CA2075637A1 - Angiotensin ii antagonists incorporating a substituted benzyl element - Google Patents

Abstract

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

Description

WOg1/12~1 2 ~ 7 ~ ~ 3 7 PCT/US91/~3 ~J

,, 1o TITLE OF T~ VENTION
ANGIOTENSIN II ANTAGONISTS INCORPORATING A
SUBSTITUTED ~ENZYL ELEMENT

BAC~GROUND OF T~E INVENTION
The present application is a continuation in part of Serial No. 479,786 filed on Febuary 13, 1990.
The Renin-angiotensin æystem (RAS) plays a . central role in the regulation of normal blood . pressure and seems to be critically involved in hypertension development and maintenance as well as conge6tive heart failure. Angiotenæin II (A II), iæ
an octapeptide hormone produced mainly in the blood du~ing the cleavage of angiotensin I by angiotensin convertlng enzyme (ACE) localized on the endothelium 2S of ~loot veæ8el6 of lung, ~idney, and many other ., .. ~ .
. - . . . : -.- ~ . . :
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. . . . . - . .
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. . -wosl/l20o~ 3 ~ ~ PCT/US9~ 93 . - :

organs. It is the end product of the renin-angiotensin ~y~tem (RAS) and is a powerful arterial vasoconstrictor that exerts its action by interacting with 6pecific receptors present on cell membranes.
One of the possible modes of controlling the RAS i6 an~iotensin II receptor antagonism. Several peptide analo~s of A II are known to inhibit the effect of this hormone by competitively blocking the receptors, but their experimental and clinical applications have l0 been limited by partial agonist activity and lack of oral absorption tM. Antonaccio. Clin. Ex~.
~Y~ n~ A4, 27-46 (1982); D. B. P. Streeten and G. ~. Anderson, Jr. - ~andbook of Bv~ertension, Clinical Pharmacolo~v of Antihy~ertensive Dru~s, ed.
15 A- E- Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984].
Recently, several non-peptide compounds have been described as A II antagonists. Illustrative of such compound~ are thoæe disclosed in ~.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. ~Eu~. J. Pharm. Ex~.
~h~2. 1~1. 13-21 (1988)] and by P.C. Wong, ~
tl._PhaL3h ~2~ Therap, 2~1. 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 245,637 discloses derivatives of 4,5,6,7-tetrahydro-2B-imidazot4,5-~]-pyridine-6-carbo~ylic acid and analogs thereof as antihypertensive agents.

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Wogl/12~1 ' ' PCT/US91/~3 ~ 2~7~37 ~1 - .

None of the compounds disclosed within this application or in any US Patent, European Applications or literature publication are of the type containing substituted heterocycles bonded through an alkyl brid,ge to a novel substituted phenyl of the type disclosed herein. The quinazolin-4(1~)-ones, triazolinone6, triazolinimines, and pyrimidinones have been disclosed in earlier U.S.
Patent applications focusing on the heterocyclic fragment of the antagonist design. The serial numbers of these applicatiGns are 351,508; 358,971;
375,655; 360,673; 375,217; and 386,328 and are hereby incorporated by reference.

BRIEF DEscRl~TIoN OF T~E INVENTION
This invention is directed to substituted heterocycles attached through a methylene bridge to novel substituted phenyl derivatives to give compounds of the Formula I, which are angiotensin II
antagonists and are useful in the treatment of hypertension and congestive heart failure. The compound6 of the invention are useful as ocular antihyperten~ives.
Specifically, the compounds of this invention contain a heterocyclic moiety which is 8ub8tituted at the 6pecified position6 and to which a methylene bridge connecting a novel substituted phenyl group as defined by the lower portion of Formula I. i~ attached. Additionally, , pharmaceutically acceptable composition~ of these novel compound8, as the sole therapeutically active ingredient and in combination with diuretics and Wos1/12~1 ~ 2 0 ~ 5 ~ 3 7 PCT/US91~ 3 ~

,,~
. - 4 -other antihypertensive agents, including beta blockers, angiotensin converting enzyme inhibitors, calcium channel bloc~ers or a combination thereof are disclosed and claimed. Further, methods of treating hypertension and congestive heart failure are described and claimed.

The compounds of this invention have central nervous system (CNS) activity. They are useful in the treatment of cognitive dysfunctions including Alzheimer's disease, amnesia and senile dementia.
These compounds also have anxiolytic and antidepressant properties and are therefore, useful in the relief of symptoms of anxiety and tension and in the treatment of patients with depressed or dysphoric mental states.
In addition, these compounds exhibit antidopaminergic properties and are thus useful to treat disorders that involve dopamine dysfunction 8uch as 8chizophrenia. The compound~ of this invention arc e8pecially u8e~ul in the treatment of these contitions in patients who are also hyperten~ive or have a congestive heart failure condition.

T~E INVEN~IQ~
This invention relates to compounds of the general Formula I:

, .

, . : - :: ' - ,' .' ' .. '. - ~ : - . -~ - 2 ~ 7 3 ~ 3 7 PCr/US91/00993 het erocycle Rll~z Rl2 -` 2S

i .

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.. . . . . .
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and the heterocycle is specifically defined as:

R'-B~
Ia ,Rl6 N--N
R1 _ I b ~ 25 L

r , .

- . . , , , :- ,. .
: . : - . . . .. . .. . ..
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wo 9~ 2 ~ 7 ~ ~ 3 ~ PCT/US91/~3 ~, :,.

Rl is:
(a) (Cl-C6)-alkYl. (C2-C6)-alkenyl or (C2-C6)-al~ynyl each of whi Ch i s unsubstituted or substituted with a substituent selected from the group consisting of:
i) aryl as defined below, ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, iv) o~, v) N~2, vi) N~(Cl-C4)-alkyl, vii) ~(cl-c4)-alkyl]2 vi i i ) N~S02R2 .
~5 ix) CF3, s) COOR2, or si) S02M~R2a; and (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consi~ting of:
i) Br, 1, Cl, F, ii) (Cl-C4)-alkyl, iii ) (Cl-C4)-alkosy, 2S iv) N02 v) CF3 vi ) S02NR2aR2a, vii ) (Cl-C4)-alkylthio .
viii) hydrosy, is) amino, ,~ s) ~C3-C7)-cycloa~kyl, ~i) (C3--Clo)--al~Dyl; ~IDt . .

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,, Wosl/l2~l ~ ~ . PCT/US91/~3 ,~,.,, ,, ~ ~;.
. ~,~,s ; - 8 -(c) an unsubstituted, monosubstituted or disubstituted heteroaromatic 5- or 6-membered cyclic moiety, which can contain one or two members selected from the group consi~ting of N, 0, S and wherein the substituents are members ~elected from the group consisting of:
i) Cl, Br, 1, or F, i i ) O~I, iii ) S~, i V ) N02 .
~) (Cl-C4)-alkyl, vi) (C2-C4)-alkenyl, vii) (C2-C4)-alkynyl, viii) (Cl-C4)-alkoxy, or ix) CF3, or (d) perfluoro-(Cl-C4)-alkyl; and B is:
(a) a ~ingle bond, (b) -S(O)n(C~2)5-, or (c) -0-; and n i 8 0 to 2; and 8 i8 0 to 5; ant Jl i6 ~a)-C(.M)-, (b) Jl and L are connected together to form a 6-carbon aromatic ring 8ubstituted with R7a, R7b, R8a and R8b or (c) Jl and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom not at Jl, substituted with R7a. R7b, R8a and R8b; and ~, .

. .. ... . .. : ..... . .
.: . . . . .
-.: .. . , : .......................... .: -.. . . . .

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: . .: , .: - . . .- -i~ ., ~ ~ : . - , :
, .. .... . .. .

: Wos1~12~] _ ~) PCT/US9~/~M~3 ;~ r 2 ~ 7 ;3 Çi t3 7 .
_ 9 _ Kl is (a)-C(=M~-, (b) Kl and L are connected together to form a 6-carbon aromatic ring substituted with R7a, R7b, R8a and R8b, or (c) Kl and L are connected together to form a 6-membered aromatic ring containin~ one nitrogen atom , substituted on the carbon atoms with R7a, R7b and R8b; and one sf al or ~l is a double bond in structures Ia lO provided that when Jl is -C(=M)- then ~l is a double bond and when Kl is -C(=M)- then ~l is a double bond.

L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom; and J2 is (a)-C(=M)-, or (b) -C(Rl7)-; and K2 is (a)-C(=M)-, or (b)-C(Rl7)-, provided that one and only one of J2 and ~2 is -C(~M)-; and one of ~2 or ~2 i~ a double bond in 8tructure Ic provided that when J2 i8 -C(~M)- then ~2 is a double bond and when ~2 i8 -C(-M)- then ~2 i8 a double bond.
M i8 O, S or NR15; and ~ R2 i8:
i (a) ~, or ~ 30 ~b~ ~C1-C6~-a1~y1; and '~

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R2a is:
(a) R2, (b) C~2-aryl, or (c) aryl; and R7a and R7b are independently (a) ~, (b) (Cl C6)-alkyl, (C2-C6)-al~enyl or (C2-C6)-alkynyl, lo (c) Cl, Br, I, F, (d) CF3, or (e) when R7a and R7b are bonded to adjacent carbon atomC, they can be joined to form a phenyl ring;
R8a and R8b are independently (a) ~, (b) aryl-(Cl-C4)-al~yl, (c) heteroaryl-(Cl-C4)-al~yl, (d) (Cl-C6)-alkyl, which i~ unsubstituted or substitutet with a substituent ~elected from the ~roup consi~ting of: -CON(R2a)2, -heteroaryl, -S(0)~-R21, -tetrazol-5-yl, -CON~S02R21, -S02N~l-heteroaryl, -S02N~COR21, -PO(OR2)2, -PO(OR2a)2, -S02N~-CN, -NR2COOR21,-0~, -NE2, ~uanidino, (Cl-C4)-al~coxy, (Cl-C4)-al~ylthio, (Cl-C4)-al~ylamino. (Cl-C4)-tial~cylamino, R2a, _coN$R2a, -0-COR2a, or aryl, (e) -CO-aryl, (f) (C3-C7)-cycloal~yl, (~) C1, ~r, I. F.

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.. wosl/12~] ~ 7 PCT/US91/~3 ~ 2~7~6~ -;

(h) -o~, ( i ) _oR2 1 ( i ) - 5~ .
(k) -S(O)n-(Cl-C4)-alkyl, (1) -COR2a, (m) -C02~, (n) -C02-(Cl-C4)-alkyl, (o) -S03~, ( P ) -NR2R2 1 (q) -NR2COR21 (r) -NR2COOR21, ( ~ ) -S02N~R2a ~
(t) -S02NR2R2a, (U ) -N02 , (v) -N~S02CF3, (W) -coNR2aR2a (x) -(Cl-C4)-~erfluoroalkyl, (y ) -COOR2, (z) -S03~, (aa) -N(R2)S02R21, (bb) -NR2CoNR4R21~
( cc ) -oc(~o)NR2lR2a (dd) -aryl, -t~502CF3 ~
~ S02N~-heteroaryl, -S02N~ICOR21.
(hh) -COM~S02R21, (i~) -PO(OR2)2 ~
(j;) -tetrazol-5-yl, (~) -CON8~tetrazol-5-yl), (11) -S02N~CN, or (mm) -heteroaryl; and . ~

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sl WO91/12001 PCT/US91i~MW3 ~ 20~63~
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R9 and RlO are independently:
(a) ~, (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, (g) when R9 and RlO are on adjacent carbons, they can be joined to form an phenyl ring, (h) perfluoro-(Cl-C6)-alkyl, (i) (C3-C7)-cycloalkyl, unsubstituted or substituted with (Cl-C6)-alkyl, (j) aryl; and X is:
(a) _o_, (b) ~S(O)n~, ( C ) -NR13_ (d) -C~20-, (e) -C~2S~O)n (f) -C~2NR13 -, ( ) ~h) -NRl3C~z-, . 2~ (i) -S~O)nC~2-, Z ~;) _C~2_, (k) -(C~2)2-' (l) ~inglc bond, or (m) -C~, wherein Y and Rl2 are ab~ent forming a -C-C- bridge to tbe carbon bearing Z and i. - - ': ' .
~` ' ' ' `' '': ' ` ' ' ' , ' - ' ~.

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:: -. --- Wosl/l2~l ~ ~ ~ PCT/US91/~3 Y is:
(a) single bond, (b) _o_, (C) ~S(O)n~, (d) -NR13_, or (e) -CH2-; and Except that ~ and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (0, N, S, SO . SO2 ) Rll and R12 are independently:
(a) H, (b) ~Cl-C6)-al~yl 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:
1) Cl, Br, I, F,

2) (Cl-C6)-alkyl,

3) t~cl-cs)-al~enyl]c~2

4) t(cl-cs)-al~ynyl]c~2 S) (Cl-Cs)-al~oxy, 6) (Cl-C5)-al~ylthio, .. 7) CF3.
- 8) 0~, 9) N02, or 10) C02R2a; and ,~ ' ' ' .

.

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.~ WO9~/~2001 ~ ~ ~ PCT/US9~ 3 ,~
-`14 _ .
(d) aryl-(Cl-C2)-alkyl, unsubstituted or - substituted with l to 5 ~ubstitutents selected from the group consisting of:
1) C1, Br, I, F, 2) (Cl-C6)-alkyl, 3) t(cl-cs)-alkenyl]c~2-4) [(Cl-C5)-alkynyl]CB2-,

5) (Cl-C5)-alkoxy,

6) (Cl-C5)-alkylthio,

7) CF3,

8) OB,

9) NO2, or

10) C02R2a; and (e) (C3-C7)-cycloalkyl; and . R13 is:
- (a) H.
(b) (Cl-C6)-alkyl, (c) aryl, `: 20 (d) aryl-(Cl-C6)-alkyl-(C=O)-, (e) (Cl-C6)-alkyl-(C=O)-, (f) r(C2-Cs)-alkenyl]CB2-, (~) r~C2-Cs)-alkynyl]CB2-, or ~h) aryl-CB2-,; and Z 1~:
( a ) -C02s, (b) -CO2-(Cl-C6)-alkyl, (c) -tetrazol-5-yl, (d) -CO-N~(tetrazol-5-yl) .~ ( e ) -CON~-S02-aryl, .

~ .

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~;' , ' ' ' ' ' ~ . . . ' i Wogl/]200~ PCT/US9l/~W3 .

(f) -CON~-S02-(Cl-C8)-alkyl, wherein the alkyl ~roup is unsubstituted or 6ubstituted with a substituent selected from the group consisting of: -0~, -S~, -O(Cl-C4>-al~yl, -S-(Cl-C4)-alkyl, -CF3, Cl, Br, F, I, -N02, -C02~- -co2-(cl-c4)-alkyl~ -N~2.
-N~[(Cl-C4)-alkyl], -N(Cl-C4-alkyl)2; and (g) -CON~-S02-perfluoro-(Cl-C4)-alkyl, (h) -CON~-S02-heteroaryl, or 1o (i) -CON~S02NR2aR2a; and (j) -S02N~CO-aryl, (k) -S02-N~CO-(Cl-C8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent ~elected from the group consisting of: -0~, -S~, -O(Cl-C4~-alkyl, -S-(Cl-C4)-alkyl, -CF3, Cl, Br, F, I, -N02, -C02~ -co2-(cl-c4)-alkyl~ _N~2, -N~t(Cl-C4)-alkyl]. -Nt(cl-c4)-alkyl]2; and (1) -S02N~CO-(Cl-C6)-perfluoroalkyl, (m) -S02N~CO-heteroaryl.
(n) -CON~S02NR2aR2a, (o) -PO(0~)2 ~
(p) -Po(O~)~OR2), or ~q) -PO~OR2)2; and 2~

~a) ~, ~b) aryl. which is unsubstituted or substituted with 1 or 2 substituents selected from the group con8isting of: Cl, Br, I, F
--~Cl-C4)-alkYl~ (Cl-C4)-alkyl, -N02, -CF3, . -S02NR2R2a, -S-(Cl-C4)-alkyl, -0~, -N~2, (C3-C7)-cycloall:yl. (C3-C10~-al~enyl:

:.:
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., . . . .- . . . .
. , . . . . , ... - - : .
. . - , - . ., . . . , . . -.

: Wogl/12001 , . PCT/USgl/~n~3 L~ 63 7 ~
.,.

(c) (Cl-C6)-alkyl~ (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of: aryl, (C3-C7)-cycloal~yl, Cl, Br, I, F, -0~, -N~2, -N~t(cl-c4)-alkyl]~ --N[(Cl-C4)-al~yl]2, -N~-S02R2a, -COOR2a, -S02N~R2a; or (d) an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6 membered ring which can contain one or two heteroatoms selected from the group consisting of N, 0, S, and wherein the substituents are members selected from the group consisting of -0~, -S~, (Cl-C4)-alkyl, (Cl-C4)-alkyloxy, -CF3, Cl, Br, I, F, or NO2;
. R16 is (a) (Cl-C10~-alkyl;
(b) substituted (Cl-C10)-alkyl in which one or two 8ubstituent(6) 8elected from the : group consisting of:
(1~ I, Br, Cl, F, ~2) hydro~y, 2S (3) (Cl-Clo)-alko~y, (4) (Cl-Cs)-alkoxycarbonyl, (5) (Cl-Cs)-acylo~y, (6) (C3-Cg)-cycloalkyl, (7) aryl, ~8) 8ubstituted aryl, in which the substituents are V and W, .

. , - , .

. ~

. . . , . - -. : - - :.-W091/1~ ~ PCI/U591/0~993 (9) (Cl-Clo)-alkyl-s(o)n~
(10) (C3-Cg)-cycloalkyl-s(o)

(11) phenyl-S(O)n,

(12) substituted phenyl-S(O)n, in which the substituents are V and W,

(13) oxo,

(14) carbo~y,

(15) NR2aR2a

(16) (Cl-C5)alkylaminocarbonyl (c) perfluoro-(Cl-C4)-alkyl (d) (C2-C10)-alkenyl, (e) (C2-C10)-alkynyl, (f) (C3-C8)-cycloalkyl, (g) substituted (C3-C8)-cycloalkyl, in which the substituent is selected from:
(1) (Cl-C~)-alkyl,or (2) (Cl-C5)-alkoxy;
(h) aryl, (i) substituted aryl, in which the substituents are V ant W, (j) aryl-(C82)r-(Ml)z-(C~2)t~
(k) substituted arYl~(C~2)r~(Ml)z~ (C~2)t-in which the aryl group is substituted with V and W, i $

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WO 91~12W~ 2 7~5, 7 Pcr/US91/oo993 Q~ s ~

(1) V{~}(C~)r~)~--(C~32)t V ~ CH~ ), ( CH~

~;;~CH~r~ (CH~

(o) ~CH~),~(~S).--(CH~ Or V
~N
( p) W 5~( CH~ C ~ ( CH~ nd (q) -t(cl-c4)-alkyl]NR2R2l, ( r ) -~ (Cl-C4~-alkyl~NR2COR21, (J ) -t (Cl-C4)-alkyl]NR2COOR21, 2S (t ) -t (Cl-C4)-al~yl]CONR2aR2a, (u) -[(Cl-C4)-allcyl]N(R2)S02R21, (v) -t(cl-c4)-al~;yl]NR2coNR4R2l~ or (W) ~~(Cl~C4)-al~Yl]OC(~o)NR2lR2a;and ~. .

. ;: ' - :
.
, , .

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, ' ~! WO 91 /12~1 ~ , PCT/US91/~X~3 .: - 19 -- --v and W are each independently selected from:
(a) ~.
(b) (Cl-C5)-alkoxy, (c) (Cl-C5)-alkyl, (d) hydroxy, (e) (Cl-Cs)-alkYl~S(o)n~
(f) -CN, (g) -N02~
(h) _NR2R2a (i ) (Cl-C5)-acyl-NR2R2a, (i ) -C02R2a, (k) (Cl-C5)-alkyl-carbonyl, (1) CF3, (m) I, Br, Cl, F, (n) hydroxy-(Cl-C4)-alkyl-, (o) carboxy-(Cl-C4)-alkyl-, (p) -tetrazol-5-yl, (q) -NR-S02CF3, or (r) aryl; and Ml is M or -C(0)-; and ; Z i 6 0 or 1; and r and t are 0 to 2; and R17 and R18 are each independently 8elected from:
(a) ~, (b) aryl-(Cl-C4)-alkyl-, (C) hetero-ry1-(Cl-C~)-a1kyl-, . ~
, .
i ~ . ., , ,.,, . :
, . . . .

. ' , : . . :, :
' ' . : .. . ::

- ' - :` : ~: ' .. ` : . ` `

.. WO91/12~1 . PCT/US91/~X~3 u~ 2~7i, ~: - 20 -(d) (Cl-C4~-alkyl unsubstituted or ~ubstituted with a 6ubstituent selected from the group consisting of -0~, -N~2, guanidino, (Cl-C4)-alkoxy, (Cl-C4)-alkylthio, S (Cl-C4)-alkylamino, (Cl-C4)-dialkylamino, COOR2a CON~R2a~ -0-COR2a. CF3;
(e) (Cl-C4)-alkenyl, (f~ -C0-aryl, (g) (C3-C7)-cycloalkyl, (h) Cl, Br, I, F, ( i ) -0~ , ( j ) -O- (Cl-C4 )-alkyl, (k) -(Cl-C4)-perfluoroalkyl.
( 1 ) -S~ , : l5 (m) -S(O)n~(Cl-C4)-alkyl, - (n) -CR0, (O) -C02R2a (p) _503~, (q) -N~2.
(r) -N~(Cl-C4)-alkyl], (s) -Nt~Cl-C4)-alkYl]2~
(t) -N~C02-(Cl-C4)-alkyl, ', ~u ) -S02NR2R2a, ~v) -C~20COR2a 2S (w) -N~-S02-(Cl-C4)-alkyl, (~) 5 or 6 membered ~aturated heterocycle containing one nitrogen atom and optionally - containing one other heteroatom 8elected from N, 0, or S, ~uch as pyrrolidine, morpholine, or piperazine, (y) aryl, .

. ', - ' ''` ' ` . " ' ~ ` ' ' ' ' : . :: ' . ' ' : . - .
.

.

,- WO91/12~1 PCTiUS99/~ ~3 , , .

(z~ heteroaryl, wherein heteroaryl is a 5 or 6 membered aromatic ring containing one or two heteroatoms ~elected from the group consisting of 0, N, or S, (aa) tetrazol-5-yl, (bb) -t(Cl-C4)-alkyl]NR2R21, (cc) -t(Cl-C4)-al~yl]NR2COR21, (dd) -t(Cl-C4)-al~yl~NR2COOR21, (ee) -t(Cl-C4)-alkyl]CONR2aR2a, lo (ff) -t(cl-c4)-alkyl]N(R2)so2R2l~
(gg) -t(Cl-C4)-alkyl]NR2CONR4R21, or (hh) ~t(Cl~c4)~alkyl]0C(=o)NR2lR2a;and R21 is (a) aryl, or (b) (Cl-C4)-alkyl, is unsubstituted or substituted with:
i) N~2, ii) NRt(Cl-C4)-alkyl], iii) N~(Cl-C4)-alkY1~2 iv) C02E, v) C02(Cl-C4)-alkyl, vl ) 0~.
vii) S03~, or viii) S2N~2;
~ or a pharmaceutically acceptable salt thereof.

.~ 3CWhesein preferr-d embodi~nt is wh-n:

~.

.

wosl/12~1 PCT/US91/~X~3 2 0~

Rl is:
(a) (Cl-C6)-alkyl or (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which i6 unsubstituted or substituted with a substituent selected from the group consisting of:
i ) (Cl-C4)-alkylthio, ii) (Cl-C4)-alkoxy, iii) CF3, lo iv) CF2CF3, or v) (C3-Cs~-cycloalkyl~
(b) perfluoro-(Cl-C4)-alkyl, or (c) (C3-C5~-cycloalkyl; and B is:
(a) single bond.
(b) -S-, or (c) -O-; and n is 0, 1, or 2; and -r Jl is (a)-C(-M)-. (b) Jl ant L are connected together to form a 6-carbon aromatic ring substituted with R7a, R7b, R8a and R8b or ~c) Jl and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom not at Jl, substituted with R7a R7b, R8a and R8b; and I

~ , . . . . .
.. . .
, . . - . . :, ~ . .. .

; .

W09l~2001 PCT/US9l/~3 ~ 2 07 ~7~
... .
: - 23 -Kl is (a)-C(=M)-, or (b) ~l and L are connected : together to form a 6-carbon aromatlc ring substituted with R7a, R7b, R8a and R8b, or (c) Kl and L are connected together to form a si2-membered aromatic ring containing one nitrogen atom substituted with R7a, R7b and R8a provided that one and only one of Jl and - Kl is -C(=M)-; and one of ~l or bl is a double bond in structure Ia provided that when Jl is -C(=M)- then ~l is a double bond and when Kl is -C(=M)- then al is a double bond.

L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom; and J2 is (a)-C(sM)-, or (b) -C(Rl7)-; and - 20 R2 is (a)-C(sM)-, or (b)-C(Rl7~-, provided that one and only one of J2 and K2 i8 -C(-M)-; and onc of g2 or ~2 i8 a touble bond in structure Ic provided that whcn J2 is -C(-M)- then ~2 i8 a double bond and when R2 iB -C~-M)- then ~2 i8 a double bond.

M is 0, S or NRl5; and : R2 i8:
(a) ~, ~b) ~C1-C6)~ y1 and ~, . , ;.": ' . ,., ' :* - , ~, . ~
' WO91/12001 ~ PCT/US91/~N~3 ;i 2G7~
3 ,0 ~
- 24 _ R2a is:
(a) R2, (b) C~2aryl, or (c) aryl; and R7a and R7b are independently (a) ~, (b) (Cl-C6)-alkYl~ (c2-c6)-alkenyl or (C2-C6)-alkynyl, (c) Cl, Br, I, F, (d) CF3, or (e) when R7a and R7b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring;

R8a and R8b are independently (a) ~, (b) aryl-(Cl-C4)-alkyl, (c) heteroaryl-(Cl-C4)-al~yl, (d) (Cl-C6)-al~yl, is unsubstituted or : substituted with a substituent 6elected from the group con~isting of: -CON(R2a)2, -heteroaryl, -S(0)~-R2l, -tetrazol-5-yl, - -CON~S02R21, -S02N~I-heteroaryl, -S02N~COR21, 2S -PO~OR2)2, -PO~OR2a)2. -S02M~-CN, -NR2COOR21,-0~, -Na2, guanidino, (Cl-C4)-alkoxy, (Cl-C4)-alkylthio, (Cl-C4)-alkylamino. (Cl-C4)-dialkylamino, _COOR2a, _coN~R2a~ -0-COR2a. or aryl, (e) -CO-aryl, (f) (C3-C7)-cycloalkyl, (g) Cl, Br, I, F, ~ . . . . ~ .

.

`

. WO91~1200~ w~
2 0~ 3 ~37: ` P~T/US9i~ 3 -~ - 25 -(h) -OH, ( i ) _oR2 1 (j) -SH, (k) -S(O)n-(Cl-C4)-alkyl, (l) -C0R2a, (m) -CO2H, (n) -CO2-(Cl-C4)-alkyl, (o) -SO3H, ( P ) -NR2R2 1 (q) -NR2COR21 (r) _NR2CooR2l ( s ) -S02NR2a, (t) -SO2NR2R2a, ( U ) -N02 ~
(v) -NHS02CF3, (W) -coNR2aR2a (x) -(Cl-C4)-perfluoroalkyl, ( y ) -COOR2, (Z) -SO3H, (aa) -N(R2)S02R21, (bb) -NRZC0NR2aR21 (cc ) -oc(~o)NR2lR2a (dd) -aryl, (eo) -N~SO2CF3, 2S (~ S02NB-hetcroaryl, (~) -S02N~COR21, (hh) -CONRS02R21, (ii) -PO(OR2)2~
(j~) -tetrazol-5-yl, ~ 30 (kk) -CONR(tetrazol-5-yl), `~ (11) -SO2NRCN, or (mm) -hetesoaryl: a~d .

. . . . . . :.. : .
~ : . . :

- . , :

, : . -.: ~ . . . -: . , . - . . : ~- :
, ...

~ WO91/12~1 207.~;~ PCT/US91/~3 ~

. .. .

R9 and RlO a r e independently:
(a) ~, (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, (g) when R9 and RlO are on adjacent carbons.
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; ant X is:
(a) _o_, (b) ~S(O)n~.
(c) _NR13 (d) -C~20-, (e) -C~2S()n~
(f ) -C~2NR13 -, (~) -OC~2-, (h) -NR13C~2-, (i) ~S~O)nC~2~~
(j ) -C~2--(k) -(C~2)2-~ingle bond, or (m) -CR-, wherein Y and Rl2 are absent forming a -C-C- britge to the carbon bearing Z and Rll; and . .

, . :
`', ' : ~

~ ., . ' ' ' , .
~ ` , ., :' . ' ' ~

.~,WO91/12~] ~r~ PCT~US91~ 3 J.~ -.

Y is:
(a) ~ingle bond, (b) _o_, (c) -S(O)n-, (d) _NR13_, or (e) -C~z-; and Except that ~ and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (0, N, S, SO . S02 ) Rll and R12 are independently:
(a) ~, (b) (Cl-C6)-alXyl unsubstituted or substituted with:
(i) aryl, or (ii) (C3-C7)-cycloalXyl, (c) aryl, unsubstituted or substituted with 1 to 5 ~ubstitutents selected from the group consisting of:
1) Cl, Br, I, F, 2) ~Cl-C6)-al~yl, 3) t(cl-cs)-al~enyl]c~2 4) t(Cl-C5)-alkynyl]C~2-5) (Cl-C5)-al~oxy, 6) (Cl-C5)-alXylthio, 7) CF3 8) 0~, 9) N02, or lO) CO2R2~: and ~ .

, .

.
. .
: , .: . ' WO91/12~1 ~ ~ PCT/~591/~3 -; - 28 -(d) aryl-(Cl-C2)-alkyl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of:
1) Cl, Br, I, F, 2) (Cl-C6)-alkyl, 3) [(Cl-Cs)-alkenYl]C~2-~
4) t(Cl-Cs)-alkYnYl]C~2-~
5) (Cl-C5)-alkoxy, 6) (Cl-C5)-alkylthio, 7) CF3, 8) 0~, 9) N02, or lO) C02R2a; and (e) (C3-C7)-cycloalkyl; and Rl3 is (a) ~, . (b) (Cl-C6)-alkyl, (c) aryl, . 20 (d) aryl-(Cl-C6)-alkyl-(C=0)-, .~ (e) (Cl-C6)-alkyl-(C-O)-, f) t(C2-Cs)-alkenyl~c~2_~
~g) t~C2-C5)-alkynyl]C~2-, or ~h) aryl-C~2-,; and 2~
Z i8:
', (a) -CO2~, (b) -CO2-(Cl-C6)-alkyl, (c) -tetrazol-S-yl, (d) -CO-N~(tetrazol-5-yl~

(e) -C0111~-502-~yl, - - - . -. . : . . - - - . .
. . . . . .

WO91/~2~1 2 0`~5 63 ~ - PCT/US91/~3 (f) -CON~-S02-~Cl-C8)-alkyl, wherein the alkyl group is unsubstituted or ~ubstituted with a ~ubstituent selected from the group consisting of: -0~, -S~, -O(Cl-C4)-alkyl, -S-(Cl-C4)-alkyl, -CF3, Cl, Br, F, I, -N02, -C02~ -co2-(cl-c4)-alkyl~ _N~2, -N~[(Cl-C4)-alkyl], -Nt(Cl-C4)-alkyl]2; and (g) -CON~-S02-perfluoro-(Cl-C4)-alkyl, (h) -CON~-S02-heteroaryl, (i) -CON~S02NR2aR2a, ( j ) -S02N~CO-aryl, (k) -S02N~CO-(Cl-C8)-alkyl, wherein the alkyl group is unsubstituted or ~ubstituted with a substituent selected from the group consi8ting of: -0~, -S~, -O(Cl-C4)-alkyl, -S-(Cl-C4)-alkyl, -CF3, Cl, Br, F, I, -N02, -C2E ~ -co2-(cl-c4)-alkyl, -N~2 .
-N~t(Cl-C4)-alkyl], -Nt(Cl-C4)-alkyl]2; and (1) -S02N~lCO-(Cl-C4)-perfluoroalkyl, (m) -S02N~CO-heteroaryl, or (n) -S02N~CONR2aR2a; and Rl5 i8:
( ~
: 25 (b) ~ryl, i8 unsubstituted or 6ubstituted with l : or 2 substituents selected from the group consistin~ of Cl, Br, I, F, -0-(Cl-C4)-alkyl. (Cl-C4)-alkyl, -N02, -CF3, - -S02NR2R2a. -S-(Cl-C4)-alkyl, -0~, -N~2, (c3-c7)-cycloal~yl~ ~C3 C10~ dl~e y:

~ .

:

" , ., . , . . - :. -.` ; , .. .. . .... . . .

.. ' ` ' , ' ` ,', ~' , , ' ', , ' ' ;' ' " ' ' , - :

':, ' , ' . ' , . ' `'" '' . ~ i ' ''' . . . ' " , - ' ': ' ' ' ' ' ' . ~ ' .: : . ' . , ' ' ' - ' :' .' , ' . w09~/l2~1 ~ f,; ~ PCT/US91/~M~3 ~ 2075B37`; ~

(c) (Cl-C6~-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with one or more substituents selected from the group s consisting of: aryl, (C3-C7)-cycloalkyl, Cl, Br, I, F, -0~. -N~2, -NH~(Cl-C4)-alkyl], -N[(Cl-C4)-alkyl]2, -N~3-S02R2a, -COOR2a, -S02N~R2a; or (d) an unsubstituted. monosubstituted or disubstituted aromatic 5 or 6 membered ring which contains one or two heteroatoms selected from the group consisting of N, 0, 5, and wherein the substituents are members selected from the group consisting of -0~, -S~, (Cl-C4)-alkyl, (Cl-C4)-alkyloxy -CF3, ? Cl, Br, I, F, or N02;

R is:
(a) (Cl-Clo)-alkyl;
(b) substituted (Cl-C10)-alkyl in which one or two substituent(s) is (are) selected from:
(1) hydroxy, (2) (Cl-Cs)-alkoxy, (3) (Cl-Cs)-alkosycarbonyl, (4) phenyl, (5) carbo~y, `- (6) C(-O)NH-(Cl-Cs)-alkyl, (c) aryl, or (d) dryl substituted vith V and W and -~. .

.
~ : . ... ,; : . .
.
A
' ` ` ' '` .. ~ ` '` ~ " . ``' `
' `' ', '' ~" ` ' ' , ' , '` ' ` , . ` " ~ ' " `
` ` ' ' ', .'` ' ' , ~
.
` ' ` ` ' ' , ' ' `
' ` .. . ~ ' , ,' ' ~,- W091/12~1 PCT/US91/~93 ,, ,~,;-, 207563 ~ 7 ;;
' '' -.

v and W are selected from:
(a) ~.
(b) (Cl-C5)-alkoxy, (c) (Cl-C5)-alkyl, (d) hydroxy, (e) -CN, (f) _N02, ( g ) _NR2R2a (h) -C02R2a, lo (i) -CF3, (j) I, Br, Cl, F, (k) hydroxy-(Cl-C4)-alkyl-, .
(l) tetrazol-5-yl, (m) -Nl~-S02CF3 (n) -t(Cl-C4)-alkyl]NR2R21, () -t(Cl-C4)-alkyl]NR2COR21, (p) -[(Cl-c4)-alkyl]NR2cooR
" (q) -[(Cl-C4)-alkyl~CONR2aR2a, (r) -t(Cl-C4)-alkyl~N(R2)SO2R2l, (s) -t(Cl-C4)-alkyl]NR2CONR4R2l, or (t) ~t(Cl~c4)-alkYl~oc(-o)NR2lR2a;and R17 and R18 are independently ~a) ~, 2S ~b) aryl-~Cl-C4)-alkyl-, (c) heteroaryl-~Cl-C4)-alkyl-, : ~d) ~Cl-C4)-alkyl, unsubstituted or substituted with a substituent selected from the group consi~ting of: -OR, -NR2, guanidino, ~Cl-C4)-alkoxy, (Cl-C4)-alkylthio, ~Cl-C4)-alkylamino. (Cl-C4)-dialkylamino, -COO~Z~, -CONERZa, or -O-CO~Z-, CF3, ~ . . . . . .
- - ,.- ~ . ' .

.
. .

.. ~
..
,~ .; -; wosl/~2~1 PCT/US91t~W93 2 0 7 ~ 6 3 7 ~ r ~
i,-J
- 3~ -(e) (Cl-C4)-alkenyl, (f) -C0-aryl, (~) (C3-C7)-cycloalkyl, (h) Cl, Br, I, F, (i) -0~, (j) -0-(Cl-C4)-alkyl, (k) -(Cl-C4)-perfluoroalkyl, ( 1 ) - S~ , (m) -S(O)n-(Cl-C4)-alkyl, lo (n) -C~0, (O) -C02R2a (p) -S03~, ( q ) -N~I2, (r) -N~t(cl-c4)-alkyl]~
(s) -Nt(cl-c4)-alkyl]2~
(t) -N~C02-(Cl-C4)-alkyl, (u ) -S02NR2R2a, (v) -C~20COR2a, (w) -N~-S02-~Cl-C4)-alkyl, (x) 5 or 6 membered saturated heterocycle containing one nitrogen atom and optionally . containing one other heteroatom 6elected from N, 0, or S, such as pyrrolidine, morpholine, or piperazine, 2S (y) aryl, (z) heteroaryl, wherein heteroaryl is a 5 or 6 membered aromatic ring containing one.or two heteroatoms selected from the group eonsi8ting of 0, N, or S; and (aa) tetrazol-5-yl, or (bb) -~(Cl-C4)-alkyl]NR2R21, - :
.- : , .
. . . . .

.
- . ` ' ' , ``'' '' '` ' . ~

~: wosltl2ool 2~7~ ; PCT~US91/~3 (cc ) -[ (Cl-C4)-alkyl]NR2COR21, (dd) -[(Cl-C4)-alkyl]NR2COOR21, - (ee) -[(Cl-C4)-alkyl]CONR2aR2a, (ff) -t(cl-c4)-al~yl]N(R2)so2R2l~
(gg) -~(Cl-C4)-alkyl]NR2CONR4R21, or (hh) ~[(Cl~C4)-alkyl]OC(=o)NR2lR2a;and R21 iS
(a) aryl, or lO(b) (Cl-C4)-alkyl which i~ unsubstituted or ~ubstituted with:
i) N~2, ii) N~t(Cl-C4)-alkyl], iii) N~(Cl-C4)-alkYl]2.
15iv) C02~, v) C02(Cl-C4)-alkyl, vi ) OII, , vii) S03X, or viii) S02N~2; and or a pharmaceutically acceptable ~alt thereof.

Wherein a more preferred embotiment of the invention i~ when:

Rl i8 (a) (Cl-C6)-alkyl (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which i8 unsubstituted or substituted with a sub~tituent seleeted ~rom the group ~r 30 consisting of:
i ) (Cl-C4)-alkylthio, ii) (Cl-C4)-alkosy.

~I .

.~ .

. . . . :

'~: ' '`. ' . ~ ' ' I . ; '' . '. . ' ~ : ,~, , ` ,'', ' , .':` ' '` '`' . , '' . ' ' ' .
.~ ,~. ' .. -'':,, .

"' ' " ' ' ' . " ': -WO91/1200~ ,~ t~; ~ PCT/US91/~M~3 ~
~ 207563~
.; .

iii) CF3, iv) CF2CF3, or v) (C3-C5)-cycloalkyl, or (b) perfluoro-(Cl-C4)-alkyl; and B is a single bond; and n is 0 to 2; and lo Jl and L are connected together to form a 6-carbon aromatic ring substituted with R7a, R7b, R8a and R8b; or Jl and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom not at Jl, : 15 substituted with R7a, R7b, R8a and R8b; and Kl i6 -C(=M)-; and ~1 is a double bont; and L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom; and 2S J2 ic -C(R17)-; and ~2 i8 -C(-M)-; and ~ i8 a double bond; and i~ O, or NR15; ard .

`1 : . ' -- , ' .

.: . , , ,: . ; , : , ..
r. ~ : - . . . . . .
~ . , . ~:, ' , . , : - -' ' W091/12001 }
2 0 7 ~ 6 3 7 . PCT~US91~W~3 ,~, .

R2 is:
(a) ~, (b) (Cl-C6)-alkyl, or (c) (Cl-C6)-alkyl; and R2a is:
(a) R2, ( b ) benzyl, or (c) phenyl; and R7a and R7b are independently (a) ~.
( b ) (Cl-C6~-alkyl, (C2-C6)-al~enyl or (C2-C6)-alkynyl, lS ~c) Cl, Br, I, F, (d) CF3, or (e) when R7a and R7b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring;

R8a ant R8b are independently (a) ~, (b) aryl-~Cl-C4)-al~yl, (c) hetcroaryl-(Cl-C4)-al~yl, (d) ~Cl-C6)-al~yl, unsubstituted or substituted with a substituent selected from the group con~isting of: -CON(R2a)2, -heteroaryl, ~S~O)n-R21~ -tetrazol-5-yl, -CON~S02R21, -S02N~-heteroaryl, -S02N~COR21, -PO(OR2)2, PO(OR )2~ -S02N~-CN, -NR2COOR21 -0~ N~
guanid~no, (Cl-C4)-al~o~y, (Cl-C4)-al~ylthio, (Cl-C4)-al~ylamino, (Cl-C4)-tial~ylamino, -COOR2a, -CON~R2a, -O-COR2a, or aryl, i .
~ . .. . ~, , .~ , . ~ .
,- :.; , .. .
.
~; . .. . -..

WO 91/12001 ~ ~ 7 ~ 6 ~ 7 . ~ . . !; PCI`/US91/00993 ~

;-( e ) -C0-aryl, (f ) (C3-C7)-cycloalkyl, (g) Cl, Br, I. F, (h) -O~I, ( i ) -OR21, ( j ) -S~ , (}c) -S(O)n-(Cl-C4)-alkyl.
( 1 ) -coR2a (m) -C02H, (n) -C02-(Cl-C4)-alkyl, ( o ) -S03~I, ( p ) -NR2R2 1 ( q ) -NR2CoR2 1 ( r ) -NR2CooR2 (s) -502NR2a, (t ) -S02NR2R2a, ( U ) -N02, (V) -NI~S02CF3, ( W ) -coMR2aR2a - 20 (x) -(Cl-C4)-perfluoroalkyl.
( y ) -COOR2, (z) -S03~, ( aa ) -N(R2 ) S02R21, ~ bb ) -NR2CoNR4R2 1 2S (cc ) -oc~o)NR2lR2a ~dt ) -aryl, ( ee ) -N~S02CF3, (ff ) -S02N~-heteroaryl, ~leg) -S02N~ICOR21, (hh ) -CON~S02R21, ; (ii) -PO~OR2)2, tet~zol-S-yl, .
- .

- , , - ' - . . , ~ ..
; . . , . ~ . -. - : .
' . , . - ' ~ : - - : . ' ~ WO91/12~1 PCT/US91/~W3 2 0 7 ~ 6 ~

, (kk) -CONH(tetrazol-5-yl), (11) -S02N~CN, or (mm) -heteroaryl; and R9 and RlO 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, (g) when R9 and RlO are on adjacent carbons, 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) -o_, (b) ~5(0)n~~
(C) _NRl3_ (d) -C~20-, (e) ~CE~2S(O)n~
- 25 (~) -C~2NRl3 -, -OC~12- .
( h ) -NR13C82-, ~ i ) -5 ()nC~2~
( ~ ) _C~2_ , ~k) -~C~2)2-' ~1~ cing1e bond, or ; . . .

. .
;, . , ~ , ` ~ , ,, , ~ , ,~
' , -, WO91~12~1 207563~i ~ PCT/US9l/~ ~3 f~

(m) -C~=, wherein Y and R12 are absent forming a -C=C- bridge to the carbon bearing Z and Rll; and Y is :
(a) ~ingle bond, (b) _o_, (c) -S(O)n-, (d) _NR13_ or lo (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 bsnded to two heteroatoms (O, N, S, SO, SO2) Rll and Rl2 are independently:
(a) R, (b) (Cl-C6)-alkyl unsubstituted or substituted with:
(i) aryl, or (ii) (C3-C7)-cycloalkyl, (c) aryl, ~nsubstituted or substituted with 1 to 5 8ub8titutents selected from the group con8isting of:
1) Cl, Br, I, F, 2) (Cl-C6)-alkyl, 3) t(Cl-Cs)-alkenyl]C~2-, 4) ~(Cl-Cs)-alkYnYl]C~2-~
- 30 5) (Cl-Cs)-al~oxy, 6) (Cl-Cs)-alkylthio, 7) CF3.

:

.
, . .
.

., ~ . . , ,. ~ . . - . .
~; - . . . ... . :
. .
. . .
- .
.. . - , ~ , W091/12001 . ~ PCT/US91/~3 ~ t;~,.
2~7~37:

8) 0~.
9) N02, or lO) C02R2a; and (d) aryl-(Cl-C2)-alkyl, unsubstituted or s substituted with l to 5 substitutents selected from the group consisting of:
l) Cl, Br, I, F, 2) (Cl-C6)-alkyl~
3) [(Cl-C5)-alkenyl]CH2-, 4) t(cl-cs)-alkynyl]cH
5) (Cl-C5)-alko~y, 6) (Cl-C5)-alkylthio, 7) CF3.
5) OH, 9) N02. or lO) C02R2a; and (e) (C3-C7)-cycloalkyl; and Rl3 is:
(a) ~, ~) (Cl-C6)-alkyl, (c) aryl, (d) aryl-~Cl-C6~-al~yl-(C.O)-, ~e) (Cl-C6)-alkyl-(C.O)-, ~) t~C2-Cs)-al~enYl~C~2-~
~' ~g) ~C2-Cs)-alkynyl]C~2-, or ~h) aryl-CH2-,; and z is:
~a) -C02~, , (b) -C02-(Cl-C6)-al~yl, (c) -tetrazol-5-yl, J

i -~ ~ - . . .

.`, -. . . ` - . , .
., . - . ~ . . . -~` . . . .
.~ . .. . . . . .. . . .
... .. ~ ~ .
` . , . - :; . . ~, . - ~

WC~91/120~ t~ PCT/U591/~993 (d) -CO-N~(tetrazol-5-yl) (e) -CON~-SO2-aryl, (f) -CON~-S02-(Cl-C8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consi 6 tin~ of: -O~, -S~, -O(Cl-C4)-alkyl, -S-(Cl-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2, -CO2~, -co2-(cl-c4)-alkyl~ -N~2 -N~t(Cl-C4)-alkyl], -N[(Cl-C4)-alkyl~2; and (g) -CON~-SO2-perfluoro-(Cl-C4)-alkyl, (h) -CON~-S02-heteroaryl, or (i) -CON~SO2NR2aR2a; and ( j ) -S02N}~CO-aryl, (k) -SO2N~CO-(Cl-C8)-alkyl, wherein the alkyl lS 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, ' -C02~ -co2-(cl-c4)-alkyl~ _N~2, -N~(Cl-C4)-alkyl], -N[(Cl-C4)-alkyl]2; and (1) -S02N8CO-(Cl-C4)-perfluoroalkyl, (m) -SO2NFCO-heteroaryl, or ~n) -S02NFCONR2aR2a; and Rl5 i8 (a) F, ~b) aryl, unsubstituted or substituted with l or 2 substituents selected from the group consi~ting of: Cl, Br, I, F
-0-(Cl-C4)-alkyl. (Cl-C4)-alkyl, -NO2, -CF3, -S02NR2R2a, -S-(Cl-C4)-alkyl, -OE, -N~2, (C3-C7~-cycloall:yl. (C3-C10)-alkenyl :!....... . , . . : .
:. . . . - , :
,: . . . ., , ~ .

. W09~/12001 ... t ~ `^ PCT/US91~X~3 '~ ~ 2`07''~ig3S ''' (c) (Cl-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-al~ynyl each of which is unsubstituted or sub6tituted with one or more substituent~ selected from the group consisting of aryl as defined above, (C3-C7)-cycloalkyl, Cl, Br, I, F, -0~, -N~2, -N~[ (Cl-C4)-alkYl] . -Nt (cl-c4~-alkyl]2, -N~-s02R2a~ -COOR2a, -S02N~R2a; or (d) an unsubstituted, monosubstituted or lo disubstituted aromatic 5 or 6 membered ring which can contain one or two heteroatoms selected from the group consisting of N, 0, S, and wherein the 6ubstituentG are ~embers selected from the group consisting of: -0~, -S~, (Cl-C4)-alkyl, (Cl-C4)-alkylosy -CF3, Cl, Br, I, F, or N02; and is (a) (Cl-C10)-alkyl;
(b) substituted (Cl-C10)-alkyl in which one or more 8ubstituent(6) is selected from (1) hydrosy, (2) (Cl-Cs)-al~osy, ~3) (Cl-Cs)-al~o~ycarbonyl, 2S (4) phenyl, ~5) carbosy, (6) C(-O)N~-(Cl-Cs)-al~yl, (c) aryl, or (d) aryl substitutet with V and W; and .; . ~: -.
.

:; . . . -~ . . " ,,.. . . ~ ~ - , ..

's Wo9~ 9~ 1 PCT/U59~ 3 ~

,e .

v and w are selected from:
(a) ~, (b) (Cl-C5)-alkoxy, (c) (Cl-C5)-alkyl, (d) hydroxy, (e) -CN, (f) -N02.
( g ) _NR2R2a (h) -C02R2a, lo (i) -CF3, (j) I, Br, Cl, F, (k) hydroxy-(Cl-C4)-alkyl-, (1) -1~-tetrazol-5-yl, or (m) -N~-S02CF3; and R17 and R18 are independently (a) E, (b) aryl-(Cl-C4)-alkyl-, (c) heteroaryl-(Cl-C4)-alkyl-, ~d) (Cl-C4)-alkyl. unsubstituted or ~ub~titutet with a 6ubstituent ~elected from the group consi~ting of: -0~, -Na2, guanidino, (Cl-C4)-alkoxy, (Cl-C4)-al~cylthio, (Cl-C4)-allcylamino, (Cl-C4)-dialkylamino, -COOR2a, -COM~R2a, -0-COR2a, CF3;
(e) (Cl-C4)-alkenyl, (f) -C0-aryl, (g) (C3-C7)-cycloalkyl, (h) Cl, Br, 1, F, 0~, .

. ~

- , , ,. ,., - , ..
.~i, , . ~. ..

w09~/12001 1 PCT/uSsl~ 3 2 o 756 37r ~ r g ;~

(j ) -O-(Cl-C4)-alkyl, (k) -(Cl-C4)-perfluoroalkyl, ( 1 ) -S~ , (m) -S(O)n-(Cl-C4)-alkyl, (n) -CR0, (o) -C02R2a (p) -S03~, (q) -N~2.
(r) -N~[(Cl-C4)-alkyl3, lo (s) -N[(cl-c4)-alkyl]2~
(t) -N~C02-(Cl-C4)-alkyl, (u ) -S02NR2R2a, ( V ) -CR20COR2a - (w) -NR-S02-(Cl-C4)-alkyl, (x) 5 or 6 membered saturated heterocycle containing one nitrogen atom and optionally containing one other heteroatom selected from N, 0, or S, ~uch as pyrrolidine, morpholine, or piperazine, (y) aryl, (z) heteroaryl, or (aa) tctrazol-5-yl.

25 R2~
(a) aryl, or ' (b) (Cl-C4)-alkyl uhich i6 unsubstituted or : 6ubstitutet with:
i) NB2, ii) NRt(Cl-C4)-alkyl], iii) Nt(Cl-C4)-alkY132 iv) C02~1, ' .~

.

~ ' ` ' .` ~ ' ' ' ' ' ' ~' . .

WO91/12001 PcT/US91/~n~3 _ 44 -v) C02(Cl-C4)-alkyl, vi) 0~, vii) S03~, or viii) S02N~2; and or a pharmaceutically acceptable salts thereof.

The alkyl substitutents recited above denote ~trai~ht and branched chain hydrocarbons of the o length s~ecified such 8S methyl, ethyl, isopropyl, isobutyl, neopentyl, isopentyl, etc.
The alkenyl and alkynyl substituents denote alkyl groups as described above which are modified so that each contains a carbon to carbon double bond or : 15 triple bond, respectively, such as vinyl, allyl and 2-butenyl.
Cycloalkyl denotes rings composet of 3 to 8 methylene groups, each which may be substituted or unsubstituted with other hydrocarbon substituents, 20 and include for example cyclopropyl, cyclopentyl, cyclohesyl ant 4-methylcyclohe~yl.
The al~o~y substituent represent6 an alkyl group as de~cribed abovc attached through an oxygen bridge.
The aryl ~ub~tituent recited above represents 2~ phenyl or naphthyl.
The heteroaryl substituent recited above represents any 5- or 6-membered aromatic ring t containine Srom one to three heteroatoms ~elected t Srom the group consisting of nitrogen, o~ygen, and 30 sulfur, for esample, pyridyl, thienyl, furyl, imid-zolyl, nd thi-zolyl.

i .
'~'` .. ' . ' ' ' . ~, :..... . .
~: . , . . ~ . . . .
, . .
-. . .. . , . . : .
., - . .
- - - ., ~- , . .

, WO91/12~] PCT/US91/~3 2 0 7 ~

; - 45 _ Preferred compounds of the present invention which are illustrative of subclasses of Formula Ia are:

OUINA~OLIN-4(3~)-0NES:

3-[4-(1-Carboxy-l-phenyl)methoxyphenyl]methyl-6-methyl-2-propylquinazolin-4(3H)-one 2-Butyl-3-t4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-6-methylquinazolin-4(3H)-one 2-Butyl-3-~4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-6-dimethylaminoquinazolin-4(3~)-one 2-Butyl-3-[4-(l-carboxy-l-phenyl)methoxyphenyl]methy 6-(N-methoxycarbonyl)aminoquinazolin-4(3~)-one 2-Butyl-3-t4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-6-(N-methyl-N-methoxycarbonyl)aminoquinazolin-4(3~)-- 20 one 2-Butyl-3-t4-(1-carbosy-1-phenyl)methocyphenyl]methyl-6-(N-methyl-N-~80-butyloxycarbonyl)aminoquinazolin-4~3H)-one 2~
2-Butyl-3-~4-(1-carbosy-1-phenyl)methoxyphenyl~methyl-6-(N-benzyl-N-iso-butyloxycarbonyl)aminoquinazolin-4(3~)-one 2-Butyl-3-~4-(1-carbosy-1-phenyl)methosyphenyl]methyl_ 6-(N-benzyl-N-n-butyloxycarbonyl)aminoquinazolin-4(3~)-one ;
.

, . , : : .
.

- . . .

WO 91/12001 ~ L;~;~l"i?-i` PCT/US91/~3 ~ 207563~

.- -- 46 --2-Butyl-3-t4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-6-tN-benzyl-N-(N-ethyl-N-methylaminocarbonyl)]-aminoquinazolin-4(3~)-one 2-Butyl-3-[4-(1-carbo~y-1-phenyl)methoxyphenyl~methyl-6-(N-benzoyl-N-n-pentyl)aminoguinazolin-4(3~)-one 2-Butyl-3-t4-(l-carboxy-l-phenyl)metho2yphenyl~methyl-6-(N-benzoyl-N-benzyl)aminoquinazolin-4(3~)-one 2-Butyl-3-t4-(1-carboxy-1-phe~yl)methoxyphenyl~methyl-6-(N-benzyl-N n-butyryl)aminoquinazolin-4(3~)-one 2-Butyl-3-t4-(1-carboxy-1-phenyl)methoxyphenyl~methyl-6-(N-(4-chlorobenzoyl)-N-n-pentyl)aminoquinazolin-4(3~)-one 2-Butyl-3-[4-~1-carboxy-1-(2-chlorophenyl))methoxy-phenyl~methyl-6-(N-benzyl-N-iso-butyloxycarbonyl)-aminoquinazolin-4(3~)-one -2-Butyl-3-~4-(1-carboxy-1-(2-chlorophenyl))metho~y-phenyl]methyl-6-(N-benzyl-N-n-butyloxycarbonyl)-aminoquinazolin-4(3~)-one 2-Butyl-3-t4-(1-carboxy-1-(2-chlorophenyl))metho~y-phenyl]methyl-6-tN-benzyl-N-(N-ethyl-N-methyla~ino-carbonyl)]aminoquinazolin-4(3~)-one 2-~utyl-3-~4-(1-carboxy-1-(2-chlorophenyl))methoxy-phenyl]methyl-6-(N-benzoyl-N-n-pentyl)aminoquinazolin-4(3~)-one ~ : . .. . . : -, . : . ... - .

wosl/~2~
PCT/US91/~X~3 , . .
. - 47 -2-Butyl-3-t4-(l-carboxy-l-(2-chlorophenyl))methoxy-phenyl~methyl-6-(N-benzoyl-N-benzyl)aminoquinazolin-4(3H)-one 2-Butyl-3-t4-(1-carboxy-1-(2-chlorophenyl))methoxy-phenyl]methyl-6-(N-benzyl-N-n-butyryl)aminoquinazolin-4(3H)-one 2-Butyl-3-t4-(1-carboxy-1-(2-chlorophenyl))methoxy-1~ phenyl]methyl-6-(N-(4-chlorobenzoyl)-N-n-pentyl) aminoquinazolin-4(3~)-one 2-Butyl-3-~4-((1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-6-(N-benzyl-N-iso-butyloxycarbonyl)-aminoquinazolin-4(3~)-one 2-Butyl-3-t4-((1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-6-(N-benzyl-N-n-butyloxycarbonyl)-aminoquinazolin-4(3~)-one 2-Butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-6-~N-benzyl-N-(N-ethyl-N-methylamino-carbonyl)~aminoquinazolin-4~3~)-one 2S 2-Butyl-3-~4-(~1-carbosy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-6-~N-benzoyl-N-n-pentyl)aminoguinazolin-4(3~)-one 2-Butyl-3-t4-((1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-6-(N-benzoyl-N-benzyl)aminoquinazolin_ 4(3~)-one : . , . : ' .

WO 91~12001 ...; r ~ ., PCT/US91/~3 2 0 7 ~ ~;3~
,;

2-Butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-6-(N-benzyl-N-n-butyryl)aminoquinazolin-4(3H)-one 2-Butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-6-(N-(4-chlorobenzoyl)-N-n-pentyl)-aminoguinazolin-4(3~)-one 2-Butyl-3-t4-((1-carboxy-1-(2-chlorophenyl))metho~y)-3-propylphenyl]methyl-6-(N-benzyl-N-iso-but carbo~yl)aminoquinazolin-4(3H)-one 2-Butyl-3-t4-((1-carboxy-1-(2-chlorophenyl))methoxy)-3-propylphenyl]methyl-6-(N-benzyl-N-n-butyloxy-Carbonyl)aminoquinazolin-4(3H)-one 2-Butyl-3-t4-((1-carboxy-1-(2-chlorophenyl))methoxy)-3-propylphenyl~methyl-6-tN-benzyl-N-(N-ethyl-N-methylaminocarbonyl)~aminoquinazolin-4(3~)-one 2-9utyl-3-t4-((1-carboxy-1-(2-chlorophenyl))methoxy)-3-propylphenyl~methyl-6-(N-benzoyl-N-n-pentyl)amino-guinazolin-4(3~)-one 2-~utyl-3-t4-(~1-carboxy-1-(2-chlorophenyl))methoxy)-3-propylphenyl]methyl-6-~N-benzoyl-N-benzyl)amino-quinazolin-4(3~)-one 2-~utyl-3-~4-((1-carboxy-1-(2-chlolophenyl))methoxy)-: 30 3-propylphenyl~methyl-6-(N-benzyl-N-n-butyryl)-aminoquinazolin-4(3~)-one ~,.. .. . . , ... - : . .
.
.. . : . - : - -. : ... . . , . , ~ .............. :

:' ' ' . - " ' ' ' ' . .
. ' . ': . ' .. :' . ' ' , :

. .. . ~- . . .. . - . ::

WO9~/12~1 ~ 2 p 7 a 6 3 7 . PCr/US91/00993 .~,, - 49 _ 2-Butyl-3-[4-((1-carboxy-1-(2-chlorophenyl))methoxy)-3-propylphenyl]methyl-6-(N-(4-chlorobenzoyl)-N-n-pentyl)aminoquinazolin-4(3~)-one 2-Butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-chloro-5-methoxyphenyl]methyl-6-(N-methyl-N-iso-butyloxy-carbonyl)aminoquinazolin-4(3~)-one 3-t4-((1-Carboxy-l-phenyl)methoxy)-3-chloro-5-methoxy-phenyl~methyl-6-(N-methyl-N-iso-butylo~ycarbonyl)-amino-2-propylquinazolin-4(3H)-one 3-[4-((1-Carboxy-l-phenyl)methoxy)-3-propylphenyl]-methyl-6-(N-methyl-N-iso-butyloxycarbonyl)amino-2-propylquinazolin-4(3~)-one 2-Butyl-3-t4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-6-methylsulfonylquinazolin-4(3~)-one 2-Butyl-3-[4-(l-carboxy-l-(2-chlorophenyl)~meth phenyl~methyl-6-methylquinazolin-4(3E)-one 2-Butyl-3-t4-(1-carboxy-1-(2-chlorophenyl))methoxy-phenyl~methyl-6-methyl6ulfonylquinazolin-4(3~)-one 2-Butyl-3-t4-(1-carbosy-1-(2-methylphenyl))methoxy-phenyl~methyl-6-methylsulfonylquinazolin-4(3~)-one 2-Butyl-3-t4-(1-carboxy-1-(2-metho~yphenyl))metho~y-phenyl~methyl-6-methylsulfonylquinazolin-4(3~)-one `:

. . .
..

,. , ~ -. .
.. . . . :

WO9l/l2~1 r ~ PCT/US9l/~93 - 2~1~P5.~

2-Butyl-3-t4-(l-carboxy-1-(2,6-dimethylphenyl))-methoxyphenyl]methyl-6-methylsulfonylquinazolin-4(3~)-one 2-Butyl-3-t4-(1-carboxy-1-(2-trifluoromethylphenyl))-methoxyphenyl]methyl-6-methylsulfonylguinazolin-4(3~)-one 2-Butyl-3-[4-(i-carboxy-1-(2-dimethylaminophenyl))-10 methoxyphenyl]methyl-6-methylsulfonylquinazolin_4(3~)_ one 2-Butyl-3-[4-(1-carbo~y-1-(2-chlorophenyl))methoxy- .
phenyl]methyl-5-hytroxymethylquinazolin-4(3~)-one 2-Butyl-5-carbomethoxy-3-[4-(1-carboxy-1-(2-chloro-phenyl))methosyphenyl]methylquinazolin-4(3~)-one 2-~utyl-5-carbomethoxy-3-t4-(1-carboxy-1-(2-chloro-phenyl))methoxyphenyl]methyl-6-methylquinazolin-4(3~)-one 2-Butyl-3-t4~ carboxy-1-(1-naphthyl~)methoxyphenyl]-methyl-6-methylquinazolin-4(3~)-one 2-Butyl-3-t4-(1-carbo~y-1-phenyl)methosy-3-chloro-phenyl]methyl-6-methylquinazolin-4(3~)-one 2-8utyl-3-t4-(1-carbosy-1-phenyl)methosy-3-methyl-phenyl]methyl-6-methylquinazolin-4(3~)-one 2-Butyl-3-t4-(1-carbosy-1-phenyl)methosy-3-ethyl-phenyl]methyl-6-methylguinazolin-4(3~)-one .
.
:' ~ , - . .
:~; , .

. , .

,, ; ,; . . ':

;. W091~12~1 ; PCT~US91/00~3 2-Butyl-3-~4-(1-carboxy-1-phenyl)metho~y-3-allyl-phenyl]methyl-6-methylquinazolin-4(3~)-one 2-Butyl-3-[4-(1-carbo~y-1-phenyl)metho~y-3-propyl-phenyl]methyl-6-methylquinazolin-4(3~)-one 6-Methyl-2-propyl-3-[4-(1-(tetrazol-5-yl)-1-phenyl)-methoxyphenyl]methylquinazolin-4(3~)-one lo 2-Butyl-6-methyl-3-[4-(l-(tetrazol-5-yl)-1-phenyl)_ methoxyphenyl]methylguinazolin-4(3~)-one 2-Butyl-6-dimethyamino-3-[4-(1-(tetrazol-5-yl)-1-phenyl)metho~yphenyl]methylquinazolin-4(3~)-one 2-Eutyl-6-(N-methoxycarbonyl)amino-3-r4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl]methylguinazolin-4(3~)-one 2-Butyl-6-(N-methyl-N-methoxycarbonyl)amino-3-[4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl~methyl-quinazolin-4(3~)-one 2-~utyl-6-(N-methyl-N-iso-butylosycarbonyl)amino-3-~4-(1-(tetrazol-5-yl)-1-phenyl)metho~yphenyl~methyl-quinazolin-4(3~)-one 2-Butyl-6-methylsulfonyl-3-t4-(1-(tetrazol-5-yl)-1-phenyl)methosyphenyl]methylquinazolin-4(3~)-one 2-Butyl-6-methyl-3-t4-(1-(tetraZ01-5-yl)-1-(2-chloro-phenyl))metho~yphenyl]methylquinazolin-4(3~)-one `' ' " ~
, ', `' ' ''` ' " ``, ' ,'' .

Wosl/12~1 2 0 7 5 PCT/US91/00993 ~
6 3~

2-Butyl-6-methylsulfonyl-3-[4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))methoxyphenyl~methylquinazolin-4-(3~)-one 2-Butyl-6-methylsulfonyl-3-[4-(1-(tetrazol-5-yl)-1-(2-methylphenyl))methoxyphenyl]methylquinazolin-4-(3~)-one 2-Butyl-6-methylsulfonyl-3-[4-(1-(tetrazol-5-yl)-1-(2-methoxyphenyl))methoxyphenyl]methylquinazolin-4-(3X)-one 2-Butyl-6-methylsulfonyl-3-[4-(1-(tetrazol-5-yl)-1-(2,6-dimethylphenyl))methoxyphenyl~methylquinazolin-4(3~)-one 2-Butyl-6-methylsulfonyl-3-t4-(1-(tetrazol-5-yl)-1-(2-trifluoromethylphenyl))methoxyphenyl]methylquinazolin-4(3~)-one 2-Butyl-6-methylsulfonyl-3-t4-(1-(tetrazol-5-yl)-1-' (2-dimethylaminophenyl))methoxyphenyl~methyl-3 suinazolin-4(3~)-one 2-~utyl-5-hydrosymethyl-3-t4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))metho~yphenyl]methylquinazolin-4-(3~)-one ;
2-Butyl-5-carbomethoxy-3-t4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))mcthoxyphenyl~mcthylquinazolin .. 4(3~)-one .

. :: ~ . .
~. : , , , ; . : . .
I -. ; ; . - ~ , , .~ , .
- .. ..

WO91~12WI ~ PCT/US9l/~X~3 2 07 5~
, . .

2-Butyl-5-carbometho~y-6-methyl-3-[4-(l-(tetrazol-5-yl)-1-(2-chlorophenyl))metho~yphenyl]methylquinazolin-4 ( 3~)-one 2-Butyl-6-methyl-3-t4-(1-(tetrazol-5-yl)-1-(1-naphthyl))methoxyphenyl3methylquinazolin-4(3~)-one 2-Butyl-3-~4-(1-((N-phenylsulfonyl)carboxamido)-l-(2-chlorophenyl))methoxyphenyl]methyl-6-methyl-10 sulfonylquinazolin-4(3H)-one N-Methyl 2-butyl-3-[4-(1-carboxy-1-(2-chlorophenyl))-methoxyphenyl)methyl-6-methylsulfonylquinazolin-4(3~)-imine Preferred compounds of the present invention which are illustrative of subclasses of Formula Ib are:

DIHYD~O~L~ZQLQnEs:
2-Benzyl-5-butyl-4-[4-(1-carbo~y-1-(2-chlorophenyl))-methoxyphenyl~methyl-2,4-tihydro-3~-1,2,4-triazol-3-one 2S 2-Benzyl-5-butyl-4-t4-((1-carboxy-1-(2-chlorophenyl))-metho~y)-3-methylphenyl~methyl-2,4-dihydro-3~-1,2,4-triazol-3-one 2-Benzyl-5-butyl-4-t4-((1-carboxy-i-(2-chlorophenyl))-methosy)-3-allylphenyl~methyl-2,4-dihydro-3~-1,2,4-triazol-3-one .

. . .
. ~, .
: - .
~ . ' . ' ~`

wosl/12~l PCT/US91/~W~3 ;, ~n~

2-Benzyl-5-butyl-4-t4-((1-carbo~y-1-(2-chlorophenyl))-methoxy~-3-propylphenyl]methyl-2,4-dihydro-3~-1,2,4-triazol-3-one 2-Benzyl-4-t4-(1-carbo~y-1-(2-chlorophenyl))methoxy-phenyl~methyl-2,4-dihydro-5-propyl-3~-1,2,4-triazol-3-one 2-Butyl-4-t4-(1-carboxy-1-(2-chlorophenyl))methoxy-phenyl]methyl-2~4-dihydro~5-propyl-3~ 2~4-tria 3-one 4-~4-(l-Carboxy-1-(2-chlorophenyl))methoxyphenyl]-methyl-2,5-dibutyl-2,4-dihydro-3~-1,2,~-triazol-3-one lS
4-t4-(1-Carboxy-1-(2-chlorophenyl)~methoxyphenyl]-methyl-2-cyclopentyl-2,4-dihydro-5-propyl-3~-1,2,4-triazol-3-one 5-Butyl-4-t4-(1-carboxy-1-(2-chlorophenyl))metho~y-phenyl]methyl-2,4-dihydro-2-carbometho~ymethyl-3~-1,2,4-triazol-3-one 5-Butyl-4-~4-~1-carbo~y-1-(2-chlorophenyl))methoxy-2S phenyl]mcthyl-2-carboxymethyl-2,4-dihydro-3~-1,2,4-triazol-3-one 5-Butyl-4-t6-(1-carboxy-1-(2-chlorophenyl))methoxy-phcnyl~methyl-2,4-tihydro-2-hydroxymethyl-3~-1,2,4-triazol-3-one 5-Butyl-4-r4-(1-carboxy-1-phenyl)methoxyphenyl~methyl-2~4-dihydro-2-(2-carboxyphenyl)-3~ 2~4-triazol-3-one .

, . .

... .

.. . . - ;
.. .
: .

W091/1200] PcT/US91/~X~3 5-Butyl-4-[4-(1-carboxy-l-phenyl)methoxyphenyl]methyl-2-(2-chlorophenyl)-2,4-dihydro-3~-1,2,4-triazol-3-one 5-Butyl-4-r4-((1-carboxy-1-phenyl)methoxy)-3-methyl-phenyl]methyl-2-(2-chlorophenyl)-2,4-dihydro-3~-1,2,4-triazol-3-one 5-Butyl-4-[4-((1-carboxy-1-phenyl)methoxy)-3-allyl-phenyl]methyl-2-(2-chlorophenyl)-2,4-dihydro-3~-1,2,4-lo triazol-3-one 5-Butyl-4-[4-((1-carboxy-l-phenyl)methoxy)-3-propyl-phenyl~methyl-2-(2-chlorophenyl)-2,4-dihydro-3~-1,2,4-triazol-3-one 5-Butyl-4-[4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-2,4-dihydro-2-(2-trifluoromethylphenyl)-3~-1,2,4-triazol-3-one 5-Butyl-4-t4-(l-carboxy-l-phenyl)methoxyphenyl]meth 2,4-dihydro-2-(2-methylphenyl)-38-1,2,4-triazol-3-one 5-Butyl-4-t4-~1-carbo~y-1-phenyl)methoxy)-3-methyl-phenyl~methyl-2,4-dihydro-2-~2-methylphenyl)-3~-1,2,4-triazol-3-one 5-Butyl-4-t4-((1-carboxy-1-phenyl)methoxy)-3-allyl-phenyl~methyl-2,4-dihydro-2-(2-methylphenyl)-3~-1,2,4-triazol-3-one 5-Butyl-4-t4-~l-carboxy-1-phenyl)methoxy)-3-propyl-phenyl~methyl-2,4-dihytro-2-(2-methylphenyl)-38-1,2,4-triazol-3-one . ~ -- : , .. . . .
. . . ..

.

. wosl/l20o~ , PCT/US91/~3 207~63:7 ~

5-Butyl-4-t4-(1-ca~boxy-1-phenyl)methoxyphenyl]methyl-2,4-dihydro-2-(2-nitrophen-yl)-3~-i,2,4-triazol-3-one 5-Butyl-4-t4-(1-carboxy-1-phenyl)methoxyphenyl~methyl-2,4-dihydro-2-(2-hydroxymethylphenyl)-3H-1,2,4-triazol-3-one 5-Butyl-4-t4-(l-carboxy-l-phenyl)methoxyphenyl]methyl-2,4-dihydro-2-(2-chloro-4-metho~yphenyl~-3~-1,2,4-lo triazol-3-one 5-Butyl-4-t4-(1-carboxy-1-(2-chlorophenyl))methoxy-phenyl]methyl-2,4-dihydro-2-(2-chlorophenyl)-3~-1,2,4-triazol-3-one 5-Butyl-4-t4-(l-carboxy-l-(l-naphthyl))methoxyphenyl]-methyl-2,4-dihydro-2-(2-chlorophenyl)-3~-1,2,4-triazol-3-one 5-Butyl-4-r4-(1-carboxy-1-(2-methylphenyl))methoxy-phenyl~methyl-2,4-dihydro-2-(2-chlorophenyl)-3~-1,2,4-triazol-3-one S-~utyl-4-[4-~1-carbo~y-1-(2-i~opropylphenyl))methoxy-phenyl~methyl-2,4-dihydro-2-(2-chlorophenyl)-3~-1,2,4-triazol-3-one - 5-Butyl-4-t4-N-(l-carboxy-1-(2-chlorophenyl))methyl-aminophenyl]methyl-2,4-tihydro-2-(2-chlorophenyl)-3~-1,Z,4-triazol-3-one ~ .

: . . . .
, .
' ~',' ', .
, WO 91/12001 2 0 7 5 6 3 7 PCr/US91/00993 ~.r~ it ~
" .
"
S-Butyl-4-[4-N-(l-carboxy-1-(2-chlorophenyl))methyl-N-methylaminophenyl]methyl-2,4-dihydro-2-(2-chloro-phenyl)-3~-1,2,4-triazol-3-one 5-Butyl-4-[4-N-(l-carboxy-1-(2-chlorophenyl)~ethyl-N-butylaminophenyl]methyl-2,4-dihydro-2-(2-chloro-phenyl)-3~-1,2,4-triazol-3-one 5-Butyl-4-t4-(1-carboxy-1-(2-chlorophenyl))methyl-lo thiophenyl~methyl-2~4-dihydro-2-(2-chlorophenyl)-3 1,2,4-triazol-3-one 5-Butyl-4-[4~ carboxy-1-(2-chlorophenyl))methyl-sulfonylphenyl]methyl-2,4-dihydro-2-(2-chlorophenyl)-lS 3~-l.2,4-triazol-3-one 2-Benzyl-S-butyl-4-t4-(1-carboxy-1-(2-chlorophenyl))-methoxyphenyl~methyl-2,4-dihydro-3~-1,2,4-triazol-3-one 2-Benzyl-5-butyl-2,4-dihydro-4-~4-(1-(tetrazol-5-yl)-l-(2-chlorophenyl))methoxyphenyl]methyl-3~-1,2,4-triazol-3-one 2~ 2-Benzyl-2,4-dihydro-5-propyl-4-~4-(l-(tetrazol-5-yl)-1-(2-chlorophenyl))methoxyphenyl~methyl-3~-1,2,4-triazol-3-one 2-Butyl-2,4-dihydro-5-propyl-4-t4-(1-(tetrszol-5-yl)-1-~2-chlorophenyl))methoxyphenyl]methyl-3~-1,2,4-triazol-3-one .~ .
, . . . .
- ~ . .:. .
, . . : . . . ..
. : ., ~ ;: . . , - , .
~, . . ' - ' - .'. ' ' . ' ,;. WO91/1200] ~;~ ` PCT/US91/~M~3 5-Butyl-2,4-dihydro-4-[4-(1-(tetrazol-5-yl)-1-phellyl)-methoxyphenyl]methyl-2-(2-trifluoromethylphenyl)-3~-1,2,4-triazol-3-one 2-Butyl-2,4-dihydro-5-propyl-4-t4-(1-(tetrazol-5-yl)-1-(2-methylphenyl))methoxyphenyl]methyl-3~-1,2,4-triazol-3-one 2-Cyclopentyl-2,4-dihydro-5-propyl-4-t4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))~ethoxyphenyl]methyl-3~-1,2,4-triazol-3-one 5-Butyl-2,4-dihydro-2-carbomethoxymethyl-4-[4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))methoxyphenyl]-methyl-3~-1,2,4-triazol-3-one 5-Butyl-2-carboxymethyl-2,4-dihydro-4-t4-(1-(tetrazol 5-yl)-1-(2-chlorophenyl))methoxyphenyl~methyl-3~-1,2,4-triazol-3-one 5-Butyl-2,4-dihytro-2-hydroxymethyl-4-[4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))methoxyphenyl~methyl-3~-1,2~4-triazol-3-one 2S 5-Butyl-2,4-dlhydro-2-(2-casboxy)phenyl-4-t4-(1-- (tetrazol-5-yl)-1-phenyl)methoxyphenyl]methyl-3~-1,2,4-triazol-3-one 5-Butyl-2,4-dihydro-2-(2-chlorophenyl)-4-t4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl]methyl-3~-1.2.4-tli~Zo1-3-o~e .' ~

' . . ' . ' - .
.,. , ~.
-' ' -. - ' ~ - wosl/l2001 2 0 7 5 6 3 7 pcT/us91/~s3 ,.P,~ s..
i - 59 -5-Butyl-2,4-dihydro-2-(2-methylphenyl)-4-t4-(1-(tetrazol-5-yl)-1-phe~yl)methoxyphenyl~methyl-3~-1,2,4-triazol-3-one 5-Butyl-2,4-dihydro-2-(2-nitrophenyl)-4-[4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl]methyl-3H-1,2,4-triazol-3-one 5-Butyl-2,4-dihydro-2-(2-hydroxymethylphenyl)-4-t4-(1-(tetrazol-5-yl)-l-phenyl)methoxyphenyl~methyl-3H
1,2,4-triazol-3-one 5-Butyl-2,4-dihydro-2-(2-chloro-4-methoxyphenyl)-4-~ 4- (1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl]methyl-3~-1,2,4-triazol-3-one 5-Butyl-2,4-dihydro-2-(2-chlorophenyl)-4-[4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl)~metho~yphenyl]-methyl-3E-1,2,4-triazol-3-one 5-Butyl-2,4-dihydro-2-(2-chlorophenyl)-4-~4-(1-: (tetrazol-5-yl)-1-(1-naphthyl)methoxyphenyl]methyl-3~-1,2,4-triazol-3-one 2S 5-~utyl-2,4-dihydro-2-(2-chlorophenyl)-4-~4-(1-(tetrazol-5-yl)-1-(2-methylphenyl))methoxyphenyl]-methyl-3~-1,2,4-triazol-3-one 5-Butyl-4-~4-N-(l-carbo~-1-(2-chlorophenyl))methyl-aminophenyl~methyl-2,4-dihydro-2-(2-chlorophenyl)-3~-1,2,4-triazol-3-one .

.

,, . , - . . . - .

. , - . . , - ., : - - .. .
- , . -~ WOgl/12~1 ~ pcT/us9lt~9s3 5-Butyl-4-t4-N-(l-(tetrazol-5-yl)-1-(2-chlorophenyl))-methyl-N-methylaminophenyl]methyl-2,4-dihydro~2-(2-chlorophenyl)-3~-1,2,4-triazol-3-one 5-Butyl-4-t4-N-(l-(tetrazol-5-yl)-1-(2-chlorophenyl))-methyl-N-butylaminophenyl]methyl-2,4-dihydro-2-(2-chlorophenyl)-3~-1,2,4-triazol-3-one 5-Butyl-4-[4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))-methylthiophenyl~methyl_2,4-dihydro-2_(2_chloro-phenyl)-38-1,2,4-triazol-3-one 5-Butyl-4-t4-(1-tetrazol-5-yl)-1-(2-chlorophenyl))-methylsulfonylphenyl]methyl-2,4-dihydro-2-~2-chloro-phenyl)-3~-1,2,4-triazol-3-one 5-Butyl-4-[4-(1-(N-phenylsulfonyl)carboxamido-l-phenyl)methoxyphenyl~methyl-2,4-dihytro-2-(2-chloro-phenyl)-3~-1,2,4-triazol-3-one 5-Butyl-4-t4-(1-~N-methylsulfonyl)carboxamido-l-phenyl)metho~yphenyl]methyl-2,4-dihydro-2-(2-chloro-phenyl)-3~-1,2,4-triazol-3-one 5-Butyl-4-t4-(~ -trifluoromethyl8ulfonyl)carbox-amido-l-phenyl)metho~yphenyl]methyl-2,4-dihydro-2-(2-chlorophenyl)-3~-1,2,4-triazol-3-one N-Methyl 5-butyl-4-~4-(1-carboxy-1-phenyl)methoxy-phenyl]meth~1-2,~-dihydro-2-(2-chlorophenyl)-3~-1,2,4-triazol-3-imine , - . ~

~ 2 0 7 5 6,~ PCT/VS91/~X~3 Preferred compounds of the present invention which are illustrative of subclasses of Formula Ic are:

P~ IN-~(3~-ONES:

3-t4-(l-carboxy-l-phenyl)methoxyphenyl~methyl-6 methyl-2-propylpyrimidin-4(3~)-one 2-Butyl-3-[4-(1-carbo~y-1-phenyl)methoxyphenyl]methyl-10 6-methylpyrimidin-4(3~)-one 2-Butyl-3-[4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-6-phenylpyrimitin-4(3~)-one 2-Butyl-3-[4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-6-(2-chlorophenyl)pyrimidin-4(3H)-one 2-Butyl-3-[4-~1-carboxy-1-phenyl)methosyphenyl]methyl-5,6-dimethylpyrimidin-4(3H)-one 2-Butyl-3-t4-(1-carbosy-1-phenyl)methoxyphenyl~methyl-` 5-(2-chlorophenyl)pyrimitin-4(3H)-one 2-Butyl-3-~4-tl-carboxy-1-phenyl)methoxyphenyl]methyl-2S 5-~2-methylphenyl)pyrimitin-4(3H)-one 2-Butyl-3-t4-(1-carboxy-1-(2-chlorophenyl))methoxy-- phenyl~methyl-6-methylpyrimitin-4(3H)-one 2-Butyl-3-t4-(1-carboxy-1-(2-chlorophenyl))metho~y-phenyl~methyl-6-methylpyrimidin-4(3'd)-one ~, . .. .
. . . : . . . . . . ..
- . . .
. .. ~ . ;. , .. - -WO91~2001 ~ PCT/US91/~W~3 2 ~7 5 6'3,7; ~
!." ~ .

2-Butyl-3-[4-(1-carboxy-1-(2-methylphenyl))methoxy-phenyl~methyl-6-methylpyrimidin-4(3~)-one 2-Butyl-3-~4-(1-carbo~y-1-(2-methoxyphenyl))methoxy-phenyl]methyl-6-methylpyrimidin-4(3~)-one 2-Butyl-3-[4-(1-carboxy-1-(2,6-dimethylphenyl))-methoxyphenyl]methyl-6-methylpyrimidin-4(3~)-one lo 2-Butyl-3-[4-(l-carboxy-l-(2-trifluoromethylphenyl)) methoxyphenyl]methyl-6-methylpyrimidin-4(3~)-one 2-Butyl-3-t4-(1-carboxy-1-(2-dimethylaminophenyl))-methoxyphenyl]methyl-6-methylpyrimidin-4(3~)-one 2-Butyl-3-t4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-6-methyl-5-phenylpyrimidin-4(3~)-one 2-Butyl-3-t4-(1-carbo~y-1-phenyl)methoxyphenyl]methyl-6-methyl-5-(pentafluoroethyl)pyrimidin-4(3~)-one 2-Butyl-3-~4-(1-carboxy-1-phenyl)metho~yphenyl~methyl-: 5-(2-chlorophenyl)-6-methylpyrimidin-4(3~)-one 2S 2-Butyl-3-t4-~1-carbo~y-1-phenyl)methoxyphenyl~methyl-5-~2,6-dichlorophenyl)-6-methylpyrimidin-4(3~)-one 2-Butyl-3-t4-(1-carboxy-l-phenyl)methoxyphenyl]methyl-6-methyl-5-(2-trifluoromethyl~henyl)pyrimidin-4(3~)-one 2-Butyl-3-t4-((1-carboxy-1-phenyl)methoxy)-3-methyl-phenyl~methyl-6-methyl-5-phenylpyrimidin-4(3~)-one .

. .

., .
. ' '~ ` , ' .. ~ ' ~

-.WO91/12001 ~ PcT/ussl/~n~3 - 207~637 `
: - 63 -2-Butyl-3-[4-((1-carboxy-1-phenyl~metho~y)-3-methyl-phenyl]methyl-6-methyl-5-(pentafluoroethyl)pyrimidin-4(3H)-one 5 2-Butyl-3-t4-((l-carboxy-l-phenyl)metho~y)-~-methyl-phenyl]methyl-5-(2-chlorophenyl)-6-methylpyrimidin-4(3~)-one 2-Butyl-3-t4-((1-carbo~y-1-phenyl)methoxy)-3-methyl-lo phenyl]methyl-5-(2~6-dichlorophenyl)-6-methyl-pyrimidin-4(3~)-one 2-Butyl-3-t4-((1-carboxy-1-phenyl)methoxy)-3-methyl-phenyl]methyl-6-methyl-5-(2-trifluoromethylphenyl)-pyrimidin-4(3~)-one 2-Butyl-3-t4-((1-carboxy-1-phenyl)methoxy)-3-chloro-phenyl]methyl-6-methyl-5-phenylpyrimidin-4(3~)-one 2-Butyl-3-t4-~(1-carboxy-1-phenyl)methoxy)-3-chloro-phenyl~mcthyl-6-methyl-5-(pentafluoroethyl)pyrimidin-4~3~)-one 2-Butyl-3-t4-((1-earboxy-1-phenyl)methoxy)-3-chloro-phenyl]methyl-5-(2-chlorophenyl)-6-methylpyrimidin-4(3~)-one 2-Butyl-3-t4-((1-carboxy-1-phenyl)methoxy)-3-chloro-phenyl~methyl-5-(2,6-dichlorophenyl)-6-methyl-pyrimidin-4(3~)-one . .

.~ .
.

- . .. - . . -~', ;. ; ' '. ' ' ~ . ' ::' - ' " ' ' ' ' .

~ WO 91/12001 2 0 7 S 6 3 ~ ` PCT/US91/~W3 ~

k ~ ~ r-~ ~ ~
. - 64 -2-Butyl-3-[4-((1-carboxy-1-phenyl)methoxy~-3-chloro-phenyl]methyl-6-methyl-5-(2-trifluoromethylphenyl)-pyrimidin-4(3~)-one 2-Butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-6-methyl-5-phenylpyrimidin-4(3~)-one 2-Butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-6-methyl-5-(pentafluoroethyl)pyrimidin-4(3~)-one 2-Butyl-3-t4-((1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-5-(2-chlorophenyl)-6-methylpyrimidin-4(3~)-one 2-Butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-5-(2,6-dichlorophenyl)-6-methyl-pyrimidin-4(3~)-one 2-Butyl-3-t4-((1-carboxy-1-phenyl)methoxy)-3-propyl-- phenyl]methyl-6-methyl-5-(2-trifluoromethylphenyl)-pyrimitin-4(3~)-one 2-Butyl-3-t4~ carboxy-1-(2-chlorophenyl))methoxy)-3-propylphenyl~methyl-6-methyl-5-phenylpyrimidin-4(3~)-one 2-~utyl-3-t4-((1-carboxy-1-(2-chlorophenyl))methoxy)-3-propylphenyl]methyl-6-methyl-5-(pentafluoroethyl)-30 pyrimidin-4~31~)_one .~

.

, ':` , ` ' - '' ' -',:

WO91/~ 2 0 7 ~ 6 3 7 PCT/US91/~3 .s,;, , .. . .

2-Butyl-3-[4-((1-carboxy-1-(2-chlorophenyl))~ethoxy)-3-propylphenyl]methyl-5-(2-chlorophenyl)-6-methyl-pyrimidin-4(3B)-one 2-Butyl-3-[4-((1-carboxy-1-(2-chlorophenyl))methoxy)-3-propylphenyl]methyl-5-(2,6-dichlorophenyl)-6-methyl-pyrimidin-4(3B)-one 2-Butyl-3-[4-((1-carboxy-1-(2-chlorophenyl))methoxy)-3-propylphenyl]methyl-6-methyl-5-(2-trifluorometh phenyl)pyrimidin-4(3B)-one 2-Butyl-3-~4-(1-carboxy-1-(2-chlorophenyl))methoxy-phenyl]methyl-5-hydroxymethylpyrimidin-4(3B)-one 2-Butyl-5-carbomethoxy-3-[4-(1-carboxy-1-(2-chloro-phenyl))metho~yphenyl]methylpyrimidin-4(3~)-o~e 2-Butyl-5-carbomethoxy-3-[4-(1-carboxy-1-(2-chloro-phenyl))methoxyphenyl]methyl-6-methylpyrimidin-4(3B) one 2-Butyl-3-~4-(1-carboxy-1-(1-naphthyl))metho~yphenyl]-methyl-6-methylpyrimidin-4(3B)-one 6-Methyl-2-propyl-3-~4-(1-(tetrazol-5-yl)-1-phenyl)-metho~yphenyl]methylpyrimidin-4(3B)-one 2-Butyl-6-methyl-3-t4-(1-(tetrazol-5-yl)-1-phenyl)-metho~yphenyl]methylpyrimidin-4(3B)-one - - :
` ' , ` - ', - , ' .' . :' . . ' -' ..
.- : ' ' . ,,, . ~ -. . ., . - .,: :'; - -. - , ~ . - . .
.

, WO91/12~1 ~ ' PCT/US91/~3 ~
207~637 2-Butyl-5,6-dimethyl-3-t4-(l-(tetrazol-5-yl)-l-phenyl)methoxyphenyl]methylpyrimidin-4(3~)-one 2-Butyl-6-phenyl-3-[4-(1-(tetrazol-5-yl)-l-phenyl)-methoxyphenyl]methylpyrimidin-4(3H)-one 2-Butyl-6-(2-chlorophenyl)-3-t4-(l-(tetrazol-5-yl)-l-phenyl)methosyphenyl]methylpyrimidin-4(3~)-one 10 2-Butyl-5-(2-chlorophenyl)-3-[4-(l-(tetrazol-5-yl) phenyl)methoxyphenyl]methylpyrimidin-4(3~)-one 2-Butyl-6-methyl-3-[4-(1-(tetrazol-5-yl)-1-(2-chloro-phenyl))methoxyphenyl]methylpyrimidin-4(3~)-one 2-Butyl-6-methyl-3-t4-(1-(tetrazol-5-yl)-1-(2-chloro-phenyl))methoxyphenyl]methylpyrimidin-4(3~)-one 2-Butyl-6-methyl-3-t4-(1-(tetrazol-5-yl)-1-(2-methyl-phenyl))methoxyphenyl]methylpyrimitin-4(3~)-one '~ 2-Butyl-6-methyl-3-t4-(1-(tetrazol-5-yl)-1-~2-metho~
phenyl))metho~yphenyl~methylpyrimidin-4(3E)-one 2-Butyl-6-methyl-3-t4-(1-(tetrazol-5-yl)-1-(2,6-~ dimethylphenyl))methosyphenyl]methylpyrimidin-4(3~)-; one 2-Butyl-6-methyl-3-t4-(1-(tctrazol-5-yl)-1-(2-tri-fluoromethylphenyl))metho~yphenyl]methylpyrimidin-; 4~3~)-one -, - . .

',' ~ . .- '. ~ - ' . . ', , :

. . .
... .. . . . . . .
..
-:', "'' . '' -. " .- ' . .. ' ~
. . . . .

., WO92/12~1 bU (~O~ I PCT/US91/~X~3 , ~:
- 67 _ 2-Butyl-6-methyl-3-[4-(1-(tetrazol-5-yl)-1-(2-dimethylaminophenyl))methoxyphenyl]methylpyrimidin-4(3~)~one 2-Butyl-5-hydro~ymethyl-3-[4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))methoxyphenyl]methylpyrimidin-4(3~)-one 2-Butyl-5-carbomethoxy-3-[4-(1-(tetrazol-5-yl)-1-(2-10 chloro~henyl))methoxyphenyl]methylpyrimidin-4(3l~)-one 2-Butyl-S-carbomethoxy-6-methyl-3-[4-(1-(tetrazol-5-yl)-1-(2-chlorophenyl))methoxyphenyl]methylpyrimidin-4(3~)-one 2-But,yl-6-methyl-3-t4-(1-(tetrazol-5-yl)-1-(1-naphthyl))methoxyphenyl]methylpyrimidin-4(3H)-one 2-Butyl-3-t4-(1-((N-phenylsulfonyl)carbo~camido)-l-; 20 phenyl)methoxyphenyl]methyl-5-(2-chlorophenyl)-6-methylpyrimitin-4(3~)-one 2-Butyl-3-t4-(1-((N-methyl8ulfonyl)carbosamito)-1-(2-chlorophcnyl))metho~yphenyl]methyl-5-(2-chloro-t 2S phenyl)-6-methylpyrimidin-4(3~)-one 2-Butyl-3-t4-(l-((N-trifluoromethylsulfonyl)carbox-amido)-1-(2-chlorophenyl))metho~yphenyl~methyl-5-(2_ chlorophenyl)-6-methylpyrimidin-4(3~)-one N-Methyl-2-Butyl-3-t4-(1-carbosy-1-(2-chlorophenyl))-methoxyphenyl]methyl-5-(2-chlorophenyl)-6-methyl-pysilCidlD-4(33)-iDline .

~ . : . : . . .. . .

. . . . . .~ , . . . .
.
. .
... - .. : . . , : -.
.. . . ... . . . . .. .
., : - - . .
.-, . :. . .: ~ -- . WO 91/12001 ` ' ` ' PCr/US91fO0993 ;~ 207~6~
.

G~N~RAL nEI~Qa~ FOR P~E2ARATION OF COMPO~D~_QE
GEN~RAL FOXnm~A_I~

The method~ described in PA~I_I AND PART II
below illustrate the preparation of angiotensin II
antagonists of Formula I. There are several general approaches to the synthesis of antagonists of Formula I, and it is taken as a general principle that one or another method may be more readily applicable for the lo preparation of a given antagonist; some of the approaches illustrated below may not be readily applicable for the preparation of certain antagoni~ts of Formula I.
It should be recognized that antagonists of Formula I consist of a heterocyclic component designated above by formulas Ia through Ic 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:

l. A heterocycle, designated abo~e with Formulas Ia throu~b Ic i8 prepared as described in ~ below. Then the htterocycle i 8 al~ylated at a nltro~en atom with a ~ubstltuted benzyl halite or p8eudohalide gi~ing an al~ylatcd heterocycle in the Schemes below, this al~ylating agent is often de8i~nated a6 "Ar-C~2Q where Q is a halide (-Cl,Br,I) or p~cudohalide (-OMs, OTs, OTf). In some cases, al~ylation may ta~e place at more than one nitrogen atom of the heterocycle, and in these ca~es, 8eparation by fractional crystallization or by chromotographic mcthods may be necessary for . :... . :
~. - ....
, ..
- , .

- W091/~2001 PCT/US91/~3 ;: ~2 0 ~

, ., isolation of the desired product. In some cases, the alkylation ~tep produces a fully-as6embled antagoni~t of Formula I, except that functional groups in the al~ylating agent or in the heterocycle may be pre6ent in protected form and require deprotection steps to be carried out to complete the synthe~is. In other cases, the al~ylation is carried out with a substituted benzylic halide o. pseudohalide ("Ar-CH2Q"), but here the alkylation step is followed by subsequent ~teps which are required to as6emble 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 ~ 11 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 Pa~t II below. In most cases where this general approach is used, the sub6tituted benzyl component which is introduced during the synthesis of the heterocycle must be subjected to further synthetic transformations in order to complete the -2S 8ynthe8~ of the antagonist of Formula I. In the Scheme6 8hown below in ~ART II, this substituted benzyl component is de6ignated as "-C82Ar," and i6 usually introduced by an al~ylation step with a substituted benzyl halide or pseudohalide designated ArC82-Q (where Q i~, for e~ample, Cl, Br, T, F, OTs, or OMs), or is introduced by a route which starts with a substituted benzyla3ine, designated "ArC82 M2". The required substituted benzylamine '' '. :: - . . . : :
-. . ~ . . . .
.

-, ' .- . ' . - ~.
.:
- . ~ ; . -:: . . . , :

WO 91/12001 .: , . i PCI/US91~00993 - 2075~
. ...
,, ~o derivatives may be prepared by standard methods, for example from the substituted benzylic halides or pseudohalides ("ArC~2-Q"). Substituted benzyl halides or pseudohalides which are useful in the s preparation of al~ylated heterocycles described in PART I are illustrated by those listed below in Table 1. Substituted benzyl amines which are useful in the preparation of the al~ylated heterocycles described in ~A~I I are illustrated by those listed below in Table 2. In cases where these benzylic halides, pseudohalides and amines are not commercially available, they are prepared as described in Part II
below or by standard methods of organic synthesis.
Subsequent steps which may be requiret to complete the synthesis of antagonists of Formula I are desribed in ~A~ II below.
The compounds of this invention may be resolved using techniques known in the art. The diastereomeric salts or esters of the enantiomers are separated and the desired compound i8 the more active stereoisomer. The compounds of this invention, their pharmaceutically acceptable salts and their prodrug forms are included within the scope of this invention.

-~ WO 91~2WI PC'r/US91~00993 ;~ 2 0 7 5~3 7 .. ..
:: --7 1--Table 1 CH2Elr CH2E3r CH213r (~H3 ~f -OCH2Ph OCH~Ph OCH2Ph CH29r CH29r CH29r Cl~ C~ H3 OCH2Ph OCH2Ph OCH2Ph CH29r CH~9r CH~9r CN CO~CH3 CH~Ol~gD~S
CH29r CH~Elr CH2aI~3 SCH,Ph NO~ CH~OT9DIS
CH~9r CH~9r OCH,Ph X~,Ph ;` .

r , ~ . , . : , . . .
~ ` ' ; ` ' ': ' '' `. -? . -:

WO 91/12001 ' ~ pcr/us91/oo993 207~637; `- ~
L.'i . --72--Table 2 CH2 NH2 CH2NH2 C~12 NH2 5 (~

NO2 OCH2Ph CO2CH3 ~H3 CNOCH2Ph CH,Ol~Dl~S
CH2NH2 CH2NH2 CH,NH, l S ~ ~H3 SCH,Ph OCH,Ph OCH,Ph CH2NH, CH2NH2 '' 20 OCH2Ph OCH,Ph :, .. , . .. . - ~ - . ~ -t. ' ' ' ' ' ' ,~ , `
,.. ... .. . ...
. ' ' ' . : . .

j WO91/12001 2 0 7 ~ 6 3 7 PCT/US91/~3 . .
. -73-Abbreviations used in the schemes and examples are listed in Table 3.

Table 3 s Rea~ents NBS N-bromosuccinimide AIBN Azo(bis) isobutyronitrile l0 DDQ Dichlorodicyanoquinone Ac2O acetic anhydride TEA triethylamine DMAP 4-dimethylaminopyridine PPh3 triphenylphosphine lS TFA trifluroacetic acid TMS-Cl trimethylsilyl chloride Im imidazole AcSK potassium thioacetate : p-TsO~ p-toluenesulfonic acid ; 20 FMOC-Cl 9-Fluorenylmethylosycarbonyl . chlorite Solvents:

~ 25 DMF dimethylformamite i ~OAc (AcOB) acetic acid EtOAc (EtAc) ethyl acetate ~ex hesane T~F tetrahydrofuran 30 DMSO dimcthylsulfoside MeOE methanol iPrO~ isopropanol .

t .... . . .
' ' ' - `:
. , '`~ . , .
., . ,. i , . . ..

:' . :, ',: ` ~ ''' ' . ~ : ' ' `` ' '',' ' ~ ~ ' '- ' ~, , wosl/~20o~ 7 ~ PCT/US91/~0993 ' 207~63~;~7.

Qth~s:

rt room temperature TBDMS t-butyldimethylsilyl S OTf OSO2CF3 Ph phenyl FAB-MS (FSBMS) Fast atom bombardment mass spectroscopy NOE Nuclear Overhauser Effect 10 SiO2 silica gel trityl triphenylmethyl Bn benzyl PART I: Preparation of the heterocycles shown in Formulas Ia. Ib. and Ic.

A. P~aration of ~uinazolinon~s (Formula Ia) ; 20 Rl - B~N
CH2 Ar - ~ . .

~ . . . .. .

! WO 91~12~1 ~ , PCT/US91/~Y~3 ,,~i,, i~
207~6~7 .i -75-Scheme I-l illustrates the preparation of 1,2-disubstituted quinazolin-4(1~)-ones of Formula Ia wherein Jl = -C(0)- and B is a single bond. An appropriately substituted anthranilonitrile is acylated using the requisite acyl chloride. The resulting amide is alkylated with sodium hydride and the appropriate alkyl halide (or pseudohalide). The resulting tertiary amide is then rearran~ed/cyclized with basic hydrogen pero~idel.

. - . .

.

.
.
~ - ' .

WO91~12001 2~6`~`7 ~ PCI`/US91fO0993 ~

: --7 6--S C~E;tll~; I -1 H~ N~ E~ ~N DMAP. 3'~ N~7b CI~~Cl2 (or DMF) H (2~
~1) No ~ DMF R7 -ArCH~Q R~
CH~Ar 2 0 NJ~>( ~'~ R7 b ~IDO~ OH~ Ll 1 ~' M~O~ ~1,0 R' ~", ~ t CH" Ar O ~r. ~
Ar s 1~ o~ do~n d OJ ln tho g-norlc tructur- Fornulo I

-- ' .

.

- . - :.

. wos1/~2~ PCT/US91/~3 ,,," ,,-,"", 20756~
... .

2-Substituted quinazolinones may be prepared from substituted anthranilonitriles as described in the literature and illustrated in Scheme I-2. The appropriately substituted anthranilonitrile is acylated using the requirite acyl chloride then cyclized using basic hydrogen peroside.

SC~EME I-2 "~-R ' 'ICOCl. I:t,N ~R~-H7N R Dffl~', C~l,Cl, R' J~o CN
(~) R~ 2) *-N,O,, N 011 "~X
H,O. ~OH R~ ~O

; 2S Scheme I-3 shows an alternate preparation of 2-~ub~tituted quinazolinones startinE, with the corre~pondin~ anthranilic acid. The appropriately substituted anthranilic acid is treated with two equivalents of the requisite acyl chlorite in DMF
with triethylamine and DMAP at O-C. This is then heated to llO-C for two hours after which time esce88 - ammonium carbonate is added.2 ~-.. -., wos1~12~1 PCT/US91/~3 ~ 2 Q 7 ~ 6 ~

~-R ' R~COCl, Et~N ~b H~N R~b DM~P. DMF, he~t I `r\R~b COOH th~n ~xc~ Rl ~
t7) (N~)~CO3 H
(6) lS Scheme I-4 illustrates the general preparation of 2,3-tisubstituted quinazolin-4-~3~)-ones of Formula Ia, wherein B is a single bond and Kl is -C(0)-. An appropriately sub~tituted 2-substitutet quinazolinone (see Scheme I-~ or Scheme I~) is alkylated using 60tium hydride and the appropriate al~yl halide (or pseudohalide). This reaction sometimes gives ~ome 0-alkylated product, generally le6s than 20% of the i60lated reaction products.

.. .
:: . ... - -.. - .
-.: . -. . .: : , , -... . . . . ~ .

. . . --.. ... . . . .
.
- . - - ~ ~
- . . . . .. . - -~./ WO 91/12001 r~ r~, r~ ^ PCI~/US91~00993 ~ 207~637 , ................................................ ..

S C~I~;ME I - 4 ~?7 " R7 ~
~R7b 1~ NaH DMF ~R7 ~\Rtlb ~ b H
( 6 ) CH2 Ar 15Schemes I-S. I-~. and 1=1 provide an alternate route to compounds of Formula Ia, wherein B
is a single bont and Kl is -C(0)-.
Two methods for preparing 3,1,4-benzo2azones are illustrated in Scheme I-5. Substituted anthranilic acid6 may be acylated and cyclized by heating them in DMF with an scyl chloride, triethylamine and DMAP.3 Alternatively, they may . also bc prepared by heating an appropriately sub6tituted anthranil with an acyl chloride in pyridine.4 The nece~ary al~yl amine may then be prepared from the al~yl halide (or pseudohalide) usin~ the standard literature procedures (~h~m~
I=g).5 Then, the amine and the 3,1,4-benzo~azone are heated to~cther to give the desired 2,3-di~ub~tituted quinazolinone ~ (~cheme I-7).

,. . . .
.
- ,- : - `

.

,~ WO 91/12001 2 0 7 5 6~ 7 ~ .. . `~ , PCl'~'US91fOO993 ~

S C~IE~E I -~7' R-b ~R
\DM~. DMF
~1.77~ R7b ~R D
0 R' ~
/ (10) o~R~ pyrld~r~. h-rt (O~

5S~E~

ArCH2Q ~ ArCH2NH2 (3) (11) `~ . . ` .. . . . . . . . `

:. ` . . . . . :

wo 91~2~1 ~ b~ PC~US9l/~W~3 ", SC~EME I-7 ~ ~CH2MH~ ) 1o R ~ o DMF. h~t (10) CH2-Ar (12) Substituted 2-al~ylthioquinazolin-4(3~)-ones wherein ~1 is -C(0)- and B i6 -S- may be prepared from their corresponding substituted anthranilic acids as shown in Scheme I-8. The amine from ~hgm~
I=g can be converted to its isothiocyanate upon treatment with thiophosgene. This may then be reacted ~ith an approprlately sub6tituted anthranilic acid to give the des~red 3-al~yl-2-mercapto-quin-azolin-4~3~)-one.6 A second al~ylation of the mercapto group then gives the desiret 2-al~ylthio-3-al~ylquinazolin-4(3~)-one.7 i .
,:, . ' ' :

.: ~- . . . .

~, WO 91/12001 ~ PCI~/US91/00993 2075'6'37 ' , S~' ~, '' -.
. --82--SC~IEME I-8 ArCH2NH2 C12CS ArCH2-N=C=S

(11) (13 R7~

~R~ A
H2N~R~b R7~ R7b COOH ~[~_ Nl ~ R~ b - 15 HS ~o CH2- Ar (14) ~ ArCH2N=C=S
( 1 3 R7~

~R7b 2S D~3U ~1 -s~~o R1_X
C~- P.r (15) i 1. , ~ . :. , ~ ~. - - . :
'' . ' ' ' ' ~, , , .i `

`~': , ' ' ' ~ . ' ' ' . .

!~ Wo91/12001 2 0 7 ~ 6 ~7, ~ PCT~US91/~ ~3 : ~ .

Similarly, 2-alkoxyquinazolin-4(3E)-ones wherein Xl is -C(O)- and B is -O- may be prepared from their corresponding substituted anthranilic acids as shown in ~heme 9,8 Alkylation with the appropriate alkyl halide according to the methods developed by Lange and Sheibley 9 then gives the final product 17.

SC~EME I-9 R'-OR

COOH CN H
2 0 ~ 7 )8N~OR' ( l ~ ) R' - OH
R7.
~yR7b 2 5 u~R7.
~ T R
ArCH~O( 3 ) R' - O~o I

C~Ar

(17) ; ~ WO 91~12001 V~ PCr/l~S91~00993 2 ~ ; 3 ~, ~

Scheme I-10 illustrates a possible route to the isomeric 1,2-disub6tituted quinazolin-4(1~)-ones wherein J1 i6 -C(0)- and where ~ is -S- or -0-. An anthranilonitrile can be acylated with an alkyl haloformate or an al~ylthiol haloformate.10 This may then be deprotonated and alkylated with the appropriate al~yl halide to give the intermediate carbamate nitrile shown.11 Conversion of the intermediate then could occur when the material is treated with basic hydrogen peroxide to yield the desired product 20.

S-~EME I-10 Q7. R7.

H,N~ ;R~

(1) DMF N~ R7 c ~ ) 2S C~
(19) ~ R7 b 3 ~19) ~~/ R~-r7~ R~-~OH
Cl~2Ar ( 2~

. .

- , , ' ' ; - : . ~:-, - .

.
' - : . ' ' ' ~ ' , . ~

. . : . .
. ~ . , :
- - . . ~ . . :- , .. : .

wosl/l20o~ PCT/US91/~3 ~ 2D~7.~63~
~, , ; -85-Scheme I-ll illustrates the method by which a 2-amino-3-al~ylquinazolinone can be made. The 2-mercaptoquinazolinone (14) shown in Sche~ 1-8 can be treated with sulfuryl chloride to give the corresponding 2-chloroquinazolinone.12 Di6placement of the chloride with an Rl amine then gives 2Q with B = NH 13 SCHEM~ I-ll 15HS~ ~ll Ar - CH2 ( 14) Ar-CH2 7 b 20R'-NH, N~o R 3 R~
2 S CH2Ar ( 20) - 5~hs3~_~=lZ illu8trate8 the methot by which a 2-amino-1-al~ylguinazolinone can be made. The products from Schem~ I-10 can be u8ed a8 a 8ynthetic intermediate if the initial Rl i8 a protecting group 1 such a~ benzyl or t-butyl.14 Deprotection and WO91/12~] PCT/US91/~3 2~ 6~

subjection of the resulting 2-mercapto-1-alkyl-quinazolinone to the same conditions used in ~cheme L=ll Will result in the formation of the d~sired 2-amino-1-al~ylquinazolin-4(1~)-one. Alternatively, the sulfide may be displaced directly by an Rl amine as ~hown in Scheme I-13 (Rl-S- and Rl-N~2 may or may not have the same Rl).
SC~EME I-12 ~j 1 ) d-prot-ot ( prot ~t lng Oroup) Ar-C)~
(21) I~
Ar - CH~
Ar-t 2~) ( Z3) i :
. . . .
, .

, . : , ~ ., .' ~

, wos~/12~l PC~S91~ ~3 2~7563~
~
.

SC~EME I-13 Rl ~S'~ }' N~
l 0 Ar-CH2 Ar-CH2 The preparation of quinazolinones of general Formula Ia bearing substituted C-6 amino groups may be accomplished as illustrated in Schemes I-14 through I-16. In order to prepare these terivatives, the amide group of a 6-nitroguinazolin-4(3E)-one is usually first protected with an acid labile protecting group as shown in Scheme I-14. For instance, reaction of the ~eneralizet 6-nitroguinazolin-4~3~)-one (24) with a base such as 80tium hydride in DMF followed by addition of 2S bis(4-metho2yphenyl)methyl chloride affords the N-protected derivative 25. The nitro group of 25 may be reduced to the amine 26 by reduction with hydrogen over pallatium on carbon. The amine (26) may then be reacted with a variety of reagents ~nown to form derivatives of amines such as al~yl- or aryl-carbo~ylic acid chlorides, chloroformates, sulfonyl and sulfamoyl chlorides, isocyanates and , . ~ - .
- . - .
.

, ., , . ': .
:, .
.
~ -. . .

.; W091/12~1 PCTtUS9if~3 , . - .

isothiocyanates. Scheme I-14 illustrates the derivatization of amine 26 with a generalized chloroformate to afford substituted carbamate6 such as 27. The acylation of amine 26 with a chloroformate is best carried out in the presence of a strong base such as sodium hydride to deprotonate the amine. This anion then reacts readily with chloroformates to give the substituted carbamates 27. The carbamate (27) may be isolated, then deprotonated with lithium bis(trimethylsilyl)amide and alkylated to give the N,0-disubstituted carbamates 28. Alternatively, this process may be carried out in one flask by first deprotonating the aniline (i.e. with sodium hytride in DMF), reacting lS the anion with an acyl halide or chloroformate, then treating the intermetiate with an equivalent of a strong base such as lithium bis(trimethylsilyl)amite and finally adding an al~ylating agent to obtain 28.
The carbamoyl-substituted quinazolinones 27 and 28 may be cleanly teprotectet under acidic contitions such as trifluoroacetic acit-anisole to afford the hetcrocycles 29 ant 30 re~pectively.

~ ' .' ', . - -;~ ' ~ ~ ' '' ' - ' ' ,., : ' ' ' ' .

.
' ' . ~ . :

-,. . ; ~ . . - , - . . .
.
. -'. : - ' ~ -. . -' .. -. . ' : . :
.

WO 91/12001 20 7!j'63 7 PCI`/US91~00993 . ~"~, S C~IEME I -14 R' ~ ) ~n Dtl H 24 ~o~ R' - B
~70~

~, , o~ c ~ ~n D~
R' - ~ ~ `O
Il OAC I~ ~ A~ I OC~ O) C 1 1~0~

2 0 ~ , O
R' ~ ) A~- l R' - 9 ~~ ~O~M~7 2 ~ A, ~R~
R~ - 9 ~ R~
8 3~ 29 .

:. . : . . -, . ., : : . - , , :

- ::

~,, Wosl/12~l P~USslf~3 J
20~ ~3 7 :- -90-SC~EME I-15 R'~ ~ R7b H
R7;~R~ b R7~ ~o R'~ NCO~ CN~Cl~
¦ ~r~ol~ H 31 ,~

Scheme 1-15 illustrates the reaction of amine 25 with isocyanates to give disubstituted ureas (31). Tetrasubstituted and trisubstituted ureas such as 34 and 35 may be prepared from the benzyl carbamate 27 as shown in Scheme 1-16. Thus, treatment o~ 27 with the magnesium ~alt of a 6econd~ry amlne ~ormed srom the secondary amine and mcthylmagneoium bromlde a~ort8 the trisubstituted urea 3Z. Trisubstituted ureas (32) may be N-al~ylated by depsotonation of the remaining hydroeen with lithium bis(trimethylsilyl)-amide sollowed by al~ylation with an al~yl iodide to give 33. The urea-substituted quinazolinones 32 and 33 may be cleanly deprotected under acidic conditions ~uch s trlfluolo-cetic cid-ari801e to fford the - . . , ~
~ ~ . , . - .. .. ,:
.. . ~ , ~ , .
- . : , .,, :
- - , ~

-: .;
. . -, WO9~/12W1 2 0 7 5 6 3 7 PCT/US91/~H~3 .
, 3 ~ ` ' `' ` f heterocycles 34 and 35 respectively. The amine 26 (Scheme 1-14) may be derivatized or converted to other functional groups using chemical procedures well known to those ~killed in the art. After the appropriate 6-substituent ha~ been constructed the protecting group may be removed by treatment with trifluoroacetic acid in the presence of anisole as illustrated in Schemes I-14 through I-16. The heterocycles obtained in this manner may be incorporated into Angiotensin II Antagonists of general Formula Ia as described in Part II.

.
,:

.. . . .
~ .

; WO91/12001 ;~ ., P~T/US91/~M~3 `~ 2075~

SC~E-'~E I-l~

V~ R~

R'-1!1 Slv. h~ R'~
~oJ~ ~0 ~L~
R7~

p~ ~ ~ o , ~ Rl - 77 J~ -' 20 R~

For a gcneral review of the synthesis and reactivity of 2,3-disubstituted pyrido~2,3-d] or t3.4-d~ or t3,2-d~ or t4~3-d]pyrimitin-4~3~o-one see A.R. Katritz~y, et al.. Com~rehen~ive ~rt--~r-~ic Cbe~;~tlv, vol. 3, 201 (19B4) and W.J.
Irwin, et al.. Advance6 in ~eterocyclic Che~istry, vol. lO, 149 (1969) , .: ~ . ,I ., - - ; ~ , , -. . ~. . ` :

.~ ; i , ~' , ' ' , ' ; . `
.~ " " ' " ' . ~

WO91/~2W1 2 0 7 5 6 3 7 PCT~US91/~3 . ' ` . ' .
: -93-QUIMAZOLINONE R~FERENCES

1 E.C. Taylor, R.J. Knopf, A.L. Borror, l~ Am.
Che~, Soc. (1960) 82, 3152.
R.L. McKee, M.~. Mc~ee, R.W. Bost, J. Am. Chem.
~Q~ (1946) 68, 1902.
A. Rhan, R.~. Saksena, Phar~azie (1988) 43 ~. 12.
2 M.T. Bogert, W.F. ~and, ~. Am. Chem. Soc. (1906) ~, 94.
3 See A. ghan, reference 1.
L.A. Errede, J.J. McBrady, ~.T. Oien, J. Or~.
Chem. (1977) 42, 656.
L.A. Errede, J. Or~. Chem. (1976) 41 1763.
L.A. Errede, ~.T. Oien, D.R. Yarian, J. Or~.
~hem. (1977) 42, 12.
4 R. Wunsch, A.J. Boulton, Ad~. ~et. Chem. (1967) 8, pp 326-9, and references therein.
I.R. Gambhir, S.S. Joshi, J. Ind. Chem. Soc.
(1964) 41, 47.
Bayley, Stranding, Knowle6, ~trahedron. Lett.
(1978) 3633.
Rolla, 1. Ore. Chem. (1982) 47, 4327.
Gib~oD, Bradshaw, An~ew. Chem. Int. Ed. En~l.
(1968) 7, 919.
6 R.G. Dave, G.S. Mewada, G.C. Amin, J. Ind. Che~.
~oc. (1960) 37, 595.
7 J.E. McCarty, L.L. ~aine~, C.A. VanderWerf, J.
Am. Chem. Soc. (1960) ~2, 964.
P.N. Bhargava, P. Ram, Bull. Chem. SOC, J~
(1965) ~, 342.
M.R. Chaurasia, A.R. Sharma, ~eterocycle~ (1983) 2Q, 1549, WO 9~/12~1 ~' f` i.,~ PCT/US9i/~M~3 207~637 ~
-~4-R. Lempert, G. Doleschall, Ch-em Ber. (1963) 96, 1271.
. Singh, K.S. Narang, J. Ind. Chem. Soc. (1963) 40, 545.
M.S. Dhatt, K.S. Narang, J, ~n ~ Chem. Soc.
(1954) 31, 787.
M.S. Dhatt, R.S. Narang, 1 Ind. Chem Soc.
(1954) ~1. 864.
D.S. Bariana, ~.S. Sachdev, ~.S. Narang, J. In~
1o Chem. Soc. (1955) ~, 647.
8 Griess, Ber. Deut. Chem. Ges. (1869) 2. 415 9 N.A. Lan~, F.E. Sheibley, J. Am. Che~, Soc.
(1933) 55, 1188.
~.B. Milne, S.L. Razniak, R.P. Bayer, D.W. Fish, J. Am. Chem. Soc. (1960) ~2. 4582.
E.J. Corey, M.G. Bock, A.P. ~ozi~owski, A.V.R.
Rao, D. Floyt, B. Lipshutz, Tetrahedron Lett.
(1978) 1051.
M. Bergmann, L. Zerva~, ~er. (1932) 65 1192.
11 R.L. Dannley, M. Lu~in, J. Or~. Ch~m- (1957) 22, 2~8.
R. Zi~uc~, N.J. Livcrton, A.B. Smith, J.
Chem. Soc. ~19B6) lQ,B 2451.
12 D.J. ~rown, Fu5ed Pvrimidine~, Part I
QuinazolineB, (1967), J. Wiley ~ Sons, p. 222.
13 D.J. Brown, Fus~LPyrimidines, Part I
Quina201ines, (1967~, J. Wiley ~ Sons, p. 323.
14 T.W. Greene, protective Grou~s in Or~niL
Synthesi~, ~1981), J. Wiley ~ Son8, pp. 193-217.

:

... . .
t .
t -. .~ . , ., . . ; . : ~ :-, .

Wo91/l2~ 2 0 7 ~ 6 3 7 PCT/US91/~K~3 ,~,,i,. . .
'~4~- , , ` J

B. Preparation of triazolinones, triazolinethiones and triazolinimines (Formula ~b ,Rl6 lo N- N
R'-B
CH2 Ar lS
The compounds of Formula Ib can be prepared by a variety of methods typified by those describet below in Schemes I-17to I-28. General synthetic methots for 2,4,5-trisubstituted-1,2,4-triazolin-3(4~)-ones ant -triazolin-3(4~)-thiones are discussed in boo~6 or review articles 8uch as:
(l) C. Temple ant J.A. Monteomery, "Triazoles:
1,2,4" (Vol. 37 Or The Chemistry o~
ae~erocyclic C~o~Qyn~ A. Weis8berger ant E.C. Taylor, eds.), Wiley-Inter~cience, New Yor~, 1981, pp. 365-442.
(2) J.B. Polya, Com~rehen~ive ~eterocvclic Chemistry. The Structure. Reactions, ~y~thesi8 and Use~ of ~eterocyclic 3 Compounds, A.R. Katritz~y and C.W. Rees, eds., Vol. 5, Pergamon Press, Osford, 1984, pp. 733-790.
;

. . , ,~

,. ~ - . ~ .
.
.. . . . . ~ .
: . ~ .
` ~ . ' . ' : ' .. ' -' . . ..
' . ' - . - -,.

W091/12~1 ~ PCT/US9l/~3 ., ' (3) J.H. ~oyer, ~eterocvclic Com~ounds, R.C.
Elderfield, ed., Vol. 7, John Wiley ~ Sons, New York, 1961, pp. 384-461.

In general, the compounds of Formula Ib are constructed in 6uch a way that Nl and N2 of the triazole ring are derived from hydrazine or a hydrazine derivative, while N4 of the triazole and the 4-(arylmethyl) substituent are derived directly or indirectly from a suitably substituted benzylamine (or isocyanate or isothiocyanate) or from a benzyl halide (or methanesulfonate, p-toluenesulfonate, etc.).
Although the Reaction Schemes described below are reasonably general, it will be understood by those 6killed in the art of organic synthesis that one or more functional groups present in a given compound of Formula Ib may render the molecule incompatible with a particular synthetic 6equence.
In such a case an alternative route, an altered order of steps, or a strategy of protection and deprotection may be employed. In all case6 the particular reaction conditions (including reagents, solvent, temperature, and time) should be cho8en 80 that they are consistent 2S w~th the nature of the functionality prcsent in the moleculc.
The Reaction Schemes below have been ~eneralized for simpliCity. It is to be understood that the "ArC~2" sub8tituent pre8ent at N4 of the triazole derivatives or in their precursors is any substitutet arylmethyl moiety consistent with the deflnition of the N4 substituent in Formula I or , . :
~ . . ' - ' " -.

.

:,; WO91/12001 ~ Or7i5 ~3i~ PCT/VS91~W~3 .
_97-which may be transformed to such a grouping either before or after the assembly of the triazole ring system. Such transformations may involve protection and/or deprotection steps, a6 described above in the "General Methods~ section or other modifications. It is also to be understood that in most of the Reaction Schemes, the "ArC~2" (Ar = aryl) substituent is consistent with the definition of Formula I.
It is further to be understood that in the generalized schemes below, unless specified otherwise, the Rl and Rl6 groups represent functionalized or unfunctionalized alkyl, aryl, heteroaryl, aralkyl, and the like. The moiety, Rl6Q, represents an alkylating agent in which Rl6 is typically a functionalized or unfunctionalized alkyl or aralkyl group, while Q is a leaving group such as chloro, bromo, iodo, methanesulfonate, or ~-toluenesulfonate. In structures showing an "~"
group double-bonded to a carbon atom (as in 2~ and products derived therefrom), M is 0 or S.

. . . . .
. . . .
.
, . . .

. .

Wo 91/1200~ ;2~0~`6~ Pcr/us9l/oo993 -RI~ACTI0I~ SC~EME I-17 O O O
Il 11 11 5R1 CNHNH2 + ArCH2NCO R1 CNHNHCNHCH2Ar ~kO
10NaOH or NaOEt N--N
Rl ~N~O
~Ar R~ 6X . N--N
bas e . ~

.

. , ' . `

: W091/12~1 2 ~ 7 5 6 3 7 PCT/US9l/~3 ~ a ~ ) C;
_99_ - One of the most widely used routes to 2,4,5-trisubstituted-2,4-dihydro-3~-1,2,4-triazol-3-ones (2,4,5-trisubstituted-1,2,4-triazolin-3(4~)-ones) is shown in Reaction Scheme I-17 in its adaptation for the 6ynthesi~ of compounds of Formula Ib. Reaction of a carbo~ylic acid hydrazide 1 (readily obtained from the corresponding ester) with the appropriate arylmethyl i60cyanate ~ gives the l-acyl-4-(arylmethyl)semicarbazide 3. The isocyanate ~ itself is obtainable by well-known methods from various sources, including the (arylmethyl)amine (by phosgene treatment), the arylmethyl halide (by treatment with cyanate anion), and the arylacetic ! acid or derivative (via Curtius rearrangement of the 1~ acyl azide). Upon heating in the presence of hydroxide or alkoxide, cyclization of ~ to the triazolinone 4 occurs. Finally, in the presence of a base (e.g., sodium hydride, sodium ethoxide, sodium hydro~ide, or potassium carbonate), g is converted to the trisubstituted triazolinone S on treatment with a suitable alkylating a~ent R16Q, where R16 i8 alkyl, aralkyl, etc., and Q i8 bromo, iodo, chloro, methane~ulfonate, p-toluenesulfonate, and the like.
Such reaction pathway8 have been described by D.L.
2S Temple, Jr., and W.G. Lobeck, Jr., U.S. Patent 4,487,773 ~1984), R.E. Gammans, D.W. Smith, and J.P.
~evich, ~.S. Patent 4,613,600 (1986), and (in part) . Gehlen and W. Schade, Li~ki~ ~nnh Chem., 675, 180 ~1964), G. Palazzo, U.S. Patent 3,657,845 (1974), and K.~. Bauptmann and K. Zeile, British Patent 971,606 (1964). A modified approach to an intermediate of ~' , - . , . . - . -. - : - , -.. . . - , ~ - .. . .
. ,: . ,, , ' : ' , , - ., . . - ~ :
., . , , , . ... .. . .. . - .
., , , . , . ~ ~
- . : .
.. . ' - ~ .'- ', ' . ' .' ' :
. , . . . -. . .
., . ~ .

~, WO9~/12~] ,,~,',~l''.~i.. l,'.~ PcT~uS9l/~xn3 207563`7` ~
.. ..
:- --100--.
type ~ and its subseguent cyclization to a triazolinone analogous to 4 have been reported by ~.
~rebabecky and J. Beranek, Collect. Czech. Chem.
Commun,., 50, 779 (1985).
. .
REACTIO~ SC~EME I-18 NH HCl H2NNHCO2Et HCl, EtOH ll 8 RlCN~ R1COEt ~
< 1 OC.

~0 R16=H
H

ArCH2NH2 20N~nHCO2Et 1o , R

RlCOEt ~
Ar A hi~hly useful alternative route to 4 i8 shown in Reaction Scheme I-18. This approach has been te~cribed by M. Pesson, S. Dupin, and M.
Antoine, Com~t. Rend.. 2~. 285 (1961) and R. Un and A. I~izler, Chim. ~ urc., ~, 113 ~1975)~
Addition of ethyl carbazate (~) to the imidate . , .
` ' ' . ' . . . '' - .

~ . ; . . -WO91/12~1 2 0 7 5 B ~.7 `~ ` C. rCTius9l/~y~3 ,....................................... . .
,; -.
: -101-(which is readily prepared from the corresponding nitrile 6) yields an adduct 9, which can be converted to the triazolinone 4 on heating ~ith the (arylmethyl)amine lO (typically at temperatures from 70-150-C.). As in Reaction Scheme I-17, 4 can be al~ylated to give the trisubstituted triazolinone 5.

REACTIO~ SC~EME I-l9 R10NlWI~
NH HCl1 ) It,CO~ NCO~Et 1 ) 12 Il , __ R~COE~2) ClCO~Et. Et~N R~COEt Z) Et~N

Rl=~ryl r~o ~ lo Ro N--NAr CH~ X N--N
2 0 R'--~N~ R~ J~N~O
H b~
13 l~

The procedures of Reaction Scheme8 I-17 and I-18 are not 8uitable for the introduction of most aryl or heteroaryl 8ub8tituent8 at N2. In contra8t, the proceture8 of Reaction Scheme8 I-l9 to I-22 are c8pecially well ~uited for the 8ynthesi8 of compounds of Formu1- Ib having ary1 or heteroaryl .

` ' ' : ' ~ -- , . . .
.-. . . .
.~ . . . .. . . .. . . .

.
/ ~ ..

wosl/l2~l 2 0 7 S ~ ? PCT/US9l/~3 substituents at N2, since the triazolinone ring is constructed with the N2-~ub~tituent in place, whereas the N4-substituent is introduced subse~uently by alkylation. Reaction Scheme I-19 presents a route patterned after that reported by ~. Yabutani, K.
Taninaka, M. Rajioka, R. Takagi, ~. Matsui, K. Sutoh, and M. Yamamoto, European Patent Application 220, 952 (1987). The N-carbethory imidate 11 (obtained by reaction of 7 with ethyl chloroformate) is treated with an arylhydrazine 1~ (or analog), typically at about 40-50-C,) in the presence of a tertiary amine such as triethylamine which effects cyclization to the triazolinone 1~- In the presence of a æuitable base (e.~., sodium hydride, sodium alkoxide, sodium hydroxide) treatment of 1~ with the appropriate ArC~2Q, where Q = bromo, iodo, chloro, methane-sulfonate, p-toluenesulfonate, and the like, yields the N4-alkylated product l~- A variant of the method using a thioimidate has been described by M.
Xajioka, ~. Xurono, X. Okawa, and M. ~arada, U.S.
Patent No. 4,318,731 (1982).
REACTI~a S~aE~E 1-20 l o R'NHN~ c R'CCl I H2N~02Et --RlCNHCO~Et --~ . R~
*O,.
16 17 lB
~ -- _ =ar .

WO9l/l2WI ,~ PCT/US91/~3 An alternative route to the N2-substituted triazolinone intermediate 1~ is shown in Reaction Scheme I-20. This chemistry has been described by T.N~ Ghosh and M.V. Betrabet, J. India~ Ch~m. Soc., 7, 899 (1930), S. Bellioni, Ann. Chim. ~Rome), ~2.
187(1962), G. Palazzo and G. Picconi, Boll. Chim.
Farm., lQ~, 217 (1966), and British Patent 1,021,070 (1966). An acid chloride 16 is heated with urethane (17) (typically at 80-100C.), to give the acylurethane 18. Reaction of 18 with an arylhydrazine 12 and phosphorus pento~ide ~usually in toluene or ~ylene at reflux) gives 1~, which can then be further alkylated on N4 as in Reaction Scheme I-19. A (thioacyl)urethane modification of this pathway has been reported by D.L. Temple, Jr., and W.G. Lobeck, Jr., U.S. Patent 4,4B7,773 (1984).

REACTION SC~EME I-21 R H,N~NH2 R R 1 2 N_N,R' R1CCl - R1CNHCN~ - R' H

__ __ R'=aryl ~0 . ~1 ' ~ . , ' - ' . . ' ' .- : .

.:
. . :, .
: . , , . : .- - . ' ' -- ~

WO9~/lZ~0l 2075'6~,3~ I'CI/US9l/~0993 A variation of Reaction Scheme I-20, 6hown in Reaction Scheme I-21, has been described by P.
Gold-Aubert, D. Melkonian, and L. Toribio, ~
Chim. Acta, 47, 1188 (1964) and A.L. Langis, U.S.
Patent 3,499,000 (1970). The readily prepared acylurea 19 upon heating with an arylhydrazine 1~ (at about 150-200-C.) is converted to the triazolinone intermediate 13.

REACTION SC~EME I-22 ,R' NN~' ( PhO) 2PN3 N--N
R'CCO2H ~ R'NHNH2 ~ ~'CCO2H ~-- R ~N~
lS Et~N. ~ H

R'=~ryl ~0 In a qùite different approach (Reaction Scheme I-22), L. Maravetz, U.S. Patent 4,705,557 (19B7) and G. Theodoridi~, International Patent Application W087/03782 (1987) disclose condensing an 2S a-keto acid 2Q with the arylhydrazine lZ to give derivatives such as 21, which can be converted to the triazolinone intermediate 1~ by heating with diphenylphosphoryl azide and triethylamine (typically at 75-115-C.). In the last 8tep, an intermediate acyl azite loses nitrogen and undergoes the Curtius rearrangement to an i~ocyanate, which undergoes ring closure. As shown in Reaction Scheme I-l9, 1~ can then be al~ylated on N4 to give the trisubstituted triazolinone 1~-wosl/12wl ~s537~i PCT/US91/~93 ,, .

SC~
o ArcH~ cM RlN~ -- .~.rO~ O or ArC~ R' 22 23 2~ 25 ¦ R' C( OM~
~O or S 27 N~OH or N~OEt ,R . .
N--N

Ar 2,4,5-Trisubstituted-2,4-tihytro-3~-1,2,4-triazole-3-thiones (2,4,5-trisubstituted-1,2,4-triazolin-3(4~)-thiones) cannot generally be prepared by routes analogous to those in Reaction Schemes I-17 to I-22 becau~e of thc propensity for al~ylation to occur on sul~ur rather than on the open ring nitrogen. It is thus preferable to have all of the substituents in place at the time o~ the ring closure - to ~orm the heterocycle. A8 shown in Reaction Scheme I-23, ~or certain R16 ~roups (e.g., R16 C~3), reaction o~ the hydrazine derivative 2~ with the appropriate isocyanate or i80thiocyanate 22 yields the 2,4-disubstituted semicarbazide or thiosemicarbazide 24. Acylation o~ 24 g~ve8 2~, which can be cyclized upon heating with hytroside or al~oslde to ~ive th- tri~ub~tituted tli-zo~i~o~e or .
I

_ , ' ' ` " ; " ,'~ '' ', ' '' ~` ' ~ " ' ' . ' , '. ,; '. '. . . ' ' . ' ' ' W09ltl2001 2~ PCT/US91/~X~3 triazoli~ethione ~. This approach has been detailed by J.M. Kane and F.P. Miller, U.S. Patent 4,775,688 (1988) and G.~. Duffin, J.D. Rendall, and ~.R.J.
Waddington, J. Che~. SQ~I, 3799 (1959). Alternative methods of ring closure, cuch a~ heating 24 with the orthoester 27, can al~o be utilized.

REACTI0~ SC~EME~ 24 o R10NHNH (R'C)20 or R~NHNHCR1 ArCH2NCM ArCH~NH~NN/ CR' Rl = ~ryl N~OH or N~o~Ct ~R~
a R '~N~
Ar In Reaction Scheme I-24, acylstion of an aryl- or heteroaryl hydrazine gives 2~. which can be reacted with the isocyanate or isothiocyanate 22 to yield the l-acyl-2.4-disub~tituted-semicarbazide or -thiosemicarbazide 22- Cyclization of 29 upon heating with hydroxide or al~oxide af~ords the triazolinone or triazolinethione 30. This chemistry has been descri~ed by ~. Gehlen and W. Schade, Li~hie~ e~D~ Che~,, 675, 180 (1964).

- - : . .
:- - -: . - - -~:
~ - - ' ' . . - , ~ ~

.- WO 9~/~200~
,~2Q~37 Pc~ S9l/oo993 *

, =, --107--REACTI O~ S CEE;ME I - 2 5 , R , R'-C~ e arC4?~:M
CNW~ 2) N~EIH, ~R ~rCH~SR' 3~ 32 ryl N~OII or N~OI!;C ,C}~R"
N--N
R' The method of F. Russo, M. Santagati, and G.
Pappalardo t nn. Chim. (Rome~ 2. 351 (1972)]
(Reaction Scheme I-45) is useful for the synthe~i~ of trisubstituted tsiazolinones and triazolinethiones having benzylic sub~titucnts at N2. Treatment of a hydraz1de 1 with an aromatic or heteroaromatic aldehyde followet by reduction with sodium ~orohydride give8 the sub~tituted hydrazide ~l.
Reaction of ~1 with the isocyanate or i80thiocyanate Z2 affords the semicarbazide or thiosemicarbazide derivative ~Z, which is cyclized to the triazolinone or triazolineth~one ~ upon heating with hydro~ide or al~oxide., .
." - . . . , . ~.
- , . . . .
.. . ...
,~ , ' , ' ' '~' .' .'' . "' . ''", ' ~ .. ' " . ' . -. .~ - . . - . :

WO 91/12001 ~5~ Pcr/us9lioo993 ~0756~7 6~
~ -108-. .
REA~TION Sc~E~ 26 NH HCl I HCl RlCOEt t R'6MHNH2 ' RlCNHNHRl6 ArCH2NCM
1 0 2 2 _~N~

~Ar M~O or S 26 In another approach (Reaction Scheme I-26), imidate 7 is treated with a substituted hydrazine 2 (especially an aryl or heteroaryl hydrazine) to give the amidrazone 34. ~esting 34 with the isocyanate or isothiocyanate 2~ gives the triazolinone or triazolinethione ~. Syntheses of this type have been reported by M. Santus, Acta Pol. PhaLm_, 37, 293 (1980); T. Bany, RQ~s~_Çh~_. 42, 247 (1968); and, T.
Bany ant M. Dobosz, ; ~ , 26/27, 23 (1971).

3~

. . .,. ~, ., - -.
, ' - , . .

. ~ .
, ', ': . ., : ' . ' . .. ' ' .
-. . . . . . . . . ~
... - . . . .. . , -. -,- -WO 91/12001 2 07 5 6 3 7 PCr/lJS91/00993 , , -- .

REACTIOI~ SCHEME I-27 PhCONCS ,, ~I
ArCH2NH2ArCH~NHCNH~ _ ArCH~NHC= NH ~
1 o 35 36 10R' CllHNJS~ NH O
36 1 1l 1l, --ArCI12NHCNlMlCR

I H~ DMF, ~ ..

ArCH~NHCNHN~2 _ R~N~ (~

. ¦ R~X
Rl ~
2 5 ~--N

4~

.

~ . . . .
~` .. . . . . .

' , ", ,' - .: ~ ' .'. '. - ' . : - . -WO 91/12001 ~ PCI/US91J00993 ~é 207~6~7 ~

A route to 2,4,5-trisubstituted-2,4-dihydro-3~-1,2,4-triazol-3-imines (2,4,5-trisubstituted-1,2,4-triazolin-3(4~-imines) is outlined in Reaction Scheme I-27 Reaction of the (arylmethyl)amine lQ
with benzoyl isothiocyanate (or by other means) gives the substituted thiourea ~, which is methylated to prepare the isothiourea derivative ~. Compound 36 can be transformed to the acylaminoguanidine 37 by reacting with the hydrazide 1 or to the lo aminoguanidine 38 by reacting with hydrazine. Ring closure of 37 by heating in DMF or cyclization of 38 with carboxylic acid 39 at elevated temperature affords the aminotsiazole 40, which can be separated from the isomer 41. Such pathways have been lS describet by G.J. Durant, G.M. Smith, R.G.W.
Spickett, and S.~.B. Wright, J. ~. Che~., 2, 22 (1966) and E. Akerblom, Acta Che~. Scan~., 12. 1135 (1965). Finally, alkylation of 40 with the appropriate Ar-C~2-Q (where Q is a leaving group such as iodo, bromo, chloro, p-toluenesulfonate, or methanesulfonate) leads to the triazolinimine ~2, which can be separated from any other i~omers or by~products formed during the reaction. This method ha6 been de~cribed by E.B. Akerblom and D.E.S.
2S Campbell, 1~ Medl Che~ , 1~, 312 (1973).

- - .
:' , ' ' ' .~
.

: . :

.

-:; Wos1/12~1 ~V~
PCT/US91/~W~3 . ~,, .
, - -111-REACTION SC~EME I-28 SM~ArCH2NH~ ~: 'NR' ' O N~?
R~ ~ H~NN~t~H2Ar ~ o 43 44 ~5 ,R' N~OH ~r NllOEt N--N N--N
R~ ~N~NCH2Ar ~6 - The route 6hown in Reaction Scheme I-28 utilizes chemi~try reported by E. Akerblom, &~a Chem. Scand., l2. 1135 (1965). The substituted isothiourea g~ i~ treated with amine lQ to give the ~minoguanidine derivative 44. Acylation o~ 44 with th- acld chlorlde l~ provides the intermediate 45, which can be cyclized by heating with hydroside or al~oside. The desired tritzolinimine 46 is separated ~rom the isomeric product 47.

.

. . . . . ~ .
.
. ~. , ~, .
.... . ...

; WO91/12001 .~-~'. .. ' PCT/US91/~M~3 ~;~ 207~637 ~
, ", 11~-C. ~re~rat.ion.of PvrimidinQn~ (Formul~ Ic) The compounds of Formula Ic whereiD either J2 or K2 is -C(0)- are synthesized as illustrated in Schemes 1-49 to I-60 below.

N~Ja R ~
CH2Ar - Pyrimidinones of formula Ic (wherein J2 is -C(0)-) substituted in the 1,2,5, and 6-positions may 2 be synthesized as shown in Sche~-l=2~. Amidines with an Rl substituent may be reacted with a n-carbonyl ester to give a 4-hydro~ypyrimitine.
Conversion of the hydro~y group to a chloride then to an amine can be achieved by first treatin~ the 2 4-hydrosypyrimidine with POC13 then with ammonia.
~eaction of the 4-aminopyrimidine with the appropriate al~yl halide followed by treatment with aqueous hydro~ide gives the substituted pyrimidin-4(1~-one.

. . . . .
. ; ,'' ' , ~ ' . - .

.

.. . .. . . ..

.. WO 91~12001 Z~ ,! " PCT/U591/~X~3 ,,, ,~ . , , . ~ . .
:- -113-SC~E~ I-29 OH
Et OOC ~R1 ~ N~Rl 3 / \ ( I ) o ~ R R~ /~NJ~Rl 7 ~) Poc13 N~ ~ Rle ~ l) ArC~2Q
2) NH3 1 R~/~N R17 2) nq. OH- . :

2 0 Nl~
R~ 7 I

CH2Ar -Q is a leaving group (-Cl,-Br,-I,-OTs, etc).

.
,, " , , !. ', .
!. , ~ ' ,' ` - , ~, ' ` ~ '`

,;

, WOsl/12~l 2 0 7 ~ 6 ~ ~ ~CT/US9l/~993 ~

Scheme I-30 provides the method by which the isomeric (wherein ~2 is -C(0)-) 2,3,5, and 6-substituted pyrimidinones may be synthesized. A
~-carbonyl ester is converted into its corresponding ~-aminocrotonate with ammonia.3 This is then acylated with an Rl-containing acyl chloride (RlC0Cl) and cyclized to a 3,1-o~azin-4-one. When the 3,1-oxazin-4-one is reacted with the substituted benzylamine, the desired fully substituted pyrimidinone 4 results.4 SC~E~ I-30 R" R"
o~R NH~OH , H2N ~
O ~ Et O ~ OEt ~'-COCl HN ~ Rle 2S ~ ~OO ~ Et R~ ~ O R17 CH2Ar .
: . . . : .
.: - . :
- . , . .. ~ :
- . -. -W091/12~1 2 0 7 5 6 3 7 PCT/US91/~3 ,v'?

Alternatively, Schem~ I-31 shows how an R6 imidate may be converted to an amidine with the substituted benzylamine, followed by treatment with an appropriately substituted ~-carbonyl ester to give the desired pyrimidinone 4.5 SC~EM~E I-3l NH Rl ~
CH2NH2 ~ NH
R1 OMe CH2Ar R~7 NJ~O

, E;l ~N
CH2 Ar .. . . , . ~ . : , ~.

: -- . . , ; , ., ' : ~ - ' -- WO91/12001 ~, ',, ~; t,~ - PCI`/US91/00993 ~ 207~6~7 ;` -116-.
A third alternative i~ illu~trated in Schem~ I-52. A simple amidine can be reacted with an appropriately substituted ~-carbonyl ester to give the 3-unsubstituted pyrimidinone. This can then be al~ylated at the 3-position with ~0~ in methanol (or with Na~ in DMF) and the appropriately substituted alkyl halide to give 4.

SC~EM~ I-32 Rl 7 R17 Rl NH~ ~ R

KOH, MbOH N
ArCH2Q R~

2~ 1 CH2Ar --., . - :
" ,...... . .
,' .' :' - ~
- ~ - . . . -. . . .

~ u ~ ~ v ~ ~
WOs~/l2~1 ~ PCT/US91/~W93 ' ., .

Scheme I-33 illustrates the general synthesi6 of pyrimidinones of Formula Ic in which B
is a sulfur atom. Thiourea when condensed with a ~-carbonyl ester gives the 2-thiouracil. This can be bis-trimethylsilylated using hexamethyldisilazane, then alkylated sequentially on the l-nitrogen atom and then on the sulfur atom using chemistry developed by ~. Vorbruggen and P. Strehlke.6 By this method, one can then obtain compounds of Formula Ic wherein J2 is -C(0)- and B is a sulfur atom.

..

. ~ ,' .

- WO 91/~200l 2 0 637 PCr/US91/00993 SC~E~33 OH
H2 N Et OOC ~Rl B Nl~Rl B

S ~H2 O~Rl 7HS ~N 1R

OT~5;
TMS 2 NH ~RR 1 B

T~; S

AgCl04 NJ~Rl B
ArCHzQ HS~N~
CH2 Ar (3) o Rl - Q R

CH2 Ar (3) Q ls 9r, Cl, I, F. OTs. OTf. etc.

- . , . - , , - - , : .

r `` . . : . : ................... , , : :

' - : , : - - : , : ' :

~ i 2 0 7 ~6~ 7 PCT/US91/~3 _`,'J .: ~
.' .,.

The isomeric 2,3-dialkylated thiouracils may be synthesized as shown in Scheme I-34. Thiourea can be condensed with an appropriately substituted n carbonyl ester to give the 5,6-disubstituted-2-thiouracil.7 This may then be alkylated sequentially at the sulfur with an Rl halide, and then at the nitrogen atom with an appropriately substituted alkyl halide to give the tesired tetrasubstituted pyrimidinone 4.

SC~EME I-34 R17 Rl7 H2No ~ Rl8 , ~
S ~ 2O ~ OEt HS ~ O

Rl7 Na~ DMF , ~ N ~ Rl B
R -Q~S ~

- 2S R'7 ~,R' 8 Na~ DMFR ~ ~ o ArCHzQ
CH2Ar . . ' ' ~ , - ' :', ~ : ` `

WO 91/1200~ f~ ` PC~/US91/OOY93 ., ; -120-Alternatively, as illustrated in S~h~me I-35, an isothiocyanate can be converted into a thiourea by the addition of ammonia.8 Thi6 can then be condensed with the appropriately substituted ~-carbonyl ester to give the 3,5,6-trisubstituted-2-thiouracil.9 Alkylation at the sulfur atom with base and an Rl halide then gives the desired pyrimidinone 4.

SC~EM~ I-35 A CH Cl2CS ~ 3 , I

CH2Ar CH2Ar R~7 o~Rl~ Rl7 OEt ~R
-- ~ HS1~ N ~_ , CHzAr ~17 3 0 ~5 ~O
CH~Ar - '; , .,: , ' ' ` , ' . , ' ' ''~ ' ' `" ., ' .

~. : . -:

WO 91tl2~1 2 0 7 ~ ~ ~.7~ - i3~ pcT/vs9l~oo9s3 ~: -121-Scheme_I-36 provides a method by which the 2-alko~y-1-alkylpyrimidinones may be synthesized. An appropriately substituted ~-keto amidel is cyclized with carbonyl diimidazolell and converted to the corresponding uracil upon treatment with the appropriately substituted primary amine.12 The uracil can then be converted to the 2-alkoxy-1-alkylpyrimidinone by treatment with an Rl orthoester.13 Alternatively, Scheme I-37 shows how the methods of Wittenburgl4 mig,ht be employed to accomplish the same transformation.

SC~EME I-36 t7 O
o~R N~N~N
O~l2 R"
0~ ArCH2NH2 o~o o o ,~ C Rl O) ,CH ~RR
l 7 DMF R' ~ 17 3C C~l~)lr CN,Ar -- : . - : .

wo 91~2001 2 o 7 ~f~3~ d ~ t~ PCI/US91/00993 ~

, . . ,,~ ', SC~ ;M~ I -3 7 O O

~7 ~X 2 ArCH~O
O~NH2 0 o~l7 H
O O

~ 2 0 ~RRl ~ t P~ o) ,CH ~1 7 o CH2Ar CH2Ar ..

` . .

`"'' . ' , , .~ , , "' ' " " ' ' ," '' '......... ' " .' "~' ' '.
~" ', "~ ,'` . ' . ,, ' ."' ' ' ' ,' . . ' ' '' ' ', ' ~ , ' ~ , " . ,, , ' ",` . " . ' .'' . ' ' .' ' ~ ' ' ' ' ' ' ' ' ' ' . ' ,, ' '' . ' . .

i, W091/12~1 2 0 7 5 6 3 7 PCT/USg~ W3 ", ~ ~ r~ t~

., Scheme I-38 ~hows how the isomeric 2-alko~y-3-alkylpyrimidinone6 can be prepared. The primary amine can be converted into an i~ocyanatel5, then converted to the corresponding urea by treatment with ammonia. Reaction of the urea with an appropriately substituted ~-keto e~ter then gives the 3-substituted uracil.16 Conver~ion of the uracil to the corresponding 2-alko~y pyrimidinone is achieved using an Rl orthoester.17 Alternatively, a ~-aminocrotonate can be reacted with the isocyanate, as shown in Scheme I-3918, then alko~ylated with an Rl orthoester.
The ~-keto esters used in the preceding schemes can be synthesized readily from ethyl hydrogen malonate and an R17 acid chloride as shown in Scheme 1-40.19 R17 may be alkyl or aryl.
Alkylation of this material with an alkyl halide (Rl&-Q) is achieved using sodium hydride in DMS0 or by other classical methods. R18 may be alkyl or aralkyl suitably protected, if necessary, 80 as not to react with Na~.
Scheme I-41 illustrates the preparation of the 5-slko~ycarbonyl moiety and the cosresponding 5-amino derivatives.

. ",, .- ., .- . --. , ' ~: ' '' , .
' ,~ Wo 91/12001 J ~S ~ Pcr/US9l/oo993 ~, ~i 2075637 . --124--S C HE~
0~
COCl C
ArCH2NH2 N
CH2Ar NH~ ¦
,~
O NH Rl 7 ~1 CH2 Ar ~y 2 0 O OEt Rl 7 Rl 7 O~O tR O)~( H

I
CH2 Ar CH2 Ar ; . . - , . - . .
- . . . .
-. ,, - ~ , . '-, ,. ~ , . . - - .
. . . ~. .

,. . , , ~ . . . ....... . : . .
. - - , . . .

WO 91tl2001 ;~ V 7 ~ ~ ~ 7 Pcr/US9l/oo993 - i --125--S C~E~E I - 3 9 \C H2NJ~ , N~
l S N O Et HO N
CH2Ar CH2Ar I

.'~ ` .

.. . , : ` .

~ ~ . . , .. ~ . , ~ ~ . . . . . . . .

WO 91/12001 ~ PCr/US91/00993 1 7 ~ 6 3 7 S C~EI~; I - 4 0 0 0 o O
Et O OH Rl 7_ COC; ~? OEt O O
N2H, DMSO Rl 7~0Et SC~IEME. I -41 RJ~IH R17 ~fOOEt CH,Ar EtO~fOOEt R1~N~O
CH2Ar COOEt Ho~nonn. Curtlur. or Rl7 8ch~ 1dt R-arrong-l~ntr N~H2 Rl)~
~1~2Ar 'i', ,'-: ' ',';'. ' . ' ' '' ' ~. , '', ,- '- : ,': . -, :. ,. . . . -. ~ . . . - .
,. , . . . , ~`, ' " ' , ' , " '' , ' . ` ' ' ' ', ' . ", ' ' '' " .~ ' ~ " . . ' ' - WO91/1200~ ~U ( 3 b ~ ~ PCT/US9l/~XW3 :r -127-1. ~. Wunsch, A.J. Boulton, Adv. ~et. Chem.
(1967), 8, 326-9 and reference~ therein.

2. D.J. Brown, E. ~oerger, S.~. Mason, J. Chem.
~Q~l (1955) 4035.

3. V. Prelog, et al, ~ (1945) 28 1684.

4 . ~ . B. Kagan, M.Y.~. Suen, Bull. Soc. Chim. Fr.
lo (1966) 1819.
W. Steglich, E. Buschmann, 0. ~ollitzer, An~ew.
Chem Int. ~d. En~l. (1974) 13 533.
F. Eiden, B.S. Nagar, ~aturwissenschaften (1963) 50 43.
A. Krantz, B. ~oppe, J. Am. Chem. Soc. (1975) 97 6590.

5. A. Sitte, E. Paul, Chem. Ber. (1969( 102 615.

6 ~ Vorbruggen, P. Strehlke, Chem. Ber. (1973) 106 3039.

7. D.J. Brown, The Pyrimitines, (1962), J. Wiley SOns, p. 300.
8. D.J. Brown, The Pyrimidines, (1962), J. Wiley Sons, P. 437.

9. R.G. Dave, G.5. Mewada, G.C. A3in, J. Ind.
Chem. Soc. (1960) 37 595.
M. Sano, Chem. Pharm. Bull. (1962) 10 313.
C. Piantadosi, V.G. Skulason, J.L. Irvin, J.M.
` Powell, L. ~all, J. Med. Chem. (1964) 7 337.

..

., , , .. .
, - : : .

., .
.

wosl~l200~ ' PCT/US9~/~M~3 , ~ .

lO. M.R. Jain, Ind. J. Chem. ~1963) 1 274.
P.C. Kuzma, L.E. Brown, T.M. ~arris, J. Or~.
~h~m. (1984) 49 2015.

5 11. S. De Bernardo, M. Weigele, J. Or~. Cbem.
(1977) 42 109.

12. T. Kinoshita, ~. Tanaka, S. Furukawa, Chem.
Pharm. Bull. (1986) 34 1809.

13. F. Yoneda, T. Nagamatsu, M. Takamoto, Chem.
Phar~. Bull. (1983) 31 344.

14. Wittenburg, An~ew. Chem. (1965) 77 1043.

15. S. Ozaki, Chem. Rev. (1972) 72 457.
. .
16. Gabriel, Colman, ~ (1904) 37 3657.

17. F. Yoneda, T. Nagamatsu, M. Takamoto, Chem, ~harm. Bull. (1983) 31 344.

18. R. Behrend, F.C. Meyer, Y. Buckholz, L
~nn. Chem. (1901) 314 200.

~9. W. Wierenga, ~.I. Skulnick, Ors. Svn. (91983) 61, 5.

~ .

.~ .

, : . . . .
- . . - : . . .

WO91/12~1 2 07 ~ 63 7 PCT/USgl/~3 ,~ ..

PART II: Preparation of substituted benzyl derivatives of the ~eneral Formula I
Preparation of compounds of Formula I
starting from the heterocycles or benzyl-substituted heterocycles described in Part I is illustrated in the following Schemes and descriptions.
The synthesis of Angiotensin II Anta~onists incorporating a substituted benzyl group as ~hown in Formulas Ia through Ic may be accomplished by two general approaches. In the more convergent approach, a heterocyclic compound (as described in Part I) is deprotonated with a base and alkylated on a nitrogen atom with a benzylic halide or pseudohalide ("Ar-C~2Q") bearing the appropriate ~ubstituents R9, RlO, Rll, Rl2, X, Y and Z, which leads directly to AII Antagonists described by Formulas Ia to Ic.
Following the alkylation of the heterocycle, it may be neccessary to perform additional synthetic 6teps such as ester hydrolysis or the removal of protecting ~roups in order to complete the preparation of the desired product. ror the synthesis of certain derivatives, the alkylation of the heterocylic compound may be performed with a substituted benzyl halite o~ p~eudohalide which contains a subset o~ the 2S desired substituents (e.g. R9, RlO and X). In these ca~e6, the alkylation step is then followed by additional reactions which are required to assemble the sub~tituted benzyl element of the AII
Antagoni6t. In an alternative approach, compounds with structures describet by Formulas Ia through Ic may be synthesized in a linear fashion from a benzyl .. . .

. . . .~.

wosl/l2~ ` ' PCT/US91/~X~3 ~

, element which is introduced at the be~inning of, or during the preparation of the heterocyclic moiety.
Examples of the preparation of Angiotensin II
Antagoni~ts described by Formulas Ia-lc by each of these major approaches are illustrated in the following schemes.
The preparation of the quinazolinone ~-derivative of Formula Ia wherein: ~1 = -C(0)-, Jl and ~ are connected together to form a 6-carbon aromatic lo ring substituted with a methyl group at position 6, B
is a single bond, Rl is n-butyl, R9, R10, Rll are hydrogen, X= 0, Y= a single bond, Z= C02~ and Rl2 i~
phenyl appears in Scheme II-l and in Example 1 of the Experimental section. Deprotonation of p-cre~ol (1) 15 with a strong base such as potassium hydride in DMF
in the presence of an appropriate crown ether such as 18-crown-6, followed by the addition of methyl 2-bromophenylacetate (2) affords the 2-phenoxy ~ubstituted phenylacetic ester 3. Reaction of ester 20 3 with N-bromosuccinimide (CC14 reflux, AIBN
catalyst), effects benzylic bromination providing the alkylating agent 4. Deprotonation of 2-butyl-6-methylguinazolin-4(1~)-one (5) with sotium hydride in DM followed by the addition of the 25 alkylatine agent 4, re~ults in a mi~ture of the products of al~ylation at the two nitrogen and the `. o~ygen atoms. The desired product (6) in which al~ylation has occured on the nitrogen at po~ition 3 i8 the predominant product, and may be puri~ied from 30 the reaction mixture by chromatographic methods or fractional recrystallization. Al~aline hydrolysis of r the ester group of 6 affords the AII Antagonist 7 of Formula Ia.

- . , . ~ -; , - : . ~ .
-`' ' - ', ' ' ' ', , , . . , ~ . : - .
. ~ ~ ' ` `' " ' '` - :, . . . ' .

." . . :, .. ,.~;~ .
, ~ wosl/l2~l 2 07 ~6 3 7 PCT/USsl/~M~3 ., ,,, ~ -,,, , .. :; ; ., SC~E~_IL-" Nr O~J CC~;. r rl~
~4C8~ ~02CH3 3 ~CH3 o~ ~ n ~o2CH~ DtlF O
~O,C~

~
~o tl-O~ ~OH
~¢~
~O,H

The ~ynthesis of Angiotensin II Antagonists lncorporatlng a ~ubstitutet benzyl elemcnt definet by 2S For~ulas Ia-Ic may also be accomplished by the al~ylatlon reaction of a heterocycle (a~ deEcribed in Part I) with a benzylic intermediate bearing a subset of the desired substituents. For instance when it is desired to allow R9 ant R10 to be hytrogen, 3 al~ylatio~ of heterocycle (5) in the presence of a base with 4-benzylosybenzyl chlorite affords the .

~ . , .
; :
. , . .-,.. ~ ; , ~. ~,. ...
- ~ ~

WO 91~12001 ~ r~ PCr/US91/00993 ~
~ ~7~

protected phenol 8 as shown in Scheme II-2. The benzyl ether is next removed by hydrogenolysis using hydrogen and an appropriate catalyst such as Pd/C, Pd(0~)2/C or Pt/C which affords the intermediate phenol 9. The phenolic proton is then deprotonated with a base such as sotium hydride in DMF, and the phenolate is alkylated with a 2-bromophenylacetic ester such as 10 to provide ester 11. Finally, the ester is hydrolyzed and the carboxylic acid (12) of Formula Ia where Rll is hydrogen, R12 is 2-methylphenyl and Y is a single bond is obtained.

.

i:
~ . .. .
~ . :

"

~ '. ' Wo 91/12001 ~ f~7 PCr/US91/00993 ; .
~; .. ..
_ 133 --SC~IEME II-2 H3 _~ ~,, Pd~C
~ nO MaOH
E~nO
~H3 ,~H, ,~ Er ,~

D Hl 10 ~CO~
~3 1 ) N-OH. ~0~1 2 ~ Kl ,¢~J

2 S ¢~CO~H

i ~r,' 't ~ ' '' . ' " , ' . ' i`' ` ' ' ~ ' I . '' ., . ~ .
'~ ' " " "` ' . " ' ' `` . .. ~ . ' . . '. '. ': :' '' ..... ': . . : ' ' ' ' ' .

~, . . .

Wosl/12001 ~ ,7~ i . f ~ PCT~US91/~N~3 Substituted 2-bromophenylacetic esters are typically employed in the synthesis of compounds of general Formulas Ia-Ic when it i8 desired that Rll be hydrogen, R12 be a 6ubstituted phenyl group, Y is a single bond and Z is a carboxylic acid. These substituted 2-bromophenylacetic esters (14) are readily prepared from substituted phenylacetic acids (13) by a ~ell-Volhard-Zelinsky reaction as shown in Scheme II-3. Alternatively, substituted lo 2-bromophenylacetic esters may also be obtained from benzaldehydes (lS) as shown in Scheme II-4. Reaction of the substituted benzaldehydes (15) with trimethylsilyl cyanide affords the trimethylsilyl-cyanohydrins 16. Treatment of 16 with anhytrous hydrochloric acid in methanol or ethanol produces the hydro~y esters 17, and subsequent reaction with carbon tetrabromide and triphenylphosphine provides the substituted 2-bromophenylacetic esters 14.

2~ R R ~.r ~O~H 1 ) 90~ r~

' ' ' :'~
': . .' ~ ' ~ ,. .
-- WO 91~12001 2 0 7 ~ 6 3 ~ ` PCI~/US91/00993 . - - 135 -' S C~IEI~ I I - 4 1 B-cro~n-6 ~ ~:1, EtO!I

R OH R Br ~o~E~ PPh~, CBr, ~O~Et A ~trategy similar to that 6hown in Scheme II-l is applied when a substituent other than hydrogen at Rll i8 desired as ~hown in Scheme II-5.
Intermediate phenosyphenylacetic esters such as 3 are deprotonated with strong bases such as lithium bis~trimethyl6ilyl)amide iD TBF ant can then be reacted with an al~ylatine a~ent such as an al~yl halide or me~ylate. In this case, reaction of the anion der~ved rrom pheno~yester 3 with methyl iodide a~ords the methylated protuct 15. Reaction of 15 with N-bromosuccinimide gi~es bromide 16, which i~ in turn uset for al~ylation of a heterocyclic compound from Part I. Scheme II-5 illustrates the al~ylation of heterocycle 5 with bromide 16 which after ester hydrolysis arfords scid 17.

:

-., . , ,. ,.. . . . , , , , ~ . - , . . -.

: ~ , , : .

.~ ~., - . .. . . .
.
: . . . ~ . -,s wosl~l2i~1 2 i $~ PCT/US91i~3 ,13~CH~ W ~C oJ3~C~ CCl~ r-r~u ~~

~r HjC~ NhH DMr 1~ N~Otl, ~OH H~C

~ O~H

The synthe~i~ of compount 22 of Formula Ia wherein: Kl ~ -C(0)-, Jl ant L are connected together to ~orm a 6-carbon aromatic ring sub~tituted with a methyl ~roup t po~tlon 6, ~ a single bond, Rl.
2S n-butyl, R9, RlO and Rll are H, ~- O, Y- CH2, Z~ C02H
and Rl2- phenyl i 8 shown in Scheme II-6. In thi 8 esample, p-hydrosybenzyl alcohol (~8) is selecti~ely al~ylated at the phenollc hydrosyl group uith mcthyl bromoacetate when they are reflu~ed with potassium carbonate in acetone. A~ter the remaining hydrosyl group ~8 protected a~ a tert-butyld~methylsilylether, thi- etber ~19) m-y then be dep~otonated with -.

.~ .
. .. ..

.. . .

~ 2 0 7- ~ Ç 3 7 PCT/US91/~3 "i~
.. - 137 - --~trong base such as potassium bis(trimethylsilyl)amide and reacted with an - alkylating agent in a manner similar to that shown for intermediate 3 in Scheme II-5. Alkylation of ether 19 with benzyl bromide provides 20. Silylether hydrolysis of 20 and bromination of the resulting alcohol affords an alkylating agent (21) which is then used to alkylate a heterocyclic compound from Part I. Alkylation of the anion derived from heterocycle 5, followed by ester hydrolysis affords the AII Antagonist 22 shown in Scheme II-6.

HD~ X~ c--ton ,[~D~; ~) I~Sl le 2) t-Du~S~Cl ~ t9 2) PhC~Dr D~U, C~Cl~ `Co~

n ~u~Nr, ~IF o~r ~) c~r~ ~ o~
2S o 21 ~ c~
c~ 1) ~n Dff 1 ) ~OH ~OH

~ 4J3' ~2 - . ~ ..

- . -, : : .
~ ~ , . .. .
, ., ~ :
.
- -~ ., .
- ' ~ ':
" , , :., . . : . ~, :

W091/12W1 ~7~ . ` PCT/US91/~M~3 ~

. .

Scheme II-7 illustrates the preparation of an antagonist of Formula Ia wherein~ C(0)-, and L are connected together to form a 6-carbon aromatic ring sub6tituted with a methyl group at position 6, B= a single bond, Rl= n-butyl, R9, R10 and Rll are ~, ~ is a single bond, Y= 0, Z= C02H and, R12= phenyl. In thi~ example, the ~ell-Volhard-Zelinsky reaction converts 4l-methyl-phenylacetic acid (23) to the alpha-bromoester 24, which is in turn reacted with the potassium 6alt of phenol to yield 25. Benzylic bromination of 25 provides alkylating agent 26 which is then reacted with a heterocyclic species described in Part I. When the sodium salt of heterocycle 5 is alkylated with the bromide 26 in DMF, followed by alkaline hydrolysis of the resulting ester, the AII Antagonist (27) of general Formula Ia is obtained.

SC~EME II-7 ~D,C~ t ~ 30Cl~. Cr~ I~O~C~ P nol 2) 1~011 ~ ~ cro~-O

Z~ lu~

~ c~
~ c~
N-- Dt~ ~ 33 2) ~0~ ~on ~

.

. .
.

'` ' ` ' : ' ' `'' . ~ . .

: WOgl/1200~ ~ 7 5 ~ ~ 7 PCT/~S9l/~3 "
,,`,:J,~ .

Scheme II-8 illustrates the preparation of analogs of Formula Ia wherein: Kl = -C(0)-, Jl and L
are con~ected together to form a 6-carbon aromatic ring substituted with a methyl group at position 6, B= a single bond, Rl= n-butyl, R9 and R10 are ~, ~= a 6ingle bond, R12 is phenyl, Z= C02~ and X i6 either methyne or methylene. A Reformatsky reaction is first employed to prepare methyl 3-hydro~y-3-(4-methylphenyl)-2-phenylpropanoate (27) from the starting materials shown in Scheme II-8. When heated in the presence of p-toluenesulfonic acid in benzene 27 is dehydrated to the trans-6tilbene derivative 28, and then benzylic brominatio~ of 28 gives the alkylating agent 29. Deprotonation of a heterocycle such as 5 with sodium hydride in DMF and treatment with 29 gives adduct like 30. Alkaline hydrolysis of 30 affords a product 31, in which X is a methyne group (Rll is absent) doubly bonded to the carbon atom bearing 8ubstituents R12 and Z as shown in Scheme II-8. Catalytic hydrogenation of 31 gives the derivative 32 where X is a methylene group and Rll is a hydrogen atom.

.. . - - .. . . . .
. ~ ..
-. . . . . -W0 91~12001' d ~ PCl/US91/00993 ;,' 2075637 SC~EME II-8 ~ H~

OH ~f NI~ I EIN ~, ~ CCl~, r~lux ~2V

~H~ OH
DM' ~0J M30H ,~3J
~C~H, ~ 31 ~CH, 2 0Pd~: Et OAC ~
~3J
~o, 32 Scheme II-9 lllu~trates the preparation of an analog ~38) wherein~ -C(O)-, Jl and L sre connected together to form a 6-carbon aromatic ring ~ubstituted with a methyl group at position 6, B i8 a ~ingle bond, Rl is n-butyl, R9, R10 ant Rll are hydrogen, R12 i8 2-chlorophenyl and Z is a tetrazole group. In this synthesis, the e~ter group of ~ inter~ediate 33 i- converted to a nitrlle prior to -~ , . . , . - -'~ ', . ' . ~ -. - - ~. ...: -, - ,. .

; Wo 9~ 2 0 7 ~ 6 3 7 PCT~US91/~93 alkylating a heterocycle (Part I) with this 6ubstituted benzyl element. Thus, reaction of ester 33 with ammonia in methanol, followed by dehydration of amide 34 produces nitrile 35. 8enzylic bromination affords 36, which then may be reacted with the 60dium salt of a heterocycle such as 5 in DMF to give an intermediate li~e 37. Finally, reaction of a nitrile like 37 with trimethyl~tannyl azide in refluxing toluene gives tetrazoles related to 38 as shown in Scheme II-9.
SChE~

~ , ~OH ,~f POCl,, Et ,N

2 0 ~ 3 3 ~ 3 ~ H, ~ ~ ~
O ~ ~ N~ I 5 ~N CCl~. r-rlWt ¢~`CN D!~F

~ ~~~H~
~ t) ~9 ~ ;) IDA`~ ~
N ~,JI~ 38 `:

;
~.`

WO91/120DI ~ r PCMJ591/OU993 ~;

The preparation of a derivative of Formula I
analogous to tetrazole 38 (Scheme II-9) in which X is a methylene group, Y is a single bond and R12 is phenyl, is shown in Scheme II-ll. In thi6 synthesis, phenylacetonitrile is deprotonatet with lithium bi6(trimethylsilyl)amide and then alkylated with the tert-butyldimethylsilylether of p-hydroxymethylbenzyl bromide (preparation of bromide 39 i6 shown in Scheme II-10) to yield nitrile 40. The silylether group in lo compound 40 i~ directly converted to the bromide 41 with carbon tetrabromide, triphenylphosphine and acetone in dichloromethane (Mattes, ~.; Benezra, C.
Tetrahedron Lett., 1987, 1697). Al~ylation of the sodium salt of heterocycle 5 with bromide 41, followed by reaction of 42 with trimethylstannyl azide in refluxing toluene yields the tetrazole 43.

~f l~H~. ~F J3~H

2 5 t -11u~9iCl. DM1~ bSDD~fi l-PrEt~N, C~Cl~ 53 i :
.
: ~ .
:

; wos1/12~1 ~U ~ PCT/US91~93 SC~EME II-ll 1 ) U N( 9 ~ ~F ~D~S
~N ~MPA -73 C ~J PPh~, CE~r~
'J~ ~ CN

0 ~r~ 5 _~
N N~ ~13J
~N

1 ) ~5nN~
toul-n- r-~ux Z ) )DA~ ~,J
~ ~3 E~" "`r .

2S Scheme II-12 illustrates the preparation of a derivative of Formula Ia wherein: Kl ~ -C(0)-, and L are connected together to form a 6-carbon aromatic ring cubstltuted w~th a methyl group at position 6, Rl is n-butyl, B is a sin~le bond, R9, RlO and Rll are ~, S. 0, ~- a ~ingle bond, Rl2 is 2-methylphenyl, and 2 i8 a phosphonic acid group.

. - .

, . .

. ~
.- .

. . .. . . . . .

~ WO 91/1200] . PCI~/US91/t~0993 , ~. 2~7~3~
,, .
-: - 144 -Reaction of o-tolualdehyde with dimethyl-phosphite in the presence of triethylamine affords the phosphonate e6ter 44. Bromination of the hydro~yl group of 44 with carbon tetrabromide and triphenylphosphine in dichloromethane gives bromide 45. Deprotonation of p-hydroxybenzyl alcohol with sodium hydride in DMF followed by addition of bromide 45 affords intermediate 46. A second bromination reaction (CBr4, PPh3, C~2C12) converts alcohol 46 to the bromide 47 which is then used to alkylate a heterocyclic compound described in Part I. Scheme II-12 illustrates the case where the anion of heterocycle 5 is reacted with bromide 47 to give upon workup, the phosphonate mono-ester 48. Pho6phonic acid 49 may be obtained by treatment of the mono-methyl ester 48 with trimethylsilyl bromide.

SC~EM~ II-12 2 0 OH Ek ~C~ t~O)~OH G~~ P~h,. C~, ~~)~
~:11, ~t ~N ~CH~ ~ CH~Cl~ ~CH~

2 5 ~( OJ~ P~- Cllr~ O~rr N ~ D~ ~ OM~)~ CH~Cl~ o~oM-)~

oJ3~ ~S~ o~
D~ ~OY~OY ~90~01~, ., .

- : :
- ' ,. '., . .. ~ - . . -, . - ~ .
.

W091/12001 2 0 7 ~ } ~ PCT/US9l/~3 .

The synthesis of a derivative of Formula Ia where Z i8 an acyl-sulfonamide group is illustrated in Scheme II-13. Reaction of a carboxylic acid of general Pormula Ia 6uch as 7 (Scheme II-l~ with 1,l'-carbonyldiimidazole in T~F at elevated temperatures gi~es an acylimidazolide which may be reacted with a 6ulfonamide (benzenesulfonamide in this example) and DB~ in TEF to provide the target compound (50) where Z is the acyl-6ulfonamide group.

,[~ --N~

,~ 2) PhSO,N~,, D~U ,~

(3~Co,H ~N~

~0 t Prccursors for the 8ynthesi6 o~ AII
Anta~oni~t8 incorpor~ting a 8ub8tituted benzyl element wherein either 8ub8tituent8 R9 or RlO are non-hytro~en may include 8ub8tituted p-cresols, . .

, . . . .: . - . ..
: . . . - , ~ .
: .. . . . - ~ . .
.

W09l/1200l 207~ y'~i"; PCT/US91/~H~3 ~

, 4-hydroxybenzyl alcohols, 4-hydroxybenzaldehydes, 4-hydroxybenzoic acids and their esters as shown in Schemes II-14-16.
Commercially available benzyl alcohol6 6uch as 3-chloro-4-hydroxy-5-methoxybenzyl alcohol (51) may be selectively alkylated by alpha-bromophenyl-acetic esters when they are refluxed together in the presence of bases such as anhydrous potassium carbonate, giving 2-phenoxyesters like 52 shown in Scheme II-14. Conversion of the benzyl alcohol group in 52 to a bromide (CBr4, PPh3, C~2Cl2) affords alkylating agent 53. A heterocyclic compound from Part I is then alkylated with bromide 53, and the product is hydrolyzed to giving a derivative of lS gcneral Formulas Ia-Ic as described previously.

~EE~E II-14 Cl~H ~~o~ton . ho~t O~H

~1 ¢~0~ ~CC~M~

PPh,, c~, o CH~Cl~ ~CO~

~. ' '- ' ' : ' - , - , ~ .
'.' , `' '' ' ~ ' ' ." '' ' . ' : .

.. ... ..
.
. ~.. - -.

W09l/l~ U ~ 5 ~ ~ 7 , ;~ PCT/US91/~3 Scheme II-15 illu~trates the u6e of commercially available 3-ethosy-4-hydroxybenzaldehyde (54) to prepare an AII Antagonist of Formula Ia bearing a 3-etho~y group (R9) on the 6ubstituted benzyl element. Alkylation of the phenolic group of 54 with methyl 2-bromophenylacetate gives the aldehyde 55 which i8 then reduced to a benzyl alcohol with 60dium borohydride in methanol or ethanol. The alcohol i6 converted to the bromide 56, which may be used to alkylate a heterocyclic compound defined in Part I to afford an AII Antagonist of general Formula Ia-Ic.

c2~o HD K2CO3 C2H~O~CHD
~f ~cet one, re~lux ,~1 54 ~ ~ 55 C~H,O~r 2S l) N~J~. ~tOH ll ,J
2) PhCH~. C~r~ 0'`~' CHZcl2 ~ 56 Substituted 4-hydro~ybenzoic e8ters are also convenient prccur80r8 for the 8ynthesis of the 8ubstituted benzyl element defined in AII Antagonist~

.~ . .

, . . .
,: '' '-' , .. ' ' ~ . ... ' . ':
.. , . . : . ~ ' ' ' . .: " '~

' ,- . ' - , :~ ':. . '' -, . .: - .

~ W091/l2001 PCT/US9l/~3 of Formulas Ia-Ic. In this approach, the phenolic hydroxyl group is usually first protected with a suitable protecting group, the ester is then seduced to a hydroxymethyl grGup, and deprotection affords a 4-hydroxybenzyl alcohol derivative. Scheme II-16 illustrates the preparation of an alkylating agent (60) where R9 and R10 are 3,5-dichloro substituents using this sequence starting from methyl 3,5-dichloro-4-hydroxybenzoate (57). Silylation of phenol 57 followed in turn by lithium aluminum hydride reduction of the ester and silylether deprotection afforts 3,5-dichloro-4-hydroxybenzyl alcohol (58). Phenol 58 may then be selectively al~ylated with methyl 2-bromophenylacetate. Reaction Of the alcohol 59 with carbon tetrabromide ant triphenylphosphine then protuces the bromide 60 which may be used to alkylate a heterocyclic compound described in Part I.

A

. `
.' . '` ' ' ' .

.
. . ~ .
'' ,.

:. WO91~J2001 2075637 " PCI/US9~/00993 4~` ij J ~ ` .! ' S C~EME I I -16 Cl ,CO~r~ 1 ) t-~uM~SlCl Cl ~C~CO~
11 J D~P, CH~Cl~ ~f .c.ton~. r~lf ux HO ~ 2) L~ AIH., SHF HO~ ~r Cl 57 3) n-8u~NF, I~F Cl 5~ `CO~Me Cl~ PPh~, Cl~r~ Cl~

~O~C~l CH~Cl~ C

A variety of 2-sub~tituted pbenols are selectively carbosylated when refluxed with carbon tetrachloride, 50~ aqueou~ ~odium hydro~ide and powdered copper (European Patent Application ~193,853, 10-Scpt-86) to ar~ord the correspondin~
~ub~tituted 4-hydro~ybenzoic acids This reaction ', may be atded to the ~ynthetic sequence when it is convenient to derive the desired substituent on the benzyl portion of the tar~et AII ~nta~onist ~rom a readily available 2-~ub~titutet phenol Thi~
strate~y i8 illustrated ~or the preparation of derivative 64 ~hown in Schemc II-17 Carboylation o~ 2-cthylphenol provides 3-ethyl-4-hytro~ybenzoic '~

~ .

.. . . . .
~ ~ . . . .
.. . . . . .... . . .
: . ~ . . .. . .. . .

. .
, ~ . . .

. ; , . .

... - : -. . . .

; WO91~12~01 ~ 2~n~ PCT~US91/~93 ~075~3~

~~ - 150 -acid (61). Acid 61 is then esterified, silylated, reduced and desilylated to give the 3-ethyl-4-hydro~y-benzyl alcohol 62. Alcohol 62 may then be used to complete the synthesis of AII Antagonist 64 shown in Scheme II-21 using the previously discussed methodology.

SC~EME II-17 1 ) ~~ H250~
C,H,~ C CO2H 2) t-~U~251Cl ~J CCl~, Cu 2~ DM~P. CH2C12, HD S0% N~OH ~D~ 61 3) LlAlH,. THF
ho~t 4) n- E~u~NF, l~F

HO~H~CO2M~. K~CO~ ~r 62 ~otono. roFlux ~
2) PPh3, C9r~ ~
CH2Cl2 63 O
2) NrO~ ~OH
0~CO2H ~4 - , .: .

. - - . : ~ :
:: ~ ..

~,7' WO 91/12~
~ 2 0 7 ~6 3 7~ ~ i; PCr/USgl/~93 ..~

The Clai6en rearrangement of phenyl-allyl-ethers offers another useful technique for the introduction of alkyl substitutents (R9 or R10) at the meta position of the substituted benz~l element.
In Scheme II-lB, 4-hydroxybenzyl alcohol is selectively allylated and then silylated to afford mixed ether 65. Claisen rearrangement at lB5-C of ether 65 provides the allylphenol 66 which is then alkylated with methyl 2-bromophenylacetate. The silylether 67 is then converted to the bromide 68.
Alkylation of the heterocycle 5 with bromide 6B, followed by alkaline hydrolysis affords the AII
Antagonist 69 shown in Scheme II-18 and described in Example 2 of the experimental section.

Wo 91/12001 2 0 i '~6 ~ Pcr/usgl/~3 , -- 1~2 --SC~IEME II-18 o~ f ~OT~DMS

~ 2) c-l~un- ~Cl ~2D0C , ~
D~AP. CH~Cl~ ¦
OH O~ OH

~ ~--O~BDMS
,~
~:~Co~. o-c on-. ~ O PPh~. Cl~r~

[~CO~CH, ~CO2CH3 CH~Cl~ r-ton-~\~3 r ,~H, H ~1-0~ ~OH
CO,CH3 N H. D~

2S ~o ~O, H
~J

. . ` . ~ .

- WO91~12~1 2,,7s~3 7 PCT/US91~X~3 ,;- ` ;, i "~ i ~if ~

A variation of the Clai~en rearrangement strategy for the introduction of the R9 or Rl~
substituents was employed for the preparation of AII
Antagonist 75 a~ shown in Scheme II-19. In thi~
~ynthesis, the Claisen rearrangement of the allyl ether derived from methyl 4-hydro~ybenzoate (70) afforded phenol 71. Phenol 71 was silylated, the intermediate ester was reduced with lithium aluminum hydride, and then desilyiated to produce 3-allyl-4-lo hydroxybenzyl alcohol (72). ~ydrogenation of 72,followed by alkylation of 73 with methyl 2-bromo-phenylacetate and then bromination gave the alkylating agent 74. Alkylation of the quinazolinone 75 with bromide 74, followed by al~aline hydrolysis of the lS resulting ester (76) afforded the AII Antagonist 77 6hown in Scheme II-19 and described in Example 6 in the experimental section.

WO 91/12001 ~ P ~ PCI`/US91/00993 ~ 207-5637 ~
. , .

SCI~E~E II-l9 ~CH~ CH3 ~ y ~C~H ~OH
- t3U~,SlCl l I
DnAP, CH~Cl~ ~ *. ~ C
2~ LlAlH,. ~llr ~ LtOH
3) n-rlu~N~, 7,~ T T

,CH~ J~
CO~. c-t on, ~ ~
1 5 ~o~Ctl~ o~ ~
Yo n~r 2~ v~n~. c~r,. c~c~ ~CO2CH3 2 0~ ~N~O ~ ~~N~O

~ ~o~o~ ~

2 5 ~C~ ~to2H

7~ 77 .
: . :

. .
.
'^ . : ' .. ' - '~ -' . .. .. . .

~ W091~l2~1 PCr~US9lf~3 2 ~ 7` -The Clai6en rearrangement strategy for the introduction of a meta-alkyl ~ubstituent onto the ~ubstituted benzyl element of an AII Antagonist of Formulas Ia-Ic may be exercised twice when it i8 desired that both R9 and RlO be meta-alkyl substituent6. Thus, allyl phenol 71 may be converted to its 0-allylether and subjected to a second Claisen rearrangement to provide the phenol (78~ shown in Scheme II-20. Silylation of phenol 78, followed by catalytic hydro~enation, reduction of the ester ~roup with lithium aluminum hydride and bromination (CBr4, PPh3, C~2Cl2) gives the benzyl bromide 79.
Alkylation of heterocycle 5 with the bromide 79, followed by silylether deprotection provides an lS intermediate phenol 80. The phenolic hydro~yl group of 80 may then be alkylated with an alpha-bromoester and the ester hydrolyzed to yield the acid 81 in which R9 and R10 are meta-propyl groups as shown in Scheme Il-20.

- WO91/12~1 PCT/US91/~X~3 i~ 2`~ 3~

co, on . r-rlu~ ~P. CIL~l. ~r OO-C. ¢~ ) 4. ~ ~ 60 7~ ~) PPh,. CBr,. C~Cl~

r ,~
~' f~ --'-~ r~ ~
2) n-Ou~Nr, ~ J~ 702) I~OK t~Rl ,1~
~h The synthesis of compounts of Formula Ia wherein: Kl . -C(0)-, Jl and L are connected together to form a 6-carbon aromatic ring sub6tituted with a methyl group at position 6, B- a single bond, Rl=
n-butyl, R9, RlO and Rll are 8, Y- a single bond, Z=
2S C02R Rl2- phenyl, and ~ NR, are presented ~n Schemes II-21 and II-22. To access these analog6, a heterocycle (lc. 5) defined in Part I is al~ylated with p-nitrobenzyl bromlde to yield nitro compounds such as 82 in Scheme II-21. Catalytic hydrogenation of the nitro group provide6 an aniline derivative (83) which i8 then al~ylated by an alpha-bromoester, The re~ulting e6ter is subseguently hydrolyzed to afford a derivative of Formulss Ia-Ic (84) where ~.
N8.

. .

- : - .

, - . . : -Wos1/12~1 .'' -. PCr/~Sgl/00~93 207~j63'7 Y ' ' SC~ME II-~l ~f H, D~ ~ f H~
H ~ J
o ~2 ~ H3 ~13 ~O,H 54 The prcparation o~ AII Antagonists of Formula6 Ia-Ic similar to 84 in Scheme II-21 but having ~- NR may be accomplished by methodology shown in Scheme II-22. The substituted aniline (83) presented above, may be readily convertet to the N-tcrt-butylcarbamate (BOC) 85. Carbamates such as 85 may be deprotonated at the amide nitrogen atom when reacted with bases such as sodium hydride in . W091~2~1 PCT/US91/~X~3 37 ~?;~

DMF, and then reacted with an alkyl halide (e.g.
allyl bromide). Subsequent treatment of the intermediate with trifluoroacetic acid removes the BOC group providing the mono-alkylated aniline derivative 86. The aniline nitrogen in 86 may be deprotonated again with sodium hydride in DME and al~ylated a second time with a substituted alpha-bromoester and then hydrolyzed to afford the targeted AII Antagonists (87) of Formulas Ia-Ic where X= NR.
SC~EM~ II-22 H, DM' OC~O ~b ~r F~ ~N C*Cl~ I
J3~ B3 I~OC~ es CH~Cl~
20 ~N H

25 ~ ~
H 2) N~ON ~OH ~CO~H

Schemes II-23 and II-24 illustrate routes for the 8ynthe8is of AII Antagoni6ts of general Formula~ Ia-Ic for cases in which it is desirable to ~ wosl/12~ 7-~B~ PCT/US91/~W~3 159 ~

introduce the benzyl element at the beginning of or during the preparation of the heterocyclic moiety.
Scheme II-23 i~ ba6ically an adaptation of Scheme I-3B (also ~ee Scheme I-37), whereby the N4-~ubstituent i~ present at the time the triazolinonering is formed, while the N2- ~ubstituent i~
introduced sub6equently by alkylation. The eEter carbetho~yhydrazone intermediate (88) i~ prepared as in Scheme I-38. An alkylatin~ a~ent such as 4 (Scheme II-l) i6 reacted with an alkali metal azide such as lithium azide in dimethylsulfoxide or dimethylformamide, generally at ambient temperature, to give the azide derivative 89. This is reduced to the amine 90, for example by treatment of 89 with triphenylphosphine in tetrahydrofuran at ambient temperature, followed by addition of water. ~eating the ester carbetho~yhydrazone 88 with the amine at about 50-80-C yields the N4- substituted triazolinone 91. Treatment of 91 with a base 6uch as sodium hydride in a solvent 6uch as anhydrous dimethylformamide and further treatment with an alkylating agent (e.g., an alkyl bromide, iotide, methanesulfonate, or p-toluenesulfonate, a benzyl bromide or chloside) yields the N2- alkylated product 2S 92. Saponi~ication o~ the ester (e.g., by sodium hydro~ide in aqueou6 methanol) provides the final product 93.

wosl/12~~ pcT/ussl/~x~3 207~7 160 -~CEEME II-23 R' NH, Cl Rl,~CO,Et f ~, H,NNCO, EC
OEt OEt 8 8 0 0~ ~..... , oJ~l~ .rh (3~o~CH~ Dt~10 ~CO~CH~ ~) K~O

N_NH

,~R N~l O ~J

90~O,Cl~, ~ R'~
N--N ?~--N
~O R ~N~O
0~ 0~
~ o,c~ ~

This scheme represcnts an adaptation of Scheme I-39, which is valuable for the preparation of tria~olinones substituted with an aryl or hetero~ryl Wogl/l2~1 PCT/US9l/~3 l; 207~637 . ; , , - 161 - .

substituent at N2. Thus, the aryltriazolinone intermediate 94 (see Reaction Scheme I-39 and accompanying discussicn) is treated with a base, such as sodium hydride in a ~olvent like N,N-dimethyl-J formamide (DMF) to form the anion. Further treatmentwith a bromide such as 4 (Scheme II-l) yields the N4-alkylated trizolinone 95. Saponification of the ester (e.g., by sodium hydro~ide in aqueous methanol) followed by acidification affords the final product 96.
~C~EME II-24 R'f, NH~ Cl 1) ~,cc, Rl~-CO~Et ~
OEt 2) Cl-CO~. r~- OEt El~ N. ~i Ar R~ Ar1 ) N-H N~--N
H O ~ R~ ~N
94 ~ ~ OJ3J

~CO2CH

Ar N--N
2 5 R' ~N~) ~ol~ ~o~

~02H
9~

, ,. 1 .

W09l/12~1 PCT/US91/~X~3 The compounds of this invention form ~alts with various inorganic and organic acids and bases which are also within the scope of the invention.
Such salts include ammonium ~alts, alkali metal 6alts li~e sodium and potassium 6alts, al~aline earth metal ~alts like the calcium and magne6ium salts, salts with organic bases; e.g., dicyclohe2ylamine salts, N-methyl-D-glucamine, ~alts with amino acid6 like arginine, lysine, and the li~e. Also, 6alts with lo organic and inorganic acids may be prepared; e.g., HCl, HBr, ~2S04, ~3P04, methane-sulfonic~
toluenesulfonic, maleic, fumaric, camphorsulfonic.
The non-toxic, physiologically, acceptable salts are preferIed, although other salts are also useful;
e.g., in isolating or purifying the product.
The 6alts can be formed by conventional means such as by reacting the free acid or free base forms of the product with one or more equivalent6 of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent 6uch as water which i8 then removet in vacuo or by freeze-drying or by eschanging the cations of an existing salt for another cation on a suitable ion exchange re6in.
Angioten6in II (AII) is a powerful aIterial vaooconstrictOr, and it eserts its action by interacting with specific receptors present on cell membrane6. The co3pound8 described in the present invention act as competitive antagonists of AII at the receptor6. In order to identify AII antagonists and determine their efficacy in vitro, the following two ligand-receptor binding assays were e6tablished.

:

Receptor binding a~say using rabbit aortae membrane ~reDaration Three frozen rabbit aortae (obtained from Pel-Freeze Biological~) were suspended in 5 mM
Tris-0.25M Sucrose, p~ 7.4 buffer (50 mL) homogenized, and then centifuged. The mixture 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
lo MgC12 buffer containing 0.2% Bo~ine Serum Albumin and 0.2 mg/mL Bacitracin and the suspension was used for lO0 assay tubes. Samples tested for screening were done in duplicate. To the membrane preparation (0.25 mL) there was added 125I-SarlIle8-angiotensin II tobtained from New England Nuclear](lO mL; 20,000 cpm) with or without the test sample and the mi~ture was incubated at 37-C for 90 minutes. The misture was then diluted with ice-cold 50 mM Tri~-0.9Z NaCl, p~ 7.4 (4 mL) and filtered through a glass fiber filter (GFIB Whatman 2.4l~
diameter). The filter was soaked in ~cintillation cocktail (10 mL) and counted for ratioactivity using ~ackard 2660 Tricarb liquid scintillation counter.
The inhibitory concentration (ICso) of potential AII
antagonist which gives 50% displacement of the total specifically bound l25I-SarlIle8-angiotensin II wa6 presented as a mea8ure of the efficacy of such compounds as AII antagoni~ts.

W091/12~1 PCTiUS91/~3 '' 207~63i`''''`~';''j- ~
; - 164 -Receptor assay usin~ Bovine adrenal cortex preparation Bovine adrenal corte~ wa~ 6elected as the 60urce of AII receptor. Weighed ti6sue ~O.l g i6 needed for lO0 as6ay tubes) was 6uspended in Tris ~Cl (50 mM), p~ 7.7 buffer and homogenized. The homogenate was centrifuged at 20,000 rpm for 15 minutes. Supernatant was discarded and pellets resuspended in buffer [Na2~P04 (lO mM)-NaCl (120 mM)-disodium EDTA (5 mM) containing phenylmethane sulfonyl fluoride (PMSF)(O.l m~)]. (For 6creening of compounds, generally duplicates of tubes are used).
To the membrane preparation (0.5 mL) there was added 3~-angiotensin II (50 mM) (lO mL) with or without the lS test ~ample and the misture was incubated at 37-C for l hour. The misture was then diluted with Tri6 buffer (4 mL) and filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter wa6 soaked in scintillation coc~tail (lO mL) and counted for radioactivity using Pac~ard 2660 Tricarb liquid ~cintillation counter. The inhibitory concentration (IC50) of potential AII antagonist which gives 50%
di~placement of the total specifically bound 3~-angiotensin II wa6 presented as a measure of the efficacy of 8uch compounds as AII antagonists.
The potential antihypertensive effects of the compounds described in the present invention may be evaluated u~ing the methodology described below:
Male Charles Rlver Sprague-Dawley rats (300-375 gm) were ane~thetized with methohesital (Brevital; 50 mg/~g i.p.) and the trachea was cannulated with PE

; . -WO91/12~1 2 07 5 6 3 7 PCr/USg~ 3 ", :, ,, - , ~ ,.,, . ';

205 tubing. A 6tainless ~teel pithing rod (l.5 mm thic~, 150 mm long) was inserted into the orbit of the right e~e and down the 6pinal column. The rats were immediately placed on a ~arvard Rodent Ventilator (rate - 60 6trokes per minute, volume -l.l cc per lO0 grams body weight). The right carotid artery was ligated, both left and right vagal nerves were cut, and the left carotid artery was cannulated with PE 50 tubing for drug admini~tration, and body temperature was maintained at 37-C by a thermostati-cally controlled heating pad which received input from a rectal temperature probe. Atropine (l mg/kg i.v.) was then administered, and lS minutes later propranolol (l 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.
U6in~ the methodology described above, repre6entative compounds of the invention were evaluated and ~ound to e~hibit an activity of at least ICso ~ 50 mM thereby demonstrating and confirming the utility of the compounds of the invention a6 effective AII antagoni6ts.
Thu~, the compounds of the invention are u8eful in treating hyperten8ion. They are also of value in the management of acute and chronic congestive heart failure, in the treatment of secondary hyperaldosteronism, primary and 8econdary pulmonary hyperaldosteronism, primary and secondary pulmonary hypertension, renal failure and renal . `''. .

WO 91/12001 ~ Pcr/US9l/oo993 ''~''" ~ .
''''' 2075637 -, vascular hypertension, and in the management of vascular disorders such as migraine or Raynaud'~
disease. The application of the compounds of this invention for these and similar disorders will be apparent to tho~e 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 6uch treatment with typical pharmaceutical formulations such as lo tablets, capsules, injectables, as well as topical ocular formulations in the form of solutions, ointments, inserts, gels an~ the like.
Pharmaceutical formulations prepared to treat intraocular pre6sure would typically contain about 0.1% to 15% by weight, and preferably 0.5X 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 6uch as tablets, capsules or elisirs for oral administra-tion, 6uppositories for rectal administration, sterile solutions or suspengions for parenteral or intramuscular administration, and the like. ~he compounds of this invention can be administered to patient8 (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 dioease, the patient'g weight, speclal tiets then being followed by a patient, concurrent medication, and other factorg which those gkilled in ' ~ ': , - ' ' Wogl/12~1 ~ PCT~USgl~W~3 -~ 207~637 , ! - ' . .

the art will recognize, the dosage range will generally be a~out 1 to 1000 mg per patient per day which can be administered in ~ingle 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 this invention can also be administered in combination with other antihyperten-sive~ and/or diuretics and /or angioten~in 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, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydro-chloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, 80tium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamtcrene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethosylline 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 li~e, as well aQ admi~tures and combinations thereof.

.

wosl/l2~l 2~$~7 ~. .., PCT/US91i~3 ~

Typically, the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they r are given 6ingly.
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 (65-2000 mg), felodipine (5-60 mg), nifedipine (5-60 mg), and nitrendipine (5-60 mg). In addition, triple drug combinations of hydrochlorothiazide (15-200 mg) plus miloride (5-20 mg) plus angiotensin II antagonist of this invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plus timolol maleate (5-60) plus an angiotcnsin II antagonist of this invention (0.5-250 mg) or hydrochlorothiazide (15-200 mg) and nifedipine ~5-60 mg) plus an angiotensin II antagoni~t of thi~
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 basi~ as nece8~ary to permit divided daily do8age and, as noted above, the dose will vary depending on the nature and ~everity of the di8ea8e, weight of patient, special diets and other factors.

~ , wosl/l2~1 2 ~ 7 ~ ~ 3 ~ PCT/US91/~3 ., .

Typically, these combinations can be formulated into pharmaceutical compositions as di6cussed below.
About l to 100 mg of compound or mi~ture of compounds of Formula I or a physiologically acceptable salt i6 compounded with a phy~iologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.
Illustrative of the adjuvants which can be incorporated in tablets, capsule6 and the li~e are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an e~cipient such as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized 6tarch, alginic acid and the like; a lubricant 6uch 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 i8 a capsule, it may contain, in addition to material6 of the above type, a liguid carrier such as ~atty oil. Various other materials may be present as coatings or to otherwise modify the phy6ical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or eli~ir may contain the active compound, ~uCrose as a sweetening agent, methyl and propyl parabens as preservative6, a dye and a flavoring such as cherry or orange flavor.

W09~/~2~1 ~ PCT/US91t~

- 17,~ _ -Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by di~solving or suspendin~ the active 6ubEtance in a vehicle such as water for injection, a naturally occuring vegetable oil li~e se6ame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicie li~e ethyl oleate or the li~e. Buffers, preservative~, antio~idants and the li~e can be incorporated as required.
lo The compounds of thi~ invention are al60 useful to treat elevated intraocular pressure and can be adminiEtered to patients in need of such treatment with typical pharmaceutical formulations such as tablet6, cap6ules, injectables, as well a6 topical lS ocular formulations in the form of solutions, ointments, inserts, gel6 and the li~e. Pharmaceutical formulations prepared to treat intraocular pressure would typically contain about 0.1% to 15~ by weight, and preferably 0.5% to 2.0Z by weight of a compound Of this invention.
Thus, the compounds of the invention are useful in treating hypertencion. They are also of value in the mana~emcnt of acute and chronic conge~tive beart failure, in the treatment of 2S ~econdary hyperaldo8teronism, primary and 8econtary pulmonary hypertension, renal failure such a6 diabetic nephropathy, glomerulonephritis, scleroderma, and the li~e, renal vascular hypertension, left ventricular dy6function, diabetic retinopathy, and in the management of va8cular disorder6 such as mi~raine or Raynaud'6 di~ease. The application of the . , .

WO9~/12~1 2075`6~:7 PCT/US9~ 3 compounds of this invention for these and similar disorder will be apparent to those s~illed in the art The u6eful central nervou6 sy6tem (CNS) activities of the compound~ of thi6 invention are demon6trated and exemplified by the ensuing a66ays.

COG~ITlVE F~N~TION ASS~

10 The efficacy of these compound6 to enhance cognitive function can be demonstrated in a rat passive avoidance as6ay in which cholinomimetics such as physo6tigmine and nootropic agent6 are ~nown to be active. In thi6 assay, rat6 are trained to inhibit lS their natural tendency to enter dar~ areas. The te6t apparatus u6ed con6ists of two chamber~, one of which is brightly illuminated and the othcr is dar~. Rats are placed in the illuminated chamber and the elap~ed time it ta~e6 for them to enter the dar~ened chamber 20 i6 recorded. On entering the dar~ chamber, they receive a brief electric shoc~ to the feet. The test animals are pretreated uith 0.2 mg/~g of the muscarinic anta~oni~t copolamine which di-rupt~
learning or are treated with copolamine and the 2S compound which io to be tested for possible reversal of the copolamine effect. Twenty-four hours later, the rat~ are returned to the illuminated chamber.
Upon return to the ~lluminated chamber, normal young rats who have been oubjected to this training and who 30 have been treated only with control vehicle ta~e lon~er to re-enter the dar~ chamber than test animal~
who have been esposed to the apparatu8 but who ~ave wos1/12~~ !' PCT/US91/~W3 ~U~ 3 ~

not received a shock. Rats treated with scopolamine before training do not show thi6 hesitation when tested 24 hours later. Efficacious test co~pounds 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.l mg/kg to about l00 mg/kg.

1o A~XIOLYTIC ASSAY

The anxiolytic activity of the invention compounds can be demonstrated in a conditioned emotional response (CER) assay. Diazepam is a clinically useful an~iolytic which is active in this assay. In the CER protocol, male Sprague-Dawley rats (250-350 g) are trained to press a lever on a variable interval (VI) 60 6econd 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) periots in a fi~et LlDlL2D2L3 sequence. During both periots (L or D), pres~ing a lever telivers 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 indepentent shock presentation schedule of VI 20 seconts. Lever pressing is suppresset during the dark periods reflecting the formation of a conditioned emotional response (CER).

woslJl2~l 2 0 7 ~ 6 3 7 . ~ - - ` PCT/U~91/~3 . . ~

Drug testing in this paradigm is carried out under extinction conditions. During e~tinction, animals learn that responding for food in the dark is no lon~er punished by shoc~. Therefore, response c rates grad~ally increase in the dar~ periods and animals treated with an anxiolytic drug show a more rapid increase in response rate than vehicle treated animals. Compounds of this invention should be efficacious in this test procedure in the ran~e of from about 0.1 mg/kg to about 100 mg/kg.

DEPRESSION 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 suspended 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 e~perimenter to assign to each animal an identity code and to measure latency, duration and frequcncy of immobile periods.
Compounds of this invention should be efficacious in this test procedure in the range of from about 0.1 mg/kg to about 100 mgtkg.

~. ' .

W091/12~1 2 0 7 ; `- ~ ` PCT/US91/~3 SC~IZOP~RENIA ASSAY

The antidopaminer~ic activity of the compounds of this invention can be demonstrated in an apomorphine-induced sterotypy model. A clinically useful antipsychotic drug that is used as a po6itive control in this a6say i6 haloperidol. The as6ay method is based upon the observation that stimulation of the dopaminergic system in rats produces 6tereo-typed motor behavior. There is a strong correlationbetween the effectiveness of classical neuroleptic drugs to block apomorphine-induced stereotypy and to prevent schizophrenic 6ymptoms. Stereotyped behavior induced by apomorphine, with and without pretreatment with test compounds, is recorded using a ~eypad linked to a microcomputer. Compounds of the inven-tion should be efficacious in this assay in the range of from about O.l mg/kg to about lOO mg/kg.
In the treatment of the clinical conditions noted above, the compounds of this invention may be utilized in compositions such as tablet6. capsules or elixir6 for oral administration, suppositorie6 for rectal administration. sterile solutions or suspen-sions fo~ parenteral or intramuscular administration, 2S and the li~e. The compound8 of thi~ invention can be administered to patient8 (animal8 and human) in need of ~uch treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary ~rom patient to patient depenting upon the nature and ~everity of disease, the patient~s weight, special diets then being followed by a patient, concurrent medication, and other factors WOgl/12001 2-0-7~63~ ` ~` PC~/~S9l/oogg3 which those skillea 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 lo may be combined with other cognition-enhancing agents. These include acetylcholinesterase inhibitors such as heptylphysostigmine and tetrahydroacridine (T~A; tacrine), muscarinic agonists such as oxotremorine, inhibitors of angiotensin-converting lS enzyme such as octylramipril, captopril, ceranapril, enalapril, lisinopril, fosinopril and zofenopril, centrally-acting calcium channel blocker6 and 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 o~ the compounds of this invention with other antidepressants are of use.
These include tricyclic antidepre~sants such a6 nortriptyline, amitryptyline and trazodone, and monoamine 02idase inhibitors such as tranylcypromine.
In order to obtain maximal antipsychotic activity, the compounds of this invention may be combined with other antipsychotic agents such as promethazine, fluphenazine ant haloperidol.

.

.
..

wosl/12~ PCT/US91/~X~3 ~

,~ - .

The following examples illustrate the preparation of the compounds of Formula I and their incorporation into pharmaceutical compositions and as uch are not to be considered as limiting the c invention set forth in the claims appended hereto.

~am~le 1 2-Butyl-3-t4-(1-carboxy-1-phenyl)metho~yphenyl]-methvl-6-methvlq~ olin-4(3~)-one ~ep A: Preparation of 2-n-butyl-6-methylquin-azolin 4(1~)-one To a solution of 3.0 g (20 mmol) of 2-amino-5-methyl benzoic acid in 20 mL of dry DM~ at O-C was added 200 mg of DMAP followed by 6.07 g (60 mmol) of triethylamine and 5.02 g (40 mmol) of valeryl chloride. The resulting mixture was stirred at O-C for 30 min. The mixture was heated to 110-C
and monitored by TLC for the formation of the intermediate quinoxazolone (Rf-0.8, 40% EtOAc/
hexane). Following complete formation of the intermediate 10 g (100 mmol) of (N~4)2CO~ was added cautiously. ~eating was continued to ensure consumption of the quino~azolone and formation of the polar (R~-0.4, 40X EtOAc/hcxane) quinazolin-4(1~)-one. The reaction mi~ture was concentrated in vacuo and the residue was ta~en up in 50 mL of ether and 50 mL of water. The mi~ture was filtered and the filtrate tiscarded after washing the residue with 20 mL of ether. The residue was recry6talized from MeO~
to give 1~07 g (25%) of the title compound as a white crystalline solid.

WO91/12~1 2 0 7S 6 3 7 PCT~US91/~3 H NMR (300 M~z, CDC13, ppm): ~ O.94 (t, 3~, J=6.7 ~z), 1.50 (m, 2~), 1.83 (m, 2~), 2.49 (s, 3~), 2.78 (t, 2~), 7.60 (m, 2~), 8.05 (m, 1~).
Anal (Cl3~l6N20) C~

Ste~ B: Preparation of methyl 2-(4-methylphenoxy)-~henvlacetate To a suspension of R~ (212 mg, 1.0 eq) in DMF (3 mL) was added a solution of p-cresol (200 mg;
1 85 mmol) in DMF (2 mL) followed by 18-crown-6 (50 mg, 0.2 eq). After stirring the reaction 45 minutes until the foaming subsides, a solution of methyl 2-bromophenylacetate (424 mg, 1.O eq) in DME (1 mL) was added, resulting in a purple solution that slowly faded to yellow. The reaction mixture was stirred 2.5 hours and was then concentrated in vacuo. The residue was chromatographed on a flash silica column (130 x 30 mm) eluted with 5% ethyl actate/hexane to yield 281 mg (62%) of the title compound (Rf = 0.38, 5% ethyl acetate/hexane), 1~ NMR (300 M~z, CDC13, ppm): ~ 2.3 (s, 3~), 3.75 (s, 3~), 5.6 (6, lF), 6.8-6.9 (d, 2~), 7.0-7.1 (d, 2~), 7.3-7.45 (m, 3F), 7.5-7.6 (d, 2~).
FAB-MS: m/e 257 (M+l).5 Preparation of methyl 2-(4-bromomethyl-pheno~v~phenylacetate A solution of the product of Step B (50 mg, 0.205 mmol) NBS (33 mg, 0.9 eq) and AIBN (5 mg, catalytic amount) in CC14 (2 mL) wa8 heated to reflux for 2 hours, and then concentrated in ~acuo. The residue was chromatographed on a flash silica column .
- .
.

:

WO91/12~] PCT/US91/~K~3 S' '" ':
~Q7S~37 --(20 x 140 mm) eluted with 5% ethyl acetate/hexane to yield 32 mg (48%) of product (Rf = 0.17, 5~/. ethyl acetate/hexane).
lH r~MR (300 MXz, CDC13, ppm): ~ 3.75 (6, 3H~, 4.5 (s, 2H), 5.65 (s, 1~), 6.9-7.0 (d, 2~), 7.3-7.35 (d, 2~), 7.35-7.5 (m, 3~), 7.5-7.6 (d, 2H).

Preparation of 2-butyl-3-[4-(1-carbomethoxy-l-phenyl)methoxyphenyl]methyl-6-methyl lo ~uinazolin-4(3~)-one To a suspension of NaH (3 mg, 1.05 eq) in DMF (800 mL) at OoC was added 20 mg (0.0925 mmol) of the product of Step A and the reaction mixture was stirred for 15 minutes until the turbidity subsided.
Next a solution of the product of Step C (31 mg, 1.0 eq) in DMF (0.2 mL) was added, the reaction was stirzed for 18 hours, and then concentrated in vacuo. The residue was chromatographed on a flash silica gel column (120 x 20 mm) eluted with 15% ethyl acetate/hexane to yield 23 mg (53%) of the title compound (Rf = 0.15, 15% ethyl acetate/hexane~.
1~ NMR (300 M~z, CDC13, ppm): ~ O.9-1.0 (t, 3~), 1.3-l.S (m, 2~), 1.65-1.8 (m, 2~), 2.5 (s, 3~
2.7-2.8 (t, 2~), 3.75 (8, 3~), 5.3 (~, 2~), 5.~ (s, 1~), 6.85-6.95 (d, 2~), 7.05-7.15 (d, 2~), 7.35-7.45 (m, 3~), 7.5-7.6 (m, 4~), B.l (s, 1~).
FAB-MS: m/e 471 (M+l).

WO91/12~1 ~- 2075~37 PCr/USgli~3 ,, ,. ,,, ., ~,.
! , ~ . ..

Ste~ ~: Preparation of 2-butyl-3-t4-(1-carboxy-1-phenyl~methoxyphenyl]methyl-6-methyl-guinazolin-4(3~)-one To a solution of the product of Step D (22 mg, 0.047 mmol) in MeO~ (5 mL) was added 1 N NaO~ (2 mL). The reaction mixture was stirred 0.5 hours, and was then concentrated in vacuo. The residue wa6 taken up in water and acidified to p~=2 with 1 N
HCl. Next, the aqueous layer was partitioned with lo chloroform and extracted 3 times. The combined organic layers were dried ~MgSO4), filtered and the filtrate concentrated in vacuo to yield 15 mg (65%) of the title compound (Rf = 0.40, hexaneJethyl acetate/acetic acid (75:23.5:1.5~).
1~ NMR (300 M~z, CDC13, ppm): ~ O.B-0.9 (t, 3F), 1.2-1.4 (m, 2~), 1.55-1.7 (m, 2~), 2.45 (s, 3~), 2.65-2.75 (t, 2~), 5.2-5.4 (br s, 2~), 5.6 (s, 1~), 6.9-7.0 (d, 2~), 7.05-7.15 (d, 2~), 7.35-7.45 (m, 3~), 7.5-7.65 (m, 4F), 8.1 (s, lF).
FAB-MS: m/e 457 (M+l).
~x~m~le 2 2-~utyl-3-t4-((1-carbo~y-1-phenyl)methoxy)-3-allyl]-Step A: Preparation of 4-(2-propen-1-yloxy)benzyl alcohol To a su6pension of Na~ (130 mg; 4.33 mmol) in DMF (5 mL) at O-C under nitrogen was addet a solution of 4-hydroxmethylphenol (512 ~g: 4.12 mmol) in DMF (5 mL). After stirring 5 minutes at room wosl/l2~~ PCT/US91/~M~3 2~75637 `''''' temperature, a solution of allyl bromide (375 mL, 4.33 mmol) in DMF (5 mL) was added dropwise. The reaction was stirred for 20 minute6 at O-C, then quenched with water and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with 4~/. HCl, saturated Na~C03, and then brine, and dried (MgS04), filtered and concentrated in vacuo to yield 650 m~ (97%) of the title compound.
lH NMR (300 MHz, CDC13, ppm): ~ 7.27 (dd, 2~), 6.90 (apparent d, 2~), 6.i2-5.98 (m, 1~), 5.41 (apparent dd, 1~), 5.29 (dd, lH), 4.58 (s, 2~), 4.52 (dd, 2~), 1.93 (br s, 1~).

Ste~ B: Preparation of 4~tert-butyldimethylsilyl-oxvmethvl~henvl-(2-propen-1-vl) ether To a solution of the product of Step A (650 mg, 3.96 mmol) in C~2C12 (20 mL), cooled to O-C.
under nitrogen, was added triethylamine (612 mL, 4.39 mmol) and a solution of tert-butyldimethylsilyl chloride (631 mg; 4.19 mmol~ in C~2C12 (2 mL). After stirring at room temperature for 18 hours, the reaction mixture was diluted with ethyl acetate (60 mL), washed with water, and saturated so,dium bicarbonatc, and then dried (MgS04). The filtrate was concentrated in vacuo to afford 1.1 g of the title compound which was used crude in the next reaction (Rf ~ 0.45, 5% ethyl acetate/hexanes).
1~ NMR (300 M~z, CDC13, ppm): d 7.24 (d, 2E), 6.89 (d, 2~), 6.15-6.00 (m, 1~), 5.42 (apparent d, 1~), 5.30 (apparent d, 1~), 4.68 (s, 2~), 4.53 (apparent dd, 2~), 0.95 (s, 9~), 0.12 (s, 6~

... ~.

Wogl/12~1 2 0 ~ ~ 6 3 7 PCT/US91~93 . . .

Ste~ C: Preparation of 4-tert-butyldimethylsilylo~y-methvl-2-allvlphenol The product of Step B (0.51 g, 1.83 mmol) wa~ heated to 200C under a nitrogen atmosphere for 5 r hours. The crude reaction mi~ture was dissolved in eluant and chromatographed on silica (MPLC, 5/95 ethyl acetate/hexane) to afford 178 mg (35%) of the title compound (Rf = 0.11, 5% ethyl acetate/hexanes).
1~ NMR (300 M~z, CDC13, ppm~: ~ 7.10 (unsymmetrical d, 2H), 6.78 (d, 2~), 6.09-5.94 (m, 2~), 5.21-5.11 (m, 2H), 5.00 (s, lH), 4.67 (s, 2~), 3.40 (d, 2~), 0.95 (s, 9~), 0.11 (s, 6~).
FAB MS: m/e = 277 (M+l).

Ste~ D: Preparation of methyl 2-(4-tert-butyl-dimethylsilyloxymethyl-2-allylphenoxy)-~-phenvlacetate To a suspension of K~ (1.3 eq) in DMF (1 mL) was added a solution of the product of Step C (157 mg, 0.566 mmol) in DMF (1 mL), followed by 18-crown-6 (30 mg; 0.2 eq~. The reaction mixture was stirred for 5 minutes at room temperature. A solution of methyl 2-bromophenylacetate (168 mg, 0.735 mmol) in DffF (1 mL) was sdded, followed by a catalytic amount 2S of potassium iodide. The reaction was heated to 80-C
for 0.5 hours then stirred at room temperature for 16 hours. After concentration in vacuo, the residue was partitioned between water and ethyl acetate. The combined organic layers were wa8hed with water, brine, then dried (MgS04). After filtration and concentration in vacuo, the residue was chromato-graphed on silica (MPLC, ethyl acetate/hesanes (5/95)) to afford 158 mg (66%) of the title compound (Rf 0.22, 5% ethyl acetate/he~anes).
.

wosl/12~~ PCT~US41/~X~3 207~637 lH NMR (300 M~z, C~C13, ppm): 8 7.64-7.57 (dd. 2H), 7.46-7.35 (m, 3~), 7.17-7.06 (m, 2~), 6.72 (d, 1~), 6.12-5.98 (m, 1~), 5.65 (s, 1~), 5.11-5.04 (m, 2~), 4.66 (s, 2~), 3.72 (s, 3~), 3.53 (d, 2~), 0.95 (s, 9H), 0.10 (s, 6~).
FAB MS: consistent with structure.

Step E: Preparation of methyl 2-(4-bromomethyl-2-allvl~henoxY~-2-~henvlacetate lo To a cooled (0C) solution of the product of Step D (156 mg, 0.366 mmol) in C~3CN (2 mL), were added carbon tetrabromide (182 mg, 0.55 mmol) and triphenylphosphine (144 mg, 0.55 mmol). After 30 minutes at O-C, the reaction mixture was allowed to warm to room temperature, at which point acetone (40 mL, 0.55 mmol) was added. After 16 hours at room temperature, the reaction mixture was filtered, the filtrate was concentrated in vacuo, and the residue was purified on a silica gel fla~h chromatography column eluted with 5% ethyl acetate/hexanes to afford 86 mg (63 %) of the title compound (Rf=0.13, 5% ethyl acetate/hexanes).
1~ NMR (300 M~z, CDC13, ppm): ~ 7.67-7.57 (dd, 2~), 7.47-7.37 (m, 3~), 7.27-7.13 (m, 2~), 6.72 (d, 1~), 6,16-5.98 ~m, lE), 5.68 (6, 1~), 5.20-5.08 (m, 2~), 4.49 (s, 2~), 3.73 (s, 3~), 3.54 (d, 2~).
FAB MS: consistent with structure.

Step F: Preparation of 2-Eutyl-3-t4-((1-carbomethoxy-1-phenyl~methosy)-3-allylphenyl]methyl-6-~ethyl~uinazolin-4(3 ~-one To a suspension of NaE (0.514 mmol) in DMF
(2 mL) was added 92 mg (0.428 mmol) of 2-butyl-6-W091/l2~l 2 ; 7 5 6 ~ 7 ~ PCT/US91~ 3 . .

methylquinazolin-4(3~)-one (Step A of E~ample 1) and the reaction mi~ture was stirred for 30 minutes at room temperature. A solution of the product of Step E (177 mg, 0.471 mmol) in DMF (1.5 mL) was added, and the reaction was stirred at room temperature for 18 hour6. The reaction mixture wa6 then concentrated in vacuo and partitioned between water and ethyl acetate.
The combined organic layers were washed with water then brine, dried (MgS04), filtered, and concen-trated in vacuo. The residue was chromato~raphed onsilica ~MPLC, hexanes/ethyl acetate (4/1)) to afford 96 mg (44 %) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ 8.08 (s, lH), 7.6-7.49 (br s, 4~), 7.42-7.28 (m, 3~), 7.09-7.01 (br s, 1~), 6.93-6.83 (br dd, 1~), 6.66 (d, lH), 6.08-5.92 (m, 1~), 5.60 (s, 1~), 5.36-5.22 (br s, 2~), 5.12-4.98 (m, 2~), 3.68 (s, 3~), 3.48 (d, 2~), 3.48 (d, 2H), 2.72 (t, 2~), 2.48 (s, 3~), 1.80-1.65 (m, 2~), 1.40 (q, 2~), 0.90 (t, 3~).
FAB MS: m/e = 511 (M+l).

Ste~ G: Preparation of 2-~utyl-3-t4-((1-carboxy-l-phenyl)methoxy)-3-allylphenyl]methyl-6-~ethvl~uinazolin-4(3F~-one To a solution of the product of Step F (20 m~, 0.039 mmol) in MeOF (2 mL), were added 4 drops of water and 2.0 N NaOF (22 mL, 0.043 mmol). After stirrin~ for 18 hours at room temperature, the reaction mixture was concentrated in vacuo, dissolved in water/T~F, and treated with ~Cl (0.15 mL, 1.0 N) at room temperature for 30 minutes. The reaction mixture was then concentrated in vacuo and . .:

.

2 0 7 5 ~ 3 7 ~ f`~ PCI~/US91/00993 chromatographed on a Sephadex L~-20 column eluted with MeO~ to afford 19 mg of crude product, which was recrystallized from MeO~ to yield 2 m~ (10%) of the title compound.
H ~IR (300 M~z, CD30D, ppm): ~ 8.05 (s, lE), 7.70 ~d, 1~), 7.63-7.48 (m, 3~), 7.44-7.28 (m, 3L), 7.08 (s, 1~), 6.99-6.92 (m, lH), 6.83 (d, lH), 6.07-5.92 (m, 3H), 5.73 (s, 1~), 5.40 (s, 2~), 5.08-5.88 (m, 2~), 3.46 (br s, 2~, 2.80 (t, 2~), 2.51 (s, 3~), 1.68-1.57 (m, 2~), 1.43-1.28 (m, 2H), 0.88 (t, 3~).
FAB MS: m/e = 497 (M+l).

Exa~ 3 2-Butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-propyl-Dhe~yllmethyl-6-methvl~uinazoli~-4(3~-one Step A: Preparation of 2-Butyl-3-[4-((1-carbomethox~-l-phenyl)methox~)-3-propylphenyl]methyl-6-methvl~uina~olin-4(3~)-one To a solution of the product of Example 2, Step F (20 mg, 0.039 mmol) in C~2C12 (2 mL), wa6 added Wil~inson's catalyst (7.6 mg). The reaction mixture was hydrogenated at 40 psi, room temperature 2S for 4.5 hours. A~ter concentration in vacuo, the re8idue was chromatagraphet on silica (MPLC, hexanes/ethyl acetate (4/1) to afford lS mg (78%) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ 8.10 (8, lE), 7.63-7.54 (m, 4F), 7.46-7.36 (m, 3~), 7.02 (apparent 8, 1~), 6.89 (dd, lF), 6.63 (d, l~j, 5.62 (8, 1~), .
. . . ~ .

wosl/~2~l ~.PCT/US9l~ 3 ~:j ; "; ,, 20'~5637 5.32 (br s, 2~), 3.71 (s, 3H), 2.79-2.63 (m, 4~), 2.50 (s, 3~), 1.80-1.60 (m, 2~), 1.48-1.34 (m, 2~), 1.02-0.87 (m, 6~).
FAB-MS: m/e = 513 (M+l).

Step B- Preparation of 2-Butyl-3-[4-((1-carbo~y-1-phenyl)methoxy)-3-propylphenyl~methyl-6-methylquinazolin-4(3~1)-one To a solution the product of E~ample 3, Step A (11 mg; 0.22 mmol) in MeO~ (2 mL) was added NaO~
(1.5 eq, 2.0 N) and a few drops of water. After stirring for 20 hours at room temperature, the reaction mi~ture was concentrated in vacuo, dissolved in water/T~F, treated with ~Cl (5 eq) for 30 minutes at room temperature, concentrated in ~acuo, and chromatographed on a Sephadex L~-20 column eluting with MeO~ to afford 11 mg (99%) of the title compound.
H NMR (300 M~z, CD30D, ppm): ~ 8.19 (s, 1~), 7.88 (d, 1~), 7,68 (d, 1~), 7.58 (dd, 2~), 7.48-7.33 (m, 20 3~). 7.18 (s, 1~), 7.08 (d, 1~), 6.84 (d, 1~), 5.70 (s, 1~), 5.48 (s, 2R), 3.15-3.03 (m, 2~), 2.69 (t, 2~), 2.53 (s, 3~), 1.72-1.5 (m, 4~), 1.49-1.34 (m, 2B), 0.98-0.84 (m, 6~).
FAB-MS: m/e . 499 (M+l).

~ J8UI~L-4 2-Butyl-3-t4-((1-carbo~y-1-phenyl)methosy)-3-chloro-~henvllmethvl-6-methyl~uinazolin-4(3~-one S~e~ A Preparation of methyl 2-(2-chloro-4-methyl_ zhe~no~-2-~henvlacetate To a suspen6ion of 0.282 g (7.04 mmol) of a 60% oil dispersion of sodium hydride in DMF was added - : .
. . .. ~ . , '' ' ' ' ' ' ' ' ' ' , , ' .
.. ~ . .
'' ' . ,, '` - . ', ~ ~ , ' " -WOgl/~2~l PCT/US91/~K~3 207~637 r 1.00 g (7.04 mmol~ of 2-chloro-4-methylphenol and the mi~ture was ~tirred under an N2 atmosphere at room temperature. After 10 minutes, a solution of 1.94 g (8.45 mmol) of methyl 2-bromophenylacetate dissolved c in 10 mL of DMF was added and the reaction was stirred an additional 1.5 hours. The reaction was then diluted into ethyl acetate, washed with water, dried (MgS0~), filtered and evaporated. The residue was purified on a silica gel flash chromatography lo column eluted with 4% ethyl acetate/hexane to afford 1.70 g (83%) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ 2.20 (s, 3H), 3.70 (s, 3~), 5.60 (s, 1~), 6.70-6.80 (d, 1~), 6.85-6.95 (d, 1~), 7.20 (br s, 1~), 7.20-7.30 (m, 3~), 15 7 55-7.65 (m, 2F).
EI-MS: m/e 290 (M+).

~te~ B: Preparation of methyl 2-(2-chloro-4-bromo-methvl~henoxy~ h~nYla~ 9_ 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 re~lus for 7 hours, then an additional 0.20 g of NBS was added. The reaction was re~luxed for 48 hours, then cooled and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 10% ethyl acetate/hexane to afford 0.730 g (34%) of the title Co~pound, E NMR (300 M~z, CDC13, ppm): ~ 3.70 (s, 3~), 4.40 (s, 2~), 5.65 (s, 1~), 6.75-6.85 (d, 1~), 7.10-7.20 (d, 1~), 7.30-7.45 (m, 4~), 7.55-7.65 (m, 2~).
FAB-MS: m/e 369 (M~l).

WO91/12~ PCT/US91/~93 '" ''"'J' 2 ~ ~ i a 3 ~ ~ ;?

Ste~ C: Preparatio~ of 2-butyl-3-[4-((1-carbomethoxy-l-phenyl)methoxy)-3-chlorophenyl]methyl-6-methvl~uinazolin-4(3~)-one To a half suspension of 62 mg (0.287 mmol) of the product of Step A of Example l in l.O mL of anhydrous DMF was added 12 mg (1.05 eq) of a 60% oil dispersion of sodium hydride and the reactio~ mi~ture was stirred under an N2 atmosphere. After stirring 10 minutes at room temperature, a solution of 0.127 g lo (1.2 eq) of the product of Step B dissolved in 1.0 mL
DME was added to the solution of the anion. The reaction mixture was then stirred overnight, then partitioned between water and ethyl acetate. The organic layer was separated, dried (MgS04), filtered lS and evaporated in vacuo. The residual oil was purified on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 76 mg (52%) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ O.87-0.94 (t, 3~), 1.32-1.45 (m, 2~), 1.67-1.78 (m, 2~), 2.42 (s, 3~), 2.66-2.72 (t, 2~), 3.70 (s, 3~), 5.30 (br 8, 2~), 5.60 (s, 1~), 6.77 (d, 1~), 6.94 (dd, lE), 7.18 (s, 1~), 7.33-7.42 (m, 3~), 7.53-7.61 (m, 4~), 8.06 (s, 11~) .
FAB-MS: m/e 505, 507 ~M~l, 3:1 ratio).

Step D: Preparation of 2-butyl-3-t4-((l-carboxy-l-phenyl)methoxy)-3-chlorophenyl]methyl-6-mgthvl~uinazolin-4(3~)-one To a solution of 72 mg of the protuct of Step C dis601ved in 2 mL of methanol, wa8 added 0.25 mL of a l N 601ution of NaO~ and the reaction mi~ture .. . . . . .

., .

wosl/l2~ PCT/VS9l/~3 207a637 - 188-was stirred at room temperature for 3 days. The reaction mi~ture was then adjusted to p~ 7 with 1 N
~Cl, caoncentrated in vacuo, and the residue was applied to a silica gel flash chromatography column and eluted with CHC13/MeO~/N~40~ (80:15:1).
Evaporation of the purified fractions and drying in vacuo afforded 50 mg (71%) of the title compound.
1~ NMR (300 M~z, CD30D, ppm): ~ O.92-0.98 (t, 3H), 1.37-1.48 (m, 2~), 1.66-1.77 (m, 2H), 2.54 (s, 3H), lo 2.78-2.84 (t, 2~), 5.40 (s, 2H), 5.68 (s, 1~), 7.01-7.10 (m, 2~), 7.31-7.44 (m, 4~), 7.58-7.72 (m, 4H), 8.07 (s, lH).
FAB-MS: m/e 491, 493 (M+l, 3:1 ratio).

1s Exam~le_5 3-t4-((1-Carboxy-l-phenyl)methoxy)-3-chloro-5-methoxy-phenyl~methyl-6-(N-methyl-N-iso-butyloxycarbonyl)-amino-2-propvlquinazolin-4(3~)-one Ste~ A: Preparation of 2-propyl-6-nitro-quinazolin-4(1H)-one To a su6pension of 48.94 g (0.3 mol) of 3-nitro-5-amino-benzonitrile in 500 mL of CH2C12 was added 63 mL of Et3N, 3 g DMAP and lastly, dropwise, 45.5 g (0.45 mol) of butyryl chloride. A mild exothermic reaction ensued. The mixture was allowed to stir for 2 days (monitored by TLC with 50%
EtOActhesanes). The solution was wa6hed with 1 N HCl 30 (2 s 100 mL), water (1 s 100 mL), 8aturated NaHC03 (2 x 100 mL), brine (1 x 100 mL) and dried over MgS04.
The 6uspension was filtered and concentrated in :

W091/12~1 PCT~US91/~3 2 ~ 7 ~ 6 ~

vacuo. The residue was suspended in a mi~ture of 600 mL of MeOE and 200 mL of water in a three neck round bottom flask. To this was added gradually 140 mL of 5 N NaOH (0.7 mol) ~olution followed by the dropwise addition of 80 mL of 30% H202 (0.7 mmol) solution (exothermic). The mixture was reflused overnight, cooled to room temperature and filtered. The filtrate was acidified with 1 N ~Cl cooled to 5-C and filtered. The guinazolinone was recrystallized from hot MeOH to give 38 g (54%) of the title compound as pale brown fine crystals.
1~ NMR (300 M~2, CDC13, ppm): ~ 1.10 (t, 3~, J=7.8 ~z~, 1.93 (m, 2H), 2.79 (t, 2~, J=7.3 ~z), 7.81 (d, lH, J-8.9 Hz), 8.55 (dd, 1~, J=2.4, 8.8 ~z), 9.14 (d, , J=2.4 ~z), 10.72 (br s, 1~).

Ste~ B: Preparation of 3-(4,4'-dimethoxybenzhydryl)-2-~ro~yl-6-nitro-~ui~A~Q~ L-one To a suspension of 1.01 g (33.7 mmol) of 80%
sodium hydride in 20 mL of dry DMF was added at O-C
7.5 g (32 mmol) of the product of Step A as a solid.
The reaction misture was diluted with a further 50 mL
of DMF to assist stirring. After hydrogen evolution was complete, a solution of 8.8 g (33.7 mmol) of 2S 4,4'-dimetho~ybenzhydryl chloride in 20 mL of dry DMF
was added dropwise. The reaction misture was stirred overnight and then poured into 300 mL of 0.1 N NaOR.
The precipitate was collected by filtration and dried under vacuum to give 12.1 g (94%) of a yellow solid.
l~-NMR (300 MJz, CDC13, ppm): ~ O.87 (t, 3~, J.7,3 ~z), 1.58 (br m, 2~), 2.72 (t, 2~, J~7.8 ~z), 3.80 (8, 6~), 6.88 (d, 4~, J=9 Jz), 7.19 (d, 4~, J=9.0 ~z), 7.73 (d, 1~, J=8.9 Ez), 8.48 (dd, 1~, J-2.8, 9.0 ~z), 9.08 (d, 1~, J.2.8 ~z).

.; ~ , . . .

.

wos~/12~l PCT/US9l/~93 i. ~

- lgO -Step C: Preparat~on 6-amino-3-(4,4'-dimethoxybenz-hvdrvl~-2-~ro~vl-~uinazolin-4~3~)-one A solution of 12.1 g (26.0 mmol) of the product of Step B dissolved in 250 mL of EtOAc was hydrogenated under atmospheric pres6ure over three days in the presence of three portions of 1.2 g of10%
Pd/C added daily. The mi~ture was filtered through celite and concentrated in ~acuo to give an oil. The product was purified by flash chromatography over lo silica gel eluted with 50% EtOAc/hexanes to give 7.8 g (72%) of the amine.
l~_NMR (300 M~z, CDC13, ppm): ~ O.82 (t, 3~, J=7.2 Hz), 1.49 (br m, 2~), 2.61 (t, 2~, J=7.81 ~z), 3.79 (s, 6~), 3.90 (br s, 2~), 6.85 (d, 4~, J=8.8 ~z), 7.08 (dd, 1~, J=2.8, 8.7 ~z), 7.20 (d, 4~, J-8.4 ~z), 7.42 (d, 1~, J=2.7 Hz), 7.47 (d, 1~, J=8.7 Hz).

Ste~ D: Preparation of 3-(4,4'-dimethoxybenzhydryl)-6-(N-methyl-N-isobutylo~ycarbonyl)-amino-2-2~ pro~vl-quinazolin-4(3~)-one To a suspension of 81.5 mg (2.7 mmol) of 80~/.
Na~ in 3 mL of try DMF at O-C under nitrogen was added dropwise a ~olution of 1.03 g (2.5 mmol) of 6~amino-3-(4,4'-dimetho~ybcnzhydryl)-2-propylquinazoli 2S n-4(3~)-one dissolved in 3 mL of DMF. The resulting mi~ture was stirred for 30 minutes and then treated with 0.35 mL (2.7 mmol) of neat isobutylchloroformate.
The solution was stirred for 30 minutes and then treated with 2.97 mL (2.97 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in ~ . The dar~
solution was stirred for a further 30 minutes at O-C
and then was treated with 0.2 mL (3.26 mmol) of neat WO 91tl2~1 2 0 7 5 6 3 7 PCT/VS91/~ ~3 . .

iodomethane. The mixture was stirred overnight at room temperature, poured into 50 mL of EtOAc and washed consecutively with water (2xlO mL), brine (lxlO mL) and dried over MgS04. The product was purified by flash chromatography over silica gel eluted with 30% EtOAc/hexanes to give 0.9 g (71%) of the title compound as an oil.
l~_NMR (300 M~z, CDC13, ppm): S O.82-0.91 (m, 6~), 0.96 (d, 3~, J=6.8 Hz), 1.52 (m, 2~), 1.88 (m, lH), 2.67 (br t, 2~), 3.35 (s, 3~), 3.80 (s, 6~), 3.90 (d, 2H, J=6.6 Hz), 6.87 (d, 4~, J=8.8 ~z), 7.20 (d, 4~, J=8.8 ~z), 7.61 (m, 1~), 7.78 (m, 1~), 8.01 (d, 1~, 2R).

Ste~ E: Preparation of 6-(N-methyl-N-isobutyloxy-carbonvl)-amino-2-~ro~vl~uinazolin-4~3~-one The product of Step D (0.9 g, 1.7 mmol) was added to 3.0 mL of a 10:1 mixture of trifluoroacetic acid and anisole. The solution was stirred for 4 hours, concentrated in vacuo and the residue was purified by flash chromatography over silica gel eluted with 50% EtOAc/hexanes to give 0.47 g (B8%) of the title compound as a white solid.
l~_NMR (300 M~z, CDC13, ppm): ~ 0.89 (d, 6~, J=6.7 ~Z). 1.07 ~t, 3~, J~7.4 ~z), 1.92 (m, 2~), 2.76 (t, 2B, J.7.8 ~z), 3.40 (8, 3~), 3.93 (d, 2~, J.6.6 ~z), 7.70 ~m, 2~), 8.10 (d, 1~, J.2.6 ~z).

Step F: Preparation of methyl 2-(2-chloro-4-hydroxy-methvl-6-methoxy~henosv)-2-phcnyl~s~tate To a 801ution of O.500 g ~2.65 mmol) of 3-chloro-4-hydroxy-5-methoxybenzyl alcohol (Bader) . . . : ,, , , " : :, .

WO91/12001 ' .~ PCT~US91/~3 207~63~

and 0.668 g (1.1 eq) of methyl 2-bromophenylacetate dissolved in 5 mL acetone was added 0.733 g (2 eq) of anhydrous potassium carbonate and the reaction mix~ure was 6tirred and reflu~ed overnight. The reaction mixture wa~ cooled to room temperature, filtered and evaporated in vacuo. The residual oil was purified on a ~ilica gel flash chromatography column eluted with 357. ethyl acetate/hexane to afford 0.570 g (64%) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ 1.65-1.75 (t, 1~), 3.70 (s, 3~), 3.80 (s, 3H), 4.55 (d, 2~), 5.75 (s, lH), 6.80 (s, lH), 6.90 (s, 1~), 7.30-7.40 (m, 3~), 7.50-7.60 (m, 2~).
FAB-MS: m/e 337, 339 (M+l, 3:1 ratio).

Step G: Preparation of 2-(4-bromomethyl-2-chloro-6-metho~vphenoxY)-2-phenylacetate To a ~tirred and cooled (O-C) solution of 0.570 g (1.69 mmol) of the product of Step A
dissolved in 6 mL of C~2C12 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 hour8. The mi~ture was then evaporated in vacuo and purified on a silica gel fla~h chromatography column eluted with 20% ethyl acetate/he~ane to afford 0.580 g (86%) of the title compound.
1~ NMR (300 M~z, CDCl3, ppm): ~ 3.75 (s, 3~), 3.80 (s, 3~), 4.35 (s, 2~), 5.65 (~ ), 6.80 (~, 1~), 6.95 (8, 1~), 7.30-7.40 (m, 3~), 7.50-7.60 (m, 2~).
FAB-MS: m/e 398, 400, 402 (M+l).

( 2 0 7 5 ~ 3 7 PCTfU~9l/~X~3 Ste~ ~: Preparation of 3-[4-((1-carbomethoxy-1-phe~yl)methoxy~-3-chloro-5-methoxyphenyl]-methyl-6-(N-methyl-N-iso-butyloxycarbonyl)-amin~-2-~ro~ylQuinazolin-4(3~-one To a half suspension of 80 mg (O.252 mmol) of the product of Step F in O.5 mL of anhydrous DMF
was added 10.6 mg (1.05 eq) of a 60% oil dispersion of sodium hydride and the reaction mi~ture was stirred under an N2 atmosphere. After stirring 40 minutes at room temperature, a 601ution of 0.111 g (1.1 eq) of the product of Step G di~solved in 0.5 mL
DMF was added to the solution of the anion. The reaction mixture was then stirred overnight, then partitioned between water and ethyl acetate. The organic layer was separated, dried (MgS04), filtered and evaporated in vacuo. The residual oil was purified on a silica gel flash chromatography column eluted with 40% ethyl acetate/hesane to afford 100 mg (63%) of the title compound.
1~ NMR (300 MHz, CDC13, ppm): ~ O.84-1.01 (m, 9~), 1.58-2.02 (m, 3~), 2.63-2.6B (t, 2H), 3.38 (s, 3~)~
3.71 (s, 3~), 3.73 (6, 3F), 3.91 (d, 2H), 5.20-5.30 (br s, 2H), 5.72 (8, lH), 6.58-6.64 (m, 1~), 6.68 (d, lK), 7.28-7.34 (m, 3~), 7.48-7.55 (m, 2H), 7.61 (d, 1~), 7.72 (t, 1~), 8.07 (d, 1~).
FAB-MS: m/e 636, 638 (M+l, 3:1 ratio).

S~e~ I: Preparation of 3-t4-((1-carbo~y-1-phenyl)-methoxy)-3-chloro-5-methOXyphenyl]methyl-6-(N-methyl-N-iBo-butylOSyCarbonyl)amino-2 propvlguinazolin-4(3~)-one To a 601ution of 97 mg (0.15 mmol) of the product of Step ~ dissolved in 2 mL of methanol, was WO91/12~ ; PCT/US9lt~W~3 207~37 194 -added 0.25 mL of a 1 N solution of NaO~ and the reaction mi~ture was stirred at room temperature for 2.5 hours. The reaction mi~ture was then adjusted to p~ 6 with 1 N ~Cl, caoncentrated in vacuo, and the residue was applied to a silica gel flash chromato-graphy column and eluted with C~C13/MeOH/NH4OH
(80:15:1~. Evaporation of the purified fractions and dryin~ in vacuo afforded 60 mg (63%) of the title compound.
10 1~ NMR (300 MHz, CDC13, ppm): ~ O.88-1.06 (m, 9H), 1.68-1.82 (m, 2H), 1.85-2.04 (m, lH), 2.76 (t, 2H), 3.43 (s, 3E), 3.68 (s, 3H), 3.95 (d, 2H), 5.38 (s, 2~), 5.67 (s, lH), 6.68 (d, lH), 6.74 (d, lH), 7.26-7.33 (m, 3H), 7.48-7.54 (m, 2H), 7.72 (d, lH), 7.82 (dd, lH), 8.14 (d, 1~).

~a~le 6 3-t4-((1-Carboxy-l-phenyl)methosy)-3-propylphenyl]-methyl-6-(N-methyl-N-iso-butyloxycarbonyl)amino-2-~ro~yl~uinazolin-4(3H~-one Step A: Preparation of methyl 4-(2-propen-1-yl)-osvbenzoate A 2 L flas~ was equipped with a mechanical 6tirrer, a reflu~ condenser and A stopper, then charged with 50.05 g (0.329 mol) of methyl 4-hydrosybenzoate, 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 mi~ture was stirred and reflu~ed for 14 hour8. The mi~ture was cooled to room temperature, filtered and concentrated W091~1200~ ~'PCT/US91/~3 ~ 2~7aG37 - 195 - .

to an oil. The residual oil was purified by distillation (97 C @ 0.03 mm Hg) to afford 53.52 (86%) of the title ccmpound.
1~ NMR (300 M~z, CDC13, ppm): ~ 3.84 (6, 3~), 4.56 S (d, J=7 ~z, 2~), 5.28 (dd, J=3,12 Hz, 1~), 5 40 (dd, J=3,19~z, 1~), 5.96-6.10 (m, lH), 6.90 (d, J=10 ~z, 2~), 7.96 (d, J=10 ~z, 2H).
FAB-MS: m/e 193 (M+l).

lo Step B: Preparation of methyl 4-hydroxy-3-(2-propen-l-vl)benzoate A solution of 15.05 g (78.3 mmol) of the product of Step A in 25 mL of 1,2-dichlorobenzene uas magnetically stirred and refluxed (183-C) under an argorJ atmosphere for 18 hours. At thi~ point, the reaction mixture was cooled to room temperature and applied to a 6 cm diameter by 18 cm silica gel flash chromatography column and eluted with 25X ethyl acetate-hexane to separate the 1,2-dichlorobenzene, then with 40% ethyl acetate-hexane to elute the product. The product fractior.s were concentrated in ~acuo and the residual oil was crystallizet from hexane to afford 13.70 g (91%) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ 3.42 (d, J-8 Hz, 2~), 3.88 (s, 3H), 5.14-5.20 (m, 2H), 5.48 (6, lH), 5.94-6.06 (m, lH), 6.82 (d, J=12 Hz, lH), 7.80-7.85 (m, 2H).
FAB-MS: m/e 193 (M+l).
~te~ C: Preparation of methyl 4-(tert-butyldimethyl_ Eilylo~rv)-3-(2-propen-l-yl~benzoate To a solution of 5.168 g (26.9 mmol) of the product of Step B in 50 mL of dichloromethane was Wo9l/l2~l 2 Q ~ PC~/US91~ 3 added 4.40 mL (~.95 mmol) of triethylamine, 4.46 g (2.95 mmol) of tert-butyldimethylchlorosilane, 0.100 g of 4-dimethylaminop~ridine, and the reaction mixture was stirred at room temperature for 2 hours.
The mixture was then diluted with 50 mL dichloro-methane, washed with 100 mL 1 N hydrochloric acid, dried (MgS04), filtered and evaporated. The residual oil (7.993 g, 97Z) was used in the next step without further purification.
10 1~ NMR (300 MHz, CDC13, ppm): ~ 0.24 (s, 6~), 1.02 (s, 9~), 3.36 (d, J=8 Hz, 2H), 3.84 (s, 3~), 4.98-5.08 (m, 2H), 5.88-6.03 (m, lF), 6.78 (d, J=ll Hz, lH), 7.76-8.40 (m, 2~).
FAB-MS: m/e 307 (M+l).

Ste~ ~: Preparation of 4-(tert-butyldimethyl-silylQæ~3-(2-~ro~en-1-vl)benzvl alcohol To a magnetically 6tirred 601ution of 8.523 g (28.0 mmol) of the product from Step C in 35 mL of anhydrous IHF was added 15.0 mL of a 1.O M solution of lithium aluminum hydride in T~F, and the reaction mixture wa6 6tirred under a nitrogen atmosphere for 2 hour6. At thi6 point, the reaction was quenched by cautious adtition of 10 mL water, the resulting precipitate was dissolved by addition of 1.0 N
hydrochloric acid and the product was e~tracted into ethyl acetate. The organic layer was separated, dried (MgS04), filtered and evaporated in vacuo to afford 7.258 g (93%) of the title compound.
30 lB NMR (300 M~z, CDC13, ppm): ~ O.20 (s, 6H), 1.00 (s, 9~), 3.34 (d, J-B Hz, 2~), 3.84 (8, lH), 4.57 (6, 2~), 4.97-5.07 (m, 2~), 5.88-6.03 (m, 1~), 6.86 (d, wosl/l2~] PCT/US91/~3 .",j',,,, 2~7~637 - 197 ~

J=10 Hz, 1~). 7.05-7.14 (m~ 2~).
FAB-MS: m/e 279, 261 (M+l).

Step E Preparation of 4-hydroxy-3-(2-propen-1-yl)-benzYl alcohoL___ _ -To a solution of approximately 7.26 g (2.6 mmol) of the crude product of Step D, dissolved in 50 mL of anhydrous T~F was added 26 mL (2.6 mmol) of tetra-n-butylammonium fluoride and the reaction lo mixture was stirred at room temperature for 16 hours. The mixture was then evaporated in vacuo and the residual oil was purified on a silica gel flash chromatography column eluted with 5%
methanol/chloroform to afford 3.386 g (797.) of the title compound as a colorless oil.
1~ NMR (300 MHz, CDC13, ppm): ~ 2.12 (br s, lH), 3.35 (d, J=8 Hz, 2~), 4.54 (s, 3F), 5.05-5.15 (m, 2~), 5.90 (br s, 1~), 5.90-6.05 (m, lH), 6.70 (d, J=10 ~z, lH), 7.02-7.10 (m, 2~).
FAB-MS: m/e 165 (M~l).
Ste~ F: Preparation of 4-hydro~y-3-propylbenzyl alcohol To a solution of 0.370 g (2.25 mmol) of the 2S product Or Step E dissolved in 25 mL of absolute ethanol was added 53 mg of a 5% rhodium on carbon catalyst and the mixture was shaken under a 40 p6ig pressure of hydrogen on a Parr apparatus. After 30 minutes, the reaction mixture was removed, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 35% ethyl acetate/hexane to afford the title compound.

wosl/12~l PCT/US91/~M~3 20 7~63 7 - 198 -1~ NMR (300 M~z, CDC13, ppm): ~ O.95 (t, J=8 Hz, 3~), 1.55-1.6B (m, 2~), 2.22 (br s, l~), 2.57 (t, J=8 ~z, 2~, 4.56 (s, 2~), 5.93 (br 6, lH), 6.66 (d, J=10 ~z, l~j, 7.00 (dd, J=2, 10 ~z, lH), 7.08 (d, J=2 ~z, l~).
r FAB-MS: m/e 167 (M+l).

Ste~ G: Preparation of methyl (4-hydroxymethyl-2-propvlphenoxv~-2-~henylacetate To a solution of 0.484 g (2.91 mmol) of the product of Step F dissol~ed in 12 mL of acetone were added 0.667 g (2.91 mmol) of methyl 2-bromophenyl-acetate, 0.804 g (5.82 mmol) of anhydrous K2C03 and the mixture was stirred and heated at reflux for 5 hour~. The mixture was then cooled, filtered and evaporated in vacuo. The residual oil was purified on a silica gel flash chromatography column eluted with 30X ethyl acetate/hexane to afford 0.75S g (83Z) of the title compound.
1~ NMR (300 MJz, CDC13, ppm): ~ O.95 (t, J=8 ~z, 3~), 1.58 (br s, 1~), 1.60-1.75 (m, 2H), 2.70 (t, J=8 ~z, 2~), 3.68 (s, 3~), 4.57 (m, 2~), 5.62 (s, l~), 6.68 (d, J-lO ~z, 1~), 7.07 (dd, J=2, lO ~z, 1~), 7.16 (d, J~2 ~z. 1~), 7.32-7.44 (m, 3~), 7.55-7.60 (m, 2~).
FAB-MS: m/e 315 (M~l).

Step ~ Preparation of methyl (4-bromomethyl-2-pro~vl~heno~cY)-2-phenvlacetate To a stirred (O-C) solution of 0.750 g (2.31 mmol) of ~he product of Step G, and 0.949 g (2.86 mmol) of carbon tetrabromide dissolved in 7 mL of methylene chloride was added 0.751 g of triphenyl-phosphine (2.86 mmol) in portions. After the ' WO 91/12001 2 0 7 5 6 3 7 PCr/U~gl/~0993 ~, . ., ~

- 199 - ~ ;

addition was complete, the reaction mixture was stirred and allowed to warm to room temperature over 1 hour. The reaction mixture was then e~aporated in vacuo, and the residue was purified on a silica gel flash chromatography column eluted with 10% ethyl acetate/hexane to afford 0.703 g (78Z) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ 0.95 (t, J=8 ~z, 3~), 1.60-1.75 (m, 2H), 2.70 (t, J=8 Hz, 2~), 3.69 (s, lo 3~). 4.44 (s, 2~), 5.62 (s, 1~), 6.64 (d, J=10 ~z, 1~), 7.12 (dd, J=2, 10 ~z, 1~), 7.lB (d, J=2 ~z, 1~), 7.34-7.44 (m, 3~), 7.53-7.58 (m, 2~).

Ste~ I: Preparation of 3-[4-((1-carboxmethoxy-1-phenyl)methoxy)-3-propylphenyl]methyl-6-(N-methyl-N-iso-butyloxycarbonyl)amino-2-~ropvl~uinazolin-4(3~)-one To a solution of llS mg (0.36 mmol) of the product of Step E from Example 5 in 1.5 mL of anhydrous DMF wa~ added 15.0 mg (0.36 mmol) of a 60%
oil dispersion oS sodium hydride and the reaction mixture WAS stirred under an N2 atmosphere. After stirring 45 minutes at room temperature, a solution of 0.137 g (0.36 mmol) of the product of Step ~
dissolved in 0.5 mL DMF was added to the solution of the anion. The reaction mixture was then stirred an addltional hour at room temperature, then partitioned between water and ethyl acetate. The organic layer wa6 separated, dried (MgS04), filtered and evaporated in ~acuo. The residual oil waB purified on a silica gel flash chromatography column eluted with 35% ethyl acetate/hexane to afford 0.060 g (49%) of the title compound.

Wosl/~2~1 i ~ PCT/US9l/~3 20~5637 1~ NMR (300 MRz, CDC13, ppm): ~ O.85 (d, 6~), 0.92 (t, 3~), 0.96 (t, 3H), l..55-2.00 (m, 5E), 2.60-2.75 (m, 4~), 3.36 (s, 3H), 3.77 (s, 3~), 3 90 (d, 2~), 5.28 (br s, 2~), 5.57 (s, 1~), 6.63 (d, 1~), 6.85 (dd, 1~), 6.99 (d, 1~), 7.30-7.42 (m, 3~), 7.50-7.60 (m, 2E), 7.55 (dd, lH), 7.60 (d, 1~), 8.08 (d, 1~).
FAB-MS: m/e 614 (M+~).

Step J: Preparation of 3-t4-((1-carbo~y-1-phenyl)-methoxy)-3-propylphenyl]methyl-6-(N-methyl-N-iso-butyloxycarbonyl)amino-2-propylquin-azolin-4(3H)-one To a solution of 60 mg (0.098 mmol) of the product of Step I dissolved in 2 mL of methanol, was added 0.25 mL of a 1 N solution of NaO~ and the reaction mixture was stirred at room temperature for 4 hours. The reaction mi~ture was then adjusted to p~ 7 with 1 N ~Cl, caoncentrated in vacuo, and the residue was applied to a ~ilica gel flash chromato-graphy column and eluted with 10% MeO~tC~C13.Evaporation of the purified fractions and drying in vacuo afforded 33 mg ~57X) of the title compound.
1~ NMR ~300 M~z, CD30D, ppm): ~ 0.88-1.05 (complex, 12 ~), 1.56-1.67 (m, 2~), 1.72-1.84 (m, 2~), 25 1.87-2.00 (m, 1~), 2.55-2.65 (m, lE). 2.75-2.86 (m, 3~), 3.42 (s, 3~), 3.95 (d, 2~), 5.38 (br s, 2~), 5.43 (s, 1~), 6.85 (d, 1~), 6.94 (dd, 1~), 7.05 (d, lB), 7.28-7.38 (m, 3~), 7.62-7.70 (m, 2~), 7.71 (d, 1~), 7.83 (dd, 1~), 8.15 (d, 1~).
FAB-MS: m/e 600 (M+~

W091/12~1 PCT/US91/~3 ~; 207~637 ' '` ' "i' ' ' ' ~ample 7 5-Butyl-4-[4-(1-carboxy-1-phenyl?metho~yphenyl]methyl-chloro~henyl)-2.4-dihvdro-3~-1.2.4-triazol-3-one ~te~ A: Preparation of ethyl valerimidate (Free Base) A 12.7 g (76.7 mmol) sample of ethyl valerimidate hydrochloride (prepared from valero-nitrile, ethanol, and hydrogen chloride gas asdescribed by A.J. ~ill and I. Rabinowitz, J. Am.
Chem. Soc., 1926, 48, 734) was dissolved in 33% (w/w) potassium carbonate solution (made by di~solving 15 g of K2C03 in 30 mL f ~2) and immediately e~tracted with either (3x40 mL). The combined ether layers were dried over Na2S04, filtered, and concentrated in vacuo to give 7.09 g (72%) of the product as a clear oil, which was used directly in the ne~t step.
1~ NMR (300 MHZ~ CDC13, ppm): ~ 0.88 (t, J=7 ~z, 3~), 1.24 (t, J= 7~z, 3~), 1.31 (m, 2~), 1.50 (m, 2~), 2.19 (t, J=7.5 ~z, 2~), 4. 06 (q, J=7 ~z, 2~), 6. 84 (br s, 1~).

Ste~ B: Preparation of ethyl N-carbetho~yvaler-imidate A solution of 6.5 g (50.J mmol) of ethyl valerimidate (free base) in 90 mL of dry CH2C12 was ~reated with 7.71 mL (5.60 g, 55.3 mmol) of triethylamine. The resulting solution was stirred unter N2 at -lO-C in an ice-6alt bath as a solution of 4.81 mL (5.46 g, 50.3 mmol) of ethyl chloroformate in 10 mL of CH2C12 was added dropwi6e over 25 ~......

WO 91/12001 ' PCr/US91/00993 i~ ; . , r~
2~75~37 --minute~. Upon completion of the addition, the cooling bath was removed, and the mixture wa~ stirred at room temperature for 2 hour~. Next, the solvent was removed by evaporation in vacuo. The residue was ta~en up in he~ane and filtered to remove triethyl-amine hydrochloride. Concentration of the filtrate yielded 7.08 g (70%) of the product as a yellow oil, suitable for use in the next ~tep without further purification. NMR indicated a mixture of syn and anti isomers. TLC (98:2 CH2C12-MeO~) showed a close pair of spots, ~f 0.48, 0.52.
lH NMR (200 MHz, CDC13, ppm): ~ O.86 (distorted t, J=7.5 ~z, 3~), 2.15-2.35 (m, 8~), 2.4-2.65 (m, 2~), 2.19, 2.35 (t, J=7.5 ~z, 2H total), 4.0-4.2 (m, 4~).
EI-MS: m/e 201 (M+).
Ste~ C: Preparation of 5-butyl-2-(2-chlorophenyl)-2.4-dihydro-3~-1.2.4-triazol-3-one _ To a solution of 285 mg (2 mmol) of (2-chlorophenyl)hydrazine (generated from the hydrochloride by partitioning between ether and 1 N
Na2C03) in 3 mL of toluene was added 442 mg (2.2 mmol) of ethyl N-carboetho~yvalerimidate (E~ample 4 Step B). The mixture was heated at 45-50-C for 45 minute6. At this time the mixture was treated with 307 mL (223 mg, 2.2 mmol) of triethylamine and then heated overnight at 95-C. The mi~*ure was cooled and concentrated in vacuo. Flash chromatography of the residue on 8ilica gel (~radient elution with 0.6-2%
30 methanol in C~2C12) gave 257 mg (51X) of the product as an off-white ~olid, mp 103-104-C, homogeneous by TLC in 19:1 C~2C12-MeO~.

WO91/12001 PCT~US91i~3 207~637 1~ NMR (200 M~z, CDC13, ppm): ~ O.92 (t, J=7 Hz, 3E), 1.38 (m, 2~), 1,68 (m, 2~), 2.57 (t, J=7.5 ~z, 2~), 7.3-7.55 (m, 4H), 12.04 (br s, lH).
FAB-MS: m/e 252 (M+i).
Analysis for C12~14ClN30 Calcd: C, 57.26; ~, 5.61; N, 16.69 Found: C, 57.31; H, 5.69; N, 16.58 Ste~ D: Preparation of 5-butyl-4-[4-(1-carbo-methoxy-l-phenyl)methoxyphenyl]methyl-2-(2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one A mixture of 64 mg (0.254 mmol) of the product of Step C, 6.1 mg (0.254 mmol) of sodium hydride, and O.5 mL of DMF was 6tirred under N2 at room temperature for 2.5 hours. To this was then added 100 mg (0.299 mmol) of methyl 2-(4-bromomethyl-phenoxy)-2-phenylacetate (from Example 1, Step C), dissolved in a minimal amount of DMF. Stirring was continued for 48 hours. The mixture was then partitioned between 5 mL E20 and 8 mL EtOAc, and the aqueous layer was further extracted with 2 x 8 mL
~tOAc. The combined organic layers were washed with 2 x 10 mL H20 and 1 s 10 mL brine, and dried over 2S anhydrou5 Na2S04. The filtrate was evaporated in vacuo, and the residue flash chromatographed over 40 mL silica gel (gradient elution with 0.5% to 2,0%
methanol in CH2C12) to give 62 mg of the title compound as a colorle88 oil (48Z), homogeneou~ by TLC
in 50:1 CH2C12-MeOH.

- . .

W091J12~1 PcT/ussl~x~3 207a6~7 ; ~

lH NMR (400 M~z, CDC13 ppm): ~ 0.85 (t, J=7.3 ~z, 3~), 1.33 (m, 2~), 1.56 (m, 2~), 2.42 (t, J=7.6 ~z, 2H), 3.72 (5, 3~), 4.81 (s, 2H), 5.61(s, 1~), 6.86-6.95 (m, 2H), 7.10-7.60 (m, 11~).
FAB-MS: m/e 506 (M+l).

Step E: Preparation of 5-Butyl-4-t4-(1-carboxy-l-phenyl)methoxyphenyl]methyl-2-(2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one A solution of 49 mg (0.097 mmol) of the above ester (Step D) in THF was treated with 0.5 mL
(5 equivalents) of 1 N NaOH in MeOH at room temperature for 2 days. Volatiles were evaporated and the residue taken up in 1.2 mL MeO~, acidified to pH 2 by addition of sufficient 1 N HCl/MeO~. After evaporating the volatiles, the residue was triturated with chloroform and the salt was filtered off over a pad of celite. After removal of volatiles in ~acuo, the residue was flash chromatographed over 14 mL
silica gel (gradient elution with 2% to 20% methanol in C~2C12) to afford 37 mg of the title compound as a glassy solid.
1~ NMR (400 MHz, CD30D, ppm): ~ O.89 (t, J=7.4 Hz, 2S 3~). 1.37 (m, 2E), 1.56 (m, 2~), 2.57 (t, J~7.5 ~z, 2~), 5.61 (~, lH), 7.00-7.10 (m, 2H); 7.25-7.70 (m, 11~1) .
FAB-MS: m/e 492 (M+l), 530 (M+K).

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Exam~le 8 5-Butyl-4-[4-((1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-2-(2-chlorophenyl)-2,4-dihydro-38-1.2.4-triazol-3-one _ Ste~ A: Preparation of 5-Butyl-4-t4-((1-carbo-metho~y)-l-phenyl)methoxy]-3-propylphenyl]-methyl-2-(2-chlorophenyl)-2,4-dihydro-3~-lo 1~2.4-triazol-3-one This compound was prepared by the same procedure as for Example 7, Step D, except that methyl 2-(4-bromomethyl-2-propylphenoxy)-2-phenyl-acetate (the product of Example 6, Step ~) was used lS as the alkylating agent. After chromatographic purification, a 96Z yield of the desired material was obtained.
18 NMR (400 M~z, CDC13, ppm): ~ 0.85 (t, J=7.4 ~z, 38~, 0.93 (m, 3~), 1.32 (m, 28), 1.60 (m, 2~), 1.68 (m, 28), 2.43 (t, J=7.7 8z, 28), 2.67 (t, J=7.7 8z, 28), 3.69 (s, 38), 4.80 (s, 2~), 5.62 (s, lH), 6.67 (d, J=8.4 8z, 1~), 7.00-7.60 (m, 1l8).
FAB-MS: m/e 548 (M+l).

S~e~ B: Preparation of S-butyl-4-t4-((l-carboxy-l-phenylmetho~y)-3-propylphenyl]methyl-2-(2-chlorophenyl)-2,4-dihydro-3~-1,2,4-triazol-.3-one Thi6 compount was prepared from the product of Step A by the 6ame procedure a6 for E~ample 7, Step E. After chromatographic purification, a 50~
yield of the title compound wa~ obtained, homogeneous on TLC (9:1 C~2Cl2/MeO8).

wosl/~2~1 PCT/US91~ 3 207a6~7 - 20~ -lH NMR (400 M~Z, CDC13, ppm~: ~ 0.82 (t, J=7.4 ~z, 3H), 0.91 (t, J=7.4 Ez, 3E), 1.40 (m, 2~), 1.55 (m, 2~), 1.63 (m, 2H), 2.41 (t, J=7.4 ~z, 2H), 2.66 (t, J=7.3 ~z, 2~), 4.80 (s, 2~), 5.60 (s, 1~), 6.68 (d, J=6.0 Hz, 1~), 6.95-7.60 (m, 11~).
FAB-MS: m/e 534 (M+l).

E~am~le 9 10 2-Benzyl-5-butyl-4-t4-(1-carbosy-1-(2-chloro-phenyl))methoxyphenyl~methyl-2,4-dihydro-3~-1.2.4-triazol-3-one Ste~ A: Preparation of ethyl valerate carbethoxy-hvdr~z~ne To a solution of 7.0 g (25.3 mmol) of ethyl valerimidate hydrochloride (prepared by method of A.J. ~ill and I. Rabinowitz, J. Am. Chem. Soc., 1926, 48, 734) in 35 mL of dry ethanol stirred under N2 at 20 -78-C was added dropwise a solution of 24 g (23 mmol) of ethyl carbazate in 35 mL of dry ethanol.
Precipitation occurred during the addition, which too~ 20 minutcs and was accompanied by a ri6e in the internal temperature of -50-C. The misture was allowed to stand at 5-C for 60 hours and then filtered. The filtrate was concentrated, then flash chromatographed on a silica gel column (elution with 9B.5-1.5 C~2C12-MeO~), yielding 3.06 g (61~) of a clear oil, homogeneous by TLC in 97:3 C~2C12-MeO~;
NM* suggested a misture of syn and anti isomers.

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. ., : - .
.

Wo91~2~1 . ~CT/~S91/~3 2 0 7~ 6 3 7 - . : -1~ NMR (200 M~z, C'DC13, ppm): ~ 0.91 (t, J=7 ~z, 3H), 1.2-1.4 (m, 8H), 1.4-1.6 (m, 2H), 2.2-2.4 (m, 2~), 3.95-4.3 (m, 4~), 6.91, 8.11 (br s, 1~ total).
FAB-~5: m/e 217 (M+l).

S~p B: Preparation of methyl 2-bromo-2-(2-chloro-~henyl~acetate A mi~ture of 5.00 g (29.3 mmol) of 2-chloro-phenylacetic acid and 2.67 mL (36.6 mmol) of thionyl lo chloride was stirred and refluxed as 1.51 mL of bromine was slowly added through an addition funnel.
After the addition was complete, the reaction mixture was refluxed overnight, then cooled to room temperature. Methanol (25 mL) was cautiously added, the reaction mixture was ~tirred an additional 1 hour and was then evaporated to an oil. The residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 2.13 g (28%) of the title compound.
1~ NMR (300 M~z, CDC13, ppm): ~ 3.8 (s, 3~), 5.95 (s, 1~), 7.25-7.45 (m, 3~), 7.7-7.8 (m, 1~).

S~ Preparation of methyl 2-(2-chlorophenyl)-2-(4-methylpheno~y~4ce~te To a 6tirret (O-C) suspension of 0.530 g (4.63 mmol) of a 35% oil dispersion of potassium hydride in 5 mL of anhytrous DMF was added 0.50 g ~4.63 mmol) of p-cre801 and 0.050 g of 18-crown-6.
After stirring at room temperature for 15 minutes, a solution of 1.22 g (4.63 mmol) of the product of Step B in 5 mL of DMF was 810wly addet. The reaction mixture was 8tirred and allowed to warm to room 2 ~ 7 ~ , 7 - ` PCr~l~S9lfO0993 ~

temperature during 45 minutes. The reaction mixture was then partitioned between ethyl acetate and water, 6eparated, dried (MgSO4), filtered and evaporated in vacuo. The residue wa6 purified on a ~ilica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 1.03 g (77%) of the title compound.
1~ NMR: (300 M~z, CDC13, ppm): ~ 2.25 (s, 3~), 3.8 (s, 3~), 6.12 (s, 1~), 6.85 (d, 2H)~ 7.05 (d, 2~), lO7.28-7.35 (m, 2~), 7.40-7.45 (m, 1~), 7.63-7.70 (m, lH).
EI-MS: m/e 290, 292 (M+).

S~e~ D: Preparation of methyl 2-(4-bromomethyl-15phenoxv)-2-(2-chloro~h~nyl~acetate To a solution of 0.200 g (0.69 mmol) of the product of Step C dissolved in 2 mL of carbon tetra-chloride was added 0.117 g (0.95 eq) of N-bro~osuc-cinimide and ca. 10 mg (catalytic amount) of AI~N.
The reaction mixture was stirred and refluxed under a nitrogen atmosphere for 30 minutes, then cooled and concentrated in vacuo. The resitual oil was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to ~fford O.lB6 g (73%) of the title compound.
1~ MMR (300 M~z, CDC13, ppm): ~ 3.8 (s, 3~), 4.5 (~, 2~), 6.15 (s, 1~), 6.85-6.95 (d, 2~), 7.25-7.35 (m, 4~); 7.4-7.5 (m, 1~), 7.6-7.7 (m, 1~).
EI-MS: m/e 368, 370, 372 (M+l, 10:13:3 ratio).

/

W091/12~1 2 0 7 ~ 6 3 7 Ste~ ~: Preparation of methyl 2-[4-(azidomethyl)-~heno~vl-2-~2-ChlQro~hen-vl)acetat~
A concentrated stirred solution of the product of Step D in anhydrous dimethylsulfoxide (DMS0) is treated at ambient temperature with lithium azide ~25% e~cess) portionwise. The mi~ture is then stirred at ambient temperature under protection from moisture for about 1 hour, or until TLC indicates complete reaction. The mixture is then partitioned between ether (or ethyl acetate) and water. The organic phase is washed repeatedly with ~2~ then dried over MgS04, filtered, and concentrated. The residue may be purified by chromatography on silica gel.
Ste~ F: Preparation of methyl 2-[4-(aminomethyl)-phenoxyl-2-(2-chlorophenyl~acetate A solution of the product of Step E in dry tetrahydrofuran is treated protionwi6e with triphenylphosphine (1 equivalent~. The 601ution is stirred under N2 at ambient temperature. After about 2 hours, when ga6 evolution has ceased, ~2 (1 eguivalent) i8 added, and the solution i6 concentrated in vacuo, and the residue is chromatographed on 6ilica gel to give the title compound.

Step G: Preparation of 5-butyl-4-[4-(1-carbo-methoxy-1-(2-chlorophenyl)~methosy-phenyl]methyl-2,4-dihydro-3~-1,2,4-triazol-3-one A mixture of approximately eguimolar quantities of ethyl valerimidate carbethosyhydrazone w09l~l2~1 .., , PCr/US91~009 (from Step A) and methyl 2-[4-(aminomethyl)pheno~y]-2-(2-chlorophenyl)acetate (Step F) in ethanol is stirred at 800C under N2. After about 2 hours, or when TLC indicate~ complete reaction, the mi~ture is cooled and concentrated to dryness. The residue is re-concentrated from CH2C12 and then chromato-graphed on silica gel to yield the title compound.

Step ~: Preparation of 2-benzyl-5-butyl-4-[4-(1-carbomethoxy-1-(2-chlorophenyl))-metho~y-phenyl]methyl-2,4-dihydro-3H-1,2,4-triazol-3-one A mixture of the above ester (Step G), sodium hydride (3 equivalents), and dry DMF is lS stirred under N2 at room temperature for 2 hours.
Next, benzyl bromide (5 equivalents) is added, and stirring at room temperature is continued for an additional 1.5 hours or until TLC indicate6 complete reaction. The mixture is quenched by cautious addition of sufficient acetic acid to destroy the excess sodium hydrite and then partitioned between ethyl acetate and ~2 The ethyl acetate phase is wa6hed repeatedly with ~2~ then dried (Na2S04), ~iltered, and concentrated in vacuo. Chromatography of the residue on silica gel affords the title compound.

Step I- Preparation of 2-benzyl-5-butyl-4-[4-(1-carboxy-1-(2-chlorophenyl))methoxyphenyl~-m~thvl-2.4-dihvdro-3F-1.2.4-triazol-3,-~o,~,,e, A solution of the above ester (Step ~) in methanol is treated with 2.5 N NaO~ (10 equivalents).

Wogl/l2~1 2 0 ~ ~ 3 ~ PCT/US9l/~W3 ~",~, - - ..

The 601ution is stirred at room temperature for about 2 hour6 or until TLC indicates complete reaction.
Then the solution is diluted with ~2 and acidified to p~=2 with ~ilute ~Cl. The product is collected on a filter or e~tracted with ethyl acetate and washed with dilute ~Cl (p~=2). If necessary, the title compound is further purified by chromatography on 6ilica gel.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I

I

or a pharmaceutically acceptable salt thereof wherein:
heterocycle is:

Ia Ib Ic 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, 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) NHSO2R2, ix) CF3, x) COOR2, or xi) SO2NHR2a; and (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group cons isting of:
i) Br, 1, Cl, 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, an unsubstituted, monosubstituted or disubstituted heteroaromatic 5- or 6- membered cyclic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the substituents are members selected from the group consisting of:
i) Cl, Br, F, I, 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 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 J1 is (a)-C(=M)-, (b) J1 and L are connected together to form a 6-carbon aromatic ring substituted with R7a, R7b, R8a and R8b or (c) J1 and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom not at J1, substituted with R7a R7b, R8a and R8b; and K1 is (a)-C(=M)-, (b) K1 and L are connected together to form a 6-carbon aromatic ring substituted with R7a, R7b R8a and R8b or (c) K1 and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom , substituted on the carbon atoms with R7a, R7b and R8b; and one of al or b1 is a double bond in structures Ia provided that when J1 is -C(=M)- then b1 is a double bond and when K1 is -C(=M)- then a1 is a double bond.

L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom; and J2 is (a)-C(=M)-, or (b) -C(R17)-; and K2 is (a)-C(=M)-, or (b)-C(R17)-, provided that one and only one of J2 and K2 is -C(=M)-; and one of a2 or b2 is a double bond in structure Ic provided that when J2 is -C(=M)- then b2 is a double bond ant when K2 is -C(=M)- then a2 is a double bond.
M is O, S or NR15; and R2 is:
(a) H, or (b) (C1-C6)-alkyl; and R2a is:
(a) R2, (b) benzyl, or (c) phenyl; and R7a and R7b are independently (a) H, (b) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl, (c) Cl, Br, I, F, (d) CF3, or (e) when R7a and R7b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring;

R8a and R8b are independently (a) H, (b) aryl-(C1-C4)-alkyl, (c) heteroaryl-(C1-C4)-alkyl, (d) (C1-C6)-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: -CON(R2a)2, -heteroaryl, -S(O)n-R21, -tetrazol-5-yl, -CONHSO2R21, -SO2NH-heteroaryl, -SO2NHCOR21, -PO(OR2)2, -PO(OR2a2), -SO2NH-CN, -NR2COOR21,-OH, -NH2, guanidino, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylamino. (C1-C4)-dialkylamino, -COOR2a, CONHR2a, -O-COR2a, or aryl, (e) -CO-aryl, (f) (C3-C7)-cycloalkyl, (g) Cl, Br, I, F, (h) -OH , (i) -OR21, (j) -SH, (k) -S(O)n-(C1-C4)-alkyl, (l) -COR2a, (m) -CO2H, (n) -CO2-(C1-C4 )-alkyl, (o) -SO3H, (p) -NR2R21, (q) -NR2COR21, (r) -NR2COOR21, (s) -SO2NHR2a, (t) -SO2NR2R2a, (u) -NO2, (v) -NHSO2CF3, (w) -CONR2aR2a, (x) -(C1-C4)-perfluoroalkyl, (y) -COOR2, (z) -SO3H, (aa) -N(R2)SO2R21, (bb) -NR2CONR2aR21, (cc) -OC(=O)NR21R2a, (dd) -aryl, (ee) -NHSO2CF3, (ff) -SO2NH-heteroaryl, (gg) -SO2NHCOR21, (hh) -CONRSO2R21, (ii) -PO(OR2)2, (jj) -tetrazol-5-yl, (kk) -CONH(tetrazol-5-yl), (ll) -SO2NHCN, or (mm) -heteroaryl; 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 an 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) -CR2O-, (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)-alkosy, vi) (C1-C5)-alkylthio.
vii) CF3, viii) OH, ix) NO2, or x) CO2R2a, and (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) CF3.
viii) OH, ix) NO2, or x) CO2R2a, and (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], -N[(C1-C4)-alkyl]2; and (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], -N[(C1-C4)-alkyl]2; and (l) -SO2NHCO-perfluoro-(C1-C4)-alkyl, (m) -SO2NHCO-heteroaryl, (n) -SO2NHCONR2aR2a, (o) -PO(OR2)2, (p) -PO(OH)(OR2), or (q) -PO(OH)2; and R15 is (a) H, (b) aryl, which is unsubstitutet or substituted with 1 or 2 substituents selected from the group consisting of: Cl, Br, I, F
-O-(C1-C4)-alkyl, (C1-C4)-alkyl, -NO2, -CF3, -SO2NR2R2a, -S-(C1-C4)-alkyl, -OH, -NH2, (C3-C7)-cycloalkyl, (C3-C10)-alkenyl;

(c) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of: aryl, (C3-C7)-cycloalkyl, Cl, Br, I, F, -OH, -NH2, -NH[(C1-C4)-alkyl].
-N[(C1-C4)-alkyl]2, -NH-SO2R2a -COOR2a, -SO2NHR2a; or (d) an unsubstituted, monosubstituted or disubstituted aromatic 5 or 6 membered ring which can contain one or two heteroatoms selected from the group consisting of N, O, S, and wherein the substituents are members selected from the group consisting of -OH, -SH, (C1-C4)-alkyl, (C1-C4)-alkyloxy -CF3, Cl, Br, I, F, or NO2; and R16 is (a) (C1-C10)-alkyl;
(b) substituted (C1-C10)-alkyl in which one or two substituent(s) selected from the group consisting of:
(1) I, Br, Cl, F, (2) hydroxy, (3) (C1-C10)-alkoky, (4) (C1-C5)-alkoxycarbonyl, (5) (C1-C5)-acyloxy, (6) (C3-C8)-cycloalkyl, (7) aryl, (8) substituted aryl, in which the substituents are V and W, (9) (C1-C10)-alkyl-S(O)n, (10) (C3-C8)-cycloalkyl-S(O)n, (11) phenyl-S(O)n, (12) substituted phenyl-S(O)n, in which the substituents are V and W, (13) oxo, (14) carboxy, (15) NR2aR2a, (16) (C1-C5)alkylaminocarbonyl (c) perfluoro-(C1-C4)-alkyl (d) (C2-C10)-alkenyl, (e) (C2-C10)-alkynyl, (f) (C3-C8)-cycloalkyl, (g) substituted (C3-C8)-cycloalkyl, in which the substituent is selected from:
(1) (C1-C5)-alkyl,or (2) (C1-C5)-alkoxy;
(h) aryl, (i) substituted aryl, in which the substituents are V and W, (j) aryl-(CH2)r-(M1)z-(CH2)t-(k) substituted aryl-(CH2)r-(M1)z- (CH2)t-in which the aryl group is substituted with V and W, or (l) , (m) , (n) , (o) or (p) ; and (q) -[(C1-C4)-alkyl]NR2R21, (r) -[(C1-C4)-alkyl]NR2COR21, (s) -[(C1-C4)-alkyl]NR2COOR21, (t) -[(C1-C4)-alkyl]CONR2aR2a, (u) -[(C1-C4)-alkyl]N(R2)SO2R21, (v) -[(C1-C4)-alkyl]NR2CONR4R21, or (w) -[(C1-C4)-alkyl]OC(=O)NR21R2a;and V and W are each independently selected from:
(a) H, (b) (C1-C5)-alkoxy, (c) (C1-C5)-alkyl, (d) hydroxy, (e) (C1-C5)-alkyl-S(O)n, (f) -CN, (g) -NO2, (h) -NR2R2a, (i) (C1-C5)-acyl-NR2R2a, (j) -CO2R2a, (k) (C1-C5)-alkyl-carbonyl, (l) CF3, (m) I, Br, Cl, F, (n) hydroxy-(C1-C4)-alkyl-, (o) carboxy-(C1-C4)-alkyl-, (p) -tetrazol-5-yl, (q) -NH-SO2CF3, or (r) aryl: and M1 is M or -C(O)-; and z is 0 or 1; and r and t are 0 to 2; and R17 and R18 are each independently selected from:
(a) H, (b) aryl-(C1-C4)-alkyl-, (c) heteroaryl-(C1-C4)-alkyl-, (d) (C1-C4)-alkyl is unsubstituted or substituted with a substituent selected from the group consisting of -OH, -NH2, guanidino, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylamino, (C1-C4)-dialkylamino, -COOR2a, -CONHR2a, -O-COR2a, CF3;
(e) (C1-C4)-alkenyl, (f) -CO-aryl, (g) (C3-C7)-cycloalkyl, (h) Cl, Br, I, F, (i) -OH, (j) -O-(C1-C4)-alkyl, (k) -(C1-C4)-perfluoroalkyl, (1) -SH, (m) -S(O)n-(C1-C4)-alkyl, (n) -CHO, (o) -CO2R2a (p) -SO3H, (q) -NH2.
(r) -NH[(C1-C4)-alkyl], (s) -N[(C1-C4)-alky1]2, (t) -NHCO2-(C1-C4)-alkyl, (u) -SO2NR2R2a, (v) -CH2OCOR2a (w) -NB-SO2-(C1-C4)-alkyl, (x) 5 or 6 membered saturated heterocycle containing one nitrogen atom and optionally containing one other heteroatom selected from N, O, or S, such as pyrrolidine, morpholine, or piperazine, (y) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
i) Br, I, Cl, 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 (z) heteroaryl, wherein heteroaryl is a 5 or 6 membered aromatic ring containing one or two heteroatoms selected from the group consisting of O, N, or S, or (aa) tetrazol-5-yl, and (ab) -[(C1-C4)-alkyl]NR2R21, (ac) -[(C1-C4)-alkyl]NR2COR21, (ad) -[(C1-C4)-alkyl]NR2COOR21, (ae) -[(C1-C4)-alkyl]CONR2aR2a, (af) -[(C1-C4)-alkyl]N(R2)SO2R21, (ag) -[(C1-C4)-alkyl]NR2CONR4R21. or (ah) [(C1-C4)-alkyl]OC(=O)NR21R2a;and R21 is:
(a) H, or (b) (C1-C4)-alkyl, is 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.

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. The compound of Claim 1 of structural formula or a pharmaceutically acceptable salt thereof.

7. A compound of structural formula 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 as defined below, 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) NHSO2R2, ix) CF3, x) COOR2, or xi) SO2NHR2a; and (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
i) Br, I, Cl, 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) an unsubstituted, monosubstituted or disubstituted heteroaromatic 5- or 6-membered cyclic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the substituents are members 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 R2 is:
(a) H, or (b) (C1-C6)-alkyl; and R2a is:
(a) R2, (b) CH2-aryl, or (c) aryl; and R8a and R8b are independently (a) H, (b) aryl-(C1-C4)-alkyl, (c) heteroaryl-(C1-C4)-alkyl, (d) (C1-C6)-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: -CON(R2a)2, -heteroaryl, -S(O)n-R21, -tetrazol-5-yl, -CONHSO2R21, -SO2NH-heteroaryl, -SO2NHCOR21, -PO(OR2)2, -PO(OR2a)2, -SO2NH-CN, -NR2COOR21,-OH, -NH2, guanidino, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylamino, (C1-C4)-dialkylamino, -COOR2a, -CONHR2a, -O-COR2a, or aryl, (e) -CO-aryl, (f) (C3-C7)-cycloalkyl, (g) Cl, Br, I, F, (h) -OH, (i) -OR21, (j) -SH, (k) -S(O)n-(C1-C4)-alkyl, (l) -COR2a, (m) -CO2H, (n) -CO2-(C1-C4)-alkyl, (o) -SO3H, (p) -NR2R21, (q) -NR2COR21, (r) -NR2COOR21, (s) -SO2NR2a, (t) -SO2NR2R2a, (u) -NO2, (v) -NHSO2CF3, (w) -CONR2aR2a, (x) -(C1-C4)-perfluoroalkyl, (y) -COOR2, (z) -SO3H, (aa) -N(R2)SO2R21, (bb) -NR2CONR2aR21, (cc) -OC(=O)NR21R2a, (dd) -aryl, (ee) -NHSO2CF3, (ff) -SO2NH-heteroaryl, (gg) -SO2NHCOR21, (hh) -CONHSO2R21, (ii) -PO(OR2)2, (jj) -tetrazol-5-yl, (kk) -CONH(tetrazol-5-yl), (ll) -SO2NHCN, or (mm) -heteroaryl; 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)-alkenyl, (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 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, vi) (C1-C5)-alkylthio, vii) CF3, viii) OH.
ix) NO2, or x) CO2R2a, and (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, vi) (C1-C5)-alkylthio, vii) CF3, viii ) OH, ix) NO2, or x) CO2R2a, and (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. -5H, -O-(C1-C4)-alkyl -S-(C1-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2, -CO2H, -CO2-(C1-C4)-alkyl, -NH2, -NH[(C1-C4)-alkyl], -N[(C1-C4)-alkyl]2; and (g) -CONH-SO2-perfluoro-(C1-C4)-alkyl, (h) -CONH-SO2-heteroaryl, or (i) -CONHSO2NR2aR2a; and R21 is:
(a) H, or (b) (C1-C4)-alkyl, is 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.

8. A compound of structural formula 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 as defined below, 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) NHSO2R2, ix) CF3, x) COOR2, or xi) SO2NHR2a; and (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
i) Br, I, Cl, 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, or (c) perfluoro-(C1-C4)-alkyl; and n is 0 to 2; and R2 is:
(a) H, or (b) (C1-C6)-alkyl; and R2a is:
(a) R2.
(b) CH2-aryl, or (c) aryl; and R8b is:
(a) H, (d) (C1-C6)-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: -CON(R2a)2, -heteroaryl, -S(O)n-R21, -tetrazol-5-yl, -CONHSO2R21, -SO2NH-heteroaryl, -SO2NHCOR21, -PO(OR2)2, -PO(OR2a)2, -SO2NH-CN, -NR2COOR21,-OH, -NH2, guanidino, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylamino, (C1-C4)-dialkylamino, -COOR2a, -CONHR2a, -O-COR2a, or aryl, (g) Cl, Br, I, F, (h) -OR21, (i) -S(O)n-(C1-C4)-alkyl, (j) -COR2a, (k) -NR2R21, (l) -NR2COR21, (m) -NR2COOR21, (n) -NO2, (o) -COOR2, (P) -NR2CONR2aR21.

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, (i) (C3-C7)-cycloalkyl, unsubstituted or substituted with (C1-C6)-alkyl.

X is:
(a) -O-, (b) -S(O)n-, (c) -NR13-(d) -CH2-, or (e) -CH=, which is double bonded to the carbon bearing Z and R11; and R11:
(a) H, (b) (C1-C6)-alkyl, unsubstituted or substituted with:
(i) aryl, or (ii) (C3-C7)-cycloalkyl, (c) phenyl, 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, vi) (C1-C5)-alkylthio, vii) CF3, viii) OH, ix) NO2, or x) CO2R2a, and (d) phenyl-(C1-C2)-, 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) CF3, viii) OH, ix) NO2, or x) CO2R2a, and (e) (C3-C7)-cycloalkyl; and R13 is:
(a) H, (b) (C1-C6)-alkyl, (c) phenyl or naphthyl (d) phenyl-(C1-C6)-alkyl-(C=O)-, (e) (C1-C6)-alkyl-(C=O)-, (f) [(C2-C5)-alkenyl]CH2-, (g) [(C2-C5)-alkynyl]CH2-, or (h) phenyl-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-heteroaryl, heteroaryl is defined as an unsubstituted, monosubstituted or disubstituted heteroaromatic 5- or 6-membered cyclic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the substituents are members selected from the group consisting of:
i) Cl, Br, F, I, 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, (g) -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], -N[(C1-C4)-alkyl]2, or (h) CONH-SO2-perfluoro-(C1-C4)-alkyl, (i) CONHSO2NR2aR2a.

R21 is:
(a) H, or (b) (C1-C4)-alkyl, is unsubstituted or substituted with:
i) NH2, ii) NH[(C1-C4)-alkyl].
iii) N[(C1-C4)-alkyl]2.
iv) CO2H, v) CO2(C1-C4)-alky, vi) OH, vii) SO3H, or viii) SO2NH2.
9. The compound of Claim 6 which is or a pharmaceutically acceptable salt thereof.
wherein:
R1 is:
(a) (C1-C6)-alkyl, (C1-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substitured with a substitutent selected from the group consisting of:
i) phenyl ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, iv) CF3, (b) phenyl, substituted or substituted with 1 or 2 substituents selected from the group consisting of:
i) Br, I, CI, F, ii) (C1-C4)-alkyl, iii) (C1-C4)-alkoxy, iv) NO2 v) CF3 vi) SO2NR2aR2a, vii) (C1-C4)-alkylthio, or viii) (C3-C10)-alkenyl; and (c) perfluoro-(C1-C4)-alkyl; and R2 is:
(a) H, or (b) (C1-C6)-alkyl; and R2a is:
(a) R2, (b) CH2-phenyl, or (c) phenyl; and R8b is:
(a) H, (b) (C1-C6)-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of: -CON(R2a)2, -CONHSO2R21, -NR2COOR21, (C1-C4)-alkoxy, (C1-C4)-alkylthio, COOR2a, -CONHR2a (c) -CO-aryl, (d) Cl, Br, I, F, (e) -OR21, (f) -S(O)n-(C1-C4)-alkyl, (g) -NR2R21, (h) -NR2COR21, (i) -NR2COOR21, (j) -NO2, (k) -NHSO2CF3, (l) -C1-C4-perfluoroalkyl, (m) -N(R2)SO2R21, (n) -NR2CONR4R21, n is 0 to 2; 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) perfluoro-(C1-C6)-alkyl, (h) (C3-C7)-cycloalkyl, unsubstituted or substituted with (C1-C6)-alkyl, X is:
(a) -O-, (b) -S(O)n-, (c) -NR13-(d) -CH=, which is double bonded to the carbon bearing, Z and R11; and R11 is:
(a) H, (b) phenyl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of:
i) C1, Br, I, F, ii) (C1-C6)-alkyl, iii) [(C1-C5)-alkenyl]CH2-, iv) [(C1-C5)-alkynyl]Ch2-, or v) (C1-C5)-alkoxy, and (c) phenyl-(C1-C2)-alkyl, unsubsituted or substituted with 1 to 5 substituents 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-, or v) (C1-C5)-alkoxy; and Z is:
(a) -CO2H, (b) -CO2-(C1-C6)-alkyl, (c) -tetrazol-5-yl, (d) -CO-NH(tetrazol-5-yl) (e) -COHN-SO2-phenyl, (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], -N[(C1-C4)-alkyl]2; and (g) -CONH-SO2-perfluoro-(C1-C4)-alkyl, (h) -CONH-SO2-heteroaryl, heteroaryl is defined as an unsubstituted, monosubstituted or disubstituted heteroaromatic 5- or 6-membered cyclic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the substituents are members selected from the group consisting of:
i) Cl, Br, F, I, 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 (i) -CONHSO2NR2aR2a; and R21 is:
(a) H, or (b) (C1-C4)-alkyl.

10. A compound of structural formula or a pharamaceutically 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 as defined below, ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, iv) OH, v) NH2, vi) NH(C1-C4)-alkly, vii) N[(C1-C4)-alkyl]2, viii) NHSO2R2, ix) CF3, x) COOR2, or xi) SO2NHR2a; and (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
i) Br, I, Cl, 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 an unsubstituted, monosubstituted or disubstituted heteroaromatic 5- or 6-membered cyclic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the substituents are members 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 R2 is:
(a) H, or (b) (C1-C6)-alkyl; and R2a is:
(a) R2, (b) arylmethyl, or (c) aryl; 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=, which is double bonded to the carbon bearing Z and R11; and 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, vi) (C1-C5)-alkylthio, vii) CF3, viii) OH, ix) NO2, or x) CO2R2a, and (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, vi) (C1-C5)-alkylthio, vii) CF3, viii) OH, ix) NO2, or x) CO2R2a, and (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 substitued with a susbstituent 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], -N[(C1-C4)-alkyl]2; and (g) -CONH-SO2-perfluoro-(C1-C4)-alkyl, (h) -CONH-SO2-heteroaryl, or (i) -CONHSO2NR2aR2a; and R17 and R18 are each indpendently selected from:
(a) H, (b) aryl-(C1-C4)-alkyl-, (c) heteroaryl-(C1-C4)-alkyl-, (d) (C1-C4)-alkyl is unsubsituted or substituted with a substituent selected from the group consisting of -OH, -NH2, guanidino, (C1-C4)-alkoxy, (C1-C4)-alkylthio, (C1-C4)-alkylamino, (C1-C4)-dialkylamino, -COOR2a, -CONHR2a, -O-COR2a;
(e) (C1-C4)-alkenyl, (f) -CO-aryl, (g) (C3-C7)-cycloalkyl, (h) Cl, Br, I, F, (i) -OH, (j) -O-(C1-C4)-alkyl, (k) -(C1-C4)-perfluoroalkyl, (l) -SH, (m) -S(O)n-(C1-C4)-alkyl, (n) -CHO, (o) -CO2R2a (p) -SO3H, (q) -NH2, (r) -NH[(C1-C4)-alkyl], (s) -N[(C1-C4)-alkyl]2, (t) -NHCO2-(C1-C4)-alkyl, (u) -SO2NR2R2a, (v) -CH2OCOR2a (w) -NH-SO2-(C1-C4)-alkyl, (x) 5 or 6 membered saturated heterocycle containing one nitrogen atom and optionally containing one other heteroatom selected from N, O, or S, such as pyrrolidine, morpholine, or piperazine, (y) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
i) Br, I, Cl, 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, (z) heteroaryl, heteroaryl is a 5 or 6 membered aromatic ring containing one or two heteroatoms selected from the group consisting of O, N, or S, or (aa) tetrazol-5-yl, and (ab) -[(C1-C4)-alkyl]NR2R21, (ac) -[(C1-C4)-alkyl]NR2COR21, (ad) -[(C1-C4)-alkyl]NR2COOR21, (ae) -[(C1-C4)-alkyl]CONR2aR2a, (af) -[(C1-C4)-alkyl]N(R2)SO2R21, (ag) -[(C1-C4)-alkyl]NR2CONR4R21, or (ah) -[(C1-C4)-alkyl]OC(=O)NR21R2a; and R21 is (a) H, or (b) (C1-C4)-alkyl, is 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.

11. A compound of structural formula 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 as defined below, ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, iv) OH, v) NH2, vi) N[(C1-C4)-alkyl, vii) N[(C1-C4)-alkyl]2, viii) NHSO2R2, ix) CF3, x) COOR2, or xi) SO2NHR2a; and (b) aryl, wherein aryl is defined as phenyl or naphthyl unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
i) Br, I, Cl, 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 an unsubstituted, monosubstituted or disubstituted heteroaromatic 5- or 6-membered cyclic moiety, which can contain one or two members seleted from the group consisting of N, O, S and wherein the substituents are members 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 R2 is:
(a) H, or (b) (C1-C4)-alkyl; and R2a is:
(a) R2, (b) arylmethyl, or (c) aryl; and R9 and R10 are independently:
(a) H, (b) (C1-C6)-alkyl, unsubstituted or substituted with (C3-C7)-cycloakyl, (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) perflouro-(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) -CH2NR12 -, (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 and R11; and 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, vii) CF3, viii) OH, ix) NO2, or x) CO2R2a, and (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 (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], -N[(C1-C4)-alkyl]2; and (g) -CONH-SO2-perfluoro-(C1-C4)-alkyl, (h) -CONH-SO2-heteroaryl, heteroaryl is defined as an unsubstituted, monosubstituted or disubstituted heteroaromttic 5- or 6-membered cyclic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the substituents are members selected from the group consisting of:

i) Cl, Br, F, I, 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 (i) -CONHSO2NR2aR2a; and R16 is (a) (C1-C10)-alkyl;
(b) substituted (C1-C10)-alkyl in which one or two substituent(s) selected from the group consisting of:
(1) I, Br, Cl, F, (2) hydroxy, (3) (C1-C10)-alkoxy, (4) (C1-C5)-alkoxycarbonyl, (5) (C1-C5)-acyloxy, (6) (C3-C8)-cycloalkyl, (7) aryl, (8) substituted aryl, in which the substituents are V and W, (9) (C1-C10)-alkyl-S(O)n, (10) (C3-C8)-cycloalkyl-S(O)n, (11) phenyl-S(O)n, (12) substituted phenyl-S(O)n, in which the substituents are V and W, (13) oxo, (14) carboxy, (15) NR2aR2a, (16) (C1-C5)alkylaminocarbonyl, (c) perfluoro-(C1-C4)-alkyl, (d) (C2-C10)-alkenyl, (e) (C2-C10)-alkynyl, (f) (C3-C8)-cycloalkyl, (g) substituted (C3-C8)-cycloalkyl, in which the substituent is selected from:
(1) (C1-C5)-alkyl, or (2) (C1-C5)-alkoxy;
(h) aryl, (i) substituted aryl, in which the substituents are V and W, (j) aryl-(CH2)r-(M1)z-(CH2)t-(k) substituted aryl-(CH2)r-(M1)z- (CH2)t-in which the aryl group is substituted with V and W, or (l) (m) (n) (o) or (p) <IMG) ; and (q) -[(C1-C4)-alkyl]NR2R21, (r) -[(C1-C4)-alkyl]NR2COR21, (s) -[(C1-C4)-alkyl]NR2COOR21, (t) -[(C1-C4)-alkyl]CONR2aR2a, (u) -[(C1-c4)-alkyl]N(R2)SO2R21, (v) -[(C1-c4)-alkyl]NR2CONR4R21, or (w) -[(C1-C4)-alkyl]OC(=O)NR21R2a;and V and W are each independently selected from:
(a) H, (b) (C1-C5)-alkoxy, (c) (C1-C5)-alkyl, (d) hydroxy, (e) (C1-C5)-alkyl-S(O)n, (f) -CN, (g) -NO2, (h) -NR2R2a, (i) (C1-C5)-acyl-NR2R2a, (j) -CO2R2a, (k) (C1-C5)-alkyl-carbonyl, (l) CF3, (m) I, Br, Cl, F, (n) hydroxy-(C1-C4)-alkyl-, (o) carboxy-(C1-C4)-alkyl-, (p) -tetrazol-5-yl, (q) -NH-SO2CF3, or (r) aryl; and M1 is M or -C(O)-; and z is 0 or 1; and r and t are 0 to 2; and R21 is:
(a) H, or (b) (C1-C4)-alkyl, is 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.

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

2-butyl-3-[4-(1-carboxy-1-phenyl)methoxyphenyl]-methyl-6-methylquinazolin-4(3H)-one;

2-butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-allyl]-phenyl]methyl-6-methylquinazolin-4(3H)-one;

2-butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-6-methylquinazolin-4(3H)-one;

2-butyl-3-[4-((1-carboxy-1-phenyl)methoxy)-3-chloro-phenyl]methyl-6-methylquinazolin-4(3H)-one;

3-[4-((1-carboxy-1-phenyl)methoxy)-3-chloro-5-methoxy-phenyl]methyl-6-(N-methyl-N-iso-butyloxycarbonyl)-amino-2-propylquinazolin-4(3H)-one;

3-[4-((1-carboxy-1-phenyl)methoxy)-3-propylphenyl]-methyl-6-(N-methyl-N-iso-butyloxycarbonyl)amino-2-propylquinazolin-4(3H)-one;

5-butyl-4-[4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-2-(2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

5-butyl-4-[4-(1-carboxy-1-phenyl)methoxy)-3-propyl-phenyl]methyl-2-(2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one;

2-benzyl-5-butyl-4-[4-(1-carboxy-1-(2-chloro-phenyl))methoxyphenyl]methyl-2,4-dihydro-3H-1,2,4-triazol-3-one;

2-butyl-6-methyl-3-[4-((N-phenylsulfonyl)carboxamido)-1-phenyl)methoxyphenyl]methylquinazolin-4-(3H)-one;

6-(N-benzyl-N-iso-butyloxycarbonyl)amino-3-[4-(((N-phenylsulfonyl)carboxamido)-1-phenyl)methoxy-3-propyl-phenyl]methylquinazolin-4(3H)-one;

6-(N-pentyl-N-(4-chlorobenzoyl)amino-3-[4-(((N-phenyl-sulfonyl)carboxamido)-1-phenyl)methoxy-3-propyl-phenyl]methylquinazolin-4(3H)-one;

5-butyl-4-[4-(((N-phenylsulfonyl)carboxamido)-1-phenyl)methoxy-3-propylphenyl]methyl-2-(2-chloro-phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one.

13. A process for the preparation of the compound of Claim 1 comprising a reaction between the alkali metal salt of the heterocycle of Ia, Ib or Ic 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 I

16. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a thereapeutically 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, guanethidine 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, quinethazone, 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, nimotipine, nisoldipine, nitrendipine, 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.