2.63 (s, 3H), 2.65 (5, 3H), 2.85-2.95 lo (m, 2H), 5.50 (s, ZH), 5.80 (s, lH), 6.95-7.10 (m, 3H), 7.20-7.30 (m, 4H), 7.60 (d, lH).
FAB-MS: m/e 464, 466 (M+l, 3:1 ratio).

F~m~le 37 3-t4-((1-Carboxy-l-phenyl)methoxy)-3-chloro-5-methoxyphenyl~methyl-5,7-dimethyl-2-ethyl-3H-imidazo r4.5-blpyridine Step A- Preparation of methyl 2-(2-chloro-4-hydroxy-~ethyl-6-methoxy~henoxy~-2-phenylacetate Using the K2C03/acetone conditions 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 (64Z) of the title compound.
1~ NMR (300 MHz, CDC13, ppm): ~ 1.65-1.75 (t, lE), 3.70 (s, 3E), 3.80 (s, 3H), 4.55 (d, 2H), 5.75 (s, lH), 6.80 (s, lH), 6.90 (s, lH), 7.30-7.40 (m, 3H), 7.50-7.60 (m, 2H).
FAB-MS: m/e 337, 339 (M+l, 3:1 ratio).

WO91/11~ PCT/US91/00957 Ste~ B: Preparation of 2-(4-bromomethyl-2-chloro-6_ metho~y~h~noxy)-2-~henylacet~te To a stirred and cooled (0C) solution of 0.570 g (1.69 mmol) of the product of Step A dissolved in 6 mL of CH2C12 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 hours. The mixture was then e~aporated 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.
H NMR (300 MHz, CDC13, ppm): ~ 3.75 (s, 3H), 3.80 (s, 3H), 4.35 (s, 2H), 5.65 (s, lH), 6.80 (s, lH), 6.95 (s, lH), 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-t4-((1-carbometho~y-1-phenyl)methoxy)-3-chloro-5-methoxyphenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazot4,5-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-ethylimidazot4,5-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.
lH NMR (300 M~z, CDC13, ppm): ~ 1.20-1.30 (t, 3H), 2.55 (s, 3H), 2-60 (s, 3H), 2.70-2.80 (m, 2H), 3.65 (s, 3H), 3.70 (s, 3H), 5.30 (s" 2H), 5.70 (s, lH) 6.63 (s, 1~), 6-68 (s, lH), 6.90 (s, lH), 7.25-7.35 (m, 3H), 7.45-7.55 (m, 2H).
FAB-MS: m/e 494, 496 (M+l).

wo 9l/ll~g 2 0 ~ 5 6 ~ ~ PCT/US91/00957 Step D: Preparation of 3-t4-((1-carboxY-l-phenyl)-metho~y)-3-chloro-5-methoyphenyl3methyl-5,7-dimethyl-2-et~ -3~ dAzOr4.S-blpyridi~e Using the general procedure for e~ter hydrolysis described in Step E of Example 19, 0.090 g (0.18 mmol) of the product of Step C was converted to 0.070 g (80%) of the title compound.
lH NMR (300 M~z, CD30D, ppm): ~ 1.20-1.30 (t, 3E), 2.60 (s, 3H), 2.65 (s, 3H), 2.80-2.90 (m, 2H), 3.75 lo (s, 3H), 5.45 (s, 2H), 5.70 (s, lE), 6.60 (s, 1~), 6.85 (s, lH), 7.05 (s, lH), 7.35-7.45 (m, 3E), 7.45-7.55 (m, 2H).
FAB-MS: m/e 480, 482 (M+l, 3:1 ratio).

F~am~le 38 3-t4-((1-Carboxy-l-phenyl)methoxy)-3,5-dichloro-phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]
pyr~dlne Step A: Preparation of methyl 4-tert-butyldimethyl-silylo~y-3.5-dichlorobenzoate To a solution of 10.00 g (45.2 mmol) of methyl 3,5-dichloro-4-hydroxybenzoate dissolved in 100 mL of CH2C12 was added 11.06 g (90.2 mmol) of 4-dimethylaminopyridine and 8.18 g (54.2 mmol) of tert-butyldimethylChlorOSilane and the mixture was stirred under N2 for 5 hours. The reaction mixture was then filtered and the filtrate was diluted with ethyl acetate. The solution was washed with water, 1 N HCl, saturated NaHC03, dried (MgS04), filtered and WO91/11~9 PCT/US91/~gs7 i 2075627 evaporated. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 7.70 g (51%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ O.30 (s, 6~), 1.00 (s, 9H), 3.90 (s, 3H), 7.95 (s, 2~).
FAB-MS: m/e 335, 337, 339 (M+l).

Step B: Preparation of 4-tert-butyldimethylsilyloxy-lo 3~5-dichlorobenzyl alcohol To a stirred and cooled (0C) solution of 7.70 g (23.0 mmol) of the product of Step A dissolved in 50 mL of anhydrous T~F was added 23.0 mL (23.0 mmol) of a 1 M solution of lithium aluminum hydride in T~F. After the addition was complete the reaction mixture was allowed to warm to room temperature and stirred 3.5 hours. The stirred 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 was then filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1 N ~Cl, ~turated Na~C03, dried (MgS04), and e~aporated La vacuo to afford 1.83 g (26%) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ 0.30 (s, 6H), 1.05 (s, 9H), 1.80 (br s, lH), 4.55 (s, 2H), 7.22 (s, 2H).
FAB-MS: m/e 306 (M+l).

WO91/11~9 PCT/USgl/00957 2o7~627 Ste~ C: Preparation of 3,5-dichloro-4-hydro~ybenzyl ~lcohol To a solution of 1.83 g (5.96 mmol) of the product of Step B dissolved in 6 mL of '1~ was added 5.96 mL (5.96 mmol) of a 1 M solution of tetra-n-butylammonium fluoride in THF and the reaction mi~ture was stirred at room temperature 30 minutes.
The solution was then e~aporated Ln y~cuo a~d the residue was purified on a silica gel flash chromato-lo graphy column eluted with 4% methanol/chloroform to afford 0.733 g (64%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 1.90-4.10 (br, 2H) 4.60 (s, 2H), 7.27 (s, 2H).
FAB-MS: m/e 192 (M+l).

Step D: Preparation of methyl 2-(2,6-dichloro-4-hydroxymethylpheno~y)-2-~henylacetate Using the K2C03/acetone conditions for phenol alkylation described in Step A of E~ample 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 (20Z) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 1.70-1.80 (t, 3H), 2s 3.75 (s, 3H), 4.55 (d, 2H), 5.75 (s, 1~), 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).

WO91/11~9 PCT/USgl/~957 - 20~5627 Step ~: Preparation of methyl 2-(4-bromomethyl-2,6-dichloropheno~y)-2-phenyl~cet~te To a stirred and cooled (0C) ~olution of O.140 g (O.41 mmol) of the product of Step D
dissolved in 2 mL of CH2C12 was added 0.170 g (0.51 mmol) of carbon tetrabromide and 0.135 ~ (0.51 mmol) of triphenylphosphine. After the addition the reaction mixture was allowed to warm to room temper-ature and was stirred overnight. The mixture was lo then evaporated in vacuo and purified on a silica gel flash chromatography column eluted with 15/. ethyl acetate/hexane to afford 0.130 g (78Z) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 3.75 (s, 3H), 4.30 (s, 2H), 5.75 (s, lH), 7.27 (s, 2H), 7.30-7.40 (m, 3H), 7.45-7.55 (m, 2H).
FAB-MS: m/e 405 (M+l).

Ste~ F: Preparation of 3-[4-((1-carbomethoxy-1-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) was used to al~ylate 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 0.096 g (68%) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ 1.20-1.30 (t, 3~), 2.58 (s, 3H), 2.62 (s, 3H), 2.65-2.75 (m, 2H), 3.75 (s, 3H), 5.30 (s, 2~), 5-75 (s, 1~), 6.90 (s, lH), 7.00 (s, 2H), 7.25-7.35 (m, 3H), 7.45-7.55 (m, 2E).
FAB-MS: m/e 498, 500, 502 ~M+l).

WO91/11~ PCT/USgl/o~s~7 20~62~ -`

Step G: Preparation of 3-t4-((1-carboxy-1-phenyl)-methoxy)-3,5-dichlorophenyl]methyl-5,7-dimethyl-2-et~yl-3~ idazor4.5-bl~yridine Using the general procedure for ester hydrolysis described in Step E of Example 19, 0.092 g (0.18 mmol) of the product of Step F was con~erted to 0.080 g (90%) of the title compound.
lH MMR (300 M~z, CD30D, ppm): ~ 1.20-1.30 (t, 3H), 2.61 (s, 3H), 2.65 (s, 3H), 2.80-2.95 (m, 2H), 5.45 1~ (s, 2H), 5.65 (s, lH), 7.05 (s, 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).

F~ le 39 1~
3-[4-((1-Carboxy-l-phenyl)methoxy)-2-chlorophenyl]-methyl-5 7-dimethyl-2-ethyl-3H-imidazor4.5-blpyridine Step A: Preparation of methyl 2-(3-chloro-4-formyl-phenoxy)-2-phenylacetate Using the K2C03/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.
H NMR (300 MHz, CDC13, ppm): ~ 3.75 (s, 3H), 5.68 (s, lH), 6.90 (d, 1~), 7.00 (s, lH), 7.35-7.45 (m, 3H), 7.50-7.60 (m, 2H), 7.85 (d, lH), 10.30 (s, lH).
FAB-MS: m/e 305, 307 (M+l).

WO91/11~ PCT/US91/~ss7 207~627 Step B: Preparation of methyl 2-(3-chloro-4-hydr met~ylphe~oxy)-2-~henylAcetate A stirred solution of 1.49 g (4.90 mmol) of the product of Step A dissolved in 20 mL of methanol was treated with 0.093 g (2.46 mmol) of sodium borohydride at room temperature. After S minutes the reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid, and the organic layer was ~eparated. The product was washed with water, brine, dried (MES04), filtered and evaporated ~n ~acuo. The residue was purified on a ~ilica gel flash chromatography column eluted with 25% ethyl acetate/hexane to afford 1.380 g (92%) of the title compound.
1~ NMR (400 MHz, CDC13, ppm): ~ 1.80-1.85 (t, 1~), 3.75 (s, 3~), 4.70 (d, 2~), 5.60 (s, lH), 6.85 (d, lH~, 7.00 (s, 1~), 7.30-7.45 (m, 4~), 7.50-7.60 (m, 2H).

Step C: Preparation of methyl 2-(4-bromomethyl-3-chloro~henoxy)-2-phenylacetate To a stirred and cooled (O-C) solution of 1.38 g (4.51 mmol) of the product of Step D dissolved in 18 mL of CH2C12 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 was allowed to warm to room temperature and was stirred 3 hours. The miæture was then evaporated in vacuo and purified on a silica gel flash chromato-graphy column eluted with 10/. ethyl acetate/he~ane toafford 1 60 g (96%) of the title compound.

WO91/11~9 PCT/US91/~ss7 20~6~

H NMR (400 MHz, CDC13, ppm): ~ 3.75 (s, 3H), 4.55 (s, 2H), 5.60 (s, lH), 6.80 (d, lH), 7.00 (s, lH), 7.30 (d, lH), 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-t4-((1-carbometho~y-1-phenyl)methoxy)-2-chlorophenyl~methyl-5,7-dimethyl-2-ethyl-3~-imidAzor4.5-blpyridine 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 (E~ample 24, Step C) according to the proc~dure described for Step B of Example 27, which after purification afforded 0.094 g ~69%) of the title compound.
lH NMR (400 MHz, CDC13, ppm): ~ 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, lH), 6.45 (d, lH), 6.65 (d, lH), 6.90 (s, lH), 7.05 (s, lH), 7.35-7.40 (m, 3H), 7.45-7.55 (m, 2H).

FAB-MS: m/e 464, 466 (M+l, 3:1 ratio).

Step ~: Preparation of 3-[4-((1-carboxy-1-phenyl)-methoxy)-2-chlorophenyl~methyl-5,7-dimethyl-2-ethyl-3H-imidazor4.5-blpyridine Using the general procedure for ester hydrolysis 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.
lH NMR (300 MHz, CD30D, ppm): ~ 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, lH), 6.85 (d, lH), 7.05 (s, lH), 7.15 (s, lH), 7.35-7.45 (m, 3H), 7.55-7.65 (m, 2H).
FAB-MS: m/e 450, 452 (M+l, 3:1 ratio).

20756~7 F.Y~ple 40 3-[4-((1-Carboxy-1-(3-phenyl)propyloxy)phenyl3methyl-5.7-dimet~yl-2-etbyl-3~ idAzor4.5-b~pyri~i~e Step A: Preparation of 3-t4-((1-carboetho~Y-1-(3-phenyl)propo~y)phenyl~methyl-5,7-d~methyl-2-ethyl-3~I-imid~zor4~5-blpyridine To a suspension of 20 mg (0.18 mmol) of a 35~/ oil dispersion of ~H in 0.4 mL of anhydrous DMF
was added 0.050 g (0.18 mmol) of 5,7-dimethyl-2-ethyl-3-(4-hydroxyphenyl)methyl-3~-imidazot4,5-b]pyridine (Example 24, Step E) and the reaction mi~ture was stirred under N2 at room temperature. After 15 minutes, 0.050 g (0.18 mmol) of 18-crown-6 and a solution of 0.053 g (0.20 mmol) of ethyl 2-bromo-4-phenylbutanoate dissolved in 0.4 mL of DMF were added. The reaction mixture was stirred at room temperature 4 hours, then partitioned between ethyl acetate and water. The organic layer was ~eparated, washed with water, dried (MgS04), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 50% ethyl acetate/hexane to afford 0.063 g (75%) of the title COmpound.
1~ NMR (300 M~z, CDC13, ppm): ~ 1.17 (t, J=8 Hz, 3~), 1.27 (t, J=8 Hz, 3~), 2.11-2.30 (m, 2E), 2.56 (s, 3~), 2.60 (s, 3H), 2.70-2.90 (m, 4H), 4.15 (q, J~8 Hz, 2H), 4.50 (td, J=6, 7 Hz, lH), 5.35 (s, 2H), 6.74 (d, J=10 Hz, 2H), 6.86 (s, lE), 7.04 (d, J=10 Ez, 2H), 7.10-7.28 (m, 5~).
FAB-MS: m/e 472 (M+l) WO91/11~9 PCT/USgl/~ss7 207 56~7 `-``

Step B: Preparation of 3-t4-((1-carboxY-1-(3-phenyl)-propoxy)phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imid~zor4.5-bl~yridine Using the general procedure for ester hydrolysis described in Step E of E~ample 19, 0.063 g (O.13 mmol) of the product of Step A was converted to 0.047 g (80%) of the title compound.
lH NMR (300 MHz, CD30D, ppm): ~ 1.27 (t, J~8 Hz, 3H), 2.16 (m, 2H), 2.63 (s, 3~), 2.66 (s, 3H), 2.80-2.95 lo (m, 4H), 4.55 (t, J=6 Hz, lH), 5.52 (s, 2H), 6.86 (d, J=10 Hz, 2H), 7.07 (s, lR), 7.12 (d, J=10 ~z, lH), 7.15-7.32 (m, 5H).
FAB-MS: m/e 444 (M+l).

F.~rA~1e 41 3-[4-((1-Carboxy-1-(2-phenyl)ethoxy)phenyl]methyl-5,7-dimethyl-2-ethyl-3R-imidazor4 5-bl~yridine Step A: Preparation of methyl 2-(4-hydroxymethyl-~henoxy)acetate Using the K2C03/acetone conditions for phenol alkylation described in Step A of Example 30, 8.00 g (64.5 mmol) of 4-hydroxybenzyl alcohol was 25 alkylated with 11.84 g (77.4 mmol) of methyl bromo-acetate to afford 6.00 g (48%) of the title compound.
H NMR (300 MHz, CDC13, ppm): ~ 1.74 (br s, lH), 3.76 (s, 3H), 4.61 (br s, 4H), 6.86 (d, J=10 Hz, 2H), 7.26 (d, J=10 Hz, 2E).
FAB-MS: m/e 305 (M+1).

WO91/11~ PCT/US91/~957 - 285 _ Step B: Preparation of methyl 2-(4-tert-butyl-dimet~ylsilyl~y~ethy~phenoyy)~cet~te To a solution of 4.00 g (20.4 mmol) of the product of Step A dissolved in 30 mL of C~2C12 was added 5.00 g (40.8 mmol) of 4-dimethylaminopyridine and 3.69 g (24.5 mmol) of tert-butyldimethylchloro-silane and the mi~ture was stirred under N2 for 5 hours. The reaction mi~ture was then filtered and the filtrate was diluted with ethyl acetate. The solution was washed with water, 1 N HCl, saturated NaHC03, dried (MgS04), filtered and evaporated.
Drying in vacuo afforded 6.30 g (99%) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ O.09 (s, 6~), 0.94 (s, 9~), 3.80 (s, 3H), 4.63 (s, 2~), 4.68 (s, 2~), 6.86 (d, J=10 ~z, 2H), 7.26 (d, J=10 ~z, 2H).
FAB-MS: m/e 311 (M+l).

Step C: Preparation of methyl 2-(4-tert-butyl-dimethylsilyloxymethylphenoxy)-3-phenyl-propanoate A solution of 1.00 g (3.23 mmol) of the product of Step B dissolved in 4 mL of toluene was stirred under a N2 atmosphere and cooled to 0CC with an ice-water bath. To this solution was added 9.68 mL (4.85 mmol) of a 0.5 M solution of potassium bis(trimethylSilyl)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 stirred 1 hour. Several milliliters of methanol were added to consume excess base, and the reaction was partitioned wo 9~ 2 ~ 7 ~ 6 2 ~ PCT/US91/~9~7 between ethyl acetate and 1 N ECl. The organic layer was separated, washed with ~aturated NaHC03, brine, dried (MgS04), filtered and evaporated. The residue was purified on a ~ilica gel flash chromatography column eluted with 15% ethyl acetate/he~ane to afford 0.540 g (42%) of the title compound.
H NMR (300 MHz, CDC13, ppm): ~ O.09 (s, 6H), 0.94 (s, 9H), 3.24 (m, 2H), 3.70 (s, 3H), 4.64 (s, 2H), 4.80 (dd, J=6,7 Hz, lH), 6.B0 (d, J=10 Hz, 2H), lo 7-09-7-35 (m, 7H).
FAB-MS: m/e 401 (M+l).

Step D: Preparation of methyl 2-(4-hydroxymethyl-~henoxy)-3-~henyl~ro~anoate To a solution of 0.520 g (1.30 mmol) of the product of Step C dissolved in 3 mL of anhydrous T~F
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 Ln vacuo and the residue was purified on a silica gel flash chromato-graphy column eluted with 70% ethyl acetate/hexane to afford 0.230 g (62%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 1.55 (br s, lH), 3.23 (m, 2~), 3.66 (s, 3H), 4.56 (d, J=9 Hz, 2H), 4.74 (dd, J=6,7 ~z, lH), 6.83 (d, J=10 Hz, 2H), 7.10-7.30 (m, 7H).
FAB-MS: m/e 285 (M+l).

WO91/11~ PCT/US91/~ss7 2D7~627 Ste~ F: Preparation of methyl 2-(4-bromomethyl_ pheno~y~-3-~henyl~rop~noAte To a cooled (O-C) ~olution of 0.230 g (0.80 mmol) of the product of Step D dissolved in 4 mL of CH2C12 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 O-C, the reaction mixture was allowed to warm to room temperature and was stirred for an additional 6 hours. The reaction was then concentrated ~ 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.
lH NMR (300 M~z, CDC13, ppm): ~ 3.20 (m, 2H), 3.80 (s, 3H), 4.44 (s, 2H), 4.77 (dd, J=6,7 Hz, lH), 6.76 (d, J=10 Hz, 2H), 7.17-7.35 (m, 7H).

Step F: Preparation of 3-[4-((1-carboethoxy-1-(2-phenyl)ethoxy)phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazor4.5-blpyridine 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.
lH N~R (300 M~z, CDC13, ppm): ~ 1.26 (t, J=8 Hz, 3H), 2.55 (s, 3H), 2.60 (s, 3H), 2.74 (q, J=8 Hz, 2H), 3.20 (m, 2H), 3.65 (s, 3H), 4.72 (dd, J=6,7 ~z, lH), 5.34 (s, 2H), 6.70 (d, J=10 ~z, 2H), 6.83 (s, lH), 7.02 (d, J=10 Hz, 2H), 7.16-7.30 (m, 5H).
FAB-MS: m/e 444 (M+l).

WO91/11~ PCT/US91/~ss7 207~627 Step G: Preparation of 3-t4~ -carboxy-l-(2-phenyl)-etho~y)phenyl]methyl-5.7-dimethyl-2-ethyl-3~-imid~zor4.5-blpyridi~e Using the ~eneral procedure for ester hydrolysis 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.
1~ MMR (300 M~z, CD30D, ppm): ~ 1.25 (t, J=8 ~z, 3H), 2.60 (s, 3~), 4.63 (s, 3~), 4.85 (g, J=8 ~z, 2~), lo 3.18-3.25 (m, 2~), 4.78 (dd, J=6,7 Hz, 1~), 5.45 (s, 2~), 6.80 (d, J=10 ~z, 2~), 7.02-7.10 (m, 3~), 7.15-7.35 (m, 5H).
FAB-MS: m/e 430 (M+l).

T~ le 42 3-[4-((1-Carboxy-l-phenyl)methoxy)-3-(2-propen-1-yl)-phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazot4,5-b]
pyridine Ste~ A: Preparation of methyl 4-(2-propen-1-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 potassium carbonate, 80.5 mL (112.6 g, 0.932 mol) of allyl bromide and the mixture was stirred and refluxed for 14 hours. The mixture was cooled to room temperature, filtered and concentrated to an oil. The residual oil was purified by distillation (97-C @ 0.03 mm Eg) to afford 53.52 g (86~/~) of the title compound.

WO91/11~ PCT/US91/0095~

: 20756~7 1~ NMR (300 M~z, CDC13, ppm): ~ 3.84 (s, 3~), 4 56 (d, J=7 ~z, 2~ .Z8 (dd, J=3,12 Hz, 1~), 5.40 (dd, J=3,19~z, 1~), 5.96-6.10 (m, 1~), 6.90 (d, J=10 ~z, 2H), 7.96 (d, J=10 Hz, 2~).
FAB-MS: m/e 193 (M~l).

Ste~ ~: Preparation of methyl 4-hydro~y-3-(prop-2-en-l-yl)benzoate A solution of 15.05 g (78.3 mmol) of the lo product of Step A in 25 mL of 1,2-dichlorobenzene was magnetically stirred and refluxed (183-C~ under an argon atmosphere for 18 hours. At this point, the reaction mi~ture was cooled to room temperature and applied to a 6 cm diameter by 18 cm silica gel flash chromatography column and eluted with 25Z ethyl acetate-hexane to separate the 1,2-dichlorobenzene, then with 40% ethyl acetate-hexane to elute the product. The product fractions were concentrated in Y~CUO and the residual oil was crystallized from 2~ hexane to afford 13.70 g (91%) of the title compound 1~ NM~ (300 M~z, CDC13, ppm): ~ 3.42 (d, J=8 Hz, 2H), 3.88 (s, 3~), 5.14-5.20 (m, 2~), 5.48 (s, lH), 5.94-6.06 (m, lE), 6.82 (d, J=12 H~ ), 7.80-7.85 (m, 2~).
~AB-MS: m/e 193 (~+1).

Step C: Preparation of methyl 4-(tert-butyldimethyl-silylD~y)-3-~2-~ro~en-1-yl)~e~zo~t~

To a ~olution of 5.168 g (26.9 mmol) of the product of Step B in 50 mL of dichloromethane was added 4.40 mL (2.95 mmol) of triethylamine, 4.46 g WO91/11~ ~ 0 7 5 ~ 2 7 PCT/US91/00957 (2.95 mmol) of tert-butyldimethylchlorosilane,0.100 g of 4-dimethylaminopyridine, and the reaction mi~ture was ~tirred at room temperature for 2 hours. The mixture was then diluted with S0 mL dichloromethane, washed with lO0 mL 1 N hydrochloric acid, dried (MgS04), filtered and evaporated. The residual oil (7.993 g, 97%) was used in the next ~tep without further purification.
lH NMR (300 M~z, CDC13, ppm): ~ 0.24 (s, 6E), 1.02 (s, 9H), 3.36 (d, J=8 Hz, 2~), 3.84 (s, 3H), 4.98-5.08 (m, 2H), 5.88-6.03 (m, lH), 6.78 (d, J=ll Hz, lH), 7.76-8.40 (m, 2H).
FAB-MS: m/e 307 (M+l).

Step D Preparation of 4-(tert-butyldimethyl-silyloxy)3-(2-propen-1-yl)benzyl alcohol To a magnetically stirred solution of 8.523 g (28.0 mmol) of the product from Step C in 35 mL of anhydrous T~F was added 15.0 mL of a 1.0 M ~olution f lithium aluminum hydride in TJF, and the reaction - mi~ture was stirred under a nitrogen atmosphere for 2 hours. At this point, the reaction was quenched by cautious addition of 10 mL water, the re~ulting precipitate was di~solved by addition of 1.0 N
hydrochloric acid and the product was extracted into ethyl acetate. The organic layer was separated, dried (MgS04), filtered and e~aporated in ~acuo to afford 7.258 g (93%) of the title compound.
lH NMR (300 M~z, CDC13, ppm): ~ O.20 (s, 6H), 1.00 (s, 9H), 3.34 (d, J=8 Hz, 2H), 3.84 (s, lH), 4.57 (s, 2H), 4.97-5.07 (m, 2H), 5.88-6.03 (m, lH), 6.86 (d, J=10 Hz, lH), 7.05-7.14 (m, 2H).
FAB-MS: m/e 279, 261 (M+l).

~ WO91/11~9 PCT/US91/oogs7 Step F: Preparation of 4-(tert-butyldimethyl_ silyl)3-(7-prope~-1-y~benzy~ 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 was slowly added 8.131 g (31 mmol) of triphenylphosphine at 0C under a nitrogen atmosphere.
The reaction mixture was stirred 45 minutes and allowed to warm to room temperature. At this point, lo the reaction mixture was applied to a silica gel flash 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 ~iscous oil.
lH NMR (300 M~z, CDC13, ppm): ~ 0.23 (s, 6H), 1.00 (s, 9H), 3.34 (d, J=8 Hz, 2H), 4.45 (s, 2H), 4.98-5.09 (m, 2H), 5.86-6.02 (m, lE), 6 . 74 (d, J=10 Hz, lH), 7.08-7.16 (m, 2H).
~AB-MS: m/e 343, 341 (M+l).

Ste~ F: Preparation of 5,7-dimethyl-2-ethyl-3-~4-tert-butyldimethylsilyloxy-3-(2-propen-1-yl)-~henyllmethyl-3H-imidazo r 4.5-blpyridine To a solution of 1.029 g (5.9 mmol) of 5,7-dimethyl-2-ethylimidazO[4,5-b]pyridine (Example 24, Step C) dissolved in 10 mL of dry DMF was added 0.258 g (6.5 mmol) of a 60% oil dispersion of sodium hydride and the reaction mixture was stirred under a nitrogen atmosphere for 1 hour. At this point, hydrogen evolution had ceased, and a solution of 2.210 g of the product of Step E dissol~ed in 2.0 mL

WO91/11~9 PCT/USgl/00957 2 0 7 5 6 2 ~ --of dry DMF was added via ~yringe. The reaction was ~tirred an additional 2 hours at room temperature and then partitioned between ethyl acetate and water.
The organic layer was extracted, washed with brine, dried (MgS04), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 50'~ ethyl acetate-hexane.
F.vaporation of the purified fraction and drying in vacuo afforded 1.519 g (59%) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ O.16 (s, 6H), 0.96 (s, 9~), 1.27 (t, J=9 ~z, 3H), 2.57 (s, 3H), 2.60 (8, 3H), 2.76 (q, J=9 Hz, 2H), 3.28 (d, J=8 ~z, 2H), 4 93-5.03 (m, 2~), 5.33 (s, 2~), 5.81-5.95 (m, lH), 6.64 (d, J=10 Hz, lH), 6.76 (dd, J=3,10 Hz, lH), 6.86 (s, lH), 7.00 (d, J=3 ~z, lH).
FAB-MS: m/e 436 (M+l).

Step G: Preparation of 5,7-dimethyl-2-ethyl-3_[4_ hydroxy-3-(2-propen-1-yl)phenyl]methyl-3~-imidazor4.5-blpyridine 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 T~F and the reaction mixture was stirred for 2.5 hours at room temperature. The reaction mixture was then evaporated ~n 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 ~n vacuo to afford the title compound.

WO91/11~9 PCT/US91/ooss7 '' . 2075627 lH NMR (300 M~z, CDC13, ppm): ~ 1.24 (t, J=9 ~z, 3H), 2.57 (s, 3H), 2.60 (s, 3H), 2.73 (q, Jc9 Hz, 2E), 3.31 (d, J=8 Hz, 2H), 5.03-S.10 (m, 2E), 5.33 (~, 2H), 5.88-6.02 (m, lH), 6.36 (d, J=10 Ez, 1~), 6.48 (dd, J=3,10 Hz, lH), 6.84-6.89 (m, 2H), 7.37 (br 8, lH).
FAB-MS: m/e 322 (M+l).

Ste~ ~: Preparation of 5,7-dimethyl-2-ethyl-3-t4-((1-carbomethoxy-1-phenyl)metho~y)-3-(2-propen-1-yl)phenyl]-methyl-3H-imidazo~4,5-bl pyridine To a solution of 0.171 g (0.53 mmol) of the product of Step G dissolved in 2.5 mL of anhydrous DMF was added 0.023 g (0.58 mmol) of a 60% oil dispersion of sodium hydride and the reaction mixture was stirred under a nitrogen atmosphere for 30 minutes at room temperature. A solution of 0.134 g of methyl a-bromophenylacetate in 1.0 mL of DMF was then added ~ia syringe and the reaction mixture was stirred an additional 1.5 hours. The reaction mi~ture was then partitioned between ethyl acetate and water, the organic layer was separated, dried (MgS04), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 75% ethyl acetate-hexane to afford after evaporation of the purified fractions and drying in vacuo 0.212 g (8570) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 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, 2~), 3.66 (s, 3H), 4.99-5.07 (m, WO91/11~9 PCT/USgl/ooss7 207~27 2H), 5.34 (s, 2~), 5.57 (s, lH), 5.88-6.04 (m, lE), 6.59 (d, J=10 ~z, lH), 6.79 (dd, J=3,10 ~z, l~), 6.86 (s, 1~), 7.05 (d, J=3 Hz, lE), 7.30-7.40 (m, 3H), 7.48-7.56 (m, 2H).
FAB-MS: m/e 470 (M+l).

Ste~ I: Preparation of 3-~4-((1-carboxy-1-phenyl)-methoxy)-3-(2-propen-1-yl)phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazor4.5-bl~ysidine To a solution of 0.141 g (0.30 mmol) of the product of Step H dissolved in 2.0 mL of methanol was added 0.25 mL of a 1.0 N solution of sodium hydroxide and the reaction was stirred at room temperature for 2 hours. The reaction mi~ture was then adjusted to pH 7 with 1.0 N hydrochloric acid and then partitioned between ethyl acetate and water. The organic layer was separated, dried (MgS04), filtered, evaporated and then purified on a silica gel flash chromatography column eluted with chloroform-methanol-conc. ammonium 20- hydroxide (80:15:1). Evaporation of the purified fractions and drying ~a vacuo afforded 0.092 g (69%) of the title compound as a white amorphous solid.
lH NM~ (300 M~z, CD30D, ppm): ~ 1.27 (t, J=9 ~z, 3~), 2.61 (s, 3H), 2.64 (s, 3H), 2.89 (q, J=9 ~z, 2H), 3.40-3.52 (m, 2~), 4.95-5.06 (m, 2H), 5.53 (s, 2H), S.73 (s, 1~), 5.94-6.13 (m, 1~), 6.84 (d, J=10 ~z, 1~), 6.95 (dd, J=3,10 Ez, 1~), 7.06 (br s, 2H), 7.36-7.44 (m, 3H), 7.57-7.64 (m, 2~).
FAB-MS: m/e 456 (M+l).

WO 91/11999 PCI'/US91/009s7 ~ le 43 3-t4-((1-Carboxy-l-phenyl)methoxy)-3-propylphenyl]-methyl-5.7-dimet~yl-2-ethyl-3~-imidazor4.5-bl~yridine Step A: Preparation of 5,7-dimethyl-2-ethyl-3-[4-hydroxy-3-propylphenyl]methyl-3H-imidazo r4.5-blpyridine A solution of 0.255 (0.79 mmol) of the product of Example 1, Step G in 10 mL ethanol was placed in a small Parr hydrogenation flask and 50 mg of a 10% palladium on carbon catalyst was added. The reaction mixture was then shaken in a Parr apparatus under a 45 psig hydrogen atmosphere for 1 hour at room temperature. The reaction mixture was then remo~ed from the flask, filtered, evaporated and dried ~a vacuo to afford 0.239g (93%) of the title compound which was used in the next step without further purification.
lH NMR (300 MHz, CDC13, ppm): ~ O.90 (t, J=9 Ez, 3~), 1.24 (t, J=10 Hz, 3H), 1.50-1.62 (m, 2H), 2.48 (t, J=8 Hz, 2H), 2.56 (s, 3H), 2.59 (s, 3H), 2.72 (q, J=9 Hz, 2H), 5.32 (s, 3H), 6.23 (d, J=10 Hz, lH), 6.38 (dd, J=3,10 Hz, lH), 6.79 (d, J=3 Hz, lH), 6.87 (s, lH), 7.68 (br s, lH).
FAB-MS: m/e 324 (M+l).

wo gl,ll~g 2 0 7 ~ 6`2 ~ PCT/US91/~957 Step B: Preparation of 5,7-dimethyl-2--ethyl-3-t4-((l-carbomethoxy-l-phenyl)methoxy)-3-propyl-phenyllmethyl-3~-imidazor4.5-blpyridine To a solution of 0.062 g (0.19 mmol) of the product of Step A in 1.5 mL of anhydrous DM~ was 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 mi~ture had stirred 30 minutes at room temperature, hydrogen evolution had ceased, and a solution of 0.048 g of methyl 2-bromophenylacetate in 0.5 mL of dry DMF was added via syringe. The reaction mixture was stirred an additional 1.5 hours and then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgS04), 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 ~iscous oil.
lH NMR (300 MHz, CDC13, ppm): ~ O.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, lH), 6.59 (d, J=10 Hz, lH), 6.81 (dd, J=3,10 Hz, lH), 6.87 (s, lH), 6.99 (d, J=3 Hz, lH), 7.28-7.40 (m, 3H), 7.49-7.56 (m, 2H).
FAB-MS: m/e 472 (M+l).

WO91/11~ PCT/US91/~957 ~ 2075627 Step C: Preparation of 3-[4-((1-carboxy-1-phenyl)-methoxy)-3-propylphenyl]methyl-5,7-dimethyl-2-et~yl-3~-imidazor4.5-blpyridine To a ~olution of 0.042 g (0.09 mmol) of the product of Step B tissol~ed in 1.0 mL of methanol was added 0.1 mL of a 1.0 N solution of sodium hydroxide and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then adjusted to pH 7 with 1.0 N hydrochloric acid and then partitioned between ethyl acetate and water.
The organic layer was separated, dried (MgSO4), filtered, evaporated and then purified on a ~ilica gel flash chromatography column eluted with chloroform-methanol-conc. ammonium hydroxide (80:15:1). E~aporation of the purified fractions and drying L~ vacuo afforded 0.021 g (51%) of the title compound as a white amorphous solid.
lH NMR (300 MHz, CD30D, ppm): ~ O.90 (t, J=8 Hz, 3H), 1.26 (t, J=9 Hz, 3H), 1.53-1.67 (m, 2H), 2.61 (s, 3H), 2.65 (s, 3H), 2.66-2.80 (m, 2H), 2.86 (q, J=8 Hz, 2H), 5.49 (s, 2H), 5.54 (s, lH), 6.80 (d, J=10 Hz, lH), 6.90 (dd, J=2, 10 Hz, lH), 6.98 (d, J=2 Hz, lH), 7.06 (s, lH), 7.30-7.44 (m, 3H), 7.60-7.66 (m, 2H).
FAB-MS: m/e 458 (M+l).

T.~rA~1e 44 3-[4-((1-Carboxy-1-(2-methylphenYl))methoXy)-3-propyl-phenyl~methyl-5~7-dimethyl-2-ethyl-3H-imidazo~4~5-b]
~yridine WO 9~ S 6~ PCT/US91/00957 Step A: Preparation of 5,7-dimethyl-2-ethyl-3_t4-((1-carbometho~y-l-(2-methylphenyl))methoxy)-3-propylphenyl]-methyl-3H-imidazot4,5-b]
pyridi~e To a suspension of 5.9 mg (2.45 mmol) of a 60% oil dispersion of NaH in 0.8 mL of DMF was added 0.066 g (0.20 mmol) of 5,7-dimethyl-2-ethyl-3-~4-hydroxy-3-propylphenyl3methyl-3H-imidazot4,5-b]
pyridine (Example 43, Step A) and the mixture was lo stirred at room temperature. After 20 minutes, a solution of 0.060 g (2.45 mmol) of methyl 2-bromo-2'-methylphenylacetate (prepared from 2'-methylphe`nyl-acetic acid via a Hell-Volhard-Zelinsky reaction similar to Step A of Example 17) dissol~ed in 0.5 mL
of DMF was added and the reaction mixture was stirred an additional 1.5 hours. The reaction was then partitioned between ethyl acetate and water, the organic layer was separated, washed with water, dried (MgS04), filtered and evaporated Ln ~acuo. The residue was purified on a silica gel flash chromato-graphy column eluted with 50% ethyl acetate/hexane to afford 0.082 g (83%) of the title compound.
H NMR (300 M~z, CDC13, ppm): ~ O.90 (t, J=9 Hz, 3H), 1.25 (t, J=8 Hz, 3H), 1.50-1.65 (m, 2H), 2.44 (s, 3H), 2.56 (s, 3H), 2.60 (~, 3H), 2.52-2.65 (m, 2H), 2.75 (q, J=8 Hz, 2H), 3.67 (s, 3H), 5.34 (s, 2H), 5.74 (s, lH), 6.55 (d, J=10 Hz, lH), 6.78 (dd, J=2, 10 Hz, lH), 6.86 (s, lH), 6.98 (d, J=2 Hz, lH), 7.15-7.28 (m, 3H), 7.50-7.56 (m, lH).
FAB-MS: m/e 486 (M+l).

WO91/11~9 PCT/US91/00957 Ste~ B: Preparation Of 3-t4-((l-carboxy-1-(2-methyl-phenyl~)metho~y)-3-propylphenyl~methyl-5,7-~imet~yl-2-et~yl-3~-imidazor4.5-bl~yridine Using the general procedure for e~ter hydrolysis described in Step E of Example 19, 0.076 g (0.16 mmol) of the product of Step A was con~erted to 0.040 g (~4%) of the title compound.
H NMR (300 MHz, CD30D, ppm): ~ 0.88 (t, J=9 Hz, 3H), 1.27 (t, J=8 Hz, 3H), 1.50-1.65 (m, 2~), 2.49 (s, 3H), 2.62 (s, 3~), 2.65 (s, 3H), 2.~-2.70 (m, 2H~, 2.88 (q, J=8 ~-, 2H), 5.48 (s, 2~), 5.83 (æ, lH), 6.78 (d, J=10 Hz, lH), 6.90 (dd, J=2,10 ~z, lH), 6.99 (d, J=2 Hz, 1~), 7.06 (s, 1~), 7.20-7.27 (m, 3~), 7.54-7.60 (m, lH).
lS FAB-MS: m/e 472 (M+l).

~m~le 45 3-[4-((1-Carboxy-1-(2-chlorophenyl))methoxy)-3-propyl-phenyl]methyl-5,7-dimethyl-2-ethyl-3~-imidazot4,5-b]
pyridlne Step A: Preparation of 5,7-dimethyl-2-ethyl-3-[4-((1-carbomethoxy-1-(2-chlorophenyl))methoxy)-3-propylphenyl]-methyl-3H-imidazot4,5-b]
~yridine To a suspension of 6.3 mg (2.63 mmol) of a 60% oil dispersion of Na~ in 1.O mL of DMF was added 0.071 g (0.22 mmol) of 5,7-dimethyl-2-ethyl-3_~4_ hydroxy-3-prOpylphenyl]methyl-3~-imidaZO[4,5-b]
pyridine (Example 43, Step A) and the mi~ture was wo 9~ 2 0 7 ~ ~ 2 ~ PCT/US91/~9~7 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) dis~olved in O.75 mL of DMF was added and the reaction mi~ture was ~tirred an additional 2 hours. The reaction was then partitioned between ethyl acetate and water, the organic layer was ~eparated, washed with water, dried (MgS04), filtered and evaporated Ln vacuo. The residue was purified on a silica gel flash chromato-graphy column eluted with 50% ethyl acetate/hexane toafford 0.098 g (88%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ O.89 (t, J=9 Hz, 3H), 1.26 (t, J=8 Hz, 3H), 2.55 (s, 3H), 2.59 (s, 3H), 2.52-2.63 (m, 2H), 2.74 (q, J=8 Hz, 2H), 3.70 (s, 3~), 5.34 (s, 2H), 6.03 (s, lH), 6.62 (d, J=10 ~z, lH), 6.78 (dd, J=2,10 Hz, lH), 6.86 (s, lH), 6.97 (d, J=2 Hz, lH), 7.24-7.32 (m, 2H), 7.34-7.42 (m, 1~), 7.57-7.64 (m, lH).
FAB-MS: m/e 506 (M+l).

Step B: Preparation Of 3-t4-((1-carboxy-1-(2-chlorophenyl))metho~y)-3-propylphenyl]methyl-5,7-dimethyl-2-ethyl-3~-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.
lH NMR (300 MHz, CD30D, ppm): ~ O.85 (t, J=9 Hz, 3H~, 1.25 (t, J=8 Hz, 3~), 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 DEMANDES OU BREVETS VOLUMINEIJX

LA PRESENTE PARTIE DE ~; I I t DEMANDE OU CE BREVET
COMPP~END PLUS D'UN TOME.

CECI EST LE TOME ~ DE 2 NOTE: Pour les tomes additionels, veuillez c~ntacter le Bureau canadien des brevets ~ ~7~7 J U IVI BO APPLI CATIO NS /PATENTS

THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE
THAN ONE VO~UME

THIS IS VOLUME 1 -_ OF

NOTE: Ear additicnat v~lumes please c~ntacl the Canadian Patent Office

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I wherein:

or a pharmaceutically acceptable salt thereof wherein:
R1 is:
(a) (Cl-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of:
i) aryl as defined below in Rl(b), ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, iv) OH, v) NH2, vi) NH(Cl-C4)-alkyl, vii) N[(Cl-C4)-alkYl)]2, viii) NH502R2, ix) CF3, x) COOR, or xi) S02NHRa; 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) Br, Cl, F, I, ii) (C1-C4)-alkyl, iii) (C1-C4)-alkoxy, iv) NO2 , v) CF3 vi) SO2NRaRa, vii) (C1-C4)-alkythio, viii) hydroxy, ix) amino, x) (C3-C7)-cycloalkyl, xi) (C3-C10)-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, O, S and wherein the heteroaryl is substituted,mono- or disubstituted with substituents selectet from the group consisting of:
i) Br, Cl, F, I, ii) OH, iii) SH, iv) N02, v) (C1-C4)-alkyl, vi) (C2-C4)-alkenyl, vii) (C2-C4 )-alkynyl, viii) (C1-C4)-alkoxy,or ix) CF3,or (d) perfluoro-(C1-C4)-alkyl; and -A1- A2-A3-A4-A5- is:

when A4 and A5 are absent, then -Al-A2-A3- is:

(a) (b) (C) (d) (e) (f) (g) (h wherein a represents a single bont in these definitions of A in structure I but, hereafter will represent a double bont.

(i) (j) (K) (L) (M) (N) (O) (P) (q) (r) (s) (t) (U) (V) W) (X) (y) (z) (ba ) (bb) (bc) (bd) when A4 is present and A5 is absent, then -A1-A2-A3-A4- represents:

(be) (bf) (bg) (bh) (bi) (bj) (bk) (bl) (bm) (bn) (bo) (bp) (bq) (br) (bs) (bt) (bu) (bv) (bw) (bx) (by) (bz) (ca) (cb) (cc) (cd) (ce) (cf) (cg) (ch) (ci) (cj) (ck) (cl) (cm) (cn) (co) (cp) (cq) (cr) when A4 and A5 are present, then -A1-A2-A3-A4-A5-are:

(cs) (ct) (cu) (cv) (cv) and B is:
(a) a single bond, (b) -S(O)n(CH2)s-, or (c) -O-; and n is 0 to 2; and s is 0 to 5; and D is (a) -O-, or (b) -N(R6)-; and G is:
(a) -O-, or (b) -S(O)n; and T is -S-, -O- or -N(R20)-; and R2 is:
(a) H, or (b) (C1-C6)-alkyl; and R2a is:
(a) R2.
(b) CH2-aryl, or (c) aryl; and R4 groups are independently:
(a) H, (b) (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, each of which is unsubstituted or substituted with:
i) OH, ii) (C1-C4)-alkoxy, iii) CO2R2, iv) OCOR2, v) CONHR2a, vi) CON(R2a)2, vii) N(R2a)C(=O)R2, viii) NH2, ix) (C1-C4)-alkylamino, x) di[(C1-C4)-alkyl]amino, xi) -S-(C1-C4)-alkyl, xii) aryl, xiii) heteroaryl, (c) C1, Br, I, F, (d) CF3, (e) CO2R2a, (f) C(=O)N(R2a)2, or (g) -C(=O)-aryl, (h) (C3-C7)-cycloalkyl, (i) -OR24, (i) -SH, (k) -S(O)n-(C1-C4)-alkyl, (l) -SO3H, (m) -NR2R21, (n) -NR2C(=O)R21, (o) -NR2COOR21 (p) -SO2NR2aR2a, (q) -NO2, (r) -NHSO2-(C1-C4)-alkyl, or (s) when R4 groups are on adjacent carbon atoms they may join to form a phenyl ring; and R5 is:
(a) H, or (b) (C1-C6)-alkyl or (C2-C6)-alkenyl, optionally substituted with:
i) hydroxy, or ii) (C1-C4)-alkoxy ; and R5a is (a) R5, or (b) (C1-C4)-acyl; and R6 is:
(a) H, (b) (C1-C6)-alkyl, or (c) (C1-C6)-alkyl substituted with hydroxy;
and R6a is (a) R6, or (b) (C1-C6)-alkyl substituted with:
i) CO2R2, ii) CONHR2, iii) CON(R2)2; and R7 and R8 are independently:
(a) H, (b) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl unsubstituted or substituted with a substituent selected from the group consisting of:
i) hydroxy, ii) (C1-C4)-alkoxy, iii) (C1-C4)-alkylthio, iv) amino, v) (C1-C4)-alkylamino, vi) di(C1-C4)-alkylamino, vii) carboxy, viii) carboxamido, ix) CO2Ra, x) OC(O)Ra, or xi) guanidino, (c) phenyl or phenyl-(C1-C4)-alkyl, wherein the phenyl group is unsubstituted or substituted with a member selected from the group consisting of:
i) hydroxy, ii) halo, iii) (C1-C4)-alkyl, iv) (C1-C4)-alkoxy, (d) imidazolyl-(C1-C4)-alkyl, or (e) indolyl-(C1-C4)-alkyl; and R9 and R10 are independently:
(a) H, (b) (C1-C6)-alkyl, unsubstituted or substituted with (C3-C7)-cycloalkyl, (c) (C2-C6)-alkenyl, (d) (C2-C6)-alkynyl, (e) Cl, Br, F, I, (f) (C1-C6)-alkoxy, (g) when R9 and R10 are on adjacent carbons, they can be joined to form a phenyl ring, (h) perfluoro-(C1-C6)-alkyl, (i) (C3-C7)-cycloalkyl, unsubstituted or substituted with (C1-C6)-alkyl, (j) aryl; and X is:
(a) -O-, (b) -S(O)n-, (c) -NR13-, (d) -CH2O-, (e) -CH2S(O)n, (f) -CH2NR13-, (g) -OCH2-, (h) -NR13CH2-, (i) -S(O)nCH2-, (j) -CH2-, (k) -(CH2)2-, (l) single bond, or (m) -CH=, wherein Y and R12 are absent forming a -C=C- bridge to the carbon bearing Z and R11; and Y is :
(a) single bond, (b) -O-, (c) -S(O)n-, (d) -NR13-, or (e) -CH2-; 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 (O, N, S, SO, SO2).

R11 and R12 are independently:
(a) H, (b) (C1-C6)-alkyl, unsubstituted or substituted with:
(i) aryl, or (ii) (C3-C7)-cycloalkyl, (c) aryl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of:
i) Cl, Br, I, F, ii) (C1-C6)-alkyl, iii) [(C1-C5)-alkenyl]CH2-, iv) [(C1-C5)-alkynyl]CH2-, v) (C1-C5)-alkoxy, or vi) (C1-C5)-alkylthio, and vii) -NO2, viii) -CF3, ix) -CO2R2a, or x) -OH, (d) aryl-(C1-C2)-alkyl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of:
i) Cl, Br, I, F, ii) (C1-C6)-alkyl, iii) [(C1-C5)-alkenyl]CH2-, iv) [(C1-C5)-alkynyl]CH2-, v) (C1-C5)-alkoxy, or vi) (C1-C5)-alkylthio, or vii) -NO2, viii) -CF3, ix) -CO2R2a, or x) -OH, (e) (C3-C7)-cycloalkyl; and R13 is:
(a) H, (b) (C1-C6)-alkyl, (c) aryl, (d) aryl-(C1-C6)-alkyl-(C=O)-, (e) (C1-C6)-alkyl-(C=O)-, (f) [(C2-C5)-alkenyl]CH2-, (g) [(C2-C5)-alkynyl]CH2-, or (h) aryl-CH2-; and Z is:
(a) -CO2H, (b) -CO2-(C1-C6)-alkyl, (c) -tetrazol-5-yl, (d) -CO-NH(tetrazol-5-yl) (e) -CONH-SO2-aryl, (f) -CONH-SO2-(C1-C8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: -OH, -SH, -O(C1-C4)-alkyl, -S-(C1-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2, -CO2H, -CO2-(C1-C4)-alkyl-, -NH2--NH[(C1-C4)-alkyl], or -N[(C1-C4)-alkyl]2, (g) -CONH-SO2-perfluoro-(C1-C4)-alkyl, (h) -CONH-SO2-heteroaryl, (i) -CONHSO2NR2aR2a, (j) -SO2NHCO-aryl, (k) -SO2NHCO-(C1-C8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: -OH, -SH, -O(C1-C4)-alkyl, -S-(C1-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2, -CO2H, -CO2-(C1-C4)-alkyl, -NH2, -NH(C1-C4)-alkyl], or -N[(C1-C4)-alkyl]2, (l) -SO2NHCO-perfluoro-(C1-C4)-alkyl, (m) -SO2NHCO-heteroaryl, (n) -SO2NHCONR2aR2a, (o) -PO(OH)2, (p) -PO(OR2)2, or (q) -PO(OH)(OR2); and R20 is:
(a) H, (b) (C1-C6)-alkyl, (c) alkyl, (d) (C3-C6)-cycloalkyl, (e) (C1-C4)-acyl, (f) benzyl, or (g) phenyl; and R21 is:
(a) H, or (b) (C1-C4)-alkyl, unsubstituted or substituted with:
i) NH2, ii) NH[(C1-C4)-alkyl], iii) N[(C1-C4)-alkyl]2, iv) CO2H, v) CO2(C1-C4)-alkyl, vi) OH, vii) SO3H, or viii) SO2NH2; and R22 groups are independently:
(a) H, (b) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl, each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C3-C7)-cycloalkyl, Cl, Br, I, F, -OH, -NH2, -NH(C1-C4)-alkyl], -N[(C1-C4)-alkyl]2, -NHSO2R25, -CO2R25, (C1-C4)-alkoxyl, (C1-C4)-alkylthio, (C1-C4)-acyl, or C(=O)NH2, (c) aryl, (d) substituted aryl in which the substituents are V or W, as defined below, (e) aryl-(C1-C4)-alkyl, which can be substituted with v or W as defined below, (f) Cl, Br, I, F, (g) hydroxyl, (h) amino, (i) NH[(C1-C4)-alkyl], (j) N[(C1-C4)-alkyl]2, (k) (C1-C6)-alkoxy, (l) CF3, (m) CO2R25, (n) C(=O)N(R25)2, (o) N(R25)-C(=O)R25, (p) (C1-C4)-alkylsulfonyl, (q) (C1-C4)-alkylsulfinyl, or (r) (C1-C4)-alkylthio; and R23 is:
(a) H, (b) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C3-C7)-cycloalkyl, Cl, Br, I, F, -OH, -NH2, -NH(C1-C4)-alkyl], -N[(C1-C4)-alkyl]2, -NHSO2R25, -CO2R25, (C1-C4)-alkoxyl, (C1-C4)-alkylthio, (C1-C4)-acyl, or C(=O)NH2, (c) -C(=O)R25, (d) -CO2R25, (e) aryl, which is unsubstituted or substituted with substituents V or W, (f) aryl-(C1-C4)-alkyl, which is unsubstituted or substituted with V or W; and R24 groups are independently:
(a) H, (b) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C3-C7)-cycloalkyl, Cl, Br, I, F, -OH, -NH2, -NH(C1-C4)-alkyl], -Nt (C1-C4)-alkyl]2, -NHSO2R25, -CO2R25, (C1-C4)-alkoxyl, (C1-C4)-alkylthio, (C1-C4)-acyl, or C(=O)NH2, (c) aryl or aryl-(C1-C4)-alkyl which is unsubstituted or substituted with V or W

V and W are each intependently selected from:
(a) H, (b) (C1-C5)-alkoxy, (c) (C1-C5)-alkyl.
(d) hydroxy, (e) -S(O)n-(C1-C5)-alkyl, (f) -CN, (g) -NO2, (h) NR2R2a, (i) -[(C1-C5)-alkyl]-CONR2R2a, (i) -CO2R2a, (k) -CO-(C1-C5)-alkyl, (l) CF3, (m) I, Br, Cl, F
(n) hydroxy-(C1-C4)-alkyl-, (o) carboxy-(Cl-C4)-alkyl-, (p) -tetrazol-5-yl, (q) -NH-SO2CF3, or (r) aryl; and R25 is:
(a) H, (b) (C1-C6)-alkyl, (c) aryl, or (d) aryl-(C1-C5)-alkyl.

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.

4. The compound of Claim 1 of structural formula:

or a pharmaceutically acceptable salt thereof.

5. The compound of Claim 1 of structural formula:

or a pharmaceutically acceptable salt thereof, 6. A compound which is or a pharmaceutically acceptable salt thereof.
wherein:
R1 is:
(a) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of:
i) aryl, ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, iv) OH, v) NH2.
vi) NH(C1-C4)-alkyl, vii) N[(C1-C4)-alkyl)]2, viii) NHSO2R, ix) CF3, x) COOR, or xi) SO2NHRa; 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) (C1-C4)-alkyl, iii) (C1-C4)-alkoxy, iv) NO2 v) CF3 vi) SO2NR2aR2a, vii) (C1-C4)-alkylthio, viii) hydroxy, ix) amino, x) (C3-C7)-cycloalkyl, xi) (C3-C10)-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, O, S and wherein the heteroaryl is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
i) Cl, Br, I, F, ii) OH, iii) SH, iv) NO2, v) (C1-C4)-alkyl, vi) (C2-C4)-alkenyl, vii) (C2-C4)-alkynyl, viii) (C1-C4)-alkoxy, or ix) CF3, or (d) perfluoro-(C1-C4)-alkyl; and R2a is: H, (C1-C6)-alkyl, benzyl, or phenyl; and R4 groups are independently:
(C1-C4)-alkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl, (C3-C5)-cycloalkyl, CO2R2a Br, Cl, F, I, -NR2aR2a, S(O)n-(C1-C4)-alkyl, O-(C1-C4)-alkyl, OH, CF3, CN, hydroxy-(C1-C4)-alkyl, or phenyl, unsubstituted or substituted with:
(C1-C4)-alkyl, Br, Cl, F, I or, methoxy; and n is 0, 1 or 2, R9 and R10 are independently:
H, (C1-6)-alkyl, (C2-C6)-alkenyl, aryl, (C2-C6)-alkynyl, (C1-C6)-alkoxyl, Br, Cl, I, F or R9 and R10 join to form a phenyl ring and X is:
(a) -O-, (b) -S(O)n-, 7. A compound which is or a pharmaceutically acceptable salt thereof.
wherein:
R1 is: (C1-C4)-alkyl and cyclopropyl; and R2a is: H, (C1-C6)-alkyl, benzyl, or phenyl; and R4 groups are independently:
hydrogen, (C1-C4)-alkyl, -CO2-(C1-C4)-alkyl, CH2OH, CO2H, (C1-C4)-alkoxy or NHCH3; and R9 and R10 are: (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl, (C1-C4)-alkoxyl, Cl, Br, I, F, (C3-C8)-cycloalkyl, or aryl; and R11 is: aryl or aryl-CH2-, wherein the aryl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:

Br, Cl, F, I, (C1-C4)-alkyl, (C1-C4)-alkoxyl, NO2, CF3, (C1-C4)-alkylthio, OH, -NR2aR2a and X is: O, NR13, CH2, or -CH=, which is double bonded to the carbon bearing Z and R11; and R13 is: H, (C1-C6)-alkyl, (C1-C6)-alkenyl, aryl;
and Z is: CO2H, CO2-(C1-C4)-alkyl, 1H-tetrazol-5-yl, -CONRSO2-aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
H; (C1-C4)-alkyl, (C1-C4)-alkoxy, NO2, CF3, SO2NR2aR2a, (C1-C4)-alkylthio, hydroxy, amino, (C3-C7)-cycloalkyl, (C3-C10)-alkenyl, or -CONHSO2-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, O, S, andis unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
Br, Cl, F, I, OH, SH, NO2, (C1-C4)-alkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl. (C2-C4)-alkoxy, or CF3.

(c) -NR13-(d) -CH2O-, (e) -CH2S(O)n, (f) -CH2NR13-, (g) -OCH2-, (h) -NR13CH2-, (i) -S(O)nCH2-, (j) -CH2-, (k) -(CH2)2-, (l) single bond, or (m) -CH=, which is double bonded to the carbon bearing Z ant R11; and Z is:
(a) -CO2H, (b) -CO2-(C1-C6)-alkyl, (c) -tetrazol-5-yl, (d) -CO-NH(tetrazol-5-yl) (e) -CONH-SO2-aryl, (f) -CONH-SO2-(C1-C8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of:
-OH, -SH, -O(C1-C4)-alkyl, -S-(C1-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2. -CO2H- -NH2, -CO2-(C1-C4)-alkyl, -NH[(C1-C4)-alkyl], or -N[(C1-C4)-alkyl]2, (g) -CONH-SO2-perfluoro-(C1-C4)-alkyl, (h) -CONH-SO2-heteroaryl, or (i) -CONHSO2NR2aR2a; and R11 is: aryl-CH2- or aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
Br, I, Cl, F, (C1-C4)-alkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl, (C1-C4)-alkoxyl, NO2, CF3, SO2NR2aR2a, (C1-C4)-alkylthio, hydroxyl, -NR2aR2a;
and R13 is:
(a) H, (b) (C1-C6)-alkyl, (c) aryl, wherein aryl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
Br, I, Cl, F, (C1-C4)-alkyl, (C1-C4)-alkoxy, NO2, CF3, SO2NR2aR2a, (C1-C4)-alkylthio, hydroxy, -NR2aR2a, (d) aryl-(C1-C6)-alkyl-(C=O)-, or (e) (C1-C6)-alkyl-(C=O)-.

8. A compound of Claim 1 of structural formula:

or a pharmaceutically acceptable salt thereof wherein:

R1 is: (C1-C4)-alkyl, R4c is: hydrogen, methyl or ethyl; and R4d is: R4C, -CO2-(C1-C4)-alkyl, CH2OH, CO2H, CO2CH2 (C1-C4)-alkyl or NHCH3; and R9 and R10 are: (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl, (C1-C4)-alkoxyl, Cl, Br, I, F, or phenyl; and X is O or NR13; and R11 is: benzyl or phenyl, unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of:
Br, I, Cl, F, (C1-C4)-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, (C1-C4)-alkenyl, NO2, CF3, SO2NR2aR2a, (C1-C4)-alkylthio, hydroxyl, NR2aR2a, Z is: CO2H, CO2-(C1-C4)-alkyl or 1H-tetrazol-5-yl.

9. A compound of Claim 1 of structural formula:

or a pharmaceutically acceptable salt thereof wherein:

R1 is: (C1-C4)-alkyl, R4c is: hydrogen, methyl or ethyl; and R4d is: R4C, -CO2-(C1-C4)-alkyl, CH2OH, CO2H, (C1-C4)-alkyl or NHCH3; and R9 and R10 are: (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl, (C1-C4)-alkoxyl, Cl, Br, I, F, or phenyl; and R11 is: benzyl or phenyl, wherein phenyl is unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of:
Br, I, Cl, F, (C1-C4)-alkyl, C2-C4-alkenyl. C2-C4-alkynyl, (C1-C4)-alkoxyl, NO2, CF3, SO2NRaRa, (C1-C4)-alkylthio, hydroxyl, -NRaRa Z is: CO2H, CO2-(C1-C4)-alkyl, or 1H-tetrazol-5-yl.

10. A compound of Claim 1 of structural formula:

or a pharmaceutically acceptable salt thereof.
wherein:

R1 is: (C1-C4)-alkyl; and R4c is: hydrogen, methyl or ethyl; and R4d is: R4c, -CO2-(C1-C4)-alkyl, CH2OH, CO2H, (C1-C4)-alkyl or NHCH3; and R9 and R10 are: (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl, (C1-C4)-alkoxyl, Cl, Br, I, F, or phenyl; and R11 is: benzyl or phenyl, unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of:
Br, I, Cl, F, (C1-C4)-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, (C1-C4)-alkoxyl, NO2, CF3, SO2NR2aR2a, (C1-C4)-alkylthio, hydroxyl, -NR2aR2a Z is: CO2H, CO2-(C1-C4)-allkyl, or 1H-tetrazol-5-yl.

11. A compound which is or a pharmaceutically acccptable salt thereof.
wherein: -R1 is: (C1-C4)-alkyl, R4c is: hydrogen, methyl or ethyl; and R4d is: R4c, -CO2-(C1-C4)-alkyl, CH2OH, CO2H, CO2CR2 (C1-C4)-alkyl or NHCH3; and R9 and R10 are: (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl, (C1-C4)-alkoxyl, Cl, Br, I, F, or phenyl; and R11 is: benzyl or phenyl, wherein phenyl unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of:
Br, I, Cl, F, (C1-C4)-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, (C1-C4)-alkoxyl. NO2. CF3, SO2NR2aR2a, (C1-C4)-alkylthio, hydroxyl, -NR2aR2a R13 is: (C1-C4)-alkyl, (C2-C4)-alkenyl, or phenyl; and Z is: CO2H, CO2-(C1-C4)-alkyl, or 1H-tetrazol-5-yl.

12. The compound of Claim 1 wherein said compound or its pharmaceutically acceptable salt is selected from the group consisting of:

3-[4-(1-Carboxy-1-(2-methylphenyl))methoxyphenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

3-[4-(1-Carboxy-1-(2-bromophenyl))methoxyphenyl]methyl -5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

3-[3-Chloro-4-((1-carboxy-1-phenyl)methoxy)phenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

3-[4-(1-Carboxy-1-(3-methylnaphth-2-yl))methoxyphenyl]
methyl-7-methyl-2-propyl-3H-imidazo[4.5-b]pyridine;

3-[4-((1-Carboxy-1-phenyl)methoxy)-3-methylphenyl]-methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

3-[4-((1-Carboxy-1-(2-methylphenyl))methoxy)-3-chlorophenyl]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-((1-Carboxy-1-(2-methylphenyl))methoxy)-3-propyl-phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]-pyridine;

3-[4-((1-carboxy-1-(2-chlorophenyl))methoxy)-3-propyl-phenyl]methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]-pyridine;

3-[4-((1-Carboxy-1-(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-1-phenyl)methoxy)-3,5-dipropylphenyl]
methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine;

3-[4-N-(1-Carboxy-1-phenyl)methyl)-N-allylaminophenyl]
methyl-5,7-dimethyl-2-ethyl-3H-imidazo[4.5-b]pyridine;

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-1-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-sulfonyl)carboxamito)-1-phenyl)methoxyphenyl]methyl-3H-imidazo[4,5-b]pyridine:

5,7-Dimethyl-2-ethyl-3-[3-ethyl-4-((1-(N-phenyl-sulfonyl)carboxamido)-1-phenyl)methoxyphenyl]methyl-3H-imidazo[4,5-b]pyridine;

5,7-Dimethyl-2-ethyl-3-[3,5-dipropyl-4-((1-(N-phenyl-sulfonyl)carboxamido)-1-phenyl)methoxyphenyl]methyl-3H-imidazo[4,5-b]pyridine.

13. A process for the preparation of compound of Claim 1 comprising a reaction between the alkali metal salt of the heterocycle of I, with the substituted phenyl where the substituents are as defined in Claim 1 and Q represents a leaving group, using a polar aprotic solvent or a polar protic solvents to yield the alkylation product.

14. A process for the preparation of an intermediate used in the synthesis of the compound of claim 1 which comprises reacting the alkali metal salt of the heterocycle with the substituted benzyl group of formula wherein the substituents are as defined in Claim 1 and the Pg represents a suitable protecting group to give the desired intermediate.

15. A process for the preparation of the compound of Claim 1 which comprises reacting the intermediate with the appropriate method for deprotection, followed by treatment with a metal hydride to give the reactive alkali metal salt which reacts with the intermediate in a polar aprotic solvent where the substituents are as defined in Claim 1 and Q represents a leaving group to yield the desired product.

16. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1.

17, The composition of Claim 16 which includes another antihypertensive agent selected from a diuretic, an angiotensin converting enzyme inhibitor a calcium channel blocker and a .beta.-blocker which are members selected from the group consisting of:
amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethitine sulfate, hydralazine hydrochloride, hydrochlorothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan camsylate, benzthiazide, guinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, diflunisal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrentipine, as well as 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 antihypertensive amount of a compound of Claim 1.

20. A method of treating ocular hypertension comprising topical ocular administration to a patient in need of such treatment of an effective ocular antihypertensive amount of a compound of Claim 1.

21. A method of treating cognitive dysfunction, anxiety, or depression comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound of

Claim 1.