US 5,401,745 AGranted

Quinazolinones substituted with phenoxyphenylacetic acid derivatives

AssigneeMerck & Co., Inc.

InventorsScott W. Bagley, Prasun K. Chakravarty, Anna Chen, Daljit S. Dhanoa, Kenneth J. Fitch, William J. Greenlee, Elizabeth M. Naylor, James R. Tata, Thomas F. Walsh, David L. Williams, Jr.

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Abstract

Phenoxyphenylacetic acids and derivatives of general structural formula I ##STR1## have endothelin antagonist activity and are therefore useful in treating cardiovascular disorders, such as hypertension, postischemic renal failure, vasospasm, cerebal and cardiac ischemia, myocardial infarction, inflammatory diseases, Raynaud's disease, and endotoxic shock, and asthma.

Claims10

Dependent claims

A compound of structural formula I ##STR18## or a pharmaceutically acceptable salt thereof, wherein:

R.sup.1 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.2 -C.sub.6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of:
i) aryl as defined below,
ii) (C.sub.3 -C.sub.7)-cycloalkyl,
iii) Cl, Br, I, F,
iv) OH,
v) NH.sub.2,
vi) NH(C.sub.1 -C.sub.4)-alkyl,
vii) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
viii) NHSO.sub.2 R.sup.2,
ix) CF.sub.3,
x) COOR.sup.2, or
xi) SO.sub.2 NHR.sup.3 ;
and
(c) aryl,
(d) heteroaryl,
(e) (C.sub.1 -C.sub.4)-perfluoroalkyl,
(f) --O--(C.sub.1 -C.sub.6)-alkyl,
(g) --S(O).sub.n --(C.sub.1 -C.sub.9)-alkyl,
(h) --CONR.sup.3 R.sup.3, or
(i) --NR.sup.3 CO--O--(C.sub.1 -C.sub.4)-alkyl;
and
n is:
0 to 2;
and
J is:
(a)--C(.dbd.M)--, (b) J and L are connected together to form a 6-membered aromatic ring substituted with R.sup.5a, R.sup.5b, R.sup.6a and R.sup.6b or (c) J and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom, substituted with R.sup.5a, R.sup.5b and R.sup.6b ;
and
K is:
(a)--C(.dbd.M)--, (b) K and L are connected together to form a 6-membered aromatic ring substituted with R.sup.5a, R.sup.5b, R.sup.6a and R.sup.6b, or (c) K and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom, substituted on the carbon atoms with R.sup.5a, R.sup.5b and R.sup.6b ;
and
one of a or b is a double bond in Formula I provided that when J is --C(.dbd.M)-- then b is a double bond and when K is --C(.dbd.M)-- then a is a double bond;
L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom;
and
M is:
O, S or NR.sup.11 ;
and
R.sup.2 is:
(a) H, or
(b) (C.sub.1 -C.sub.6)-alkyl;
and
R.sup.3 is:
(a) R.sup.2,
(b) CH.sub.2 -aryl,
(c) aryl, or
(d) (C.sub.3 -C.sub.7)-cycloalkyl;
and
R.sup.4 groups are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl or (C.sub.2 -C.sub.6)-alkenyl each of which is unsubstituted or substituted with one of the following substituents,
i) --OH,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
iv) --NR.sup.3 --(C.sub.1 -C.sub.4)-alkyl,
v) --NHR.sup.3,
vi) --COOR.sup.3,
vii) --CONHR.sup.3,
ix) --CONR.sup.3 R.sup.11, or
x) (C.sub.3 -C.sub.7)-cycloalkyl,
(c) (C.sub.3 -C.sub.7)-cycloalkyl,
(d) F, Cl, Br, I,
(e) CF.sub.3,
(f) --COOR.sup.3,
(g) --CONR.sup.3 R.sup.11,
(h) --NR.sup.3 R.sup.11,
(i) --NR.sup.3 CONR.sup.3 R.sup.11,
(j) --NR.sup.3 COOR.sup.11,
(k) --SO.sub.2 NR.sup.3 R.sup.11,
(l) --O--(C.sub.1 -C.sub.4)-alkyl,
(m) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl, or
(n) --NHSO.sub.2 R.sup.11 ;
and
R.sup.5a and R.sup.5b are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.2 -C.sub.6)-alkynyl,
(c) Cl, Br, I, F,
(d) CF.sub.3, or
(e) when R.sup.5a and R.sup.5b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring;
R.sup.6a and R.sup.6b are independently:
(a) H,
(b) aryl-(C.sub.1 -C.sub.4)-alkyl,
(c) heteroaryl-(C.sub.1 -C.sub.4)-alkyl,
(d) (C.sub.1 -C.sub.6)-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of:
--CON(R.sup.3).sub.2, -heteroaryl, --S(O).sub.n --R.sup.15, -tetrazol-5-yl, --CONHSO.sub.2 R.sup.15, --SO.sub.2 NH-heteroaryl, --SO.sub.2 NHCOR.sup.15, --PO(OR.sup.2).sub.2, --PO(OR.sup.3).sub.2, --SO.sub.2 NH--CN, --NR.sup.2 COOR.sup.15, --OH, --NH.sub.2, guanidino, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkylthio, (C.sub.1 -C.sub.4)-alkylamino, (C.sub.1 -C.sub.4)-dialkylamino, --COOR.sup.3, --CONHR.sup.3, --O--COR.sup.3, or aryl,
(e) --CO-aryl,
(f) (C.sub.3 -C.sub.7)-cycloalkyl,
(g) Cl, Br, I, F,
(h) --OR.sup.11,
(i) --SH,
(j) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(k) --COR.sup.3,
(l) --CO.sub.2 H,
(m) --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl,
(n) --SO.sub.3 H,
(o) --NR.sup.2 R.sup.15,
(p) --NR.sup.2 COR.sup.15,
(q) --NR.sup.2 COOR.sup.15,
(r) --SO.sub.2 NHR.sup.3,
(s) --SO.sub.2 NR.sup.2 R.sup.3,
(t) --NO.sub.2,
(u) --NHSO.sub.2 CF.sub.3,
(v) --CONR.sup.3 R.sup.3,
(w) --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(x) --COOR.sup.2,
(y) --SO.sub.3 H,
(z) --N(R.sup.2)SO.sub.2 R.sup.15,
(aa) --NR.sup.2 CONR.sup.3 R.sup.15,
(bb) --OC(.dbd.O)NR.sup.15 R.sup.3,
(cc) -aryl,
(dd) --NHSO.sub.2 CF.sub.3,
(ee) --SO.sub.2 NH-heteroaryl,
(ff) --SO.sub.2 NHCOR.sup.15,
(gg) --CONHSO.sub.2 R.sup.15,
(hh) --PO(OR.sup.2).sub.2,
(ii) -tetrazol-5-yl,
(jj) --CONH(tetrazol-5-yl), or
(kk) --SO.sub.2 NHCN;
and
R.sup.7 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with:
(i) -aryl,
(ii) --(C.sub.3 -C.sub.7)-cycloalkyl,
(iii) --NR.sup.3 R.sup.11,
(iv) -morpholin-4-yl,
(v) --OH,
(vi) --CO.sub.2 R.sup.3, or
(vii) --CON(R.sup.3).sub.2,
(c) aryl, unsubstituted as defined below or substituted with a substituent selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CONR.sup.3 R.sup.11,
iv) F, Cl, Br or I, or
v) --COOR.sup.3 ;
R.sup.8 is:
(a) H,
(b) (C.sub.1 -C.sub.4)-alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) --OH,
ii) --NR.sup.3 R.sup.11,
iii) --COOR.sup.3,
iv) --CONHR.sup.3, or
v) --CONR.sup.3 R.sup.11 ;
R.sup.9 and R.sup.10 are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with (C.sub.3 -C.sub.7)-cycloalkyl,
(c) (C.sub.2 -C.sub.6)-alkenyl,
(d) (C.sub.2 -C.sub.6)-alkynyl,
(e) Cl, Br, F, I,
(f) (C.sub.1 -C.sub.6)-alkoxy,
(g) when R.sup.9 and R.sup.10 are on adjacent carbons, they can be joined to form a phenyl ring,
(h) perfluoro-(C.sub.1 -C.sub.6)-alkyl,
(i) (C.sub.3 -C.sub.7)-cycloalkyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl,
(j) aryl,
(k) (C.sub.1 -C.sub.6)-alkyl--S(O).sub.n --(CH.sub.2).sub.n --,
(l) hydroxy-(C.sub.1 -C.sub.6)-alkyl or dihydroxy-(C.sub.1 -C.sub.6)-alkyl,
(m) --CF.sub.3,
(n) --CO.sub.2 R.sup.3,
(o) --OH,
(p) --NR.sup.3 R.sup.11,
(q) --[(C.sub.1 -C.sub.6)-alkyl]NR.sup.3 R.sup.11,
(r) --NO.sub.2,
(s) --(CH.sub.2).sub.n --SO.sub.2 --N(R.sup.3).sub.2,
(t) --NR.sup.3 CO--(C.sub.1 -C.sub.4)-alkyl, or
(u) --CON(R.sup.3).sub.2 ;
R.sup.11 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) allyl,
(d) (C.sub.3 -C.sub.6)-cycloalkyl,
(e) (C.sub.1 -C.sub.4)-acyl,
(f) benzyl, or
(g) phenyl;
and
R.sup.14a and R.sup.14b are independently:
(a) H,
(b) F, Cl, Br, or I,
(c) --NO.sub.2,
(d) --NH.sub.2,
(e) --NH(C.sub.1 -C.sub.4)-alkyl,
(f) --N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(g) --SO.sub.2 NHR.sup.3,
(h) --CF.sub.3,
(i) (C.sub.1 -C.sub.4)-alkyl,
(j) --OR.sup.3,
(k) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(l) --NHCO--(C.sub.1 -C.sub.4)-alkyl,
(m) --NHCO--O(C.sub.1 -C.sub.4)-alkyl,
(n) --CH.sub.2 O--(C.sub.1 -C.sub.4)-alkyl,
(o) --O--(CH.sub.2)m--OR.sup.3,
(p) --CONR.sup.3 R.sup.11, or
(q) --COOR.sup.3 and
m is 2, 3, or 4;
and
R.sup.12 and R.sup.13 are on adjacent carbon atoms are joined together to form a ring structure:
##STR19## A represents:
a) --Y--C(R.sup.4).dbd.C(R.sup.4)--,
b) --Y--C(R.sup.4).dbd.N--,
c) --Y--N.dbd.C(R.sup.4)--,
d) --Y--[C(R.sup.8)(R.sup.8)]s --Y--,
e) --Y--C(R.sup.8)(R.sup.8)--C(R.sup.8)(R.sup.8)--,
f) --C(R.sup.4).dbd.C(R.sup.4)--Y--,
g) --N.dbd.C(R.sup.4)--Y--,
h) --C(R.sup.8)(R.sup.8)--C(R.sup.8)(R.sup.8)--Y--, or
i) --C(R.sup.4).dbd.C(R.sup.4)--C(R.sup.4).dbd.C(R.sup.4)--;
and
s is 1 or 2;
and
Y is --O--, --S(O).sub.n -- and NR.sup.3 ;
and
X is:
(a) --O--,
(b) --S(O).sub.n --,
(c) --NR.sup.3 --
(d) --CH.sub.2 O--,
(e) --CH.sub.2 S(O).sub.n --,
(f) --CH.sub.2 NR.sup.3 --,
(g) --OCH.sub.2 --,
(h) --NR.sup.3 CH.sub.2 --,
(i) --S(O).sub.n CH.sub.2 --, or
(j) single bond;
and
R.sup.15 is:
(a) aryl, or
(b) (C.sub.1 -C.sub.4)-alkyl, is unsubstituted or substituted with:
i) NH.sub.2,
ii) NH[(C.sub.1 -C.sub.4)-alkyl],
iii) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
iv) CO.sub.2 H,
v) CO.sub.2 (C.sub.1 -C.sub.4)-alkyl,
vi) OH,
vii) SO.sub.3 H, or
viii) SO.sub.2 NH.sub.2 ;
and
Z is:
(a) --CO.sub.2 H,
(b) --CO.sub.2 R.sup.16,
(c) -tetrazol-5-yl,
(d) --CONH(tetrazol-5-yl)
(e) --CONHSO.sub.2 -aryl,
(f) --CONHSO.sub.2 -(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of:
--OH, --SH, --O(C.sub.1 -C.sub.4)-alkyl, --S--(C.sub.1 -C.sub.4)-alkyl, --CF.sub.3, Cl, Br, F, I, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, --NH.sub.2, --NH[(C.sub.1 -C.sub.4)-alkyl], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2 ;
and
(g) --CONHSO.sub.2 --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(h) --CONHSO.sub.2 -heteroaryl,
(i) --CONHSO.sub.2 NR.sup.3 R.sup.3,
(j) --SO.sub.2 NHCO-aryl,
(k) --SO.sub.2 NHCO-(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of:
--OH, --SH, --O(C.sub.1 -C.sub.4)-alkyl, --S--(C.sub.1 -C.sub.4)-alkyl, --CF.sub.3, Cl, Br, F, I, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, --NH.sub.2, --NH[(C.sub.1 -C.sub.4)-alkyl], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(l) --SO.sub.2 NHCO--(C.sub.1 -C.sub.4)-perfluoroalkyl,
(m) --SO.sub.2 NHCO-heteroaryl,
(n) --SO.sub.2 NHCONR.sup.3 R.sup.3,
(o) --PO(OH).sub.2,
(p) --PO(OR.sup.2).sub.2, or
(q) --PO(OH)(OR.sup.2);
and
R.sup.16 is:
(a) (C.sub.1 -C.sub.4)-alkyl,
(b) CHR.sup.17 --O--COR.sup.18,
(c) CH.sub.2 CH.sub.2 --N[(C.sub.1 -C.sub.2)-alkyl].sub.2,
(d) CH.sub.2 CH.sub.2 --N[CH.sub.2 CH.sub.2 ].sub.2 O,
(e) (CH.sub.2 CH.sub.2 O).sub.y --O--[(C.sub.1 -C.sub.4)-alkyl], wherein y is 1 or 2,
(f) aryl or CH.sub.2 -aryl, where aryl is unsubstituted as defined below or substituted with CO.sub.2 (C.sub.1 -C.sub.4)-alkyl, ##STR20## R.sup.17 and R.sup.18 independently are:
(C.sub.1 -C.sub.6)-alkyl or phenyl;
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) (C.sub.1 -C.sub.4)-alkyl,
iii) (C.sub.1 -C.sub.4)-alkoxy,
iv) NO.sub.2
v) CF.sub.3
vi) SO.sub.2 NR.sup.3 R.sup.3,
vii) (C.sub.1 -C.sub.4)-alkylthio,
viii) hydroxy,
ix) amino,
x) (C.sub.3 -C.sub.7)-cycloalkyl,
xi) (C.sub.3 -C.sub.10)-alkenyl;
and
heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety selected from the group consisting of thienyl, furanyl, thiazolyl, oxazolyl, pyridyl or pyrimidinyl, which is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
i) Cl, Br, I, or F,
ii) OH,
iii) SH,
iv) NO.sub.2,
v) (C.sub.1 -C.sub.4)-alkyl,
vi) (C.sub.2 -C.sub.4)-alkenyl,
vii) (C.sub.2 -C.sub.4)-alkynyl,
viii) (C.sub.1 -C.sub.4)-alkoxy, or
ix) CF.sub.3.

284 more elements

A compound of structural formula II ##STR24## or a pharmaceutically acceptable salt thereof, wherein:

R.sup.1 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.2 -C.sub.6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of:
i) (C.sub.3 -C.sub.7)-cycloalkyl,
ii) CF.sub.3,
iii) (C.sub.1 -C.sub.4)-alkylthio,
iv) (C.sub.1 -C.sub.4)-alkoxy,
(c) (C.sub.1 -C.sub.4)-perfluoroalkyl,
(d) --CONR.sup.3 R.sup.3, or
(e) --NR.sup.3 CO--O--(C.sub.1 -C.sub.4)-alkyl;
and
n is:
0, 1, or 2;
and
J is:
(a) --C(.dbd.M)--, or (b) J and L are connected together to form a 6-membered aromatic ring substituted with R.sup.5a, R.sup.5b, R.sup.6a and R.sup.6b ;
K is:
(a) --C(.dbd.M)--, or (b) K and L are connected together to form a 6-membered aromatic ring substituted with R.sup.5a, R.sup.5b, R.sup.6a and R.sup.6b, provided that one and only one of J and K is --C(.dbd.M)--;
and
one of a or b is a double bond in Formula I provided that when J is --C(.dbd.M)--, then b is a double bond and when K is --C(.dbd.M)--, then a is a double bond;
L is:
the point of attachment of the 6-membered fused aromatic ring;
and
M is:
O, S or NR.sup.11 ;
and
R.sup.2 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl;
and
R.sup.3 is:
(a) R.sup.2,
(b) --CH.sub.2 -aryl, or
(c) aryl;
and
R.sup.4 groups are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl or (C.sub.2 -C.sub.6)-alkenyl each of which is unsubstituted or substituted with one of the following substituents,
i) --OH,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
iv) --NR.sup.3 --(C.sub.1 -C.sub.4)-alkyl,
v) --NHR.sup.3,
vi) --COOR.sup.3,
vii) --CONHR.sup.3,
ix) --CONR.sup.3 R.sup.11, or
x) (C.sub.3 -C.sub.7)-cycloalkyl,
(c) (C.sub.3 -C.sub.7)-cycloalkyl,
(d) F, Cl, Br, I,
(e) CF.sub.3,
(f) --COOR.sup.3,
(g) --CONR.sup.3 R.sup.11,
(h) --NR.sup.3 R.sup.11,
(i) --NR.sup.3 CONR.sup.3 R.sup.11,
(j) --NR.sup.3 COOR.sup.11,
(k) --SO.sub.2 NR.sup.3 R.sup.11,
(l) --O--(C.sub.1 -C.sub.4)-alkyl,
(m) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl, or
(n) --NHSO.sub.2 R.sup.11 ;
and
R.sup.5a and R.sup.5b are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.2 -C.sub.6)-alkynyl,
(c) Cl, Br, I, F,
(d) CF.sub.3, or
(e) when R.sup.5a and R.sup.5b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring;
R.sup.6a and R.sup.6b are independently:
(a) H,
(b) aryl-(C.sub.1 -C.sub.4)-alkyl,
(c) heteroaryl-(C.sub.1 -C.sub.4)-alkyl,
(d) (C.sub.1 -C.sub.6)-alkyl, is unsubstituted or substituted with a substituent selected from the group consisting of:
--CON(R.sup.3).sub.2, -heteroaryl, --S(O).sub.n --R.sup.15, -tetrazol-5-yl, --CONHSO.sub.2 R.sup.15, --SO.sub.2 NH-heteroaryl, --SO.sub.2 NHCOR.sup.15, --PO(OR.sup.2).sub.2, --PO(OR.sup.3).sub.2, --SO.sub.2 NH--CN, --NR.sup.2 COOR.sup.15, --OH, --NH.sub.2, guanidino, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkylthio, (C.sub.1 -C.sub.4)-alkylamino, (C.sub.1 -C.sub.4)-dialkylamino, --COOR.sup.3, --CONHR.sup.3, --O--COR.sup.3, or aryl,
(e) --CO-aryl,
(f) (C.sub.3 -C.sub.7)-cycloalkyl,
(g) Cl, Br, I, F,
(h) --OR.sup.11,
(i) --SH,
(j) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(k) --COR.sup.3,
(l) --CO.sub.2 H,
(m) --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl,
(n) --SO.sub.3 H,
(o) --NR.sup.2 R.sup.15,
(p) --NR.sup.2 COR.sup.15,
(q) --NR.sup.2 COOR.sup.15,
(r) --SO.sub.2 NHR.sup.3,
(s) --SO.sub.2 NR.sup.2 R.sup.3,
(t) --NO.sub.2,
(u) --NHSO.sub.2 CF.sub.3,
(v) --CONR.sup.3 R.sup.3,
(w) --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(x) --COOR.sup.2,
(y) --SO.sub.3 H,
(z) --N(R.sup.2)SO.sub.2 R.sup.15,
(aa) --NR.sup.2 CONR.sup.3 R.sup.15,
(bb) --OC(.dbd.O)NR.sup.15 R.sup.3,
(cc) -aryl,
(dd) --NHSO.sub.2 CF.sub.3,
(ee) --SO.sub.2 NH-heteroaryl,
(ff) --SO.sub.2 NHCOR.sup.15,
(gg) --CONHSO.sub.2 R.sup.15,
(hh) --PO(OR.sup.2).sub.2,
(ii) -tetrazol-5-yl,
(jj) --CONH(tetrazol-5-yl), or
(kk) --SO.sub.2 NHCN;
and
R.sup.7 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with:
(i) -aryl,
(ii) --(C.sub.3 -C.sub.7)-cycloalkyl,
(iii) --NR.sup.3 R.sup.11,
(iv) -morpholin-4-yl,
(v) --OH,
(vi) --CO.sub.2 .sup.R.sup.3, or
(vii) --CON(R.sup.3).sub.2,
(c) aryl, unsubstituted as defined below or substituted with a substituent selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CONR.sup.3 R.sup.11,
iv) F, Cl, Br or I, or
v) --COOR.sup.3 ;
R.sup.9 and R.sup.10 are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with (C.sub.3 -C.sub.7)-cycloalkyl,
(c) Cl, Br, F, I,
(d) (C.sub.1 -C.sub.6)-alkoxy, or
(e) hydroxy-(C.sub.1 -C.sub.6)-alkyl or dihydroxy-(C.sub.1 -C.sub.6)-alkyl;
R.sup.14a and R.sup.14b are independently:
(a) H,
(b) F, Cl, Br, or I,
(c) --NO.sub.2,
(d) (C.sub.1 -C.sub.4)-alkyl,
(e) --OR.sup.3,
(f) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(g) --NHCO--(C.sub.1 -C.sub.4)-alkyl,
(h) --NHCO--O(C.sub.1 -C.sub.4)-alkyl,
(i) --O--(CH.sub.2)m--OR.sup.3,
(j) --CONR.sup.3 R.sup.11, or
(k) --COOR.sup.3 and
m is 2, 3, or 4;
and
R.sup.12 and R.sup.13 are on adjacent carbon atoms are joined together to form a ring structure:
##STR25## A represents:
a) --O--C(R.sup.4).dbd.C(R.sup.4)--,
b) --O--C(R.sup.4).dbd.N--,
c) --O--[C(R.sup.8)(R.sup.8)]s --O--,
d) --C(R.sup.4).dbd.C(R.sup.4)--O--,
e) --N.dbd.C(R.sup.4)--O--, or
f) --C(R.sup.4).dbd.C(R.sup.4)--C(R.sup.4).dbd.C(R.sup.4)--;
and
s is 1 or 2;
and
X is:
(a) --O--,
(b) --S(O).sub.n --, or
(c) --NR.sup.3 --;
and
R.sup.15 is:
(a) aryl, or
(b) (C.sub.1 -C.sub.4)-alkyl, is unsubstituted or substituted with:
i) NH.sub.2,
ii) NH[(C.sub.1 -C.sub.4)-alkyl],
iii) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
iv) CO.sub.2 H,
v) CO.sub.2 (C.sub.1 -C.sub.4)-alkyl,
vi) OH,
vii) SO.sub.3 H, or
viii) SO.sub.2 NH.sub.2 ;
and
Z is:
(a) --CO.sub.2 H,
(b) -tetrazol-5-yl,
(c) --CONH(tetrazol-5-yl),
(d) --CONHSO.sub.2 -aryl, or
(e) --CONHSO.sub.2 -heteroaryl;
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) (C.sub.1 -C.sub.4)-alkyl,
iii) (C.sub.1 -C.sub.4)-alkoxy,
iv) NO.sub.2
v) CF.sub.3
vi) SO.sub.2 NR.sup.3 R.sup.3,
vii) (C.sub.1 -C.sub.4)-alkylthio,
viii) hydroxy,
ix) amino,
x) (C.sub.3 -C.sub.7)-cycloalkyl,
xi) (C.sub.3 -C.sub.10)-alkenyl;
and
heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety selected from the group consisting of thienyl, furanyl, thiazolyl, oxazolyl, pyridyl or pyrimidinyl, which is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
i) Cl, Br, I, or F,
ii) OH,
iii) SH,
iv) NO.sub.2,
v) (C.sub.1 -C.sub.4)-alkyl,
vi) (C.sub.2 -C.sub.4)-alkenyl,
vii) (C.sub.2 -C.sub.4)-alkynyl,
viii) (C.sub.1 -C.sub.4)-alkoxy, or
ix) CF.sub.3.

196 more elements

A compound of structural formula III:

##STR27## or a pharmaceutically acceptable salt thereof, wherein:
R.sup.1 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.2 -C.sub.6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of:
i) (C.sub.3 -C.sub.7)-cycloalkyl,
ii) CF.sub.3,
iii) (C.sub.1 -C.sub.4)-alkylthio,
iv) (C.sub.1 -C.sub.4)-alkoxy,
(c) (C.sub.1 -C.sub.4)-perfluoroalkyl,
(d) --CONR.sup.3 R.sup.3, or
(e) --NR.sup.3 CO--O--(C.sub.1 -C.sub.4)-alkyl;
and
n is:
0, 1, or 2;
and
R.sup.2 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl;
and
R.sup.3 is:
(a) R.sup.2,
(b) --CH.sub.2 -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) (C.sub.1 -C.sub.4)-alkyl,
iii) (C.sub.1 -C.sub.4)-alkoxy,
iv) NO.sub.2
v) CF.sub.3
vi) SO.sub.2 NR.sup.3 R.sup.3,
vii) (C.sub.1 -C.sub.4)-alkylthio,
viii) hydroxy,
ix) amino,
x) (C.sub.3 -C.sub.7)-cycloalkyl,
xi) (C.sub.3 -C.sub.10)-alkenyl;
and
(c) aryl, wherein aryl is as defined in R.sup.3 (b);
and
R.sup.4 groups are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl or (C.sub.2 -C.sub.6)-alkenyl each of which is unsubstituted or substituted with one of the following substituents,
i) --OH,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
iv) --NR.sup.3 --(C.sub.1 -C.sub.4)-alkyl,
v) --NHR.sup.3,
vi) --COOR.sup.3,
vii) --CONHR.sup.3,
ix) --CONR.sup.3 R.sup.11, or
x) (C.sub.3 -C.sub.7)-cycloalkyl,
(c) (C.sub.3 -C.sub.7)-cycloalkyl,
(d) F, Cl, Br, I,
(e) CF.sub.3,
(f) --COOR.sup.3,
(g) --CONR.sup.3 R.sup.11,
(h) --NR.sup.3 R.sup.11,
(i) --NR.sup.3 CONR.sup.3 R.sup.11,
(j) --NR.sup.3 COOR.sup.11,
(k) --SO.sub.2 NR.sup.3 R.sup.11,
(l) --O--(C.sub.1 -C.sub.4)-alkyl,
(m) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl, or
(n) --NHSO.sub.2 R.sup.11 ;
and
R.sup.5a is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.2 -C.sub.6)-alkynyl,
(c) Cl, Br, I, F,
(d) CF.sub.3, or
(e) when R.sup.5a and R.sup.5b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring;
R.sup.6a is:
(a) H,
(b) aryl-(C.sub.1 -C.sub.4)-alkyl, wherein aryl is as defined in R.sup.3 (b),
(c) heteroaryl-(C.sub.1 -C.sub.4)-alkyl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety selected from the group consisting of thiophene, furan, thiazole, oxazole, pyridine or pyrimidine, which is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
i) Cl, Br, I, or F,
ii) OH,
iii) SH,
iv) NO.sub.2,
v) (C.sub.1 -C.sub.4)-alkyl,
vi) (C.sub.2 -C.sub.4)-alkenyl,
vii) (C.sub.2 -C.sub.4)-alkynyl,
viii) (C.sub.1 -C.sub.4)-alkoxy, or
ix) CF.sub.3,
(d) (C.sub.1 -C.sub.6)-alkyl, is unsubstituted or substituted with a substituent selected from the group consisting of:
--CON(R.sup.3).sub.2, -heteroaryl, wherein heteroaryl is as defined in R.sup.6a (c), --S(O).sub.n --R.sup.15, -tetrazol-5-yl, --CONHSO.sub.2 R.sup.15, --SO.sub.2 NH-heteroaryl, wherein heteroaryl is as defined in R.sup.6a (c), --SO.sub.2 NHCOR.sup.15, --PO(OR.sup.2).sub.2, --PO(OR.sup.3).sub.2, --SO.sub.2 NH--CN, --NR.sup.2 COOR.sup.15, --OH, --NH.sub.2, guanidino, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkylthio, (C.sub.1 -C.sub.4)-alkylamino, (C.sub.1 -C.sub.4)-dialkylamino, --COOR.sup.3, --CONHR.sup.3, --O--COR.sup.3, or aryl, wherein aryl is as defined in R.sup.3 (b),
(e) --CO-aryl, wherein aryl is as defined in R.sup.3 (b),
(f) (C.sub.3 -C.sub.7)-cycloalkyl,
(g) Cl, Br, I, F,
(h) --OR.sup.11,
(i) --SH,
(j) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(k) --COR.sup.3,
(l) --CO.sub.2 H,
(m) --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl,
(n) --SO.sub.3 H,
(o) --NR.sup.2 R.sup.15,
(p) --NR.sup.2 COR.sup.15,
(q) --NR.sup.2 COOR.sup.15,
(r) --SO.sub.2 NHR.sup.3,
(s) --SO.sub.2 NR.sup.2 R.sup.3,
(t) --NO.sub.2,
(u) --NHSO.sub.2 CF.sub.3,
(v) --CONR.sup.3 R.sup.3,
(w) --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(x) --COOR.sup.2,
(y) --SO.sub.3 H,
(z) --N(R.sup.2)SO.sub.2 R.sup.15,
(aa) --NR.sup.2 CONR.sup.3 R.sup.15,
(bb) --OC(.dbd.O)NR.sup.15 R.sup.3,
(cc) -aryl, wherein aryl is phenyl or naphthyl, which is unsubstituted or substituted as defined in R.sup.3 (b),
(dd) --NHSO.sub.2 CF.sub.3,
(ee) --SO.sub.2 NH-heteroaryl, wherein heteroaryl is unsubstituted or substituted as defined in R.sup.6a (c),
(ff) --SO.sub.2 NHCOR.sup.15,
(gg) --CONHSO.sub.2 R.sup.15,
(hh) --PO(OR.sup.2).sub.2,
(ii) -tetrazol-5-yl,
(jj) --CONH(tetrazol-5-yl), or
(kk) --SO.sub.2 NHCN;
and
R.sup.9 and R.sup.10 are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with (C.sub.3 -C.sub.7)-cycloalkyl,
(c) Cl, Br, F, I,
(d) (C.sub.1 -C.sub.6)-alkoxy, or
(e) hydroxy-(C.sub.1 -C.sub.6)-alkyl or dihydroxy-(C.sub.1 -C.sub.6)-alkyl;
R.sup.14a and R.sup.14b are independently:
(a) H,
(b) F, Cl, Br, or I,
(c) --NO.sub.2,
(d) (C.sub.1 -C.sub.4)-alkyl,
(e) --OR.sup.3,
(f) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(g) --NHCO--(C.sub.1 -C.sub.4)-alkyl,
(h) --NHCO--O(C.sub.1 -C.sub.4)-alkyl,
(i) --O--(CH.sub.2)m--OR.sup.3,
(j) --CONR.sup.3 R.sup.11, or
(k) --COOR.sup.3 ;
and
m is 2, 3, or 4;
and
R.sup.12 and R.sup.13 are on adjacent carbon atoms are joined together to form a ring structure:
##STR28## A represents:
a) --O--C(R.sup.4).dbd.C(R.sup.4)--,
b) --O--C(R.sup.4).dbd.N--,
c) --O--[C(R.sup.8)(R.sup.8)]s --O--,
d) --C(R.sup.4).dbd.C(R.sup.4)--O--,
e) --N.dbd.C(R.sup.4)--O--, or
f) --C(R.sup.4).dbd.C(R.sup.4)--C(R.sup.4).dbd.C(R.sup.4)--;
and
s is 1 or 2;
and
X is:
(a) --O--,
(b) --S(O).sub.n --, or
(c) --NR.sup.3 --;
and
R.sup.15 is:
(a) aryl, wherein aryl is as defined in R.sup.3 (b), or
(b) (C.sub.1 -C.sub.4)-alkyl, is unsubstituted or substituted with:
i) NH.sub.2,
ii) NH[(C.sub.1 -C.sub.4)-alkyl],
iii) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
iv) CO.sub.2 H,
v) CO.sub.2 (C.sub.1 -C.sub.4)-alkyl,
vi) OH,
vii) SO.sub.3 H, or
viii) SO.sub.2 NH.sub.2 ;
and
Z is:
(a) --CO.sub.2 H,
(b) -tetrazol-5-yl,
(c) --CONH(tetrazol-5-yl),
(d) --CONHSO.sub.2 -phenyl or --CONHSO.sub.2 -naphthyl, wherein phenyl or naphthyl is unsubstituted or substituted as defined in R.sup.3 (b), or
(e) --CONHSO.sub.2 -heteroaryl, wherein heteroaryl is as defined in R.sup.6a (c).

168 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of structural formula I ##STR18## or a pharmaceutically acceptable salt thereof, wherein:

R.sup.1 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.2 -C.sub.6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of:
i) aryl as defined below,
ii) (C.sub.3 -C.sub.7)-cycloalkyl,
iii) Cl, Br, I, F,
iv) OH,
v) NH.sub.2,
vi) NH(C.sub.1 -C.sub.4)-alkyl,
vii) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
viii) NHSO.sub.2 R.sup.2,
ix) CF.sub.3,
x) COOR.sup.2, or
xi) SO.sub.2 NHR.sup.3 ;
and
(c) aryl,
(d) heteroaryl,
(e) (C.sub.1 -C.sub.4)-perfluoroalkyl,
(f) --O--(C.sub.1 -C.sub.6)-alkyl,
(g) --S(O).sub.n --(C.sub.1 -C.sub.9)-alkyl,
(h) --CONR.sup.3 R.sup.3, or
(i) --NR.sup.3 CO--O--(C.sub.1 -C.sub.4)-alkyl;
and
n is:
0 to 2;
and
J is:
(a)--C(.dbd.M)--, (b) J and L are connected together to form a 6-membered aromatic ring substituted with R.sup.5a, R.sup.5b, R.sup.6a and R.sup.6b or (c) J and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom, substituted with R.sup.5a, R.sup.5b and R.sup.6b ;
and
K is:
(a)--C(.dbd.M)--, (b) K and L are connected together to form a 6-membered aromatic ring substituted with R.sup.5a, R.sup.5b, R.sup.6a and R.sup.6b, or (c) K and L are connected together to form a 6-membered aromatic ring containing one nitrogen atom, substituted on the carbon atoms with R.sup.5a, R.sup.5b and R.sup.6b ;
and
one of a or b is a double bond in Formula I provided that when J is --C(.dbd.M)-- then b is a double bond and when K is --C(.dbd.M)-- then a is a double bond;
L is the point of attachment of the 6-membered fused aromatic ring optionally containing one nitrogen atom;
and
M is:
O, S or NR.sup.11 ;
and
R.sup.2 is:
(a) H, or
(b) (C.sub.1 -C.sub.6)-alkyl;
and
R.sup.3 is:
(a) R.sup.2,
(b) CH.sub.2 -aryl,
(c) aryl, or
(d) (C.sub.3 -C.sub.7)-cycloalkyl;
and
R.sup.4 groups are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl or (C.sub.2 -C.sub.6)-alkenyl each of which is unsubstituted or substituted with one of the following substituents,
i) --OH,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
iv) --NR.sup.3 --(C.sub.1 -C.sub.4)-alkyl,
v) --NHR.sup.3,
vi) --COOR.sup.3,
vii) --CONHR.sup.3,
ix) --CONR.sup.3 R.sup.11, or
x) (C.sub.3 -C.sub.7)-cycloalkyl,
(c) (C.sub.3 -C.sub.7)-cycloalkyl,
(d) F, Cl, Br, I,
(e) CF.sub.3,
(f) --COOR.sup.3,
(g) --CONR.sup.3 R.sup.11,
(h) --NR.sup.3 R.sup.11,
(i) --NR.sup.3 CONR.sup.3 R.sup.11,
(j) --NR.sup.3 COOR.sup.11,
(k) --SO.sub.2 NR.sup.3 R.sup.11,
(l) --O--(C.sub.1 -C.sub.4)-alkyl,
(m) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl, or
(n) --NHSO.sub.2 R.sup.11 ;
and
R.sup.5a and R.sup.5b are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or (C.sub.2 -C.sub.6)-alkynyl,
(c) Cl, Br, I, F,
(d) CF.sub.3, or
(e) when R.sup.5a and R.sup.5b are bonded to adjacent carbon atoms, they can be joined to form a phenyl ring;
R.sup.6a and R.sup.6b are independently:
(a) H,
(b) aryl-(C.sub.1 -C.sub.4)-alkyl,
(c) heteroaryl-(C.sub.1 -C.sub.4)-alkyl,
(d) (C.sub.1 -C.sub.6)-alkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of:
--CON(R.sup.3).sub.2, -heteroaryl, --S(O).sub.n --R.sup.15, -tetrazol-5-yl, --CONHSO.sub.2 R.sup.15, --SO.sub.2 NH-heteroaryl, --SO.sub.2 NHCOR.sup.15, --PO(OR.sup.2).sub.2, --PO(OR.sup.3).sub.2, --SO.sub.2 NH--CN, --NR.sup.2 COOR.sup.15, --OH, --NH.sub.2, guanidino, (C.sub.1 -C.sub.4)-alkoxy, (C.sub.1 -C.sub.4)-alkylthio, (C.sub.1 -C.sub.4)-alkylamino, (C.sub.1 -C.sub.4)-dialkylamino, --COOR.sup.3, --CONHR.sup.3, --O--COR.sup.3, or aryl,
(e) --CO-aryl,
(f) (C.sub.3 -C.sub.7)-cycloalkyl,
(g) Cl, Br, I, F,
(h) --OR.sup.11,
(i) --SH,
(j) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(k) --COR.sup.3,
(l) --CO.sub.2 H,
(m) --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl,
(n) --SO.sub.3 H,
(o) --NR.sup.2 R.sup.15,
(p) --NR.sup.2 COR.sup.15,
(q) --NR.sup.2 COOR.sup.15,
(r) --SO.sub.2 NHR.sup.3,
(s) --SO.sub.2 NR.sup.2 R.sup.3,
(t) --NO.sub.2,
(u) --NHSO.sub.2 CF.sub.3,
(v) --CONR.sup.3 R.sup.3,
(w) --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(x) --COOR.sup.2,
(y) --SO.sub.3 H,
(z) --N(R.sup.2)SO.sub.2 R.sup.15,
(aa) --NR.sup.2 CONR.sup.3 R.sup.15,
(bb) --OC(.dbd.O)NR.sup.15 R.sup.3,
(cc) -aryl,
(dd) --NHSO.sub.2 CF.sub.3,
(ee) --SO.sub.2 NH-heteroaryl,
(ff) --SO.sub.2 NHCOR.sup.15,
(gg) --CONHSO.sub.2 R.sup.15,
(hh) --PO(OR.sup.2).sub.2,
(ii) -tetrazol-5-yl,
(jj) --CONH(tetrazol-5-yl), or
(kk) --SO.sub.2 NHCN;
and
R.sup.7 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with:
(i) -aryl,
(ii) --(C.sub.3 -C.sub.7)-cycloalkyl,
(iii) --NR.sup.3 R.sup.11,
(iv) -morpholin-4-yl,
(v) --OH,
(vi) --CO.sub.2 R.sup.3, or
(vii) --CON(R.sup.3).sub.2,
(c) aryl, unsubstituted as defined below or substituted with a substituent selected from the group consisting of:
i) (C.sub.1 -C.sub.4)-alkyl,
ii) --O--(C.sub.1 -C.sub.4)-alkyl,
iii) --CONR.sup.3 R.sup.11,
iv) F, Cl, Br or I, or
v) --COOR.sup.3 ;
R.sup.8 is:
(a) H,
(b) (C.sub.1 -C.sub.4)-alkyl, wherein alkyl is unsubstituted or substituted with one or two substituents selected from the group consisting of:
i) --OH,
ii) --NR.sup.3 R.sup.11,
iii) --COOR.sup.3,
iv) --CONHR.sup.3, or
v) --CONR.sup.3 R.sup.11 ;
R.sup.9 and R.sup.10 are independently:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl, unsubstituted or substituted with (C.sub.3 -C.sub.7)-cycloalkyl,
(c) (C.sub.2 -C.sub.6)-alkenyl,
(d) (C.sub.2 -C.sub.6)-alkynyl,
(e) Cl, Br, F, I,
(f) (C.sub.1 -C.sub.6)-alkoxy,
(g) when R.sup.9 and R.sup.10 are on adjacent carbons, they can be joined to form a phenyl ring,
(h) perfluoro-(C.sub.1 -C.sub.6)-alkyl,
(i) (C.sub.3 -C.sub.7)-cycloalkyl, unsubstituted or substituted with (C.sub.1 -C.sub.6)-alkyl,
(j) aryl,
(k) (C.sub.1 -C.sub.6)-alkyl--S(O).sub.n --(CH.sub.2).sub.n --,
(l) hydroxy-(C.sub.1 -C.sub.6)-alkyl or dihydroxy-(C.sub.1 -C.sub.6)-alkyl,
(m) --CF.sub.3,
(n) --CO.sub.2 R.sup.3,
(o) --OH,
(p) --NR.sup.3 R.sup.11,
(q) --[(C.sub.1 -C.sub.6)-alkyl]NR.sup.3 R.sup.11,
(r) --NO.sub.2,
(s) --(CH.sub.2).sub.n --SO.sub.2 --N(R.sup.3).sub.2,
(t) --NR.sup.3 CO--(C.sub.1 -C.sub.4)-alkyl, or
(u) --CON(R.sup.3).sub.2 ;
R.sup.11 is:
(a) H,
(b) (C.sub.1 -C.sub.6)-alkyl,
(c) allyl,
(d) (C.sub.3 -C.sub.6)-cycloalkyl,
(e) (C.sub.1 -C.sub.4)-acyl,
(f) benzyl, or
(g) phenyl;
and
R.sup.14a and R.sup.14b are independently:
(a) H,
(b) F, Cl, Br, or I,
(c) --NO.sub.2,
(d) --NH.sub.2,
(e) --NH(C.sub.1 -C.sub.4)-alkyl,
(f) --N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(g) --SO.sub.2 NHR.sup.3,
(h) --CF.sub.3,
(i) (C.sub.1 -C.sub.4)-alkyl,
(j) --OR.sup.3,
(k) --S(O).sub.n --(C.sub.1 -C.sub.4)-alkyl,
(l) --NHCO--(C.sub.1 -C.sub.4)-alkyl,
(m) --NHCO--O(C.sub.1 -C.sub.4)-alkyl,
(n) --CH.sub.2 O--(C.sub.1 -C.sub.4)-alkyl,
(o) --O--(CH.sub.2)m--OR.sup.3,
(p) --CONR.sup.3 R.sup.11, or
(q) --COOR.sup.3 and
m is 2, 3, or 4;
and
R.sup.12 and R.sup.13 are on adjacent carbon atoms are joined together to form a ring structure:
##STR19## A represents:
a) --Y--C(R.sup.4).dbd.C(R.sup.4)--,
b) --Y--C(R.sup.4).dbd.N--,
c) --Y--N.dbd.C(R.sup.4)--,
d) --Y--[C(R.sup.8)(R.sup.8)]s --Y--,
e) --Y--C(R.sup.8)(R.sup.8)--C(R.sup.8)(R.sup.8)--,
f) --C(R.sup.4).dbd.C(R.sup.4)--Y--,
g) --N.dbd.C(R.sup.4)--Y--,
h) --C(R.sup.8)(R.sup.8)--C(R.sup.8)(R.sup.8)--Y--, or
i) --C(R.sup.4).dbd.C(R.sup.4)--C(R.sup.4).dbd.C(R.sup.4)--;
and
s is 1 or 2;
and
Y is --O--, --S(O).sub.n -- and NR.sup.3 ;
and
X is:
(a) --O--,
(b) --S(O).sub.n --,
(c) --NR.sup.3 --
(d) --CH.sub.2 O--,
(e) --CH.sub.2 S(O).sub.n --,
(f) --CH.sub.2 NR.sup.3 --,
(g) --OCH.sub.2 --,
(h) --NR.sup.3 CH.sub.2 --,
(i) --S(O).sub.n CH.sub.2 --, or
(j) single bond;
and
R.sup.15 is:
(a) aryl, or
(b) (C.sub.1 -C.sub.4)-alkyl, is unsubstituted or substituted with:
i) NH.sub.2,
ii) NH[(C.sub.1 -C.sub.4)-alkyl],
iii) N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
iv) CO.sub.2 H,
v) CO.sub.2 (C.sub.1 -C.sub.4)-alkyl,
vi) OH,
vii) SO.sub.3 H, or
viii) SO.sub.2 NH.sub.2 ;
and
Z is:
(a) --CO.sub.2 H,
(b) --CO.sub.2 R.sup.16,
(c) -tetrazol-5-yl,
(d) --CONH(tetrazol-5-yl)
(e) --CONHSO.sub.2 -aryl,
(f) --CONHSO.sub.2 -(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of:
--OH, --SH, --O(C.sub.1 -C.sub.4)-alkyl, --S--(C.sub.1 -C.sub.4)-alkyl, --CF.sub.3, Cl, Br, F, I, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, --NH.sub.2, --NH[(C.sub.1 -C.sub.4)-alkyl], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2 ;
and
(g) --CONHSO.sub.2 --(C.sub.1 -C.sub.4)-perfluoroalkyl,
(h) --CONHSO.sub.2 -heteroaryl,
(i) --CONHSO.sub.2 NR.sup.3 R.sup.3,
(j) --SO.sub.2 NHCO-aryl,
(k) --SO.sub.2 NHCO-(C.sub.1 -C.sub.8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of:
--OH, --SH, --O(C.sub.1 -C.sub.4)-alkyl, --S--(C.sub.1 -C.sub.4)-alkyl, --CF.sub.3, Cl, Br, F, I, --NO.sub.2, --CO.sub.2 H, --CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl, --NH.sub.2, --NH[(C.sub.1 -C.sub.4)-alkyl], --N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
(l) --SO.sub.2 NHCO--(C.sub.1 -C.sub.4)-perfluoroalkyl,
(m) --SO.sub.2 NHCO-heteroaryl,
(n) --SO.sub.2 NHCONR.sup.3 R.sup.3,
(o) --PO(OH).sub.2,
(p) --PO(OR.sup.2).sub.2, or
(q) --PO(OH)(OR.sup.2);
and
R.sup.16 is:
(a) (C.sub.1 -C.sub.4)-alkyl,
(b) CHR.sup.17 --O--COR.sup.18,
(c) CH.sub.2 CH.sub.2 --N[(C.sub.1 -C.sub.2)-alkyl].sub.2,
(d) CH.sub.2 CH.sub.2 --N[CH.sub.2 CH.sub.2 ].sub.2 O,
(e) (CH.sub.2 CH.sub.2 O).sub.y --O--[(C.sub.1 -C.sub.4)-alkyl], wherein y is 1 or 2,
(f) aryl or CH.sub.2 -aryl, where aryl is unsubstituted as defined below or substituted with CO.sub.2 (C.sub.1 -C.sub.4)-alkyl, ##STR20## R.sup.17 and R.sup.18 independently are:
(C.sub.1 -C.sub.6)-alkyl or phenyl;
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) (C.sub.1 -C.sub.4)-alkyl,
iii) (C.sub.1 -C.sub.4)-alkoxy,
iv) NO.sub.2
v) CF.sub.3
vi) SO.sub.2 NR.sup.3 R.sup.3,
vii) (C.sub.1 -C.sub.4)-alkylthio,
viii) hydroxy,
ix) amino,
x) (C.sub.3 -C.sub.7)-cycloalkyl,
xi) (C.sub.3 -C.sub.10)-alkenyl;
and
heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety selected from the group consisting of thienyl, furanyl, thiazolyl, oxazolyl, pyridyl or pyrimidinyl, which is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
i) Cl, Br, I, or F,
ii) OH,
iii) SH,
iv) NO.sub.2,
v) (C.sub.1 -C.sub.4)-alkyl,
vi) (C.sub.2 -C.sub.4)-alkenyl,
vii) (C.sub.2 -C.sub.4)-alkynyl,
viii) (C.sub.1 -C.sub.4)-alkoxy, or
ix) CF.sub.3.

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