U.S. patent application number 10/215292 was filed with the patent office on 2003-01-30 for substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade.
This patent application is currently assigned to Pharmacia Corporation. Invention is credited to Jones, Darin E., Rueppel, Melvin L., South, Michael S..
Application Number | 20030023086 10/215292 |
Document ID | / |
Family ID | 24295129 |
Filed Date | 2003-01-30 |
United States Patent
Application |
20030023086 |
Kind Code |
A1 |
South, Michael S. ; et
al. |
January 30, 2003 |
Substituted polycyclic aryl and heteroaryl uracils useful for
selective inhibition of the coagulation cascade
Abstract
The invention relates to substituted polycyclic aryl and
heteroaryl uracil compounds useful as inhibitors of serine
proteases of the coagulation cascade and compounds, compositions
and methods for anticoagulant therapy for the treatment and
prevention of a variety of thrombotic conditions including coronary
artery and cerebrovascular diseases.
Inventors: |
South, Michael S.; (St.
Louis, MO) ; Jones, Darin E.; (Ballwin, MO) ;
Rueppel, Melvin L.; (St. Louis, MO) |
Correspondence
Address: |
SENNIGER POWERS LEAVITT AND ROEDEL
ONE METROPOLITAN SQUARE
16TH FLOOR
ST LOUIS
MO
63102
US
|
Assignee: |
Pharmacia Corporation
|
Family ID: |
24295129 |
Appl. No.: |
10/215292 |
Filed: |
August 8, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10215292 |
Aug 8, 2002 |
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09574207 |
May 18, 2000 |
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6458952 |
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60134957 |
May 19, 1999 |
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Current U.S.
Class: |
544/182 |
Current CPC
Class: |
C07D 239/545 20130101;
C07D 253/075 20130101; A61P 7/02 20180101; C07D 417/12
20130101 |
Class at
Publication: |
544/182 |
International
Class: |
C07D 49/02; C07D
45/02 |
Claims
What we claim is:
1. A compound having the Formula: 46or a pharmaceutically
acceptable salt thereof, wherein; B is formula (V): 47 wherein
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are independently
selected from the group consisting of C, N, O, S and a covalent
bond with the provisos that no more than one is a covalent bond, no
more than one of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 is
O, no more than one of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and
K.sup.1 is S, one of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1
must be a covalent bond when two of D.sup.1, D.sup.2, J.sup.1,
J.sup.2 and K.sup.1 are O and S, and no more than four of D.sup.1,
D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are N; R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36 are independently selected from the group
consisting of hydrido, acetamido, haloacetamido, amidino,
guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy,
alkoxyalkyl, haloalkoxylalkyl, hydroxy, amino, alkoxyamino, nitro,
lower alkylamino, alkylthio, alkylthioalkyl, alkylsulfinyl,
alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido,
alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo,
haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl,
aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy,
carboxamido, carboxamidoalkyl, and cyano; R.sup.16, R.sup.19,
R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; B is optionally selected from the group
consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl,
C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each
member of group B may be optionally substituted at any carbon up to
and including 6 atoms from the point of attachment of B to A with
one or more of the group consisting of R.sup.32, R.sup.33,
R.sup.34, R.sup.35, and R.sup.36; B is optionally selected from the
group consisting of C3-C12 cycloalkyl and C4-C9 saturated
heterocyclyl, wherein each ring carbon is optionally substituted
with R.sup.33, a ring carbon other than the ring carbon at the
point of attachment of B to A is optionally substituted with oxo
provided that no more than one ring carbon is substituted by oxo at
the same time, ring carbons and a nitrogen adjacent to the carbon
atom at the point of attachment are optionally substituted with
R.sup.9 or R.sup.13, a ring carbon or nitrogen atom adjacent to the
R.sup.9 position and two atoms from the point of attachment is
optionally substituted with R.sup.10, a ring carbon or nitrogen
adjacent to the R.sup.13 position and two atoms from the point of
attachment is optionally substituted with R.sup.12, a ring carbon
or nitrogen three atoms from the point of attachment and adjacent
to the R.sup.10 position is optionally substituted with R.sup.11, a
ring carbon or nitrogen three atoms from the point of attachment
and adjacent to the R.sup.12 position is optionally substituted
with R.sup.33, and a ring carbon or nitrogen four atoms from the
point of attachment and adjacent to the R.sup.11 and R.sup.33
positions is optionally substituted with R.sup.34; A is selected
from the group consisting of single covalent bond,
(W.sup.7).sub.rr--(CH(R.sup.15)).sub.pa and
(CH(R.sup.15)).sub.pa--- (W.sup.7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
6, and W.sup.7 is selected from the group consisting of O, S, C(O),
(R.sup.7)NC(O), (R.sup.7)NC(S), and N(R.sup.7) with the proviso
that no more than one of the group consisting of rr and pa is 0 at
the same time; R.sup.7 is selected from the group consisting of
hydrido, hydroxy, and alkyl; R.sup.15 is selected from the group
consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl; .PSI.
is selected from the group consisting of NH and NOH; M is selected
from the group consisting of N and R.sup.1--C; R.sup.1 is selected
from the group consisting of hydrido, alkyl, alkenyl, cyano, halo,
haloalkyl, haloalkoxy, haloalkylthio, amino, aminoalkyl,
alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl,
alkoxyamino, thiol, and alkylthio; R.sup.2 is Z.sup.0--Q; Z.sup.0
is selected from the group consisting of covalent single bond,
(CR.sup.41R.sup.42).sub.q wherein q is an integer selected from 1
through 3, (CH(R.sup.41)).sub.g--W.sup.0--(- CH(R.sup.42)).sub.p
wherein g and p are integers independently selected from 0 through
3 and W.sup.0 is selected from the group consisting of O, S, C(O),
S(O), N(R.sup.41), and ON(R.sup.41), and (CH(R.sup.41)).sub.e--W-
.sup.22--(CH(R.sup.42).sub.h wherein e and h are integers
independently selected from 0 through 1 and W.sup.22 is selected
from the group consisting of CR.sup.41.dbd.CR.sup.42,
1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl,
1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,
2,6-morpholinyl, 3,4-morpholinyl, 3,5 morpholinyl, 1,2-piperazinyl,
1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl,
1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl,
3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,
2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl,
3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso
that Z.sup.0 is directly bonded to the pyrazinone ring; R.sup.41
and R.sup.42 are independently selected from the group consisting
of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl; Q is
selected from the group consisting of hydrido, with the proviso
that Z.sup.0 is other than a covalent single bond, and the formula
(II): 48 wherein D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, no more than one of D.sup.1, D.sup.2, J.sup.1,
J.sup.2 and K.sup.1 is O, no more than one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 is S, one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 must be a covalent bond when two of
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are O and S, and no
more than four of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1
are N, with the proviso that R.sup.9, R.sup.10, R.sup.11, R.sup.12,
and R.sup.13 are each independently selected to maintain the
tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, and the divalent nature of oxygen; K is
(CR.sup.4aR.sup.4b).sub.n wherein n is an integer selected from 1
through 2; R.sup.4a and R.sup.4b are independently selected from
the group consisting of halo, hydrido, hydroxyalkyl, alkyl,
alkoxyalkyl, alkylthioalkyl, and haloalkyl; E.sup.0 is E.sup.1,
when K is (CR.sup.4aR.sup.4b).sub.n wherein E.sup.1 is selected
from the group consisting of a covalent single bond, C(O), C(S),
C(O)N(R.sup.7), (R.sup.7)NC(O), S(O).sub.2, (R.sup.7)NS(O).sub.2,
and S(O).sub.2N(R.sup.7); Y.sup.0 is formula (IV): 49 wherein
D.sup.5, D.sup.6, J.sup.5and J.sup.6 are independently selected
from the group consisting of C, N, O, S and a covalent bond with
the provisos that no more than one is a covalent bond, K.sup.2 is
C, no more than one of D.sup.5, D.sup.6, J.sup.5and J.sup.6 is O,
no more than one of D.sup.5, D.sup.6, J.sup.5and J.sup.6 is S, one
of D.sup.5, D.sup.6, J.sup.5and J.sup.6 must be a covalent bond
when two of D.sup.5, D.sup.6, J.sup.5and J.sup.6 are O and S, and
no more than four of D.sup.5, D.sup.6, J.sup.5and J.sup.6 are N;
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino,
lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, alkylamino, haloalkoxyalkyl, carboalkoxy,
and cyano; Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, aminoalkylenyl, Q.sup.be wherein Q.sup.be is
hydrido, N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), and
C(NR.sup.25)NR.sup.23R.- sup.24, with the provisos that no more
than one of R.sup.20 and R.sup.21 is hydroxy, amino, alkylamino, or
dialkylamino at the same time and that no more than one of R.sup.23
and R.sup.24 is hydroxy, amino, alkylamino, or dialkylamino at the
same time; R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are independently selected from the group consisting of
hydrido, alkyl, hydroxy, aminoalkylenyl, amino, dialkylamino,
alkylamino, and hydroxyalkyl; Q.sup.s is selected from the group
consisting of a single covalent bond, (CR.sup.37R.sup.38).sub.b
wherein b is an integer selected from 1 through 4, and
(CH(R.sup.14)).sub.c--W.sup.1--(CH(R.sup.15)).sub.d wherein c and d
are integers independently selected from 1 through 3 and W.sup.1 is
selected from the group consisting of C(O)N(R.sup.14),
(R.sup.14)NC(O), S(O), S(O).sub.2, S(O).sub.2N(R.sup.14),
N(R.sup.14)S(O).sub.2, and N(R.sup.14), with the provisos that
R.sup.14 is selected from other than halo when directly bonded to N
and that (CR.sup.37R.sup.38).sub.b, and (CH(R.sup.14)).sub.c are
bonded to E.sup.0; R.sup.14 is selected from the group consisting
of hydrido, halo, alkyl, and haloalkyl; R.sup.37 and R.sup.38 are
independently selected from the group consisting of hydrido, alkyl,
and haloalkyl; R.sup.38 is optionally selected from the group
consisting of aroyl and heteroaroyl; Y.sup.0 is optionally
Q.sup.b--Q.sup.ss wherein Q.sup.ss is
(CH(R.sup.14)).sub.e--W.sup.2--(CH(- R.sup.15)).sub.h, wherein e
and h are integers independently selected from 1 through 2 and
W.sup.2 is CR.sup.4a.dbd.CR.sup.4b with the proviso that
(CH(R.sup.14)).sub.e is bonded to E.sup.0; Y.sup.0 is optionally
selected from the group consisting of Q.sup.b--Q.sup.ssss and
Q.sup.b--Q.sup.ssssr wherein Q.sup.ssss is
(CH(R.sup.38)).sub.r--W.sup.5 and Q.sup.ssssr is
(CH(R.sup.38)).sub.r--W.sup.6, r is an integer selected from 1
through 2, and W.sup.5 and W.sup.6 are independently selected from
the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl,
1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl,
3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl,
2,4benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl,
2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl,
3,6-benzofuranyl, 3,7-benzofuranyl, 2,4benzothiophenyl,
2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl,
3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl,
3,7-benzothiophenyl, 2,7-imidazo(1,2-a)pyridinyl,
3,4-imidazo(1,2-a)pyrid- inyl, 3,5imidazo(1,2-a)pyridinyl,
3,6-imidazo(1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl,
2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl,
3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl,
1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl,
2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl,
3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4benzoxazolyl,
2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl,
3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl,
3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl,
1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl,
2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl,
2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl,
3,4quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl,
3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl,
4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl,
1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl,
3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl,
3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl,
4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl,
3,4-cinnolinyl, 3,5cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl,
3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and
4,8-cinnolinyl, and each carbon and hyrido containing nitrogen
member of the ring of the W.sup.5 and of the ring of the W.sup.6,
other than the points of attachment of W.sup.5 and W.sup.6, is
optionally substituted with one or more of the group consisting of
R.sup.9, R.sup.10, R.sup.11, and R.sup.12, with the provisos that
Q.sup.b is bonded to lowest number substituent position of each
W.sup.5, Q.sup.b is bonded to highest number substituent position
of each W.sup.6, and (CH(R.sup.38)).sub.r is bonded to E.sup.0.
2. The compound as recited in claim 1 having the Formula: 50or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of aryl and heteroaryl wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.32, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.36, a
carbon adjacent to R.sup.32 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.33, a carbon
adjacent to R.sup.36 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.35, and any carbon
adjacent to both R.sup.33 and R.sup.35 is substituted by R.sup.34;
R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkylenedioxy,
haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino,
haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl,
cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl,
haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b; B is optionally selected from the
group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8
alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl,
wherein each member of group B is optionally substituted at any
carbon up to and including 6 atoms from the point of attachment of
B to A with one or more of the group consisting of R.sup.32,
R.sup.33, R.sup.34, R.sup.35, and R.sup.36; B is optionally
selected from the group consisting of C3-C12 cycloalkyl and C4-C9
saturated heterocyclyl, wherein each ring carbon is optionally
substituted with R.sup.33, a ring carbon other than the ring carbon
at the point of attachment of B to A is optionally substituted with
oxo provided that no more than one ring carbon is substituted by
oxo at the same time, ring carbons and a nitrogen adjacent to the
carbon atom at the point of attachment are optionally substituted
with R.sup.9 or R.sup.13, a ring carbon or nitrogen atom adjacent
to the R.sup.9 position and two atoms from the point of attachment
is optionally substituted with R.sup.10, a ring carbon or nitrogen
adjacent to the R.sup.13 position and two atoms from the point of
attachment is optionally substituted with R.sup.12, a ring carbon
or nitrogen three atoms from the point of attachment and adjacent
to the R.sup.10 position is optionally substituted with R.sup.11, a
ring carbon or nitrogen three atoms from the point of attachment
and adjacent to the R.sup.12 position is optionally substituted
with R.sup.33, and a ring carbon or nitrogen four atoms from the
point of attachment and adjacent to the R.sup.11 and R.sup.33
positions is optionally substituted with R.sup.34; R.sup.9,
R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino,
guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino,
lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and
cyano; R.sup.9, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are
optionally selected from the group consisting of heteroaryl and
heterocyclyl with the proviso that R.sup.9, R.sup.10, R.sup.11,
R.sup.12, and R.sup.13 are substitutents for other than B; A is
selected from the group consisting of single covalent bond and
(CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
3, and W.sup.7 is selected from the group consisting of O, S, C(O),
(R.sup.7)NC(O), (R.sup.7)NC(S), and N(R.sup.7); R.sup.7 is selected
from the group consisting of hydrido, hydroxy and alkyl; R.sup.15
is selected from the group consisting of hydrido, hydroxy, halo,
alkyl, and haloalkyl; M is selected from the group consisting of N
and R.sup.1--C; R.sup.1 is selected from the group consisting of
hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy, amino,
aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino, alkoxy,
hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R.sup.2 is
Z.sup.0--Q; Z.sup.0 is selected from the group consisting of
covalent single bond and (CR.sup.41R.sup.42).sub.q wherein q is an
integer selected from 1 through 2,
(CH(R.sup.41)).sub.g--W.sup.0--(CH(R.s- up.42)).sub.p wherein g and
p are integers independently selected from 0 through 3 and W.sup.0
is selected from the group consisting of O, S, and N(R.sup.41), and
(CH(R.sup.41)).sub.e--W.sup.22--(CH(R.sup.42)).sub.h wherein e and
h are integers independently selected from 0 through 1 and W.sup.22
is selected from the group consisting of CR.sup.41 .dbd.CR.sup.42,
1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl,
1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4 morpholinyl,
2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl,
1,3-piperazinyl, 2,3-piperazinyl, 2,6piperazinyl, 1,2-piperidinyl,
1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6piperidinyl,
3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,
2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl,
3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5Stetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso
that Z.sup.0 is directly bonded to the pyrazinone ring; R.sup.41
and R.sup.42 are independently selected from the group consisting
of hydrido, hydroxy, and amino; Q is selected from the group
consisting of hydrido, with the proviso that Z.sup.0 is other than
a covalent single bond, aryl, and heteroaryl, wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.9, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.13, a
carbon adjacent to R.sup.9 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.10, a carbon
adjacent to R.sup.13 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.12, and any carbon
adjacent to both R.sup.10 and R.sup.12 is optionally substituted by
R.sup.11; K is CHR.sup.4a wherein R.sup.4a is selected from the
group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl,
alkylthioalkyl, and haloalkyl; E.sup.0 is selected from the group
consisting of a covalent single bond, C(O)N(H), (H)NC(O),
(R.sup.7)NS(O).sub.2, and S(O).sub.2N(R.sup.7); Y.sup.0 is formula
(IV): 51 wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one can be a
covalent bond, K.sup.2 is C, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 can be O, no more than one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 can be S, one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 must be a covalent bond when two of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are O and S, and no more than four of
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 can be N, with the provisos
that R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are each
independently selected to maintain the tetravalent nature of
carbon, trivalent nature of nitrogen, the divalent nature of
sulfur, and the divalent nature of oxygen; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,
alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R.sup.16 and R.sup.19 are optionally Q.sup.b with the proviso that
no more than one of R.sup.16 and R.sup.19 is Q.sup.b at the same
time and that Q.sup.b is Q.sup.be; Q.sup.b is selected from the
group consisting of NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is
hydrido, N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), and
C(NR.sup.25)NR.sup.23R.- sup.24, with the provisos that no more
than one of R.sup.20 and R.sup.21 is hydroxy, amino, alkylamino, or
dialkylamino at the same time and that no more than one of R.sup.23
and R.sup.24 is hydroxy, amino, alkylamino, or dialkylamino at the
same time; R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are independently selected from the group consisting of
hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;
Q.sup.s is selected from the group consisting of a single covalent
bond, (CR.sup.37R.sup.38).sub.b wherein b is an integer selected
from 1 through 4, and
(CH(R.sup.14)).sub.c--W.sup.1--(CH(R.sup.15)).sub.d wherein c and d
are integers independently selected from 1 through 3 and W.sup.1 is
selected from the group consisting of C(O)N(R.sup.14),
(R.sup.14)NC(O), S(O), S(O).sub.2, S(O).sub.2N(R.sup.14),
N(R.sup.14)S(O).sub.2, and N(R.sup.14), with the provisos that
R.sup.14 is selected from other than halo when directly bonded to N
and that (CR.sup.37R.sup.38).sub.b, and (CH(R.sup.14)).sub.c are
bonded to E.sup.0; R.sup.14 is selected from the group consisting
of hydrido, halo, alkyl, and haloalkyl; R.sup.37 and R.sup.38 are
independently selected from the group consisting of hydrido, alkyl,
and haloalkyl; R.sup.38 is optionally selected from the group
consisting of aroyl and heteroaroyl; Y.sup.0 is optionally
Q.sup.b--Q.sup.ss wherein Q.sup.ss is
(CH(R.sup.14)).sub.e--W.sup.2--(CH(R.sup.15)).sub.h, wherein e and
h are integers independently selected from 1 through 2 and W.sup.2
is CR.sup.4a.dbd.CH with the proviso that (CH(R.sup.14)).sub.e is
bonded to E.sup.0.
3. The compound as recited in claim 2 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl,
C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each
member of group B is optionally substituted at any carbon up to and
including 6 atoms from the point of attachment of B to A with one
or more of the group consisting of R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and
R.sup.36 are independently selected from the group consisting of
hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy,
hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,
amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy,
carboxy, carboxamido, cyano, and Q.sup.b; A is
(CH(R.sup.15)).sub.pa--W.sup.7 wherein pa is an integer selected
from 1 through 3 and W.sup.7 is selected from the group consisting
of O, S, and N(R.sup.7) wherein R.sup.7 is selected from the group
consisting of hydrido and alkyl; R.sup.15 is selected from the
group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl
with the proviso that R.sup.15 is other than hydroxy and halo when
R.sup.15 is on the carbon bonded directly to W.sup.7; M is selected
from the group consisting of N and R.sup.1--C; R.sup.1 is selected
from the group consisting of hydrido, alkyl, cyano, halo,
haloalkyl, haloalkoxy, amino, aminoalkyl, alkylamino, amidino,
hydroxy, hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol,
and alkylthio; R.sup.2 is Z.sup.0--Q; Z.sup.0 is selected from the
group consisting of covalent single bond and
(CR.sup.41R.sup.42).sub.q wherein q is an integer selected from 1
through 2; R.sup.41 and R.sup.42 are independently selected from
the group consisting of hydrido, hydroxy, and amino; Q is selected
from the group consisting of aryl and heteroaryl, wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.9, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.13, a
carbon adjacent to R.sup.9 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.10, a carbon
adjacent to R.sup.13 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.12, and any carbon
adjacent to both R.sup.10 and R.sup.12 is optionally substituted by
R.sup.11; R.sup.9, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl,
amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy,
amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and
cyano; K is CHR.sup.4a wherein R.sup.4a is selected from the group
consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl,
alkylthioalkyl, and haloalkyl; E.sup.0 is selected from the group
consisting of a covalent single bond, C(O)N(H), (H)NC(O),
(R.sup.7)NS(O).sub.2, and S(O).sub.2N(R.sup.7); Y.sup.0 is formula
(IV): 52 wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is C, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is O, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 must be a covalent bond when two of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are O and S, and no more than four of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are N; R.sup.16, R.sup.17, R.sup.18,
and R.sup.19 are independently selected from the group consisting
of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy,
hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, alkylamino, and cyano;
R.sup.16 and R.sup.19 are optionally Q.sup.b with the proviso that
no more than one of R.sup.16 and R.sup.19 is Q.sup.b at the same
time and that Q.sup.b is Q.sup.be; Q.sup.b is selected from the
group consisting of NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is
hydrido, N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), and
C(NR.sup.25)NR.sup.23R.- sup.24, with the provisos that no more
than one of R.sup.20 and R.sup.21 is hydroxy, amino, alkylamino, or
dialkylamino at the same time and that no more than one of R.sup.23
and R.sup.24 is hydroxy, amino, alkylamino, or dialkylamino at the
same time; R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are independently selected from the group consisting of
hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;
Q.sup.s is selected from the group consisting of a single covalent
bond, (CR.sup.37R.sup.38).sub.b wherein b is an integer selected
from 1 through 3, and
(CH(R.sup.14)).sub.c--W.sup.1--(CH(R.sup.15)).sub.d wherein c and d
are integers independently selected from 1 through 2 and W.sup.1 is
selected from the group consisting of C(O)N(R.sup.14),
(R.sup.14)NC(O), S(O), S(O).sub.2, S(O).sub.2N(R.sup.14),
N(R.sup.14)S(O).sub.2, and N(R.sup.14), with the provisos that
R.sup.14 is selected from other than halo when directly bonded to N
and that (CR.sup.37R.sup.38).sub.b, and (CH(R.sup.14)).sub.c are
bonded to E.sup.0; R.sup.14 is selected from the group consisting
of hydrido, halo, alkyl, and haloalkyl; R.sup.37 and R.sup.38 are
independently selected from the group consisting of hydrido, alkyl,
and haloalkyl; R.sup.38 is optionally selected from the group
consisting of aroyl and heteroaroyl; Y.sup.0 is optionally
Q.sup.b--Q.sup.ss wherein Q.sup.ss is
(CH(R.sup.14)).sub.e--W.sup.2--(CH(R.sup.15)).sub.h, wherein e and
h are integers independently selected from 1 through 2 and W.sup.2
is CR.sup.4a.dbd.CH with the proviso that (CH(R.sup.14)).sub.e is
bonded to E.sup.0.
4. The compound as recited in claim 3 having the Formula: 53or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of hydrido, trialkylsilyl, C2-C4 alkyl,
C3-C5 alkylenyl, C3-C4 alkenyl, C3-C4 alkynyl, and C2-C4 haloalkyl,
wherein each member of group B is optionally substituted at any
carbon up to and including 3 atoms from the point of attachment of
B to A with one or more of the group consisting of R.sup.32,
R.sup.33, and R.sup.34; R.sup.32, R.sup.33, R.sup.34 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, and cyano; A is (CH(R.sup.15)).sub.pa--N(R.sup.7)
wherein pa is an integer selected from 1 through 2 and R.sup.7 is
selected from the group consisting of hydrido and alkyl; R.sup.15
is selected from the group consisting of hydrido, halo, alkyl, and
haloalkyl; M is selected from the group consisting of N and
R.sup.1--C; R.sup.1 is selected from the group consisting of
hydrido, hydroxy, hydroxyamino, amidino, amino, cyano,
hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio,
alkoxyamino, haloalkyl, haloalkoxy, and halo; R.sup.2 is
Z.sup.0--Q; Z.sup.0 is selected from the group consisting of
covalent single bond and CH.sub.2; Q is selected from the group
consisting of aryl and heteroaryl, wherein a carbon adjacent to the
carbon at the point of attachment is optionally substituted by
R.sup.9, the other carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.13, a carbon adjacent
to R.sup.9 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.10, a carbon adjacent to
R.sup.13 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.12, and any carbon adjacent to
both R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
R.sup.9, R.sup.11, and R.sup.13 are independently selected from the
group consisting of hydrido, hydroxy, amino, amidino, guanidino,
lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl,
alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy,
carboxamido, and cyano; R.sup.10 and R.sup.12 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino,
alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl,
halo, haloalkyl, and cyano; Y.sup.0 is formula (IV): 54 wherein
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are independently selected
from the group consisting of C, N, O, S and a covalent bond with
the provisos that no more than one is a covalent bond, K.sup.2 is
C, no more than one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is O,
no more than one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is S,
one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 must be a covalent
bond when two of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are O and
S, and no more than four of D.sup.5, D.sup.6, J.sup.5, and J.sup.6
are N; R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and
cyano; R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be; Q.sup.b is selected
from the group consisting of NR.sup.20R.sup.21, Q.sup.be wherein
Q.sup.be is hydrido, C(NR.sup.25)NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), with the provisos
that no more than one of R.sup.20 and R.sup.21 is hydroxy at the
same time and that no more than one of R.sup.23 and R.sup.24 is
hydroxy at the same time; R.sup.20, R.sup.21, R.sup.23, R.sup.24,
R.sup.25, and R.sup.26 are independently selected from the group
consisting of hydrido, alkyl, and hydroxy; Q.sup.s is selected from
the group consisting of a single covalent bond, CH.sub.2, and
CH.sub.2CH.sub.2.
5. The compound as recited in claim 4 having the Formula or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of ethyl, 2-propenyl, 2-propynyl, propyl,
isopropyl, trimethylene, tetramethylene, butyl, 2-butenyl,
3-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl,
2-methylpropenyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and
2,2-difluoropropyl, wherein each member of group B is optionally
substituted at any carbon up to and including 3 atoms from the
point of attachment of B to A with one or more of the group
consisting of R.sup.32, R.sup.33, and R.sup.34; R.sup.32, R.sup.33,
and R.sup.34 are independently selected from the group consisting
of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy,
isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino,
acetamido, trifluoroacetamido, N-methylamino, dimethylamino,
N-ethylamino, methylthio, ethylthio, isopropylthio,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,
amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl,
and cyano; A is selected from the group consisting of single
covalent bond, NH, and N(CH.sub.3); M is selected from the group
consisting of N and R.sup.1--C; R.sup.1 is selected from the group
consisting of hydrido, hydroxy, amino, amidino, hydroxyamino,
aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano,
methyl, ethyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, methoxyamino, methylthio, ethylthio,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and
bromo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is selected from the group
consisting of a covalent single bond and CH.sub.2; Q is selected
from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl,
3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl,
3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5isoxazolyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl,
4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and
1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the
point of attachment is optionally substituted by R.sup.9, the other
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.13, a carbon adjacent to R.sup.9
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.10, a carbon adjacent to R.sup.13
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.12, and any carbon adjacent to both
R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
R.sup.9, R.sup.11, and R.sup.13 are independently selected from the
group consisting of hydrido, amidino, guanidino, carboxy, methyl,
ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy,
hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R.sup.10 and R.sup.12 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,
amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl,
fluoro, chloro, bromo, and cyano; Y.sup.0 is selected from the
group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzen-
e, 2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-R.sup.19pyridine,
2-Q.sup.b-4-Q.sup.s-3-R.sup.16-6-R.sup.18pyrazine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.18-5-R.sup.18-4-R.sup.19pyridazine,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18pyrimidine,
5-Q.sup.b-2-Q.sup.s-3-R.sup.16-6-R.sup.19pyrimidine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-R.sup.17thiophene,
3-Q.sup.b-5-Q.sup.s-4-R- .sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R- .sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R.sup.19imidazole,
2-Q.sup.b-4-Q.sup.s-5-R.sup.17midazole,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16iso- xazole,
5-Q.sup.b-3-Q.sup.s-4isoxazole, 2-Q.sup.b-5-Q.sup.s-4-R.sup.16pyra-
zole, 4-Q.sup.b-2-Q.sup.s-5-R.sup.19thiazole, and
2-Q.sup.b-5-Q.sup.s-4-R.- sup.17thiazole; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, methyl, ethyl, isopropyl, propyl, carboxy,
amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy, hydroxy,
amino, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino,
dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio,
trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl,
ethylsulfonyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxye- thyl, and cyano; R.sup.16 and R.sup.19
are optionally Q.sup.b with the proviso that no more than one of
R.sup.16 and R.sup.19 is Q.sup.b at the same time and that Q.sup.b
is Q.sup.be; Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido,
C(NR.sup.25)NR.sup.23R.sup.24, and N(R.sup.26)C(NR.sup.25)N(R.su-
p.23)(R.sup.24), with the provisos that no more than one of
R.sup.20, R.sup.21, R.sup.23, and R.sup.24 can be hydroxy, when any
two of the group consisting of R.sup.20, R.sup.21, R.sup.23, and
R.sup.24 are bonded to the same atom and that said Q.sup.b group is
bonded directly to a carbon atom; R.sup.20, R.sup.21, R.sup.23,
R.sup.24, R.sup.25, and R.sup.26 are independently selected from
the group consisting of hydrido, methyl, ethyl, propyl, butyl,
isopropyl, and hydroxy; Q.sup.s is selected from the group
consisting of a single covalent bond, CH.sub.2, and
CH.sub.2CH.sub.2.
6. The compound as recited in claim 4 having the Formula: 55or a
pharmaceutically acceptable salt thereof, wherein; A is selected
from the group consisting of CH.sub.2N(CH.sub.3),
CH.sub.2N(CH.sub.2CH.sub.3), CH.sub.2CH.sub.2N(CH.sub.3), and
CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3); M is selected from the group
consisting of N and R.sup.1--C; R.sup.1 is selected from the group
consisting of hydrido, hydroxy, amino, amidino, hydroxyamino,
aminomethyl, 1-aminoethyl, methylamino, dimethylamino, cyano,
methyl, ethyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, methoxy, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, methoxyamino, methylthio, ethylthio,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and
bromo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is selected from the group
consisting of covalent single bond and CH.sub.2; Q is selected from
the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl,
3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl,
3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl,
4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and
1,3,5triazin-2-yl, wherein a carbon adjacent to the carbon at the
point of attachment is optionally substituted by R.sup.9, the other
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.13, a carbon adjacent to R.sup.9
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.10, a carbon adjacent to R.sup.13
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.12, and any carbon adjacent to both
R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
R.sup.9, R.sup.11, and R.sup.13 are independently selected from the
group consisting of hydrido, amidino, guanidino, carboxy, methyl,
ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy,
hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R.sup.10 and R.sup.12 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,
amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl,
fluoro, chloro, bromo, and cyano; Y.sup.0 is selected from the
group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzen-
e, 2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
2-Q.sup.b-4-Q.sup.s-3-R.sup.16-R.sup.18pyrazine,
3-Q.sup.b-6-Q.sup.s-2-R.- sup.18-5-R.sup.18-4-R.sup.19pyridazine,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R- .sup.18pyrimidine,
5-Q.sup.b-2-Q.sup.s-3-R.sup.16-6-R.sup.19pyrimidine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.s- up.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R- .sup.19imidazole,
2-Q.sup.b-Q.sup.s-5-R.sup.17imidazole,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16isoxazole,
5-Q.sup.b-3-Q.sup.s-4-R.sup.16is- oxazole,
2-Q.sup.b-5-Q.sup.s-4-R.sup.16pyrazole, 4-Q.sup.b-2-Q.sup.s-5-R.s-
up.19thiazole, and 2-Q.sup.b-5-Q.sup.s-4-R.sup.17thiazole;
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, methyl, ethyl,
isopropyl, propyl, amidino, guanidino, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-N-methylamino, dimethylamino, N-ethylamino, methylthio,
ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl,
ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and
cyano; Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, C(NR.sup.25)NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), with the provisos
that no more than one of R.sup.20, R.sup.21, R.sup.23, and R.sup.24
can be hydroxy, when any two of the group consisting of R.sup.20,
R.sup.21, R.sup.23, and R.sup.24 are bonded to the same atom and
that said Q.sup.b group is bonded directly to a carbon atom;
R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are
independently selected from the group consisting of hydrido,
methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; Q.sup.s is
selected from the group consisting of a single covalent bond,
CH.sub.2, and CH.sub.2CH.sub.2.
7. The compound as recited in claim 6 or a pharmaceutically
acceptable salt thereof, wherein; A is selected from the group
consisting of CH.sub.2N(CH.sub.3), CH.sub.2N(CH.sub.2CH.sub.3),
CH.sub.2CH.sub.2N(CH.su- b.3), and
CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3); M is selected from the group
consisting of N and R.sup.1--C; R.sup.1 is selected from the group
consisting of hydrido, hydroxy, amino, amidino, hydroxyamino,
aminomethyl, methylamino, cyano, methyl, trifluoromethyl, methoxy,
hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro,
and chloro; R.sup.2 is Z.sup.0--Q; Z.sup.0 is selected from the
group consisting of covalent single bond and CH.sub.2; Q is
selected from the group consisting of
5-amino-3-amidocarbonylphenyl, 5amino-2-fluorophenyl,
3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl,
3-amidinophenyl, 3-amino-2-methylphenyl,
5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl,
3-carboxy-5-hydroxyphenyl, 3-carboxy-5-aminophenyl, 3-chlorophenyl,
2-chlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl,
2-fluorophenyl, 3-fluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl,
3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl,
3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, 4methylphenyl,
phenyl, 3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl,
2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl,
3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y.sup.0 is selected from the group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.s is CH.sub.2.
8. A compound as recited in claim 7 or a pharmaceutically
acceptable salt thereof where said compound is selected from the
group consisting of:
2-[3-[1-[3-aminophenyl]-N-[[4-iminomethylphenyl]methyl]-5-[N,N-dimethylhy-
drazino]-2,4-dioxo-2(2H,4H)-pyrimidinyl]]acetamide;
2-[3-[1-[3-aminophenyl]-5-[N-ethyl-N-methylhydrazino]-N-[[4-iminomethylph-
enyl]methyl]-2,4-dioxo-2(2H,4H)-pyrimidinyl]]acetamide;
2-[3-[1-[3-aminophenyl]-6-fluoro-5-[N,N-diethylhydrazino]-N-[[4-iminometh-
ylphenyl]methyl]-2,4-dioxo-2(2H,4H)-pyrimidinyl]]acetamide;
2-[3-[1-[3-aminophenyl]-5-[N-(azetidin-1-yl)amino]-N-[[4-iminomethylpheny-
l]methyl]-2,4-dioxo-2(2H,4H)-pyrimidinyl]]acetamide;
2-[4-[2-[3-aminophenyl]-N-[[4-iminomethylphenyl]methyl]-6-[N,N-dimethylhy-
drazino]-3,5-dioxo-2(3H,5H)-1,2,4-triazinyl]]acetamide;
2-[4-[2-[3-aminophenyl]-6-[N-ethyl-N-methylhydrazino]-N-[[4-iminomethylph-
enyl]methyl]-3,5-dioxo-2(3H,5H)-1,2,4-triazinyl]]acetamide;
2-[4-[2-[3-aminophenyl]-6-[N,N-diethylhydrazino]-N-[[4-iminomethylphenyl]-
methyl]-3,5-dioxo-2(3H,5H)-1,2,4-triazinyl]]acetamide;
2-[4-[2-[3-aminophenyl]-6-[N-(azetidin-1-yl)amino]-N-[[4-iminomethylpheny-
l]methyl]-3,5-dioxo-2(3H,5H)-1,2,4-triazinyl]]acetamide.
9. The compound as recited in claim 2 having the Formula: 56or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of aryl and heteroaryl wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.32, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.36, a
carbon adjacent to R.sup.32 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.33, a carbon
adjacent to R.sup.36 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.35, and any carbon
adjacent to both R.sup.33 and R.sup.35 is optionally substituted by
R.sup.34; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b; A is selected from the group
consisting of single covalent bond and
(CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
3, and W.sup.7 is selected from the group consisting of
(R.sup.7)NC(O) and N(R.sup.7); R.sup.7 is selected from the group
consisting of hydrido, hydroxy and alkyl; R.sup.15 is selected from
the group consisting of hydrido, halo, alkyl and haloalkyl; M is
selected from the group consisting of N and R.sup.1--C; R.sup.1 is
selected from the group consisting of hydrido, hydroxy,
hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl,
alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl,
haloalkoxy, and halo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is selected
from the group consisting of a covalent single bond, O, S, NH, and
CH.sub.2; Q is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.13, a carbon adjacent to R.sup.9 and two atoms
from the carbon at the point of attachment is optionally
substituted by R.sup.10, a carbon adjacent to R.sup.13 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.12, and any carbon adjacent to both R.sup.10
and R.sup.12 is optionally substituted by R.sup.11; R.sup.9,
R.sup.11, and R.sup.13 are independently selected from the group
consisting of hydrido, hydroxy, amino, amidino, guanidino, lower
alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl,
alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy,
carboxamido, and cyano; R.sup.10 and R.sup.12 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino,
alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl,
halo, haloalkyl, and cyano; Y.sup.0 is formula (IV): 57 wherein
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are independently selected
from the group consisting of C, N, O, S and a covalent bond with
the provisos that no more than one is a covalent bond, K.sup.2 is
C, no more than one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is O,
no more than one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is S,
one of D.sup.5, D.sup.6, J.sup.5,and J.sup.6 must be a covalent
bond when two of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are O and
S, and no more than four of D.sup.5, D.sup.6, J.sup.5, and J.sup.6
are N; R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and
cyano; R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.bis Q.sup.be; Q.sup.b is selected
from the group consisting of NR.sup.20R.sup.21, Q.sup.be wherein
Q.sup.be is hydrido, and C(NR.sup.25)NR.sup.23R.sup.24, with the
provisos that no more than one of R.sup.20 and R.sup.21 is hydroxy
at the same time and that no more than one of R.sup.23 and R.sup.24
is hydroxy at the same time; R.sup.20, R.sup.21, R.sup.23,
R.sup.24, and R.sup.25 are independently selected from the group
consisting of hydrido, alkyl, and hydroxy; Q.sup.s is selected from
the group consisting of a single covalent bond, CH.sub.2, and
CH.sub.2CH.sub.2.
10. The compound as recited in claim 9 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl,
2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl,
4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and
1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the
point of attachment is optionally substituted by R.sup.32, the
other carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.36, a carbon adjacent to R.sup.32
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.33, a carbon adjacent to R.sup.36
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.35, and any carbon adjacent to both
R.sup.33 and R.sup.35 is optionally substituted by R.sup.34;
R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy,
hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxye- thyl,
methoxycarbonyl, ethoxycarbonyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and
Q.sup.b; A is selected from the group consisting of single covalent
bond, NH, N(CH.sub.3), N(OH), CH.sub.2, CH.sub.3CH, CF.sub.3CH,
NHC(O), N(CH.sub.3)C(O), C(O)NH, C(O)N(CH.sub.3), CH.sub.2CH.sub.2,
CH.sub.2CH.sub.2CH.sub.2, CH.sub.3CHCH.sub.2, and
CF.sub.3CHCH.sub.2; M is selected from the group consisting of N
and R.sup.1--C; R.sup.1 is selected from the group consisting of
hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl,
1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino,
methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy,
fluoro, chloro, and bromo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is
selected from the group consisting of a covalent single bond, O, S,
NH, and CH.sub.2; Q is selected from the group consisting of
phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl,
3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,
2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and
1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the
point of attachment is optionally substituted by R.sup.9, the other
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.13, a carbon adjacent to R.sup.9
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.10, a carbon adjacent to R.sup.13
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.12, and any carbon adjacent to both
R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
R.sup.9, R.sup.11, and R.sup.13 are independently selected from the
group consisting of hydrido, amidino, guanidino, carboxy, methyl,
ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy,
hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R.sup.10 and R.sup.12 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,
amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl,
fluoro, chloro, bromo, and cyano; Y.sup.0 is selected from the
group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzen-
e, 2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
2-Q.sup.b-4-Q.sup.s-3-R.sup.16-6-R.sup.18pyrazine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.18-5-R.sup.18-4-R.sup.19pyridazine,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18pyrimidine,
5Q.sup.b-2-Q.sup.s-3-R.sup.16-6-R.sup.19pyrimidine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.s- up.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R- .sup.19imidazole,
2-Q.sup.b-4-Q.sup.s-5-R.sup.17imidazole,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16isoxazole,
5-Q.sup.b-3-Q.sup.s-4-R.sup.16is- oxazole,
2-Q.sup.b-5-Q.sup.s-4-R.sup.16pyrazole, 4-Q.sup.b-2-Q.sup.s-5-R.s-
up.19thiazole, and 2-Q.sup.b-5-Q.sup.s-4-R.sup.16thiazole;
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, methyl, ethyl,
isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy,
isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl,
2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethylthio,
methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and
cyano; R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be; Q.sup.b is selected
from the group consisting of Q.sup.be wherein Q.sup.be is hydrido
and C(NR.sup.25)NR.sup.23R.sup.24, with the proviso that no more
than one of R.sup.23 and R.sup.24 is hydroxy at the same time;
R.sup.23, R.sup.24, and R.sup.25 are independently selected from
the group consisting of hydrido, methyl, ethyl, and hydroxy;
Q.sup.S is selected from the group consisting of a single covalent
bond, CH.sub.2 and CH.sub.2CH.sub.2.
11. The compound as recited in claim 10 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl,
4-amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl,
3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl,
3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl,
4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl,
3-trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl,
5-chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl,
3-thienyl, and 3-trifluoromethyl-2-pyridyl; A is selected from the
group consisting of CH.sub.2, CH.sub.3CH, CF.sub.3CH, NHC(O),
CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2; M is selected from
the group consisting of N and R.sup.1--C; R.sup.1 is selected from
the group consisting of hydrido, hydroxy, amino, amidino,
hydroxyamino, aminomethyl, methylamino, cyano, methyl,
trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio,
trifluoromethoxy, fluoro, and chloro; R.sup.2 is Z.sup.0--Q;
Z.sup.0 is selected from the group consisting of a covalent single
bond, O, S, NH, and CH.sub.2; Q is selected from the group
consisting of 5-amino-3-amidocarbonylphenyl,
5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl,
5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl,
3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl,
benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl,
3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl,
3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl,
3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl,
3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl,
2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl,
3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl,
3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl,
4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl,
3-trifluoromethylphenyl, 2-trifluoromethylphenyl,
5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl,
4-pyridyl, 2-thienyl, and 3-thienyl; Y.sup.0 is selected from the
group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.s is CH.sub.2.
12. The compound as recited in claim 9 having the Formula: 58or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of aryl and heteroaryl wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.32, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.36, a
carbon adjacent to R.sup.32 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.33, a carbon
adjacent to R.sup.36 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.35, and any carbon
adjacent to both R.sup.33 and R.sup.35 is optionally substituted by
R.sup.34; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b; A is selected from the group
consisting of single covalent bond and
(CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
3, and W.sup.7 is N(R.sup.7); R.sup.7 is selected from the group
consisting of hydrido and alkyl; R.sup.15 is selected from the
group consisting of hydrido, halo, alkyl, and haloalkyl; M is
selected from the group consisting of N and R.sup.1--C; R.sup.1 is
selected from the group consisting of hydrido, hydroxy,
hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl,
alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl,
haloalkoxy, and halo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is a covalent
single bond; Q is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.13, a carbon adjacent to R.sup.9 and two atoms
from the carbon at the point of attachment is optionally
substituted by R.sup.10, a carbon adjacent to R.sup.13 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.12, and any carbon adjacent to both R.sup.10
and R.sup.12 is optionally substituted by R.sup.11; R.sup.9,
R.sup.11, and R.sup.13 are independently selected from the group
consisting of hydrido, hydroxy, amino, amidino, guanidino, lower
alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl,
amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R.sup.10
and R.sup.12 are independently selected from the group consisting
of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl,
alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl,
carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano;
Y.sup.0 is formula (IV): 59 wherein D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 are independently selected from the group consisting of C,
N, O, S and a covalent bond with the provisos that no more than one
is a covalent bond, K.sup.2 is C, no more than one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 is O, no more than one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 must be a covalent bond when two of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are O and S, and no more than four of
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are N; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,
alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R.sup.16 and
R.sup.19 are optionally Q with the proviso that no more than one of
R.sup.16 and R.sup.19 is Q.sup.b at the same time and that Q.sup.b
is Q.sup.be; Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido, and
C(NR.sup.25)NR.sup.23R.sup.24; R.sup.20, R.sup.21, R.sup.23,
R.sup.24, and R.sup.25 are independently selected from the group
consisting of hydrido and alkyl; Q.sup.s is CH.sub.2.
13. The compound as recited in claim 12 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl,
2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl,
4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and 5-isoxazolyl, wherein a
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.32, the other carbon adjacent to
the carbon at the point of attachment is optionally substituted by
R.sup.36, a carbon adjacent to R.sup.32 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.33, a carbon adjacent to R.sup.36 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.35, and any carbon adjacent to both R.sup.33 and R.sup.35 is
optionally substituted by R.sup.34; R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36 are independently selected from the group
consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy,
ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio,
ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,
hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q.sup.b; A is
selected from the group consisting of single covalent bond, NH,
N(CH.sub.3), CH.sub.2, CH.sub.3CH, and CH.sub.2CH.sub.2; M is
selected from the group consisting of N and R.sup.1--C; R.sup.1 is
selected from the group consisting of hydrido, hydroxy, amino,
amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl,
trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio,
trifluoromethoxy, fluoro, and chloro; R.sup.2 is selected from the
group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl,
2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl,
wherein a carbon adjacent to the carbon at the point of attachment
is optionally substituted by R.sup.9, the other carbon adjacent to
the carbon at the point of attachment is optionally substituted by
R.sup.13, a carbon adjacent to R.sup.9 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.10, a carbon adjacent to R.sup.13 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.12, and any carbon adjacent to both R.sup.10 and R.sup.12 is
optionally substituted by R.sup.11; R.sup.9, R.sup.11, and R.sup.13
are independently selected from the group consisting of hydrido,
methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino,
N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and
cyano; R.sup.10 and R.sup.12 are independently selected from the
group consisting of hydrido, amidino, amidocarbonyl,
N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy,
hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy,
carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl,
N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo,
and cyano; Y.sup.0 is selected from the group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.s- up.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4R.sup.16-2-R.sup.19pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R- .sup.19thiazole, and
2-Q.sup.b-5-Q.sup.s-4-R.sup.17thiazole; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy,
hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, methylthio, ethylthio,
trifluoromethylthio, methylsulfinyl, methylsulfonyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
trifluoromethoxy, fluoro, chloro, amidosulfonyl,
N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. Q.sup.b
is selected from the group consisting of NR.sup.20R.sup.21 and
C(NR.sup.25)NR.sup.23R.sup.24, with the proviso that said Q.sup.b
group is bonded directly to a carbon atom; R.sup.20, R.sup.21,
R.sup.23, R.sup.24, and R.sup.25 are independently selected from
the group consisting of hydrido, methyl, and ethyl; Q.sup.s is
CH.sub.2.
14. The compound as recited in claim 13 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl,
4-amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl,
3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl,
3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl,
4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl,
3-trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl,
5-chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl,
3-thienyl, and 3-trifluoromethyl-2-pyridyl; A is selected from the
group consisting of CH.sub.2, CH.sub.3CH, CF.sub.3CH, NHC(O),
CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2; M is selected from
the group consisting of N and R.sup.1--C; R.sup.1 is selected from
the group consisting of hydrido, hydroxy, amino, methyl,
trifluoromethyl, fluoro, and chloro; R.sup.2 is selected from the
group consisting of 5-amino-3-amidocarbonylp- henyl,
5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl,
5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl,
3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl,
benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl,
3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl,
3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl,
3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl,
3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl,
2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl,
3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl,
3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl,
4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl,
3-trifluoromethylphenyl, 2-trifluoromethylphenyl,
5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl,
4-pyridyl, 2-thienyl, and 3-thienyl; Y.sup.0 is selected from the
group consisting of: 1-Q.sup.b-4-Q.sup.s-2-R-
.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.s- up.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.su- p.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophen- e, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.s is CH.sub.2.
15. The compound as recited in claim 14 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl,
3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl,
4-methylphenyl, phenyl, 2-imidazoyl, 3-pyridyl, 4-pyridyl, and
3-trifluoromethyl-2-pyridy- l; A is selected from the group
consisting of CH.sub.2, NHC(O), CH.sub.2CH.sub.2, and
CH.sub.2CH.sub.2CH.sub.2; M is selected from the group consisting
of N and R.sup.1--C; R.sup.1 is selected from the group consisting
of hydrido, fluoro, and chloro; R.sup.2 is selected from the group
consisting of 3-aminophenyl, benzyl, 3-chlorophenyl,
3-dimethylaminophenyl, 3-hydroxyphenyl,
3-methanesulfonylaminophenyl, 3-methylaminophenyl, 2-methylphenyl,
3-methylphenyl, phenyl, 3-trifluoroacetamidophenyl,
3-bromo-2-thienyl, 2-thienyl, and 3-thienyl; Y.sup.0 is selected
from the group consisting of 5-amidino-2-thienylmethy- l,
4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and
3-fluoro-4-amdinobenzyl.
16. A compound as recited in claim 9 where said compound is
selected from the group having the Formula: 60or a pharmaceutically
acceptable salt thereof, wherein: R.sup.2 is 3-aminophenyl, B is
3-chlorophenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and M is CH; R.sup.2 is 3-aminophenyl, B is phenyl, A is CH.sub.2,
Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is phenyl, B is
3-chlorophenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and M is CH; R.sup.2 is 3-aminophenyl, B is 2-imidazoyl, A is
CH.sub.2CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CH;
R.sup.2 is 3-dimethylaminophenyl, B is phenyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2
is 2-methylphenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is CH; R.sup.2 is phenyl, B is
3-aminophenyl, A is C(O)NH, Y.sup.0 is 4-amidinobenzyl, and M is
CH; R.sup.2 is phenyl, B is 3-amidinophenyl, A is CH.sub.2, Y.sup.0
is 4-amidinobenzyl, and M is CH; R.sup.2 is
3-(N-methylamino)phenyl, B is phenyl, A is CH.sub.2CH.sub.2,
Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is 3-thienyl, B is
phenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is
CH; R.sup.2 is 3-methylsulfonamidophenyl, B is phenyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2
is phenyl, B is 4-amidinophenyl, A is CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is CH; R.sup.2 is 3-methylaminophenyl, B is
phenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is
CH; R.sup.2 is phenyl, B is phenyl, A is CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is CH; R.sup.2 is phenyl, B is 4-pyridyl, A
is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CH;
R.sup.2 is phenyl, B is 3-pyridyl, A is CH.sub.2CH.sub.2, Y.sup.0
is 4-amidinobenzyl, and M is CH; R.sup.2 is 3-chlorophenyl, B is
4-pyridyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M
is CH; R.sup.2 is 3-methylphenyl, B is 4-phenyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2
is 3-thienyl, B is 3-chlorophenyl, A is CH.sub.2CH.sub.2, Y.sup.0
is 4-amidinobenzyl, and M is CH; R.sup.2 is 3-aminophenyl, B is
3-chlorophenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and M is CF; R.sup.2 is 3-aminophenyl, B is phenyl, A is CH.sub.2,
Y.sup.0 is 4-amidinobenzyl, and M is CF; R.sup.2 is phenyl, B is
3-chlorophenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and M is CF; R.sup.2 is 3-aminophenyl, B is 2-imidazoyl, A is
CH.sub.2CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CF;
R.sup.2 is 3-dimethylaminophenyl, B is phenyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CF; R.sup.2
is 2-methylphenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is CF; R.sup.2 is phenyl, B is
3-aminophenyl, A is C(O)NH, Y.sup.0 is 4-amidinobenzyl, and M is
CF; R.sup.2 is phenyl, B is 3-amidinophenyl, A is CH.sub.2, Y.sup.0
is 4-amidinobenzyl, and M is CF; R.sup.2 is
3-(N-methylamino)phenyl, B is phenyl, A is CH.sub.2CH.sub.2,
Y.sup.0 is 4-amidinobenzyl, and M is CF; R.sup.2 is 3-thienyl, B is
phenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is
CF; R.sup.2 is 3-methylsulfonamidophenyl, B is phenyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CF; R.sup.2
is phenyl, B is 4-amidinophenyl, A is CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is CF; R.sup.2 is 3-methylaminophenyl, B is
phenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is
CF; R.sup.2 is phenyl, B is phenyl, A is CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is CF; R.sup.2 is phenyl, B is 4-pyridyl, A
is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CF;
R.sup.2 is phenyl, B is 3-pyridyl, A is CH.sub.2CH.sub.2, Y.sup.0
is 4-amidinobenzyl, and M is CF; R.sup.2 is 3-chlorophenyl, B is
4-pyridyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M
is CF; R.sup.2 is 3-methylphenyl, B is 4-phenyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CF; R.sup.2
is 3-thienyl, B is 3-chlorophenyl, A is CH.sub.2CH.sub.2, Y.sup.0
is 4-amidinobenzyl, and M is CF; R.sup.2 is 3-aminophenyl, B is
3-chlorophenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and M is N; R.sup.2 is 3-aminophenyl, B is phenyl, A is CH.sub.2,
Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is phenyl, B is
3-chlorophenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and M is N; R.sup.2 is 3-aminophenyl, B is 2-imidazoyl, A is
CH.sub.2CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is N;
R.sup.2 is 3-dimethylaminophenyl, B is phenyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2
is 2-methylphenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is N; R.sup.2 is phenyl, B is 3-aminophenyl,
A is C(O)NH, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is
phenyl, B is 3-amidinophenyl, A is CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is N; R.sup.2 is 3-(N-methylamino)phenyl, B
is phenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M
is N; R.sup.2 is 3-thienyl, B is phenyl, A is CH.sub.2CH.sub.2,
Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is
3-methylsulfonamidophenyl, B is phenyl, A is CH.sub.2CH.sub.2,
Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is phenyl, B is
4-amidinophenyl, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M
is N; R.sup.2 is 3-methylaminophenyl, B is phenyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2
is phenyl, B is phenyl, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and M is N; R.sup.2 is phenyl, B is 4-pyridyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2
is phenyl, B is 3-pyridyl, A is CH.sub.2CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is N; R.sup.2 is 3-chlorophenyl, B is
4-pyridyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M
is N; R.sup.2 is 3-methylphenyl, B is 4-phenyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2
is 3-thienyl, B is 3-chlorophenyl, A is CH.sub.2CH.sub.2, Y.sup.0
is 4-amidinobenzyl, and M is N.
17. The compound as recited in claim 2 having the Formula: 61or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl,
C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B
is optionally substituted at any carbon up to and including 6 atoms
from the point of attachment of B to A with one or more of the
group consisting of R.sup.32, R.sup.33, R.sup.34, R.sup.35, and
R.sup.36; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b; A is selected from the group
consisting of single covalent bond and
(CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
3, and W.sup.7 is selected from the group consisting of
(R.sup.7)NC(O) and N(R.sup.7); R.sup.7 is selected from the group
consisting of hydrido, hydroxy and alkyl; R.sup.15 is selected from
the group consisting of hydrido, halo, alkyl, and haloalkyl; M is
selected from the group consisting of N and R.sup.1--C; R.sup.1 is
selected from the group consisting of hydrido, hydroxy,
hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl,
alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl,
haloalkoxy, and halo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is selected
from the group consisting of a covalent single bond, O, S, NH, and
CH.sub.2; Q is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.13, a carbon adjacent to R.sup.9 and two atoms
from the carbon at the point of attachment is optionally
substituted by R.sup.10, a carbon adjacent to R.sup.13 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.12, and any carbon adjacent to both R.sup.10
and R.sup.12 is optionally substituted by R.sup.11; R.sup.9,
R.sup.11, and R.sup.13 are independently selected from the group
consisting of hydrido, hydroxy, amino, amidino, guanidino, lower
alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl,
alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy,
carboxamido, and cyano; R.sup.10 and R.sup.12 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino,
alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl,
halo, haloalkyl, and cyano; Y.sup.0 is formula (IV): 62 wherein
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are independently selected
from the group consisting of C, N, O, S and a covalent bond with
the provisos that no more than one is a covalent bond, K.sup.2 is
C, no more than one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is O,
no more than one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is S,
one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 must be a covalent
bond when two of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are O and
S, and no more than four of D.sup.5, D.sup.6, J.sup.5, and J.sup.6
are N; R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and
cyano; R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be; Q.sup.b is selected
from the group consisting of NR.sup.20R.sup.21, Q.sup.be wherein
Q.sup.be is hydrido, C(NR.sup.25)NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), with the provisos
that no more than one of R.sup.20 and R.sup.21 is hydroxy at the
same time and that no more than one of R.sup.23 and R.sup.24 is
hydroxy at the same time; R.sup.20, R.sup.21, R.sup.23, R.sup.24,
R.sup.25, and R.sup.26 are independently selected from the group
consisting of hydrido, alkyl, and hydroxy; Q.sup.s is selected from
the group consisting of a single covalent bond, CH.sub.2, and
CH.sub.2CH.sub.2.
18. The compound as recited in claim 17 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of hydrido, ethyl, 2-propynyl, 2-propenyl, propyl,
isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl,
tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl,
3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl,
1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butynyl,
3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl,
2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl,
3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl,
3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,
2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl,
1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl,
3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl,
1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,
5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl,
5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl,
1-methyl4-hexenyl, 1-methyl-5hexenyl, 1-methyl-2-hexynyl,
1-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl,
1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl,
1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl,
2,2,2-trifluoroethyl, 2,2-difluoropropyl,
4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl,
5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each
member of group B is optionally substituted at any carbon up to and
including 5 atoms from the point of attachment of B to A with one
or more of the group consisting of R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and
R.sup.36 are independently selected from the group consisting of
hydrido, amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl,
methoxycarbonyl, ethoxycarbonyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and
Q.sup.b; A is selected from the group consisting of single covalent
bond, NH, N(CH.sub.3), N(OH), CH.sub.2, CH.sub.3CH, CF.sub.3CH,
NHC(O), N(CH.sub.3)C(O), C(O)NH, C(O)N(CH.sub.3), CH.sub.2CH.sub.2,
CH.sub.2CH.sub.2CH.sub.2, CH.sub.3CHCH.sub.2, and
CF.sub.3CHCH.sub.2; M is selected from the group consisting of N
and R.sup.1--C; R.sup.1 is selected from the group consisting of
hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl,
1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino,
methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy,
fluoro, chloro, and bromo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is
selected from the group consisting of a covalent single bond, O, S,
NH, and CH.sub.2; Q is selected from the group consisting of
phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl,
3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,
2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and 1,3,5triazin-2-yl,
wherein a carbon adjacent to the carbon at the point of attachment
is optionally substituted by R.sup.9, the other carbon adjacent to
the carbon at the point of attachment is optionally substituted by
R.sup.13, a carbon adjacent to R.sup.9 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.10, a carbon adjacent to R.sup.13 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.12, and any carbon adjacent to both R.sup.10 and R.sup.12 is
optionally substituted by R.sup.11; R.sup.9, R.sup.11, and R.sup.13
are independently selected from the group consisting of hydrido,
amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl,
methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino,
N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio,
ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R.sup.10 and R.sup.12 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,
amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl,
fluoro, chloro, bromo, and cyano; Y.sup.0 is selected from the
group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzen-
e, 2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
2-Q.sup.b-4-Q.sup.s-3-R.sup.16-6-R.sup.18pyrazine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.18-5-R.sup.18-4-R.sup.19pyridazine,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18pyrimidine,
5-Q.sup.b-2-Q.sup.s-3-R.sup.16-6-R.sup.19pyrimidine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.s- up.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R- .sup.19imidazole,
2-Q.sup.b-4-Q.sup.s-5-R.sup.17imidazole,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16isoxazole,
5-Q.sup.b-3-Q.sup.s-4-R.sup.16is- oxazole,
2-Q.sup.b-5-Q.sup.s-4-R.sup.16pyrazole, 4-Q.sup.b-2-Q.sup.s-5-R.s-
up.19thiazole, and 2-Q.sup.b-5-Q.sup.s-4-R.sup.17thiazole;
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, methyl, ethyl,
isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy,
isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl,
2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethylthio,
methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and
cyano; R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be; Q.sup.b is selected
from the group consisting of NR.sup.20R.sup.21, Q.sup.be, wherein
Q.sup.be is hydrido, C(N.sup.25NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), with the provisos
that no more than one of R.sup.20 and R.sup.21 is hydroxy at the
same time and that no more than one of R.sup.23 and R.sup.24 is
hydroxy at the same time; R.sup.20, R.sup.21, R.sup.23, R.sup.24,
R.sup.25, and R.sup.26 are independently selected from the group
consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and
hydroxy; Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
19. The compound as recited in claim 18 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of hydrido,ethyl, 2-propenyl, 2-propynyl, propyl,
isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2-butyl, tert-butyl,
isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl,
6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl,
3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl,
3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl,
6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl,
3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl,
4hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl,
2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and
4-aminobutyl; A is selected from the group consisting of single
covalent bond,CH.sub.2, NHC(O), CH.sub.2CH.sub.2,
CH.sub.2CH.sub.2CH.sub.2, and CH.sub.3CHCH.sub.2; M is selected
from the group consisting of N and R.sup.1--C; R.sup.1 is selected
from the group consisting of hydrido, hydroxy, amino, amidino,
hydroxyamino, aminomethyl, methylamino, cyano, methyl,
trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio,
trifluoromethoxy, fluoro, and chloro; R.sup.2 is Z.sup.0--Q;
Z.sup.0 is selected from the group consisting of a covalent single
bond, O, S, NH, and CH.sub.2; Q is selected from the group
consisting of 5-amino-3-amidocarbonylphenyl, 5amino-2-fluorophenyl,
3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl,
3-amidinophenyl, 3-amino-2-methylphenyl,
5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl,
3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl,
3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl,
3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl,
2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl,
2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl,
2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylaminophenyl,
2-methoxyphenyl, 3-methoxyphenyl, 3-methoxyaminophenyl,
3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl,
2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl,
3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl,
2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl,
3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y.sup.0 is selected from the group consisting of:
1-Q.sup.b-4Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5R.sup.18-4 R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.sis CH.sub.2.
20. The compound as recited in claim 17 having the Formula: 63or a
pharmaceutically acceptable salt therof, wherein; B is selected
from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl,
C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B
is optionally substituted at any carbon up to and including 6 atoms
from the point of attachment of B to A with one or more of the
group consisting of R.sup.32, R.sup.33, R.sup.34, R.sup.35, and
R.sup.36; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b; A is selected from the group
consisting of single covalent bond and
(CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
3, and W.sup.7 is N(R.sup.7); R.sup.7 is selected from the group
consisting of hydrido and alkyl; R.sup.15 is selected from the
group consisting of hydrido, halo, alkyl, and haloalkyl; M is
selected from the group consisting of N and R.sup.1--C; R.sup.1 is
selected from the group consisting of hydrido, hydroxy,
hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl,
alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl,
haloalkoxy, and halo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is a covalent
single bond; Q is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.13, a carbon adjacent to R.sup.9 and two atoms
from the carbon at the point of attachment is optionally
substituted by R.sup.10, a carbon adjacent to R.sup.13 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.12, and any carbon adjacent to both R.sup.10
and R.sup.12 is optionally substituted by R.sup.11; R.sup.9,
R.sup.11, and R.sup.13 are independently selected from the group
consisting of hydrido, hydroxy, amino, amidino, guanidino, lower
alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl,
amidosulfonyl, monoalkylamidosulfonyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R.sup.10
and R.sup.12 are independently selected from the group consisting
of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl,
alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl,
carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano;
Y.sup.0 is formula (IV): 64 wherein D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 are independently selected from the group consisting of C,
N, O, S and a covalent bond with the provisos that no more than one
is a covalent bond, K.sup.2 is C, no more than one of D.sup.5,
D.sup.5, J.sup.5, and J.sup.6 is O, no more than one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 must be a covalent bond when two of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are O and S, and no more than four of
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are N; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,
alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; Q.sup.b is selected from the group consisting
of NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido,
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(- R.sup.24), and
C(NR.sup.25)NR.sup.23R.sup.24; R.sup.20, R.sup.21, R.sup.23,
R.sup.24, R.sup.25, and R.sup.26 are independently selected from
the group consisting of hydrido and alkyl; Q.sup.s is CH.sub.2.
21. The compound as recited in claim 17 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl,
isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl, tert-butyl,
isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl,
2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl,
2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl,
2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,
2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl,
1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl,
1-ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,
5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl,
2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl,
1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl,
1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl,
1-ethyl-3-pentenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl,
2,2,2-trifluoroethyl, 2,2-difluoropropyl,
4-trifluoromethyl-5,5,5-trifluo- ropentyl, 4-trifluoromethylpentyl,
5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each
member of group B is optionally substituted at any carbon up to and
including 5 atoms from the point of attachment of B to A with one
or more of the group consisting of R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and
R.sup.36 are independently selected from the group consisting of
hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy,
hydroxy, amino, N-methylamino, dimethylamino, methylthio,
ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,
hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q.sup.b; A is
selected from the group consisting of single covalent bond, NH,
N(CH.sub.3), CH.sub.2, CH.sub.3CH, and CH.sub.2CH.sub.2; A is
optionally selected from the group consisting of
CH.sub.2N(CH.sub.3), CH.sub.2N(CH.sub.2CH.sub.3),
CH.sub.2CH.sub.2N(CH.sub.3), and
CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3) with the proviso that B is
hydrido; M is selected from the group consisting of N and
R.sup.1--C; R.sup.1 is selected from the group consisting of
hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl,
methylamino, cyano, methyl, trifluoromethyl, methoxy,
hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro,
and chloro; R.sup.2 is selected from the group consisting of
phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl,
3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent
to the carbon at the point of attachment is optionally substituted
by R.sup.9, the other carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.13, a carbon adjacent
to R.sup.9 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.10, a carbon adjacent to
R.sup.13 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.12, and any carbon adjacent to
both R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
R.sup.9, R.sup.11, and R.sup.13 are independently selected from the
group consisting of hydrido, methyl, ethyl, methoxy, ethoxy,
hydroxy, amino, N-methylamino, N,N-dimethylamino, methylthio,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro,
chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano; R.sup.10
and R.sup.12 are independently selected from the group consisting
of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl,
guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, carboxy, carboxymethyl, amino,
acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
methoxycarbonyl, fluoro, chloro, bromo, and cyano; Y.sup.0 is
selected from the group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.s- up.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R- .sup.19thiazole, and
2-Q.sup.b-5-Q.sup.s-4R.sup.17thiazole; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy,
hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, methylthio, ethylthio,
trifluoromethylthio, methylsulfinyl, methylsulfonyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
trifluoromethoxy, fluoro, chloro, amidosulfonyl,
N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. Q.sup.b
is selected from the group consisting of NR.sup.20R.sup.21;
C(NR.sup.25)NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.s- up.24), with the proviso
that said Q.sup.b group is bonded directly to a carbon atom;
R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are
independently selected from the group consisting of hydrido,
methyl, and ethyl; Q.sup.s is CH.sub.2.
22. The compound as recited in claim 21 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of hydrido,ethyl, 2-propenyl, 2-propynyl, propyl,
isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2-butyl, tert-butyl,
isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl,
6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl,
3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl,
3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl,
6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl,
3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl,
4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl,
2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and
4-aminobutyl; A is selected from the group consisting of single
covalent bond, CH.sub.2, CH.sub.3CH, and CH.sub.2CH.sub.2; M is
selected from the group consisting of N and R.sup.1--C; R.sup.1 is
selected from the group consisting of hydrido, hydroxy, amino,
methyl, trifluoromethyl, fluoro, and chloro; R.sup.2 is selected
from the group consisting of 5-amino-3-amidocarbonylp- henyl,
5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl,
5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl,
3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl,
benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl,
3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl,
3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl,
3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl,
3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl,
2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl,
3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl,
3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl,
4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl,
3-trifluoromethylphenyl, 2-trifluoromethylphenyl,
5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl,
4-pyridyl, 2-thienyl, and 3-thienyl; Y.sup.0 is selected from the
group consisting of: 1-Q.sup.b-4-Q.sup.s-2-R-
.sup.16-3-R.sup.17-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup- .17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.- 18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-2-R.sup.19thiophene, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.s is CH.sub.2.
23. The compound as recited in claim 22 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of hydrido,ethyl, 2-propenyl, 2-propynyl, propyl,
isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2-butyl, tert-butyl,
isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl,
6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl,
3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl,
3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl,
6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl,
3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl,
4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl,
2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and
4-aminobutyl; A is selected from the group consisting of single
covalent bond, CH.sub.2, CH.sub.3CH, and CH.sub.2CH.sub.2; M is
selected from the group consisting of N and R.sup.1--C; R.sup.1 is
selected from the group consisting of hydrido, fluoro, and chloro;
R.sup.2 is selected from the group consisting of
5-amino-2-fluorophenyl, 3-amino-2-methylphenyl,
5-amino-2-methylthiophenyl, 3-aminophenyl, 3-carboxyphenyl,
3-cyanophenyl, 3-methoxycarbonylphenyl, phenyl, and 3-pyridyl;
Y.sup.0 is selected from the group consisting of
5-amidino-2-thienylmethyl, 4-amidinobenzyl,
2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amidinobenzyl.
24. A compound as recited in claim 17 where said compound is
selected from the group having the Formula: 65or a pharmaceutically
acceptable salt thereof, wherein: R.sup.2 is 3-aminophenyl, B is
2,2,2-trifluoroethyl, A is single bond, Y.sup.0 is 4-amidinobenzyl,
and M is CH; R.sup.2 is 3-aminophenyl, B is (S)-2-butyl, A is
single bond, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is
5-amino-2-fluorophenyl, B is isopropyl, A is single bond, Y.sup.0
is 4-amidinobenzyl, and M is CH; R.sup.2 is 2-methyl-3-aminophenyl,
B is isopropyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M
is CH; R.sup.2 is 3-aminophenyl, B is ethyl, A is single bond,
Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is 3-aminophenyl,
B is ethyl, A is single bond, Y.sup.0 is 4-amidino-2-fluorobenzyl,
and M is CH; R.sup.2 is 3-aminophenyl, B is 2-propenyl, A is single
bond, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is
3-aminophenyl, B is isopropyl, A is single bond, Y.sup.0 is
4-amidino-2-fluorobenzyl, and M is CH; p1 R.sup.2 is 3-aminophenyl,
B is isopropyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M
is CH; R.sup.2 is 3-aminophenyl, B is 2-butyl, A is single bond,
Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is 3-aminophenyl,
B is (R)-2-butyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and
M is CH; R.sup.2 is 3-aminophenyl, B is 2-propynyl, A is single
bond, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is
3-aminophenyl, B is 3-pentyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is CH; R.sup.2 is 3-aminophenyl, B is
hydrido, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CH;
R.sup.2 is 3-aminophenyl, B is ethyl, A is CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is CH; R.sup.2 is 3-aminophenyl, B is
2-methypropyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M
is CH; R.sup.2 is 3-aminophenyl, B is 2-propyl, A is CH.sub.3CH,
Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is 3-aminophenyl,
B is propyl, A is single bond, Y.sup.0 is 4-amidino-2-fluorobenzyl,
and M is CH; R.sup.2 is 3-aminophenyl, B is 6-amidocarbonylhexyl, A
is single bond, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is
3-aminophenyl, B is tert-butyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is CH; R.sup.2 is 3-aminophenyl, B is
tert-butyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M is
CH; R.sup.2 is 3-aminophenyl, B is 3-hydroxypropyl, A is single
bond, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is
3-aminophenyl, B is 2-methylpropyl, A is single bond, Y.sup.0 is
4-amidino-2-fluorobenzyl, and M is CH; R.sup.2 is 3-aminophenyl, B
is butyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M is
CH; R.sup.2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single
bond, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is
3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y.sup.0
is 4-amidinobenzyl, and M is CH; R.sup.2 is 3-aminophenyl, B is
2-methoxy-2-ethyl, A is single bond, Y.sup.0 is 4-amidinobenzyl,
and M is CH; R.sup.2 is 3-aminophenyl, B is 2-propyl, A is single
bond, Y.sup.0 is 5-amidino-2-thienylmethyl, and M is CH; R.sup.2 is
3-aminophenyl, B is 2-propyl, A is single bond, Y.sup.0 is
4-amidino-3-fluorobenzyl, and M is CH; R.sup.2 is 3-carboxyphenyl,
B is 2-propyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M
is CH; R.sup.2 is 3-aminophenyl, B is 2-propyl, A is single bond,
Y.sup.0 is 4-amidino-3-fluorobenzyl, and M is CH; R.sup.2 is
3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, Y.sup.0
is 4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B is
(S)-2-butyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M is
N; R.sup.2 is 5-amino-2-fluorophenyl, B is isopropyl, A is single
bond, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is
2-methyl-3-aminophenyl, B is isopropyl, A is single bond, Y.sup.0
is 4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B is
ethyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M is N;
R.sup.2 is 3-aminophenyl, B is ethyl, A is single bond, Y.sup.0 is
4-amidino-2-fluorobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B
is 2-propenyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M
is N; R.sup.2 is 3-aminophenyl, B is isopropyl, A is single bond,
Y.sup.0 is 4-amidino-2-fluorobenzyl, and M is N; R.sup.2 is
3-aminophenyl, B is isopropyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B is
2-butyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M is N;
R.sup.2 is 3-aminophenyl, B is (R)-2-butyl, A is single bond,
Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B
is 2-propynyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M
is N; R.sup.2 is 3-aminophenyl, B is 3-pentyl, A is single bond,
Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B
is hydrido, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is N;
R.sup.2 is 3-aminophenyl, B is ethyl, A is CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B is
2-methypropyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M
is N; R.sup.2 is 3-aminophenyl, B is 2-propyl, A is CH.sub.3CH,
Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B
is propyl, A is single bond, Y.sup.0 is 4-amidino-2-fluorobenzyl,
and M is N; R.sup.2 is 3-aminophenyl, B is 6-amidocarbonylhexyl, A
is single bond, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is
3-aminophenyl, B is tert-butyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B is
tert-butyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M is
N; R.sup.2 is 3-aminophenyl, B is 3-hydroxypropyl, A is single
bond, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is
3-aminophenyl, B is 2-methylpropyl, A is single bond, Y.sup.0 is
4-amidino-2-fluorobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B
is butyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M is N;
R.sup.2 is 3-aminophenyl, B is 3-methoxy-2-propyl, A is single
bond, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is
3-aminophenyl, B is 3-methoxy-2-propyl, A is single bond, Y.sup.0
is 4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B is
2-methoxy-2-ethyl, A is single bond, Y.sup.0 is 4-amidinobenzyl,
and M is N; R.sup.2 is 3-aminophenyl, B is 2-propyl, A is single
bond, Y.sup.0 is 5-amidino-2-thienylmethyl, and M is N; R.sup.2 is
3-aminophenyl, B is 2-propyl, A is single bond, Y.sup.0 is
4-amidino-3-fluorobenzyl, and M is N; R.sup.2 is 3-carboxyphenyl, B
is 2-propyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M is
N; R.sup.2 is 3-aminophenyl, B is 2-propyl, A is single bond,
Y.sup.0 is 4-amidino-3-fluorobenzyl, and M is CH.
25. The compound as recited in claim 2 having the Formula: 66or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated
heterocyclyl, wherein each ring carbon is optionally substituted
with R.sup.33, a ring carbon other than the ring carbon at the
point of attachment of B to A is optionally substituted with oxo
provided that no more than one ring carbon is substituted by oxo at
the same time, ring carbons and a nitrogen adjacent to the carbon
atom at the point of attachment are optionally substituted with
R.sup.9 or R.sup.13, a ring carbon or nitrogen adjacent to the
R.sup.9 position and two atoms from the point of attachment is
optionally substituted with R.sup.10, a ring carbon or nitrogen
adjacent to the R.sup.13 position and two atoms from the point of
attachment is optionally substituted with R.sup.12, a ring carbon
or nitrogen three atoms from the point of attachment and adjacent
to the R.sup.10 position is optionally substituted with R.sup.11, a
ring carbon or nitrogen three atoms from the point of attachment
and adjacent to the R.sup.12 position is optionally substituted
with R.sup.33, and a ring carbon or nitrogen four atoms from the
point of attachment and adjacent to the R.sup.11 and R.sup.33
positions is optionally substituted with R.sup.34; R.sup.9,
R.sup.11, and R.sup.13 are independently selected from the group
consisting of hydrido, hydroxy, amino, amidino, guanidino, lower
alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl,
alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy,
carboxamido, and cyano; R.sup.10 and R.sup.12 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino,
alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl,
halo, haloalkyl, and cyano; R.sup.33 and R.sup.34 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino,
alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano,
and Q.sup.b; A is selected from the group consisting of single
covalent bond and (CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein
rr is an integer selected from 0 through 1, pa is an integer
selected from 0 through 3, and W.sup.7 is selected from the group
consisting of (R.sup.7)NC(O) and N(R.sup.7); R.sup.7 is selected
from the group consisting of hydrido, hydroxy and alkyl; R.sup.15
is selected from the group consisting of hydrido, halo, alkyl, and
haloalkyl; M is selected from the group consisting of N and
R.sup.1--C; R.sup.1 is selected from the group consisting of
hydrido, hydroxy, hydroxyamino, amidino, amino, cyano,
hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio,
alkoxyamino, haloalkyl, haloalkoxy, and halo; R.sup.2 is
Z.sup.0--Q; Z.sup.0 is selected from the group consisting of a
covalent single bond, O, S, NH, and CH.sub.2; Q is selected from
the group consisting of aryl and heteroaryl wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.9, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.13, a
carbon adjacent to R.sup.9 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.10, a carbon
adjacent to R.sup.13 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.12, and any carbon
adjacent to both R.sup.10 and R.sup.12 is optionally substituted by
R.sup.11; Y.sup.0 is formula (IV): 67 wherein D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are independently selected from the group
consisting of C, N, O, S and a covalent bond with the provisos that
no more than one is a covalent bond, K.sup.2 is C, no more than one
of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is O, no more than one of
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is S, one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 must be a covalent bond when two of
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are O and S, and no more
than four of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are N;
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and
cyano; R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be; Q.sup.b is selected
from the group consisting of NR.sup.20R.sup.21, Q.sup.be wherein
Q.sup.be is hydrido, and C(NR.sup.25)NR.sup.23R.sup.24, with the
provisos that no more than one of R.sup.20 and R.sup.21 is hydroxy
at the same time and that no more than one of R.sup.23 and R.sup.24
is hydroxy at the same time; R.sup.20, R.sup.21, R.sup.23,
R.sup.24, and R.sup.25 are independently selected from the group
consisting of hydrido, alkyl, and hydroxy; Q.sup.s is selected from
the group consisting of a single covalent bond, CH.sub.2, and
CH.sub.2CH.sub.2.
26. The compound as recited in claim 25 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl,
azetidin-2-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl,
cyclohexyl, norbornyl, 7-oxabicyclo[2.2.1]heptan-2-yl,
bicyclo[3.1.0]hexan-6-yl, cycloheptyl, 2-morpholinyl,
3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl,
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,
1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl,
4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl,
4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,
2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl,
2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring
carbon is optionally substituted with R.sup.33, ring carbons and a
nitrogen adjacent to the carbon atom at the point of attachment are
optionally substituted with R.sup.9 or R.sup.13, a ring carbon or
nitrogen adjacent to the R.sup.9 position and two atoms from the
point of attachment is optionally substituted with R.sup.10, and a
ring carbon or nitrogen adjacent to the R.sup.13 position and two
atoms from the point of attachment is optionally substituted with
R.sup.12; R.sup.9, R.sup.11, and R.sup.13 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,
isopropoxy, propoxy, hydroxy, amino, N-methylamino,
N,N-dimethylamino, N-ethylamino, methylthio, ethylthio,
isopropylthio, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R.sup.10 and R.sup.12 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,
amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl,
fluoro, chloro, bromo, and cyano; R.sup.33 is selected from the
group consisting of hydrido, amidino, guanidino, carboxy, methoxy,
ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino,
ethoxyamino, acetamido, trifluoroacetamido, N-methylamino,
dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl,
methoxycarbonyl, ethoxycarbonyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and
Q.sup.b; A is selected from the group consisting of single covalent
bond, NH, N(CH.sub.3), N(OH), CH.sub.2, CH.sub.3CH, CF.sub.3CH,
NHC(O), N(CH.sub.3)C(O), C(O)NH, C(O)N(CH.sub.3), CH.sub.2CH.sub.2,
CH.sub.2CH.sub.2CH.sub.2, CH.sub.3CHCH.sub.2, and
CF.sub.3CHCH.sub.2; M is selected from the group consisting of N
and R.sup.1--C; R.sup.1 is selected from the group consisting of
hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl,
1-aminoethyl, methylamino, dimethylamino, cyano, methyl, ethyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino,
methylthio, ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy,
fluoro, chloro, and bromo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is
selected from the group consisting of a covalent single bond, O, S,
NH, and CH.sub.2; Q is selected from the group consisting of
phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl,
3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,
2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl,
4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and
1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the
point of attachment is optionally substituted by R.sup.9, the other
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.13, a carbon adjacent to R.sup.9
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.10, a carbon adjacent to R.sup.13
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.12, and any carbon adjacent to both
R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
Y.sup.0 is selected from the group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
2-Q.sup.b-4-Q.sup.s-3-R.sup.16-6-R.sup.18pyrazine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.18-5-R.sup.18-4-R.sup.19 pyridazine,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4R.sup.18pyrimidine,
5-Q.sup.b-2-Q.sup.s-3-R.sup.16-6-R.sup.19pyrimidine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-6-2-R.sup.19thiophene,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4R.sup.17thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.s- up.16-4R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R.- sup.19imidazole,
2-Q.sup.b-4-Q.sup.s-5-R.sup.17imidazole,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16isoxazole,
5-Q.sup.b-3-Q.sup.s-4-R.sup.16is- oxazole,
2-Q.sup.b-5-Q.sup.s-4-R.sup.16pyrazole, 4-Q.sup.b-2-Q.sup.s-5-R.s-
up.19thiazole, and 2-Q.sup.b-5-Q.sup.s-4R.sup.17thiazole; R.sup.16,
R.sup.17, R.sup.18, and R.sup.19 are independently selected from
the group consisting of hydrido, methyl, ethyl, isopropyl, propyl,
carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy,
hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio,
isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl,
methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, and cyano; R.sup.16 and R.sup.19
are optionally Q.sup.b with the proviso that no more than one of
R.sup.16 and R.sup.19 is Q.sup.b at the same time and that Q.sup.b
is Q.sup.be; Q.sup.b is selected from the group consisting of
Q.sup.be wherein Q.sup.be is hydrido and
C(NR.sup.25)NR.sup.23R.sup.24, with the proviso that no more than
one of R.sup.23 and R.sup.24 is hydroxy at the same time; R.sup.23,
R.sup.24, and R.sup.25 are independently selected from the group
consisting of hydrido, methyl, ethyl, and hydroxy; Q.sup.s is
selected from the group consisting of a single covalent bond,
CH.sub.2 and CH.sub.2CH.sub.2.
27. The compound as recited in claim 26 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl,
1-pyrrolidinyl, 1-piperidinyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl,
azetidin-1-yl, azetidin-2-yl, azetidin-3-yl,
7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl,
2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl,
2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,
4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl,
4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl,
3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl,
4tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl; A
is selected from the group consisting of single covalent bond,
CH.sub.2, NHC(O), CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2; M
is selected from the group consisting of N and R.sup.1--C; R.sup.1
is selected from the group consisting of hydrido, hydroxy, amino,
amidino, hydroxyamino, aminomethyl, methylamino, cyano, methyl,
trifluoromethyl, methoxy, hydroxymethyl, methoxyamino, methylthio,
trifluoromethoxy, fluoro, and chloro; R.sup.2 is Z.sup.0--Q;
Z.sup.0 is selected from the group consisting of a covalent single
bond, O, S, NH, and CH.sub.2; Q is selected from the group
consisting of 5-amino-3-amidocarbonylphenyl,
5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl,
5-amino-3-methoxycarbonylphenyl, 3-amidinophenophenyl,
3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl,
benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl,
3-carboxy-5-hydroxyphen- yl, 3-carboxymethyl-5-aminophenyl,
3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl,
3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl,
3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl,
2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl,
3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl,
3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl,
4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl,
3-trifluoromethylphenyl, 2-trifluoromethylphenyl,
5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl,
4-pyridyl, 2-thienyl, and 3-thienyl; Y.sup.0 is selected from the
group consisting of: 1-Q.sup.b-4-Q.sup.s-2-R-
.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.s- up.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.su- p.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophen- e, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.s is CH.sub.2.
28. The compound as recited in claim 25 having the Formula: 68or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated
heterocyclyl, wherein each ring carbon is optionally substituted
with R.sup.33, a ring carbon other than the ring carbon at the
point of attachment of B to A is optionally substituted with oxo
provided that no more than one ring carbon is substituted by oxo at
the same time, ring carbons and a nitrogen adjacent to the carbon
atom at the point of attachment are optionally substituted with
R.sup.9 or R.sup.13, a ring carbon or nitrogen adjacent to the
R.sup.9 position and two atoms from the point of attachment is
optionally substituted with R.sup.10, a ring carbon or nitrogen
adjacent to the R.sup.13 position and two atoms from the point of
attachment is optionally substituted with R.sup.12, a ring carbon
or nitrogen three atoms from the point of attachment and adjacent
to the R.sup.10 position is optionally substituted with R.sup.11, a
ring carbon or nitrogen three atoms from the point of attachment
and adjacent to the R.sup.12 position is optionally substituted
with R.sup.33, and a ring carbon or nitrogen four atoms from the
point of attachment and adjacent to the R.sup.11 and R.sup.33
positions is optionally substituted with R.sup.34; R.sup.9,
R.sup.11, and R.sup.13 are independently selected from the group
consisting of hydrido, hydroxy, amino, amidino, guanidino, lower
alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl,
amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R.sup.10
and R.sup.12 are independently selected from the group consisting
of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl,
alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl,
carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano;
R.sup.33 and R.sup.34 are independently selected from the group
consisting of hydrido, amidino, guanidino, alkoxy, hydroxy, amino,
alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, and
cyano; R.sup.33 is optionally Q.sup.b; A is selected from the group
consisting of single covalent bond and
(CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
3, and W.sup.7 is N(R.sup.7); R.sup.7 is selected from the group
consisting of hydrido and alkyl R.sup.15 is selected from the group
consisting of hydrido, halo, alkyl, and haloalkyl; M is selected
from the group consisting of N and R.sup.1--C; R.sup.1 is selected
from the group consisting of hydrido, hydroxy, hydroxyamino,
amidino, amino, cyano, hydroxyalkyl, alkoxy, alkyl, alkylamino,
aminoalkyl, alkylthio, alkoxyamino, haloalkyl, haloalkoxy, and
halo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is a covalent single bond; Q
is selected from the group consisting of aryl and heteroaryl
wherein a carbon adjacent to the carbon at the point of attachment
is optionally substituted by R.sup.9, the other carbon adjacent to
the carbon at the point of attachment is optionally substituted by
R.sup.13, a carbon adjacent to R.sup.9 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.10, a carbon adjacent to R.sup.13 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.12, and any carbon adjacent to both R.sup.10 and R.sup.12 is
optionally substituted by R.sup.11; R.sup.9, R.sup.11, and R.sup.13
are independently selected from the group consisting of hydrido,
hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio,
alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl,
monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy,
hydroxyalkyl, carboxy, carboxamido, and cyano; R.sup.10 and
R.sup.12 are independently selected from the group consisting of
hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl,
alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl,
carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano;
Y.sup.0 is formula (IV): 69 wherein D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 are independently selected from the group consisting of C,
N, O, S and a covalent bond with the provisos that no more than one
is a covalent bond, K.sup.2 is C, no more than one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 is O, no more than one of
D.sup.5,D.sup.6,J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 must be a covalent bond when two of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are O and S, and no more than four of
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are N; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,
alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; Q.sup.b is selected from the group consisting
of NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido, and
C(NR.sup.25)NR.sup.23R.sup.24; R.sup.20, R.sup.21, R.sup.23,
R.sup.24, and R.sup.25 are independently selected from the group
consisting of hydrido and alkyl; Q.sup.s is CH.sub.2.
29. The compound as recited in claim 28 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl,
1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl,
azetidin-3-yl, bicyclo[3.1.0]hexan-6-yl, 2-morpholinyl,
3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl,
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,
1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl,
2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl,
3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and
3-tetrahydrothienyl, wherein each ring carbon is optionally
substituted with R.sup.33, ring carbons and a nitrogen adjacent to
the carbon atom at the point of attachment are optionally
substituted with R.sup.9 or R.sup.13, a ring carbon or nitrogen
adjacent to the R.sup.9 position and two atoms from the point of
attachment is optionally substituted with R.sup.10, and a ring
carbon or nitrogen atom adjacent to the R.sup.13 position and two
atoms from the point of attachment is optionally substituted with
R.sup.12; R.sup.9, R.sup.11, and R.sup.13 are independently
selected from the group consisting of hydrido, methyl, ethyl,
methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino,
methylthio, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and
cyano; R.sup.10 and R.sup.12 are independently selected from the
group consisting of hydrido, amidino, amidocarbonyl,
N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy,
hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy,
carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl,
N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo,
and cyano; R.sup.33 is selected from the group consisting of
hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy,
hydroxy, carboxy, amino, N-methylamino, dimethylamino, methylthio,
ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,
hydroxymethyl, amidocarbonyl, cyano, and Q.sup.b; A is selected
from the group consisting of single covalent bond, NH, N(CH.sub.3),
CH.sub.2, CH.sub.3CH, CH.sub.2CH.sub.2, and
CH.sub.2CH.sub.2CH.sub.2; M is selected from the group consisting
of N and R.sup.1--C; R.sup.1 is selected from the group consisting
of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl,
methylamino, cyano, methyl, trifluoromethyl, methoxy,
hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro,
and chloro; R.sup.2 is selected from the group consisting of
phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl,
3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent
to the carbon at the point of attachment is optionally substituted
by R.sup.9, the other carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.13, a carbon adjacent
to R.sup.9 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.10, a carbon adjacent to
R.sup.13 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.12, and any carbon adjacent to
both R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
Y.sup.0 is selected from the group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R-
.sup.17-5-R.sup.18-6-R.sup.17benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.s- up.18-2-R.sup.19pyridine,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophe- ne,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19 pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.s- up.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R- .sup.19thiazole, and
2-Q.sup.b-5-Q.sup.s-4-R.sup.17thiazole; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy,
hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, methylthio, ethylthio,
trifluoromethylthio, methylsulfinyl, methylsulfonyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
trifluoromethoxy, fluoro, chloro, amidosulfonyl,
N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano. Q.sup.b
is selected from the group consisting of NR.sup.20R.sup.21 and
C(NR.sup.25)NR.sup.23R.sup.24, with the proviso that said Q.sup.b
group is bonded directly to a carbon atom; R.sup.20, R.sup.21,
R.sup.23, R.sup.24, and R.sup.25 are independently selected from
the group consisting of hydrido, methyl, and ethyl; Q.sup.s is
CH.sub.2.
30. The compound as recited in claim 29 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl, 1,1-dioxothiolan -3-yl,
oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl,
1-pyrrolidinyl and 1-piperidinyl; A is selected from the group
consisting of a single covalent bond, CH.sub.2, NHC(O),
CH.sub.2CH.sub.2 and CH.sub.2CH.sub.2CH.sub.2; M is selected from
the group consisting of N and R.sup.1--C; R.sup.1 is selected from
the group consisting of hydrido, hydroxy, amino, methyl,
trifluoromethyl, fluoro, and chloro; R.sup.2 is selected from the
group consisting of 3-aminophenyl, 2,6-dichlorophenyl,
2-hydroxyphenyl, 5amino-2-thienyl, and 3-thienyl; Y.sup.0 is
selected from the group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5- -R.sup.18-6-R.sup.19
benzene, 3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19 thiophene, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.s is CH.sub.2.
31. The compound as recited in claim 30 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl, 1,1-dioxothiolan-3-yl,
oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and
1-piperidinyl; A is selected from the group consisting of a single
covalent bond, CH.sub.2, CH.sub.2CH.sub.2 and
CH.sub.2CH.sub.2CH.sub.2; M is selected from the group consisting
of N and R.sup.1--C; R.sup.1 is selected from the group consisting
of hydrido, fluoro, and chloro; R.sup.2 is selected from the group
consisting of 3-aminophenyl, 2,6-dichlorophenyl, 2-hydroxyhenyl,
phenyl, 5-amino-2-thienyl, and 3-thienyl; Y.sup.0 is selected from
the group consisting of 5amidino-2-thienylmethyl, 4-amidinobenzyl,
2-fluoro-amidinobenzyl, and 3-fluoro-4-amidinobenzyl.
32. A compound as recited in claim 25 where said compound is
selected from the group having the Formula: 70or a pharmaceutically
acceptable salt thereof, wherein: R.sup.2 is 3-aminophenyl, B is
cycylopropyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M
is CH; R.sup.2 is 3-aminophenyl, B is cyclobutyl, A is single bond,
Y.sup.0 is 4-amidino-2-fluorobenzyl, and M is CH; R.sup.2 is
3-aminophenyl, B is cyclobutyl, A is single bond, Y is
4-amidinobenzyl, and M is CH; R.sup.2 is 3-aminophenyl, B is
cyclopropyl, A is single bond, Y.sup.0 is 4-amidino-2-fluorobenzyl,
and M is CH; R.sup.2 is 3-aminophenyl, B is cyclobutyl, A is single
bond, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is
3-aminophenyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidino-3-fluorobenzyl, and M is CH; R.sup.2 is 3-aminophenyl, B
is cyclopentyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M
is CH; R.sup.2 is 5-amino-2-thienyl, B is cyclobutyl, A is single
bond, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is
3-aminophenyl, B is cyclopropyl, A is CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is CH; R.sup.2 is 3-aminophenyl, B is
2-(2R)-bicyclo[2.2.1]-heptyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is CH; R.sup.2 is 3-aminophenyl, B is
cyclopentyl, A is single bond, Y.sup.0 is 4amidino-2-fluorobenzyl,
and M is CH; R.sup.2 is 3-aminophenyl, B is cyclohexyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2
is 3-aminophenyl, B is oxalan-2-yl, A is CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is CH; R.sup.2 is phenyl, B is
1-pyrrolidinyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and M is CH; R.sup.2 is 3-aminophenyl, B is 1,1-piperidinyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2
is 3-aminophenyl, B is 1,1-dioxothiolan-3-yl, A is single bond,
Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is
2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is CH; R.sup.2 is 3-aminophenyl, B is
1-pyrrolidinyl, A is CH.sub.2CH.sub.2CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is CH; R.sup.2 is phenyl, B is cyclobutyl, A
is single bond, Y.sup.0 is 4-amidinobenzyl, and M is CH; R.sup.2 is
3-thienyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is CH; R.sup.2 is 2,6-dichlorophenyl, B is
cyclobutyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M is
CH; R.sup.2 is 3-aminophenyl, B is cycylopropyl, A is single bond,
Y.sup.0 is 4-amidinobenzyl, and M is CF; R.sup.2 is 3-aminophenyl,
B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidino-2-fluorobenzyl, and M is CF; R.sup.2 is 3-aminophenyl, B
is cyclobutyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M
is CF; R.sup.2 is 3-aminophenyl, B is cyclopropyl, A is single
bond, Y.sup.0 is 4amidino-2-fluorobenzyl, and M is CF; R.sup.2 is
3-aminophenyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is CF; R.sup.2 is 3-aminophenyl, B is
cyclobutyl, A is single bond, Y.sup.0 is 4-amidino-3-fluorobenzyl,
and M is CF; R.sup.2 is 3-aminophenyl, B is cyclopentyl, A is
single bond, Y.sup.0 is 4-amidinobenzyl, and M is CF; R.sup.2 is
5amino-2-thienyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is CF; R.sup.2 is 3-aminophenyl, B is
cyclopropyl, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is
CF; R.sup.2 is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A
is single bond, Y.sup.0 is 4-amidinobenzyl, and M is CF; R.sup.2 is
3-aminophenyl, B is cyclopentyl, A is single bond, Y.sup.0 is
4-amidino-2-fluorobenzyl, and M is CF; R.sup.2 is 3-aminophenyl, B
is cyclohexyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and M is CF; R.sup.2 is 3-aminophenyl, B is oxalan-2-yl, A is
CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is CF; R.sup.2 is
phenyl, B is 1-pyrrolidinyl, A is CH.sub.2CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is CF; R.sup.2 is 3-aminophenyl, B is
1-piperidinyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and M is CF; R.sup.2 is 3-aminophenyl, B is 1,1-dioxothiolan-3-yl,
A is single bond, Y.sup.0 is 4-amidinobenzyl, and M is CF; R.sup.2
is 2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is CF; R.sup.2 is 3-aminophenyl, B is
1-pyrrolidinyl, A is CH.sub.2CH.sub.2CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is CF; R.sup.2 is phenyl, B is cyclobutyl, A
is single bond, Y.sup.0 is 4-amidinobenzyl, and M is CF; R.sup.2 is
3-thienyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is CF; R.sup.2 is 2,6-dichlorophenyl, B is
cyclobutyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M is
CF; R.sup.2 is 3-aminophenyl, B is cycylopropyl, A is single bond,
Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B
is cyclobutyl, A is single bond, Y.sup.0 is
4-amidino-2-fluorobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B
is cyclobutyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M
is N; R.sup.2 is 3-aminophenyl, B is cyclopropyl, A is single bond,
Y.sup.0 is 4-amidino-2-fluorobenzyl, and M is N; R.sup.2 is
3-aminophenyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B is
cyclobutyl, A is single bond, Y.sup.0 is 4-amidino-3-fluorobenzyl,
and M is N; R.sup.2 is 3-aminophenyl, B is cyclopentyl, A is single
bond, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is
5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B is
cyclopropyl, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is N;
R.sup.2 is 3-aminophenyl, B is 2-(2R)-bicyclo[2.2.1]-heptyl, A is
single bond, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is
3-aminophenyl, B is cyclopentyl, A is single bond, Y.sup.0 is
4-amidino-2-fluorobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B
is cyclohexyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and M is N; R.sup.2 is 3-aminophenyl, B is oxalan-2-yl, A is
CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is
phenyl, B is 1-pyrrolidinyl, A is CH.sub.2CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B is
1-piperidinyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and M is N; R.sup.2 is 3-aminophenyl, B is 1,1-dioxothiolan-3-yl, A
is single bond, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is
2-hydroxyphenyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is N; R.sup.2 is 3-aminophenyl, B is
1-pyrrolidinyl, A is CH.sub.2CH.sub.2CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and M is N; R.sup.2 is phenyl, B is cyclobutyl, A
is single bond, Y.sup.0 is 4-amidinobenzyl, and M is N; R.sup.2 is
3-thienyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and M is N; R.sup.2 is 2,6dichlorophenyl, B is
cyclobutyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M is
CH.
33. The compound having the Formula: 71or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of aryl and heteroaryl wherein a carbon adjacent to the
carbon at the point of attachment is optionally substituted by
R.sup.32, the other carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.36, a carbon adjacent
to R.sup.32 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.33, a carbon adjacent
to R.sup.36 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.35, and any carbon
adjacent to both R.sup.33 and R.sup.35 is substituted by R.sup.34;
R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkylenedioxy,
haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino,
haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl,
cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl,
haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b; B is optionally selected from the
group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8
alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl,
wherein each member of group B is optionally substituted at any
carbon up to and including 6 atoms from the point of attachment of
B to A with one or more of the group consisting of R.sup.32,
R.sup.33, R.sup.34, R.sup.35, and R.sup.36; B is optionally
selected from the group consisting of C3-C12 cycloalkyl and C4-C9
saturated heterocyclyl, wherein each ring carbon is optionally
substituted with R.sup.33, a ring carbon other than the ring carbon
at the point of attachment of B to A is optionally substituted with
oxo provided that no more than one ring carbon is substituted by
oxo at the same time, ring carbons and a nitrogen adjacent to the
carbon atom at the point of attachment are optionally substituted
with R.sup.9 or R.sup.13, a ring carbon or nitrogen adjacent to the
R.sup.9 position and two atoms from the point of attachment is
optionally substituted with R.sup.10, a ring carbon or nitrogen
adjacent to the R.sup.13 position and two atoms from the point of
attachment is optionally substituted with R.sup.12, a ring carbon
or nitrogen three atoms from the point of attachment and adjacent
to the R.sup.10 position is optionally substituted with R.sup.11, a
ring carbon or nitrogen three atoms from the point of attachment
and adjacent to the R.sup.12 position is optionally substituted
with R.sup.33, and a ring carbon or nitrogen four atoms from the
point of attachment and adjacent to the R.sup.11 and R.sup.33
positions is optionally substituted with R.sup.34; R.sup.9,
R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino,
guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino,
lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and
cyano; A is selected from the group consisting of single covalent
bond and (CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an
integer selected from 0 through 1, pa is an integer selected from 0
through 3, and W.sup.7 is selected from the group consisting of O,
S, C(O), (R.sup.7)NC(O), (R.sup.7)NC(S), and N(R.sup.7); R.sup.7 is
selected from the group consisting of hydrido, hydroxy and alkyl;
R.sup.15 is selected from the group consisting of hydrido, hydroxy,
halo, alkyl, and haloalkyl; M is selected from the group consisting
of N and R.sup.1--C; R.sup.1 is selected from the group consisting
of hydrido, hydroxy, hydroxyamino, amidino, amino, cyano,
hydroxyalkyl, alkoxy, alkyl, alkylamino, aminoalkyl, alkylthio,
alkoxyamino, haloalkyl, haloalkoxy, and halo; R.sup.2 is
Z.sup.0--Q; Z.sup.0 is selected from the group consisting of
covalent single bond and (CR.sup.41R.sup.42).sub.q wherein q is an
integer selected from 1 through 2,
(CH(R.sup.41)).sub.g--W.sup.0--(CH(R.s- up.42)).sub.p wherein g and
p are integers independently selected from 0 through 3 and W.sup.0
is selected from the group consisting of O, S, and N(R.sup.41), and
(CH(R.sup.41)).sub.e--W.sup.22--(CH(R.sup.42)).sub.h wherein e and
h are integers independently selected from 0 through 1 and W.sup.22
is selected from the group consisting of CR.sup.41.dbd.CR.sup.42- ,
1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl,
1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,
2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl,
1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl,
1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl,
3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,
2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5pyrrolidinyl,
3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso
that Z.sup.0 is directly bonded to the pyrazinone ring; R.sup.41
and R.sup.42 are independently selected from the group consisting
of hydrido, hydroxy, and amino; Q is selected from the group
consisting of hydrido with the proviso that Z.sup.0 is other than a
covalent single bond, aryl and heteroaryl, wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.9, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.13, a
carbon adjacent to R.sup.9 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.10, a carbon
adjacent to R.sup.13 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.12, and any carbon
adjacent to both R.sup.10 and R.sup.12 is optionally substituted by
R.sup.11; K is CHR.sup.4a wherein R.sup.4a is selected from the
group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl,
alkylthioalkyl, and haloalkyl; E.sup.0 is selected from the group
consisting of a covalent single bond, C(O)N(H), (H)NC(O),
(R.sup.7)NS(O).sub.2, and S(O).sub.2N(R.sup.7); Y.sup.AT is
Q.sup.b--Q.sup.s; Q.sup.s is (CR.sup.37R.sup.38).sub.b wherein b is
an integer selected from 1 through 4, R.sup.37 is selected from the
group consisting of hydrido, alkyl and haloalkyl, and R.sup.38 is
selected from the group consisting of hydrido, alkyl, haloalkyl,
aroyl, and heteroaroyl with the provisos that there is at least one
aroyl or heteroaroyl substituent, that no more than one aroyl or
heteroaroyl is bonded to (CR.sup.37R.sup.38).sub.b at the same
time, that said aroyl and said heteroaroyl are optionally
substituted at from one through three of the ring carbons with a
substituent selected from the group consisting of R.sup.16,
R.sup.17, R.sup.18, and R.sup.19, that said aroyl and said
heteroaroyl are bonded to the CR.sup.37R.sup.38 that is directly
bonded to E.sup.0, that is no more than one alkyl or one haloalkyl
is bonded to a CR.sup.37R.sup.38 at the same time, and that said
alkyl and haloalkyl are bonded to a carbon other than the one
bonding the aroyl or heteroaroyl; R.sup.16, R.sup.17, R.sup.18, and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy,
hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R.sup.16 and R.sup.19 are optionally Q.sup.b with the proviso that
no more than one of R.sup.16 and R.sup.19 is Q.sup.b at the same
time and that Q.sup.b is Q.sup.be; Q.sup.b is selected from the
group consisting of NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is
hydrido, N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), and
C(NR.sup.25)NR.sup.23R.sup.24, with the provisos that no more than
one of R.sup.20 and R.sup.21 is hydroxy, amino, alkylamino, or
dialkylamino at the same time and that no more than one of R.sup.23
and R.sup.24 is hydroxy, amino, alkylamino, or dialkylamino at the
same time; R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino.
34. The compound as recited in claim 33 having the Formula: 72or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl,
3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl,
3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and
5-isoxazolyl, wherein a carbon adjacent to the carbon at the point
of attachment is optionally substituted by R.sup.32, the other
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.36, a carbon adjacent to R.sup.32
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.33, a carbon adjacent to R.sup.36
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.35, and any carbon adjacent to both
R.sup.33 and R.sup.35 is optionally substituted by R.sup.34;
R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino,
N-methylamino, dimethylamino, methylthio, ethylthio,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro,
chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl,
amidocarbonyl, carboxy, cyano, and Q.sup.b; B is optionally
selected from the group consisting of hydrido, ethyl, 2-propenyl,
2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl,
sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl,
2-pentenyl, 3-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl,
2-methylbutyl, 2-methyl-2-butenyl, 3-methylbutyl,
3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,
2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl,
1-methyl-3-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl,
3-hexyl, 1-ethyl-2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl,
4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl,
5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl,
1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl,
1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl,
1-ethyl-3-pentenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl,
2,2,2-trifluoroethyl, 2,2-difluoropropyl,
4-trifluoromethyl-5,5,5-trifluo- ropentyl, 4-trifluoromethylpentyl,
5,5,6,6,6pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each
member of group B is optionally substituted at any carbon up to and
including 5 atoms from the point of attachment of B to A with one
or more of the group consisting of R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36; B is optionally selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclo[2.2.1]-heptyl,
1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl,
azetidin-3-yl, bicyclo[3.1.0]hexan-6-yl, 2-morpholinyl,
3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl,
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,
1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl,
2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl,
3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and
3-tetrahydrothienyl, wherein each ring carbon is optionally
substituted with R.sup.33, ring carbons and a nitrogen adjacent to
the carbon atom at the point of attachment are optionally
substituted with R.sup.9 or R.sup.13, a ring carbon or nitrogen
adjacent to the R.sup.9 position and two atoms from the point of
attachment is optionally substituted with R.sup.10, and a ring
carbon or nitrogen adjacent to the R.sup.13 position and two atoms
from the point of attachment is optionally substituted with
R.sup.12; R.sup.9, R.sup.11, and R.sup.13 are independently
selected from the group consisting of hydrido, methyl, ethyl,
methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino,
methylthio, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and
cyano; R.sup.10 and R.sup.12 are independently selected from the
group consisting of hydrido, amidino, amidocarbonyl,
N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy,
hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy,
carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl,
N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo,
and cyano; A is selected from the group consisting of single
covalent bond, NH, N(CH.sub.3), CH.sub.2, CH.sub.3CH,
CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2; M is selected from
the group consisting of N and R.sup.1--C; R.sup.1 is selected from
the group consisting of hydrido, hydroxy, amino, amidino,
hydroxyamino, aminomethyl, 1-aminoethyl, methylamino,
dimethylamino, cyano, methyl, ethyl, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio,
ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro,
chloro, and bromo; R.sup.2 is selected from the group consisting of
phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl,
3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent
to the carbon at the point of attachment is optionally substituted
by R.sup.9, the other carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.13, a carbon adjacent
to R.sup.9 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.10, a carbon adjacent to
R.sup.13 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.12, and any carbon adjacent to
both R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
Y.sup.AT is Q.sup.b--Q.sup.s; Q.sup.s is selected from the group
consisting of: C[R.sup.37(benzoyl)](CR.sup.37R.sup.38).sub.b],
C[R.sup.37(2-pyridylcarbonyl])](CR.sup.37R.sup.38).sub.b],
C[R.sup.37(3-pyridylcarbonyl])](CR.sup.37R.sup.38).sub.b],
C[R.sup.37(4-pyridylcarbonyl])](CR.sup.37R.sup.38).sub.b],
C[R.sup.37(2-thienylcarbonyl])](CR.sup.37R.sup.38).sub.b],
C[R.sup.37(3-thienylcarbonyl])](CR.sup.37R.sup.38).sub.b],
C[R.sup.37(2-thiazolylcarbonyl])](CR.sup.37R.sup.38).sub.b],
C[R.sup.37(4-thiazolylcarbonyl])](CR.sup.37R.sup.38).sub.b], and
C[R.sup.37(5-thiazolylcarbonyl])](CR.sup.37R.sup.38).sub.b],
wherein b is an integer selected from 1 through 3, R.sup.37 and
R.sup.38 are independently selected from the group consisting of
hydrido, alkyl, and haloalkyl, with the provisos that said aroyl
and said heteroaroyl are optionally substituted at from one through
three of the ring carbons with a substituent selected from the
group consisting of R.sup.16, R.sup.17, R.sup.18, and R.sup.19 with
the proviso that R.sup.17 and R.sup.18 are optionally substituted
at a carbon selected from other than the meta and para carbons
relative to the carbonyl of the benzoyl substituent and the
heteroaroyl substituent, that said benzoyl and said heteroaroyl are
bonded to the carbon directly bonded to amide nitrogen of the
1-(amidocarbonymethylene) group, and that is no more than one alkyl
or one haloalkyl is bonded to a CR.sup.37R.sup.38 at the same time;
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, methyl, ethyl,
amidino, guanidino, methoxy, hydroxy, amino, aminomethyl,
1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino,
methylthio, ethylthio, trifluoromethylthio, methylsulfinyl,
methylsulfonyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro,
amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and
cyano; Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21 and C(NR.sup.25)NR.sup.23R.sup.24, with the
proviso that said Q.sup.b group is bonded directly to a carbon
atom; R.sup.20, R.sup.21, R.sup.23, R.sup.24, and R.sup.25 are
independently selected from the group consisting of hydrido,
methyl, and ethyl.
35. The compound as recited in claim 34 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl,
4-amidinophenyl, 3-carboxyphenyl, 3-carboxy-5hydroxyphenyl,
3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl,
3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl,
4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl,
3-trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl,
5-chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl,
3-thienyl, and 3-trifluoromethyl-2-pyridyl; B is optionally
selected from the group consisting of hydrido,ethyl, 2-propenyl,
2-propynyl, propyl, isopropyl, butyl, 2-butyl,
(R)-2-butyl,(S)-2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl,
2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl,
4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl,
2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl,
2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl,
2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl,
3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl,
4-hydroxybutyl, 6cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl,
2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and
4-aminobutyl; B is optionally selected from the group consisting of
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl,
2-(2R)-bicyclo[2.2.1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl,
azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 1-pyrrolidinyl and
1-piperidinyl; A is selected from the group consisting of single
covalent bond, CH.sub.2, CH.sub.3CH, CH.sub.2CH.sub.2, and
CH.sub.2CH.sub.2CH.sub.- 2; M is selected from the group consisting
of N and R.sup.1--C; R.sup.1 is selected from the group consisting
of hydrido, hydroxy, amino, amidino, hydroxyamino, aminomethyl,
methylamino, cyano, methyl, trifluoromethyl, methoxy,
hydroxymethyl, methoxyamino, methylthio, trifluoromethoxy, fluoro,
and chloro; R.sup.2 is selected from the group consisting of
5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl,
3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl,
3-amidinophenyl, 3-amino-2-methylphenyl, 5amino-2-methylthiophenyl,
3-aminophenyl, benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl,
3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5aminophenyl,
3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl,
3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl,
3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl,
2,5difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl,
3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl,
3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl,
4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl,
3-trifluoromethylphenyl, 2-trifluoromethylphenyl,
5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl,
4-pyridyl, 2-thienyl, and 3-thienyl; Y.sup.AT is Q.sup.b--Q.sup.s;
Q.sup.s is selected from the group consisting of:
[CH(benzoyl)](CH.sub.2).sub.b,
[CH(2-pyridylcarbonyl)](CH.sub.2).sub.b,
[CH(3-pyridylcarbonyl)](CH.sub.2- ).sub.b,
[CH(4-pyridylcarbonyl)](CH.sub.2).sub.b, [CH(2-thienylcarbonyl)](-
CH.sub.2).sub.b, [CH(3-thienylcarbonyl)](CH.sub.2).sub.b,
[CH(2-thiazolylcarbonyl)](CH.sub.2).sub.b,
[CH(4-thiazolylcarbonyl)](CH.s- ub.2).sub.b, and
[CH(5thiazolylcarbonyl)](CH.sub.2).sub.b. wherein b is an integer
selected from 1 through 3, with the provisos that said aroyl and
said heteroaroyl are optionally substituted at from one through
three of the ring carbons with a substituent selected from the
group consisting of R.sup.16, R.sup.17, R.sup.18, and R.sup.19 with
the proviso that R.sup.17 and R.sup.18 are optionally substituted
at a carbon selected from other than the meta and para carbons
relative to the carbonyl of the benzoyl substituent and the
heteroaroyl substituent, and that said benzoyl and said heteroaroyl
substituent are bonded to the carbon directly bonded to amide
nitrogen of the 1-(amidocarbonymethylene) group; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.17 and
R.sup.18 are independently selected from the group consisting of
hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy,
and cyano; Q.sup.b is C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23,
R.sup.24, and R.sup.25 are independently selected from the group
consisting of hydrido and methyl.
36. The compound as recited in claim 35 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl,
3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl,
4-methylphenyl, phenyl, 2-imidazoyl, 3-pyridyl, 4-pyridyl, and
3-trifluoromethyl-2-pyridy- l; B is optionally selected from the
group consisting of hydrido,ethyl, 2-propenyl, 2-propynyl, propyl,
isopropyl, butyl, 2-butyl, (R)-2-butyl,(S)-2-butyl, tert-butyl,
isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl,
6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl,
3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl,
3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl,
6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl,
3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl,
4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl,
2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and
4-aminobutyl; B is optionally selected from the group consisting of
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl,
2-(2R)-bicyclo[2.2.1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl,
azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and 1-piperidinyl; A
is selected from the group consisting of a single covalent bond,
CH.sub.2, CH.sub.2CH.sub.2 and CH.sub.2CH.sub.2CH.sub.2; M is
selected from the group consisting of N and R.sup.1--C; R.sup.1 is
selected from the group consisting of hydrido, hydroxy, amino,
methyl, trifluoromethyl, fluoro, and chloro; R.sup.2 is selected
from the group consisting of 3-aminophenyl, benzyl,
2,6-dichlorophenyl, 5-amino-2-thienyl, 5-amino-2-fluorophenyl,
3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl,
3-carboxyphenyl, 3-cyanophenyl, 3-chlorophenyl, 2-hydroxyhenyl,
3-hydroxyphenyl, 3-methanesulfonylaminophenyl,
3-methoxycarbonylphenyl, 3-dimethylaminophenyl,
3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, phenyl,
3-pyridyl, 3-trifluoroacetamidophenyl, 3-bromo-2-thienyl,
2-thienyl, and 3-thienyl; Y.sup.AT is selected from the group
consisting of 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl,
5-guanidino-1-oxo-1-(4-thiazolyl)-2-pentyl,
5-guanidino-1-oxo-1-(5thiazol- yl)-2-pentyl,
5-guanidino-1-oxo-1-(4-amino-2-thiazolyl)-2-pentyl, and
5-guanidino-1-oxo-1-phenyl-2-pentyl.
37. A compound as recited in claim 33 where said compound is
selected from the group having the Formula: 73or a pharmaceutically
acceptable salt thereof, wherein: R.sup.2 is 3-aminophenyl, B is
phenyl, A is CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CH; R.sup.2 is
phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CH; R.sup.2 is
benzyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CH; R.sup.2 is
phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CH; R.sup.2 is
benzyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CH; R.sup.2 is
phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CH; R.sup.2 is
3-aminophenyl, B is phenyl, A is CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CF; R.sup.2 is
phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CF; R.sup.2 is
benzyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CF; R.sup.2 is
phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CF; R.sup.2 is
benzyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CF; R.sup.2 is
phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CF; R.sup.2 is
3-aminophenyl, B is phenyl, A is CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CCl; R.sup.2
is phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CCl; R.sup.2
is benzyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CCl; R.sup.2
is phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CCl; R.sup.2
is benzyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CCl; R.sup.2
is phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is CCl; R.sup.2
is 3-aminophenyl, B is phenyl, A is CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is N; R.sup.2 is
phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is N; R.sup.2 is
benzyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is N; R.sup.2 is
phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is N; R.sup.2 is
benzyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is N; R.sup.2 is
phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and M is N;
38. A composition for inhibiting thrombotic conditions in blood
comprising a compound of claim 1 and a pharmaceutically acceptable
carrier.
39. A method for inhibiting thrombotic conditions in blood
comprising adding to blood a therapeutically effective amount of a
composition of claim 38.
40. A method for inhibiting formation of blood platelet aggregates
in blood comprising adding to blood a therapeutically effective
amount of a composition of claim 38.
41. A method for inhibiting thrombus formation in blood comprising
adding to blood a therapeutically effective amount of a composition
of claim 38.
42. A method for treating or preventing venuous thromboembolism and
pulmonary embolism in a mammal comprising administering to the
mammal a therapeutically effective amount of a composition of claim
38.
43. A method for treating or preventing deep vein thrombosis in a
mammal comprising administering to the mammal a therapeutically
effective amount of a composition of claim 38.
44. A method for treating or preventing cardiogenic thromboembolism
in a mammal comprising administering to the mammal a
therapeutically effective amount of a composition of claim 38.
45. A method for treating or preventing thromboemboli stroke in
humans and other mammals comprising administering to the mammal a
therapeutically effective amount of a composition of claim 38.
46. A method for treating or preventing thrombosis associated with
cancer and cancer chemotherapy in humans and other mammals
comprising administering to the mammal a therapeutically effective
amount of a composition of claim 38.
47. A method for treating or preventing unstable angina in humans
and other mammals comprising administering to the mammal a
therapeutically effective amount of a composition of claim 38.
48. A method for inhibiting thrombus formation in blood comprising
adding to blood a therapeutically effective amount of a compound of
claim 1 with a therapeutically effective amount of fibrinogen
receptor antagonist.
Description
FIELD OF THE INVENTION
[0001] This invention is in the field of anticoagulant therapy, and
specifically relates to compounds, compositions and methods for
preventing and treating thrombotic conditions such as coronary
artery and cerebrovascular disease. More particularly, the
invention relates to substituted polycyclic aryl and heteroaryl
uracil compounds that inhibit serine proteases of the coagulation
cascade.
BACKGROUND OF THE INVENTION
[0002] Physiological systems control the fluidity of blood in
mammals [Majerus, P. W. et al: Anticoagulant, Thrombolytic, and
Antiplplatelet Drugs. In Hardman, J. G. and Limbird, L. E.,
editors: Goodman & Gilman's The Pharmacological Basis of
Therapeutics. 9th edition. New York, McGraw-Hill Book Co., 1996,
pp. 1341-1343]. Blood must remain fluid within the vascular systems
and yet be able to undergo hemostasis, cessation of blood loss from
a damaged vessel, quickly. Hemostasis or clotting begins when
platelets first adhere to macromolecules in subendothelian regions
of an injured and/or damaged vessels. These platelets aggregate to
form the primary hemostatic plug and stimulate local activation of
plasma coagulation factors leading to generation of a fibrin clot
that reinforces the aggregated platelets.
[0003] Plasma coagulation factors include factors II, V, VII, VIII,
IX, X, XI, and XII; these are also called protease zymogens. These
coagulation factors or protease zymogens are activated by serine
proteases leading to coagulation in a so called "coagulation
cascade" or chain reaction [Handin, R. I.: Bleeding and Thrombosis.
In Wilson, J., et al. editors: Harrison's Principles of Internal
Medicine. 12th Edition, New York, McGraw-Hill Book Co.,
1991,p.350]. Coagulation or clotting occurs in two ways through
different pathways. An intrinsic or contact pathway leads from XII
to XIIa to XIa to IXa and to the conversion of X to Xa. Xa with
factor Va converts prothrombin (II) to thrombin (IIa) leading to
conversion of fibrinogen to fibrin. Polymerization of fibrin leads
to a fibrin clot. An extrinsic pathway is initiated by the
conversion of coagulation factor VII to VIIa by Xa. The presence of
Tissue Factor and VIIa accelerates formation of Xa in the presence
of calcium ion and phospholipids. Formation of Xa leads to
thrombin, fibrin, and a fibrin clot as described above. The
presence of one or more of these many different coagulation factors
and two distinct pathways of clotting could enable the efficacious,
selective control and better understanding of parts of the
coagulation or clotting process.
[0004] While clotting as a result of an injury to a blood vessel is
a critical physiological process for mammals such as man, clotting
can also lead to disease states. A pathological process called
thrombosis results when platelet aggregation and/or a fibrin clot
blocks (i.e., occludes) a blood vessel. Arterial thrombosis may
result in ischemic necrosis of the tissue supplied by the artery.
When the thrombosis occurs in a coronary artery, a myocardial
infarction or heart attack can result. A thrombosis occurring in a
vein may cause tissues drained by the vein to become edematous and
inflamed. Thrombosis of a deep vein may be complicated by a
pulmonary embolism. Preventing or treating clots in a blood vessel
may be therapeutically useful by inhibiting formation of blood
platelet aggregates, inhibiting formation of fibrin, inhibiting
thrombus formation, inhibiting embolus formation, and for treating
or preventing unstable angina, refractory angina, myocardial
infarction, transient ischemic attacks, atrial fibrillation,
thrombotic stroke, embolic stroke, deep vein thrombosis,
disseminated intravascular coagulation, ocular build up of fibrin,
and reocclusion or restenosis of recanalized vessels.
[0005] There have been several reports of non-peptidic and peptidic
uracil compounds that act as an inhibitor of a coagulation factor
present in the coagulation cascade or clotting process. In U.S.
Pat. No. 5,656,645, Tamura et al. describe
4,5,6-substituted-3-aminopyridonyl-acetamides, 1,6-substituted
-5-aminouracinylacetamides, and 2,4-substituted-5-aminopy-
rimidinonyl-acetamides in which the amide substituents all have a
formyl group and which reportedly have activity against thrombin.
In U.S. Pat. No. 5,658,930, Tamura et al. again describe
4,5,6-substituted-3-aminopyri- donyl-acetamides, 1,6-substituted
-5-aminouracinylacetamides, and
2,4-substituted-5-amino-pyrimidinonylacetamides in which the amide
substituents all have a formyl group and which reportedly have
activity against thrombin. In PCT Patent Applications 96/18644 and
97/46207, Tamura et al. further describe 4,5,6-substituted
-3-aminopyridonylacetami- des,
1,6-substituted-5-aminouracinyl-acetamides, and
2,4-substituted-5-amino-pyrimidinonylacetamides in which the amide
substituents all have a formyl group and which reportedly have
activity against thrombin.
SUMMARY OF THE INVENTION
[0006] It is an object of the present invention to provide
compounds that are beneficial in anticoagulant therapy and that
have a general structure: 1
[0007] It is another object of the present invention to provide
methods for preventing and treating thrombotic conditions, such as
coronary artery disease, cerebrovascular disease, and other
coagulation related disorders. Such thrombotic conditions are
prevented and treated by administering to a patient in need thereof
an effective amount of compounds of Formula (I).
[0008] Various other objects and advantages of the present
invention will become apparent from the following description of
the invention.
DESCRIPTION OF THE INVENTION
[0009] The present invention relates to a class of compounds
comprising Substituted Polycyclic Aryl and Heteroaryl uracils,
which are beneficial in anticoagulant therapy for the treatment and
prevention of a variety of thrombotic conditions including coronary
artery and cerebrovascular disease, as given in Formula (I): 2
[0010] or a pharmaceutically acceptable salt thereof, wherein;
[0011] J.sup.a and J.sup.b are independently selected from the
group consisting of O and S;
[0012] J.sup.a is optionally selected from the group consisting of
CH--R.sup.6 and N--R.sup.6 wherein R.sup.6 is a linear spacer
moiety having from 1 through 4 contiguous atoms linked to the point
of bonding of a substituent selected from the group consisting of
R.sup.4a, R.sup.4b, R.sup.14, R.sup.15, R.sup.39, R.sup.40, and
R.sup.5 to form a heterocyclyl ring having 5 through 8 contiguous
members;
[0013] J.sup.b is optionally selected from the group consisting of
CH--R.sup.6 and N--R.sup.6 wherein R.sup.6 is a linear spacer
moiety having from 1 through 4 contiguous atoms linked to the point
of bonding of a substituent selected from the group consisting of
R.sub.1, R.sup.4a, R.sup.4b, R.sup.14 and R.sup.15 to form a
heterocyclyl ring having 5 through 8 contiguous members;
[0014] J.sup.a and J.sup.b are optionally independently selected
from the group consisting of CH--R.sup.6 and N--R.sup.6 wherein
R.sup.6 is a linear spacer moiety having from 1 through 4
contiguous atoms linked to the points of bonding of both R.sup.4a
and R.sup.4b to form a heterocyclyl ring having 5 through 8
contiguous members;
[0015] J.sup.a is optionally selected from the group consisting of
CH--R.sup.6 and N--R.sup.6 wherein R.sup.6 is a linear spacer
moiety having from 1 through 4 contiguous atoms linked to the
points of bonding of both R.sup.39 and R.sup.40 to form a
heterocyclyl ring having 5 through 8 contiguous members;
[0016] B is formula (V): 3
[0017] wherein D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one can be a
covalent bond, no more than one of D.sup.1, D.sup.2, J.sup.1,
J.sup.2 and K.sup.1 is O, no more than one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 is S, one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 must be a covalent bond when two of
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are O and S, and no
more than four of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1
are N with the proviso that R.sup.32, R.sup.33, R.sup.34, R.sup.35,
and R.sup.36 are each independently selected to maintain the
tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, and the divalent nature of oxygen;
[0018] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36 are independently selected from the group
consisting of hydrido, acetamido, haloacetamido, amidino,
guanidino, dialkylsulfonium, trialkylphosphonium,
dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy,
cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy,
heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,
heterocyclyl, perhaloaralkyl, aralkylsulfonyl,
aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,
halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,
cycloalkylsulfinylalkyl, cycloalkylsulfonyl,
cycloalkylsulfonylalkyl, heteroarylamino,
N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,
haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl,
heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl,
cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy,
halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy,
halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro,
lower alkylamino, alkylthio, alkylthioalkyl, arylamino,
aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,
alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl,
arylsulfonylalkyl, heteroarylsulfinylalkyl,
heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,
haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,
alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,
diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,
arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,
heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio,
alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl,
heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl,
alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,
cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower
cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl,
haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,
hydroxyalkyl, alkylenylamino, hydroxyheteroaralkyl,
haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl,
saturated heterocyclyl, partially saturated heterocyclyl,
heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl,
heteroarylalkyl, arylalkenyl, heteroarylalkenyl, carboxyalkyl,
carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,
arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,
carboxy, carboaralkoxy, carboxamido, carboxamidoalkyl, cyano,
carbohaloalkoxy, phosphono, phosphonoalkyl, diaralkoxyphosphono,
and diaralkoxyphosphonoalkyl;
[0019] R.sup.16, R.sup.19, R.sup.32, R.sup.33, R.sup.35 and
R.sup.36 are independently optionally Q.sup.b with the proviso that
no more than one of R.sup.16 and R.sup.19 is Q.sup.b at the same
time and that Q.sup.b is Q.sup.be;
[0020] R.sup.32 and R.sup.33, R.sup.33 and R.sup.34, R.sup.34 and
R.sup.35, and R.sup.35 and R.sup.36 are independently optionally
selected to form a spacer pair wherein a spacer pair is taken
together to form a linear moiety having from 3 through 6 contiguous
atoms connecting the points of bonding of said spacer pair members
to form a ring selected from the group consisting of a cycloalkenyl
ring having 5 through 8 contiguous members, a partially saturated
heterocyclyl ring having 5 through 8 contiguous members, a
heteroaryl ring having 5 through 6 contiguous members, and an aryl
with the proviso that no more than one of the group consisting of
spacer pairs R.sup.32 and R.sup.33, R.sup.33 and R.sup.34, R.sup.34
and R.sup.35, and R.sup.35 and R.sup.36 are used at the same
time;
[0021] R.sup.9 and R.sup.10, R.sup.10 and R.sup.11, R.sup.11 and
R.sup.12, and R.sup.12 and R.sup.13 are independently optionally
selected to form a spacer pair wherein a spacer pair is taken
together to form a linear moiety having from 3 through 6 contiguous
atoms connecting the points of bonding of said spacer pair members
to form a ring selected from the group consisting of a cycloalkenyl
ring having 5 through 8 contiguous members, a partially saturated
heterocyclyl ring having 5 through 8 contiguous members, a
heteroaryl ring having 5 through 6 contiguous members, and an aryl
with the proviso that no more than one of the group consisting of
spacer pairs R.sup.9 and R.sup.10, R.sup.10 and R.sup.11, R.sup.11
and R.sup.12, and R.sup.12 and R.sup.13 are used at the same
time;
[0022] B is optionally formula (VI): 4
[0023] wherein D.sup.3, D.sup.4, J.sup.3, J.sup.4 are independently
selected from the group consisting of C, N, O, and S, no more than
one of D.sup.3, D.sup.4, J.sup.3, and J.sup.4 is O, no more than
one of D.sup.3, D.sup.4, J.sup.3, and J.sup.4 is S, and no more
than three of D.sup.1, D.sup.2, J.sup.1, and J.sup.2 are N with the
proviso that R.sup.32, R.sup.33, R.sup.34, and R.sup.35 are each
independently selected to maintain the tetravalent nature of
carbon, trivalent nature of nitrogen, the divalent nature of
sulfur, and the divalent nature of oxygen;
[0024] B is optionally selected from the group consisting of
hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkenyl, C3-C8
alkylehyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl
wherein each member of group B is optionally substituted at any
carbon up to and including 6 atoms from the point of attachment of
B to A with one or more of the group consisting of R.sub.32,
R.sub.33, R.sub.34, R.sub.35, and R.sub.36;
[0025] B is optionally selected from the group consisting of C3-C15
cycloalkyl, C5-C10 cycloalkenyl, C4-C12 saturated heterocyclyl, and
C4-C9 partially saturated heterocyclyl, wherein each ring carbon is
optionally substituted with R.sup.33, a ring carbon other than the
ring carbon at the point of attachment of B to A is optionally
substituted with oxo provided that no more than one ring carbon is
substituted by oxo at the same time, ring carbons and nitrogen
adjacent to the carbon atom at the point of attachment are
optionally substituted with R.sup.9 or R.sup.13, a ring carbon or
nitrogen adjacent to the .sup.R9 position and two atoms from the
point of attachment is optionally substituted with R.sup.10, a ring
carbon or nitrogen adjacent to the R.sup.13 position and two atoms
from the point of attachment is optionally substituted with
R.sup.12, a ring carbon or nitrogen three atoms from the point of
attachment and adjacent to the R.sup.10 position is optionally
substituted with R.sup.11, a ring carbon or nitrogen atom three
atoms from the point of attachment and adjacent to the R.sup.12
position is optionally substituted with R.sup.33, and a ring carbon
or nitrogen four atoms from the point of attachment and adjacent to
the R.sup.11 and R.sup.33 positions is optionally substituted with
R.sup.34;
[0026] A is selected from the group consisting of single covalent
bond, (W.sup.7).sub.rr--(CH(R.sup.15)).sub.pa and
(CH(R.sup.15)).sub.pa--(W.sup- .7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
6, and W.sup.7 is selected from the group consisting of O, S, C(O),
C(S), C(O)S, C(S)O, C(O)N(R.sup.7), C(S)N(R.sup.7), (R.sup.7)NC(O),
(R.sup.7)NC(S), S(O), S(O).sub.2, S(O).sub.2N(R.sup.7),
(R.sup.7)NS(O).sub.2, Se(O), Se(O).sub.2, Se(O).sub.2N(R.sup.7),
(R.sup.7)NSe(O).sub.2, P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8),
P(O)(R.sup.8)N(R.sup.7), C(NR.sup.7)N(R.sup.7),
(R.sup.7)NC(NR.sup.7), (R.sup.7)NC(NR.sup.7)NR.sup.7, and
N(R.sup.7) with the proviso that no more than one of the group
consisting of rr and pa is 0 at the same time;
[0027] R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrido, hydroxy, alkyl, alkenyl, aryl,
aralkyl, aryloxy, alkoxy, alkenyloxy, alkylthio, alkylamino,
arylthio, arylamino, acyl, aroyl, heteroaroyl, aralkoxyalkyl,
heteroaralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl,
alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl,
alkylsulfinylalkyl, alkylsulfonylalkyl, heteroaryl, heteroaryloxy,
heteroarylamino, heteroaralkyl, heteroaralkyloxy,
heteroaralkylamino, and heteroaryloxyalkyl;
[0028] R.sup.14, R.sup.15, R.sup.37, R.sup.38, R.sup.40, R.sup.41
and R.sup.42 are independently selected from the group consisting
of amidino, hydroxyamino, hydrido, hydroxy, halo, cyano, aryloxy,
amino, alkylamino, dialkylamino, hydroxyalkyl, aminoalkyl, acyl,
aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido,
alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl,
aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl,
alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl,
alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,
arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,
cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl,
halocycloalkyl, halocycloalkenyl, haloalkoxy, haloalkoxyalkyl,
haloalkenyloxyalkyl, halocycloalkoxy, halocycloalkoxyalkyl,
halocycloalkenyloxyalkyl, saturated heterocyclyl, partially
saturated heterocyclyl, heteroaryl, heteroarylalkyl,
heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,
dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,
carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl,
haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl,
arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl,
aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,
cycloalkylsulfonyl, cycloalkylsulfinylalkyl,
cycloalkylsufonylalkyl, heteroarylsulfonylalkyl,
heteroarylsulfinyl, heteroarylsulfonyl, heteroarylsulfinylalkyl,
aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy, carboxyalkyl,
carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy,
trialkylsilyl, dialkoxyphosphono, diaralkoxyphosphono,
dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl with the
proviso that R.sup.37 and R.sup.38 are independently selected from
other than formyl;
[0029] R.sup.14 and R.sup.14, when bonded to different carbons, are
optionally taken together to form a group selected from the group
consisting of covalent bond, alkylene, haloalkylene, and a linear
moiety spacer selected to form a ring selected from the group
consisting of cycloalkyl ring having from 5 through 8 contiguous
members, cycloalkenyl ring having from 5 through 8 contiguous
members, and a heterocyclyl having from 5 through 8 contiguous
members;
[0030] R.sup.14 and R.sup.15, when bonded to different carbons, are
optionally taken together to form a group selected from the group
consisting of covalent bond, alkylene, haloalkylene, and a linear
moiety spacer selected to form a ring selected from the group
consisting of a cycloalkyl ring having from 5 through 8 contiguous
members, a cycloalkenyl ring having from 5 through 8 contiguous
members, and a heterocyclyl having from 5 through 8 contiguous
members;
[0031] R.sup.15 and R.sup.15, when bonded to different carbons, are
optionally taken together to form a group selected from the group
consisting of covalent bond, alkylene, haloalkylene, and a linear
moiety spacer selected to form a ring selected from the group
consisting of cycloalkyl ring having from 5 through 8 contiguous
members, cycloalkenyl ring having from 5 through 8 contiguous
members, and a heterocyclyl having from 5 through 8 contiguous
members;
[0032] .PSI. is selected from the group consisting of NR.sup.5, O,
C(O), C(S), S, S(O), S(O).sub.2, ON(R.sup.5), P(O)(R.sup.8), and
CR.sup.39R.sup.40;
[0033] R.sup.5 is selected from the group consisting of hydrido,
hydroxy, amino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aryloxy,
aralkoxy, alkoxy, alkenyloxy, alkylthio, arylthio, aralkoxyalkyl,
heteroaralkoxyalkyl, aryloxyalkyl, alkoxyalkyl, alkenyloxyalkyl,
alkylthioalkyl, arylthioalkyl, aralkoxyalkyl, heteroaralkoxyalkyl,
alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,
cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,
halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl,
halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, heteroaryl,
heteroarylalkyl, monocarboalkoxyalkyl, monocarboalkoxy,
dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl, dicyanoalkyl,
carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl,
heteroaryloxyalkyl, and dialkoxyphosphonoalkyl;
[0034] R.sup.39 and R.sup.40, when bonded to the same carbon, are
optionally taken together to form a group selected from a group
consisting of oxo, thiono, R.sup.5--N, alkylene, haloalkylene, and
a linear moiety spacer having from 2 through 7 contiguous atoms to
form a ring selected from the group consisting of a cycloalkyl ring
having from 3 through 8 contiguous members, a cycloalkenyl ring
having from 3 through 8 contiguous members, and a heterocyclyl ring
having from 3 through 8 contiguous members;
[0035] M is selected from the group consisting of N and
R.sup.1--C;
[0036] R.sup.2 and R.sup.1 are independently selected from the
group consisting of Z.sup.0--Q, hydrido, alkyl, alkenyl, and
halo;
[0037] R.sup.1 is optionally selected from the group consisting of
amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy,
hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio,
dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl,
heteroarylamino, nitro, arylamino, aralkylamino, alkanoyl,
alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,
haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono;
[0038] R.sup.2 is optionally selected from the group consisting of
amidino, guanidino, dialkylsulfonium, trialkylphosphonium,
dialkylsulfoniumalkyl, heteroarylamino, amino, nitro, alkylamino,
arylamino, aralkylamino, alkanoyl, alkenoyl, aroyl, heteroaroyl,
aralkanoyl, heteroaralkanoyl, haloalkanoyl, hydroxyhaloalkyl,
cyano, and phosphono;
[0039] R.sup.2 and R.sup.4a, R.sup.2 and R.sup.4b, R.sup.2 and
R.sup.14, and R.sup.2 and R.sup.15 are optionally independently
selected to form spacer pairs wherein a spacer pair is taken
together to form a linear moiety having from 2 through 5 contiguous
atoms connecting the points of bonding of said spacer pair members
to form a heterocyclyl ring having from 5 through 8 contiguous
members with the proviso that no more than one of the group of
spacer pairs consisting of R.sup.2 and R.sup.4a, R.sup.2 and
R.sup.4b, R.sup.2 and R.sup.14 and R.sup.2 and R.sup.15 is used at
the same time;
[0040] R.sup.2 is optionally independently selected to form a
linear moiety having from 2 through 5 contiguous atoms linked to
the points of bonding of both R.sup.4a and R.sup.4b to form a
heterocyclyl ring having from 5 through 8 contiguous members;
[0041] Z.sup.0 is selected from the group consisting of covalent
single bond, (CR.sup.41R.sup.42).sub.q wherein q is an integer
selected from 1 through 6,
(CH(R.sup.41)).sub.g--W.sup.0--(CH(R.sup.42)).sub.p wherein g and p
are integers independently selected from 0 through 3 and W.sup.0 is
selected from the group consisting of O, S, C(O), C(S), C(O)O,
C(S)O, C(O)S, C(S)S, C(O)N(R.sup.41), (R.sup.41)NC(O),
C(S)N(R.sup.41), (R.sup.41)NC(S), OC(O)N(R.sup.41),
(R.sup.41)NC(O)O, SC(S)N(R.sup.41), (R.sup.41)NC(S)S,
SC(O)N(R.sup.41), (R.sup.41)NC(O)S, OC(S)N(R.sup.41),
(R.sup.41)NC(S)O, N(R.sup.42)C(O)N(R.sup.41),
(R.sup.41)NC(O)N(R.sup.42), N(R.sup.42)C(S)N(R.sup.41),
(R.sup.41)NC(S)N(R.sup.42), S(O), S(O).sub.2,
S(O).sub.2N(R.sup.41), N(R.sup.41)S(O).sub.2, Se, Se(O),
Se(O).sub.2, Se(O).sub.2N(R.sup.41), N(R.sup.41)Se(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
N(R.sup.41), ON(R.sup.41), and SiR.sup.28R.sup.29, and
(CH(R.sup.41)).sub.e--W.sup.22-- -(CH(R.sup.42)).sub.h wherein e
and h are integers independently selected from 0 through 2 and
W.sup.22 is selected from the group consisting of
CR.sup.41.dbd.CR.sup.42, CR.sup.41R.sup.42.dbd.C; vinylidene),
ethynylidene (C.dbd.C; 1,2-ethynyl), 1,2-cyclopropyl,
1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl,
1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl,
3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl,
2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl,
2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl,
1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,
2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos
that R.sup.41 and R.sup.42 are selected from other than halo and
cyano when directly bonded to N and Z.sup.0 is directly bonded to
the uracil ring;
[0042] R.sup.28 and R.sup.29 are independently selected from the
group consisting of hydrido, hydroxyalkyl, alkyl, alkenyl, alkynyl,
aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl,
aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,
aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl,
heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,
cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,
halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl,
halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,
perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,
heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,
cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl,
cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl,
cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl,
dicarboxamidocycloalkyl, carboalkoxycyanocycloalky- l,
carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl,
acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl,
cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,
heteroarylsulfonylalkyl, heteroarylsulfinylalkyl,
aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy,
dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and
diaralkoxyphosphonoalkyl;
[0043] R.sup.28 and R.sup.29 are optionally taken together to form
a linear moiety spacer having from 2 through 7 contiguous atoms and
forming a ring selected from the group consisting of a cycloalkyl
ring having from 3 through 8 contiguous members, a cycloalkenyl
ring having from 3 through 8 contiguous members, and a heterocyclyl
ring having from 3 through 8 contiguous members;
[0044] Q is formula (II): 5
[0045] wherein D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one can be a
covalent bond, no more than one of D.sup.1, D.sup.2, J.sup.1,
J.sup.2 and K.sup.1 can be O, no more than one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 can be S, one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 must be a covalent bond when two of
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are O and S, and no
more than four of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1
can be N, with the proviso that R.sup.9, R.sup.10, R.sup.11,
R.sup.12, and R.sup.13 are each independently selected to maintain
the tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, and the divalent nature of oxygen;
[0046] Q is optionally selected from formula (III): 6
[0047] wherein D.sup.3, D.sup.4, J.sup.3, and J.sup.4 are
independently selected from the group consisting of C, N, O, and S,
no more than one of D.sup.3, D.sup.4, J.sup.3, and J.sup.4 is O, no
more than one of D.sup.3, D.sup.4, J.sup.3, and J.sup.4 is S, and
no more than three of D.sup.1, D.sup.2, J.sup.1, and J.sup.2 are N
with the proviso that R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are
each independently selected to maintain the tetravalent nature of
carbon, trivalent nature of nitrogen, the divalent nature of
sulfur, and the divalent nature of oxygen;
[0048] Q is optionally selected from the group consisting of
hydrido, alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio,
alkenyl, alkynyl, saturated heterocyclyl, partially saturated
heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,
cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl,
halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl,
haloalkenyloxyalkyl, halocycloalkoxyalkyl, and
halocycloalkenyloxyalkyl with the proviso that Z.sup.0 is selected
from other than a single covalent bond when Q is hydrido;
[0049] K is (CR.sup.4aR.sup.4b).sub.n wherein n is an integer
selected from 1 through 4;
[0050] R.sup.4a and R.sup.4b are independently selected from the
group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl,
alkyl, alkenyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl,
alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,
aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl,
haloalkyl, haloalkenyl, heteroaryl, heteroarylalkyl,
heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl,
alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl,
arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfonylalkyl,
heteroarylsulfinylalkyl, aralkylsulfinylalkyl, and
aralkylsulfonylalkyl with the provisos that halo, hydroxy, and
cyano are bonded to different carbons when simultaneously present
and that R.sup.4a and R.sup.4b are other than hydroxy or cyano when
bonded to the carbon directly bonded to the uracil nitrogen;
[0051] R.sup.4a and R.sup.4b, when bonded to the same carbon, are
optionally taken together to form a group selected from the group
consisting of oxo, thiono, and a linear spacer moiety having from 2
through 7 contiguous atoms connected to form a ring selected from
the group consisting of a cycloalkyl ring having 3 through 8
contiguous members, a cycloalkenyl ring having 5 through 8
contiguous members, and a heterocyclyl ring having 5 through 8
contiguous members with the proviso that R.sup.4a and R.sup.4b
taken together is other than oxo or thiono when the common carbon
is directly bonded to the uracil nitrogen;
[0052] E.sup.0 is E.sup.1, when K is (CR.sup.4aR.sup.4b).sub.n,
wherein E.sup.1 is selected from the group consisting of a covalent
single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,
C(O)N(R.sup.7), (R.sup.7)NC(O), C(S)N(R.sup.7), (R.sup.7)NC(S),
OC(O)N(R.sup.7), (R.sup.7)NC(O)O, SC(S)N(R.sup.7), (R.sup.7)NC(S)S,
SC(O)N(R.sup.7), (R.sup.7)NC(O)S, OC(S)N(R.sup.7), (R.sup.7)NC(S)O,
N(R.sup.8)C(O)N(R.sup.7), (R.sup.7)NC(O)N(R.sup.8),
N(R.sup.8)C(S)N(R.sup.7), (R.sup.7)NC(S)N(R.sup.8), S(O),
S(O).sub.2, S(O).sub.2N(R.sup.7), N(R.sup.7)S(O).sub.2,
S(O).sub.2N(R.sup.7)C(O), C(O)N(R.sup.7)S(O).sub.2, Se, Se(O),
Se(O).sub.2, Se(O).sub.2N(R.sup.7), N(R.sup.7)Se(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
N(R.sup.7), ON(R.sup.7), SiR.sup.28R.sup.29,
CR.sup.4a.dbd.CR.sup.4b, ethynylidene (C.dbd.C; 1,2-ethynyl), and
C.dbd.CR.sup.4aR.sup.4b;
[0053] K is optionally selected to be (CH(R.sup.14)).sub.j--T
wherein j is selected from a integer from 0 through 3 and T is
selected from the group consisting of single covalent bond, O, S,
and N(R.sup.7) with the provisos that R.sup.14 is other than
hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and
sulfhydryl when j is 1 and that (CH(R.sup.14)).sub.j is bonded to
the uracil ring;
[0054] E.sup.0 is optionally E.sup.2, when K is
(CH(R.sup.14)).sub.j--T, wherein E.sup.2 is selected from the group
consisting of a covalent single bond, C(O), C(S), C(O)O, C(S)O,
C(O)S, C(S)S, C(O)N(R.sup.7), (R.sup.7)NC(O), C(S)N(R.sup.7),
(R.sup.7)NC(S), (R.sup.7)NC(O)O, (R.sup.7)NC(S)S, (R.sup.7)NC(O)S,
(R.sup.7)NC(S)O, N(R.sup.8)C(O)N(R.sup.7),
(R.sup.7)NC(O)N(R.sup.8), N(R.sup.8)C(S)N(R.sup.7),
(R.sup.7)NC(S)N(R.sup.8), S(O), S(O).sub.2, S(O).sub.2N(R.sup.7),
N(R.sup.7)S(O).sub.2, S(O).sub.2N(H)C(O), C(O)N(H)S(O).sub.2,
Se(O), Se(O).sub.2, Se(O).sub.2N(R.sup.7), N(R.sup.7)Se(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
and N(R.sup.7);
[0055] K is optionally selected to be G--(CH(R.sup.15)).sub.k
wherein k is selected from an integer from 1 through 3 and G is
selected from the group consisting of O, S, and N(R.sup.7) with the
proviso that R.sup.15 is other than hydroxy, cyano, halo, amino,
alkylamino, dialkylamino, and sulfhydryl when k is 1;
[0056] E.sup.0 is optionally E.sup.3 when K is
G--(CH(R.sup.15)).sub.k wherein E.sup.3 is selected from the group
consisting of a covalent single bond, O, S, C(O), C(S), C(O)O,
C(S)O, C(O)S, C(S)S, C(O)N(R.sup.7), (R.sup.7)NC(O),
C(S)N(R.sup.7), (R.sup.7)NC(S), OC(O)N(R.sup.7), (R.sup.7)NC(O)O,
SC(S)N(R.sup.7), (R.sup.7)NC(S)S, SC(O)N(R.sup.7), (R.sup.7)NC(O)S,
OC(S)N(R.sup.7), (R.sup.7)NC(S)O, N(R.sup.8)C(O)N(R.sup.7),
(R.sup.7)NC(O)N(R.sup.8), N(R.sup.8)C(S)N(R.sup.7),
(R.sup.7)NC(S)N(R.sup.8), S(O), S(O).sub.2, S(O).sub.2N(R.sup.7),
N(R.sup.7)S(O).sub.2, Se, Se(O), Se(O).sub.2,
Se(O).sub.2N(R.sup.7), N(R.sup.7)Se(O).sub.2, P(O)(R.sup.8),
N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7), N(R.sup.7),
ON(R.sup.7), SiR.sup.28R.sup.29, CR.sup.4a.dbd.CR.sup.4b,
ethynylidene (C.dbd.C; 1,2-ethynyl), and
C.dbd.CR.sup.4aR.sup.4b;
[0057] Y.sup.0 is formula (IV): 7
[0058] wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is independently selected from the group
consisting of C and N.sup.+, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is O, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 must be a covalent bond when two of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are O and S, no more than three of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are N when K.sup.2 is N.sup.+, and no
more than four of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are N when
K.sup.2 is carbon with the provisos that R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are each independently selected to maintain
the tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, and the divalent nature of oxygen;
[0059] R.sup.16 and R.sup.17 are independently optionally taken
together to form a linear moiety spacer having from 3 through 6
contiguous atoms connected to form a ring selected from the group
consisting of a cycloalkenyl ring having from 5 through 8
contiguous members, a partially saturated heterocyclyl ring having
from 5 through 8 contiguous members, a heteroaryl having from 5
through 6 contiguous members, and an aryl;
[0060] R.sup.18 and R.sup.19 are independently optionally taken
together to form a linear moiety spacer having from 3 through 6
contiguous atoms connected to form a ring selected from the group
consisting of a cycloalkenyl ring having from 5 through 8
contiguous members, a partially saturated heterocyclyl ring having
from 5 through 8 contiguous members, a heteroaryl having from 5
through 6 contiguous members, and an aryl;
[0061] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, .sup.+NR.sup.20R.sup.21R.sup.22, oxy, alkyl,
aminoalkylenyl, alkylamino, dialkylamino, dialkylsulfoniumalkyl,
acylamino and Q.sup.be wherein Q.sup.be is hydrido and R.sup.20,
R.sup.21, and R.sup.22 are independently selected from the group
consisting of hydrido, amino, alkyl, hydroxy, alkoxy,
aminoalkylenyl, alkylamino, dialkylamino, and hydroxyalkyl with the
provisos that no more than one of R.sup.20, R.sup.21, and R.sup.22
is hydroxy, alkoxy, alkylamino, amino, and dialkylamino at the same
time and that R.sup.20, R.sup.21, and R.sup.22 must be other than
be hydroxy, alkoxy, alkylamino, amino, and dialkylamino when
K.sup.2 is N.sup.+;
[0062] R.sup.20 and R.sup.21, R.sup.20 and R.sup.22, and R.sup.21
and R.sup.22 are independently optionally selected to form a spacer
pair wherein a spacer pair is taken together to form a linear
moiety having from 4 through 7 contiguous atoms connecting the
points of bonding of said spacer pair members to form a
heterocyclyl ring having 5 through 8 contiguous members with the
proviso that no more than one of the group consisting of spacer
pairs R.sup.20 and R.sup.21, R.sup.20 and R.sup.22, and R.sup.21
and R.sup.22 is used at the same time;
[0063] Q.sup.b is optionally selected from the group consisting of
N(R.sup.26)SO.sub.2N(R.sup.23)(R.sup.24), N(R.sup.26)C(O)OR.sup.5,
N(R.sup.26)C(O)SR.sup.5, N(R.sup.26)C(S)OR.sup.5 and
N(R.sup.26)C(S)SR.sup.5 with the proviso that no more than one of
R.sup.23, R.sup.24, and R.sup.26 can be hydroxy, alkoxy,
alkyleneamino, alkylamino, amino, or dialkylamino when two of the
group consisting of R.sup.23, R.sup.24, and R.sup.26 are bonded to
the same atom;
[0064] Q.sup.b is optionally selected from the group consisting of
dialkylsulfonium, trialkylphosphonium,
C(NR.sup.25)NR.sup.23R.sup.24,
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24),
N(R.sup.26)C(O)N(R.sup.23)(- R.sup.24), N(R.sup.26)C(S)N(R
)(R.sup.23) C(NR.sup.25)OR.sup.5,
C(O)N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24),
C(S)N(R.sup.26)C(NR.sup- .25)N(R.sup.23)(R.sup.24),
N(R.sup.26)N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R- .sup.24),
ON(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24),
N(R.sup.26)N(R.sup.26)SO.sub.2N(R.sup.23)(R.sup.24),
C(NR.sup.25)SR.sup.5, C(O)NR.sup.23R.sup.24, and
C(O)NR.sup.23R.sup.24 with the provisos that no more than one of
R.sup.23, R.sup.24, and R.sup.26 can be hydroxy, alkoxy,
alkylamino, amino, or dialkylamino when any two of the group
consisting of R.sup.23, R.sup.24, and R.sup.26 are bonded to the
same atom and that said Q.sup.b group is bonded directly to a
carbon atom;
[0065] R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are independently
selected from the group consisting of hydrido, alkyl, hydroxy,
alkoxy, alkylenylamino, amino, alkylamino, dialkylamino, and
hydroxyalkyl;
[0066] R.sup.23 and R.sup.24 are optionally taken together to form
a linear spacer moiety having from 4 through 7 contiguous atoms
connecting the points of bonding to form a heterocyclyl ring having
5 through 8 contiguous members;
[0067] R.sup.23 and R.sup.25, R.sup.24 and R.sup.25, R.sup.25 and
R.sup.26, R.sup.24 and R.sup.26, and R.sup.23 and R.sup.26 are
independently optionally selected to form a spacer pair wherein a
spacer pair is taken together from the points of bonding of
selected spacer pair members to form the group L--U--V wherein L,
U, and V are independently selected from the group consisting of O,
S, C(O), C(S), C(J.sub.H).sub.2 S(O), SO.sub.2,
OP(OR.sup.31)R.sup.30, P(O)R.sup.30, P(S)R.sup.30,
C(R.sup.30)R.sup.31, C.dbd.C(R.sup.30)R.sup.31,
(O).sub.2POP(O).sub.2, R.sup.30(O)POP(O)R.sup.30,
Si(R.sup.29)R.sup.28, Si(R.sup.29)R.sup.28, Si(R.sup.29)R.sup.28,
Si(R.sup.29)R.sup.28OSi(R.sup.29)R.sup.28,
(R.sup.28)R.sup.29COC(R.sup.28)R.sup.29,
(R.sup.28)R.sup.29CSC(R.sup.28)R- .sup.29,
C(O)C(R.sup.30).dbd.C(R.sup.31), C(S)C(R.sup.30).dbd.C(R.sup.31),
S(O)C(R.sup.30).dbd.C(R.sup.31),
SO.sub.2C(R.sup.30).dbd.C(R.sup.31),
PR.sup.30C(R.sup.30).dbd.C(R.sup.31),
P(O)R.sup.30C(R.sup.30).dbd.C(R.sup- .31),
P(S)R.sup.30C(R.sup.30).dbd.C(R.sup.31), DC(R.sup.30)(R.sup.31)D,
OP(OR.sup.31)R.sup.30, P(O)R.sup.30, P(S)R.sup.30,
Si(R.sup.28)R.sup.29 and N(R.sup.30), and a covalent bond with the
proviso that no more than any two of L, U and V are simultaneously
covalent bonds and the heterocyclyl comprised of by L, U, and V has
from 5 through 10 contiguous member;
[0068] D is selected from the group consisting of oxygen, C.dbd.O,
C.dbd.S, S(O).sub.m wherein m is an integer selected from 0 through
2;
[0069] J.sub.H is independently selected from the group consisting
of OR.sup.27, SR.sup.27 and N(R.sup.20)R.sup.21;
[0070] R.sup.27 is selected from the group consisting of hydrido,
alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl,
alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl,
heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl,
alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,
cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,
halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl,
halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,
perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,
heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl,
arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,
heteroarylsulfonylalkyl, heteroarylsulfinylalkyl,
aralkylsulfinylalkyl and aralkylsulfonylalkyl;
[0071] R.sup.30 and R.sup.31 are independently selected from the
group consisting of hydrido, hydroxy, thiol, aryloxy, amino,
alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy,
alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,
aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl,
alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl,
alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,
arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,
cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl,
haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl,
dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl,
cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl,
cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl,
dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl,
carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl,
acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl,
phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy,
phosphonoalkoxy, dialkoxyphosphonoalkylamino,
diaralkoxyphosphonoalkylamino, phosphonoalkylamino,
dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl,
alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy,
aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino,
aralkoxysulfonylalkylamino, and sulfonylalkylamino;
[0072] R.sup.30 and R.sup.31 are optionally taken to form a linear
moiety spacer group having from 2 through 7 contiguous atoms to
form a ring selected from the group consisting of a cycloalkyl ring
having from 3 through 8 contiguous members, a cycloalkenyl ring
having from 3 through 8 contiguous members, and a heterocyclyl ring
having from 3 through 8 contiguous members;
[0073] R.sup.23 and R.sup.25, R.sup.24 and R.sup.25, R.sup.25 and
R.sup.26, R.sup.24 and R.sup.26, and R.sup.23 and R.sup.26 are
independently optionally selected to form a spacer pair wherein a
spacer pair is taken together from the points of bonding of
selected spacer pair members to form the group L--U--V wherein L,
U, and V are independently selected from the group of
1,2-disubstituted radicals consisting of a cycloalkyl radical, a
cycloalkenyl radical wherein cycloalkyl and cycloalkenyl radicals
are substituted with one or more groups selected from R.sup.30 and
R.sup.31, an aryl radical, an heteroaryl radical, a saturated
heterocyclic radical and a partially saturated heterocyclic radical
wherein said 1,2-substitutents are independently selected from
C.dbd.O, C.dbd.S, C(R.sup.28)R.sup.32, S(O), S(O).sub.2,
OP(OR.sup.31)R.sup.30, P(O)R.sup.30, P(S)R.sup.30 and
Si(R.sup.28)R.sup.29;
[0074] R.sup.23 and R.sup.25, R.sup.24 and R.sup.25, R.sup.25 and
R.sup.26, R.sup.24 and R.sup.26, and R.sup.23 and R.sup.26 are
independently optionally selected to form a spacer pair wherein a
spacer pair is taken together from the points of bonding of
selected spacer pair members to form the group L--U--V wherein L,
U, and V are independently selected from the group of radicals
consisting of 1,2-disubstituted alkylene radicals and
1,2-disubstituted alkenylene radical wherein said 1,2-substitutents
are independently selected from C.dbd.O, C.dbd.S,
C(R.sup.28)R.sup.29, S(O), S(O).sub.2, OP(OR.sup.31)R.sup.30,
P(O)R.sup.30, P(S)R.sup.30, and Si(R.sup.28)R.sup.29 and said
alkylene and alkenylene radical are substituted with one or more
R.sup.30 or R.sup.31 substituents;
[0075] Q.sup.s is selected from the group consisting of a single
covalent bond, (CR.sup.37R.sup.38).sub.b--(W.sup.0).sub.az wherein
az is an integer selected from 0 through 1, b is an integer
selected from 1 through 4, and W.sup.0 is selected from the group
consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,
C(O)N(R.sup.14), (R.sup.14)NC(O), C(S)N(R.sup.14), (R.sup.14)NC(S),
OC(O)N(R.sup.14), SC(S)N(R.sup.14), SC(O)N(R.sup.14),
OC(S)N(R.sup.14), N(R.sup.15)C(O)N(R.sup.14),
(R.sup.14)NC(O)N(R.sup.15), N(R.sup.15)C(S)N(R.sup.14),
(R.sup.14)NC(S)N(R.sup.15), S(O), S(O).sub.2,
S(O).sub.2N(R.sup.14), N(R.sup.14)S(O).sub.2, Se, Se(O),
Se(O).sub.2, Se(O).sub.2N(R.sup.17), N(R.sup.14)Se(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
N(R.sup.14), ON(R.sup.14), and SiR.sup.28R.sup.29,
(CH(R.sup.14)).sub.c--W.sup.1--(CH(R.sup.15)).sub.d wherein c and d
are integers independently selected from 1 through 4, and W.sup.1
is selected from the group consisting of O, S, C(O), C(S), C(O)O,
C(S)O, C(O)S, C(S)S, C(O)N(R.sup.14), (R.sup.14)NC(O),
C(S)N(R.sup.14), (R.sup.14)NC(S), OC(O)N(R.sup.14),
(R.sup.14)NC(O)O, SC(S)N(R.sup.14), (R.sup.14)NC(S)S,
SC(O)N(R.sup.14), (R.sup.14)NC(O)S, OC(S)N(R.sup.14),
(R.sup.14)NC(S)O, N(R.sup.15)C(O)N(R.sup.14),
(R.sup.14)NC(O)N(R.sup.15), N(R.sup.15)C(S)N(R.sup.14),
(R.sup.14)NC(S)N(R.sup.15), S(O), S(O).sub.2,
S(O).sub.2N(R.sup.14), N(R.sup.14)S(O).sub.2, Se, Se(O),
Se(O).sub.2, Se(O).sub.2N(R.sup.14), N(R.sup.14)Se(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
N(R.sup.14), ON(R.sup.14), SiR.sup.28R.sup.29, and
(CH(R.sup.14)).sub.e--W.sup.22--(CH- (R.sup.15)).sub.h wherein e
and h are integers independently selected from 0 through 2 and
W.sup.22 is selected from the group consisting of
CR.sup.41.dbd.CR.sup.42, CR.sup.41R.sup.42.dbd.C; vinylidene),
ethynylidene (C.dbd.C; 1,2-ethynyl), 1,2-cyclopropyl,
1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl,
1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl,
3,4-morpholinyl, 3,5morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl,
2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl,
2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl,
1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,
2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the provisos
that R.sup.14 and R.sup.15 are selected from other than halo and
cyano when directly bonded to N and that (CR.sup.37R.sup.38).sub.b,
(CH(R.sup.14)).sub.c, (CH(R.sup.14)).sub.e and are bonded to
E.sup.0;
[0076] R.sup.37 and R.sup.37, when bonded to different carbons, are
optionally taken together to form a linear moiety spacer having
from 1 through 7 contiguous atoms to form a ring selected from the
group consisting of a cycloalkyl ring having from 3 through 8
contiguous members, a cycloalkenyl ring having from 3 through 8
contiguous members, and a heterocyclyl ring having from 3 through 8
contiguous members;
[0077] R.sup.37 and R.sup.38, when bonded to different carbons, are
taken together to form a linear moiety spacer having from 1 through
7 contiguous atoms to form a ring selected from the group
consisting of a cycloalkyl ring having from 3 through 8 contiguous
members, a cycloalkenyl ring having from 3 through 8 contiguous
members, and a heterocyclyl ring having from 3 through 8 contiguous
members;
[0078] R.sup.38 and R.sup.38, when bonded to different carbons, are
taken together to form a linear moiety spacer having from 1 through
7 contiguous atoms to form a ring selected from the group
consisting of a cycloalkyl ring having from 3 through 8 contiguous
members, a cycloalkenyl ring having from 3 through 8 contiguous
members, and a heterocyclyl ring having from 3 through 8 contiguous
members;
[0079] R.sup.37 and R.sup.38, when bonded to the same carbon, are
taken together to form a group selected from a group consisting of
oxo, thiono, alkylene, haloalkylene, and a linear moiety spacer
having from 2 through 7 contiguous atoms to form a ring selected
from the group consisting of a cycloalkyl ring having from 3
through 8 contiguous members, a cycloalkenyl ring having from 3
through 8 contiguous members, and a heterocyclyl ring having from 3
through 8 contiguous members;
[0080] Y.sup.0 is optionally Q.sup.b--Q.sup.ss wherein Q.sup.ss is
selected from the group consisting of (CR.sup.37R.sup.38).sub.f
wherein f is an integer selected from 1 through 6,
(CH(R.sup.14)).sub.c--W.sup.1--(- CH(R.sup.15)).sub.d wherein c and
d are integers independently selected from 1 through 4, and W.sup.1
is selected from the group consisting of W.sup.1 is selected from
the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S,
C(S)S, C(O)N(R.sup.14), (R.sup.14)NC(O), C(S)N(R.sup.14),
(R.sup.14)NC(S), OC(O)N(R.sup.14), (R.sup.14)NC(O)O,
SC(S)N(R.sup.14), (R.sup.14)NC(S)S, SC(O)N(R.sup.14),
(R.sup.14)NC(O)S, OC(S)N(R.sup.14), (R.sup.14)NC(S)O,
N(R.sup.15)C(O)N(R.sup.14), (R.sup.14)NC(O)N(R.sup.15),
N(R.sup.15)C(S)N(R.sup.14), (R.sup.14)NC(S)N(R.sup.15), S(O),
S(O).sub.2, S(O).sub.2N(R.sup.14), N(R.sup.14)S(O).sub.2, Se,
Se(O), Se(O).sub.2, Se(O).sub.2N(R.sup.14), N(R.sup.14)Se(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
N(R.sup.14), ON(R.sup.14), SiR.sup.28R.sup.29, and
(CH(R.sup.14)).sub.e--W.sup.2--(CH(- R.sup.15)).sub.h wherein e and
h are integers independently selected from 0 through 2 and W.sup.2
is selected from the group consisting of CR.sup.4a.dbd.CR.sup.4b,
ethynylidene (C.ident.C; 1,2-ethynyl), and C.dbd.CR.sup.4aR.sup.4b
with the provisos that R.sup.14 and R.sup.15 are selected from
other than halo and cyano when directly bonded to N, that
(CR.sup.37R.sup.38).sub.f, (CH(R.sup.15)).sub.c, and
(CH(R.sup.15)).sub.e are bonded to E.sup.0, and Q.sup.b is selected
from other than
N(R.sup.26)N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24) or
ON(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24) when Q.sup.ss is
(CR.sup.37R.sup.38).sub.f wherein f is other than the integer
1;
[0081] Y.sup.0 is optionally Q.sup.b--Q.sup.sss wherein Q.sup.sss
is (CH(R.sup.38)).sub.r--W.sup.3, r is an integer selected from 1
through 3, W.sup.3 is selected from the group consisting of
1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl,
1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl,
1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl,
2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl,
1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl,
2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl,
2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl,
3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl,
1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,
2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl,
4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl,
2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl,
2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl,
2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl,
2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl,
3,4-tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon
and hyrido containing nitrogen member of the ring of the W.sup.3
other than the points of attachment is optionally substituted with
one or more of the group consisting of R.sup.9, R.sup.10, R.sup.11,
and R.sup.12, with the proviso that (CH(R.sup.38)).sub.r is bonded
to E.sup.0 and Q.sup.b is bonded to lowest numbered substituent
position of each W.sup.3;
[0082] Y.sup.0 is optionally Q.sup.b--Q.sup.sssr wherein Q.sup.sssr
is (CH(R.sup.38)).sub.r--W.sup.4, r is an integer selected from 1
through 3, W.sup.4 is selected from the group consisting of
1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl,
1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,
2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,
1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl,
2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl,
1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl,
2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl,
1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,
2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl,
4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl,
2H-pyran-2-one-4,5-yl, 4H-pyran -4-one-2,3-yl,
2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl,
2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl,
2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl,
3,4-tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon
and hydrido containing nitrogen member of the ring of the W.sup.4
other than the points of attachment is optionally substituted with
one or more of the group consisting of R.sup.9, R.sup.10, R.sup.11,
and R.sup.12, with the provisos that (CH(R.sup.38)).sub.r is bonded
to E.sup.0 and Q.sup.b is bonded to highest number substituent
position of each W.sup.4;
[0083] Y.sup.0 is optionally Q.sup.b--Q.sup.ssss wherein Q.sup.ssss
is (CH(R.sup.38)).sub.r--W.sup.5, r is an integer selected from 1
through 3, W.sup.5 is selected from the group consisting of
1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl,
2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl,
3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl,
2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl,
3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl,
2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl,
2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl,
3,6-benzothiophenyl, 3,7-benzothiophenyl,
2,4-imidazo(1,2-a)pyridinyl, 2,5-imidazo (1,2-a)pyridinyl,
2,6-imidazo(1,2-a)pyridinyl, 2,7-imidazo(1,2-a)pyridinyl,
3,4-imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2-a)pyridinyl,
3,6-imidazo (1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl,
2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl,
3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl,
1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl,
2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl,
3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl,
2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl,
3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl,
3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl,
1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl,
2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl,
2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl,
3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl,
3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl,
4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl,
1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl,
3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl,
3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl,
4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl,
3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl,
3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and
4,8-cinnolinyl, and each carbon and hydrido containing nitrogen
member of the ring of the W.sup.5 other than the points of
attachment is optionally substituted with one or more of the group
consisting of R.sup.9, R.sup.10, R.sup.11, and R.sup.12, with the
proviso that Q.sup.b is bonded to lowest number substituent
position of each W.sup.5 and that (CH(R.sup.38)).sub.r is bonded to
E.sup.0;
[0084] Y.sup.0 is optionally Q.sup.b--Q.sup.ssssr wherein
Q.sup.ssssr is (CH(R.sup.38)).sub.r--W.sup.6, r is an integer
selected from 1 through 3, W.sup.6 is selected from the group
consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl,
2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl,
3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl,
2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl,
3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl,
3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl,
2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl,
3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl,
2,4-imidazo(1,2-a)pyridinyl, 2,5-imidazo(1,2-a)pyridinyl,
2,6-imidazo(1,2-a)pyridinyl, 2,7-imidazo(1,2-a)pyridinyl,
3,4-imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2-a)pyridinyl,
3,6-imidazo(1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl,
2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl,
3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl,
1,5-isoindolyl, 1,6-isoindolyl, 2,4isoindolyl, 2,5-isoindolyl,
2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl,
3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl,
2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl,
3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl,
3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl,
1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl,
2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl,
2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl,
3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl,
3,8-quinolinyl, 4,5quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl,
4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl,
1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl,
3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl,
3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl,
4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl,
3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl,
3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and
4,8-cinnolinyl, and each carbon and hydrido containing nitrogen
member of the ring of the W.sup.6 other than the points of
attachment is optionally substituted with one or more of the group
consisting of R.sup.9, R.sup.10, R.sup.11, and R.sup.12, with the
proviso that Q.sup.b is bonded to highest number substituent
position of each W.sup.6 and that (CH(R.sup.38)).sub.r is bonded to
E.sup.0.
[0085] In an embodiment of compounds of Formula I or a
pharmaceutically acceptable salt thereof,
[0086] J.sup.a and J.sup.b are independently selected from the
group consisting of O and S;
[0087] B is formula (V): 8
[0088] wherein D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, no more than one of D.sup.1, D.sup.2, J.sup.1,
J.sup.2 and K.sup.1 is O, no more than one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 is S, one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 must be a covalent bond when two of
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are O and S, and no
more than four of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1
are N with the proviso that R.sup.32, R.sup.33, R.sup.34, R.sup.35,
and R.sup.36 are each independently selected to maintain the
tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, and the divalent nature of oxygen;
[0089] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36 are independently selected from the group
consisting of hydrido, acetamido, haloacetamido, amidino,
guanidino, dialkylsulfonium, trialkylphosphonium,
dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy,
cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy,
heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,
heterocyclyl, perhaloaralkyl, aralkylsulfonyl,
aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,
halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,
cycloalkylsulfinylalkyl, cycloalkylsulfonyl,
cycloalkylsulfonylalkyl, heteroarylamino,
N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,
haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl,
heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl,
cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy,
halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy,
halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro,
lower alkylamino, alkylthio, alkylthioalkyl, arylamino,
aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,
alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl,
arylsulfonylalkyl, heteroarylsulfinylalkyl,
heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,
haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,
alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,
diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,
arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,
heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio,
alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl,
heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl,
alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,
cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower
cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl,
haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,
hydroxyalkyl, alkylenylamino, hydoxyheteroaralkyl, haloalkoxyalkyl,
aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated
heterocyclyl, partially saturated heterocyclyl, heteroaryl,
heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl,
arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy,
alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido,
carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy,
carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono,
phosphonoalkyl, diaralkoxyphosphono, and
diaralkoxyphosphonoalkyl;
[0090] R.sup.16, R.sup.19, R.sup.32, R.sup.33, R.sup.34, R.sup.35,
and R.sup.36 are independently optionally Q.sup.b with the proviso
that no more than one of R.sup.16 and R.sup.19 is Q.sup.b at the
same time and that Q.sup.b is Q.sup.be;
[0091] R.sup.32 and R.sup.33, R.sup.33 and R.sup.34, R.sup.34 and
R.sup.35, and R.sup.35 and R.sup.36 are independently optionally
selected to form a spacer pair wherein a spacer pair is taken
together to form a linear moiety having from 3 through 6 contiguous
atoms connecting the points of bonding of said spacer pair members
to form a ring selected from the group consisting of a cycloalkenyl
ring having 5 through 8 contiguous members, a partially saturated
heterocyclyl ring having 5 through 8 contiguous members, a
heteroaryl ring having 5 through 6 contiguous members, and an aryl
with the proviso that no more than one of the group consisting of
spacer pairs R.sup.32 and R.sup.33, R.sup.33 and R.sup.34, R.sup.34
and R.sup.35, and R.sup.35 and R.sup.36 can be used at the same
time;
[0092] R.sup.9 and R.sup.10, R.sup.10 and R.sup.11, R.sup.11 and
R.sup.12, and R.sup.12 and R.sup.13 are independently optionally
selected to form a spacer pair wherein a spacer pair is taken
together to form a linear moiety having from 3 through 6 contiguous
atoms connecting the points of bonding of said spacer pair members
to form a ring selected from the group consisting of a cycloalkenyl
ring having 5 through 8 contiguous members, a partially saturated
heterocyclyl ring having 5 through 8 contiguous members, a
heteroaryl ring having 5 through 6 contiguous members, and an aryl
with the proviso that no more than one of the group consisting of
spacer pairs R.sup.9 and R.sup.10, R.sup.10 and R.sup.11, R.sup.11
and R.sup.12 and R.sup.13 can be used at the same time;
[0093] B is optionally selected from the group consisting of
hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8
alkenyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl
wherein each member of group B may be optionally substituted at any
carbon up to and including 6 atoms from the point of attachment of
B to A with one or more of the group consisting of R.sup.32,
R.sup.33, R.sup.34, R.sup.35, and R.sup.36;
[0094] B is optionally selected from the group consisting of C3-C15
cycloalkyl, C5-C10 cycloalkenyl, C4-C12 saturated heterocyclyl, and
C4-C9 partially saturated heterocyclyl, wherein each ring carbon is
optionally substituted with R.sup.33, a ring carbon other than the
ring carbon at the point of attachment of B to A is optionally
substituted with oxo provided that no more than one ring carbon is
substituted by oxo at the same time, ring carbons and a nitrogen
adjacent to the carbon atom at the point of attachment are
optionally substituted with R.sup.9 or R.sup.13, a ring carbon or
nitrogen adjacent to the R.sup.9 position and two atoms from the
point of attachment is optionally substituted with R.sup.10, a ring
carbon or nitrogen adjacent to the R.sup.13 position and two atoms
from the point of attachment is optionally substituted with
R.sup.12, a ring carbon or nitrogen three atoms from the point of
attachment and adjacent to the R.sup.10 position is optionally
substituted with R.sup.11, a ring carbon or nitrogen atom three
from the point of attachment and adjacent to the R.sup.12 position
is optionally substituted with R.sup.33, and a ring carbon or
nitrogen four atoms from the point of attachment and adjacent to
the R.sup.11 and R.sup.33 positions is optionally substituted with
R.sup.34;
[0095] A is selected from the group consisting of single covalent
bond, (W.sup.7).sub.rr--(CH(R.sup.15)).sub.pa and
(CH(R.sup.15)).sub.pa--(W.sup- .7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
6, and W.sup.7 is selected from the group consisting of O, S, C(O),
C(S), C(O)S, C(S)O, C(O)N(R.sup.7), C(S)N(R.sup.7), (R.sup.7)NC(O),
(R.sup.7)NC(S), S(O), S(O).sub.2, S(O).sub.2N(R.sup.7),
(R.sup.7)NS(O).sub.2, P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8),
P(O)(R.sup.8)N(R.sup.7), C(NR.sup.7)N(R.sup.7),
(R.sup.7)NC(NR.sup.7), (R.sup.7)NC(NR.sup.7)NR.sup.7, and
N(R.sup.7) with the proviso that no more than one of the group
consisting of rr and pa can be 0 at the same time;
[0096] R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrido, hydroxy, alkyl, acyl, aroyl,
heteroaroyl, and alkoxyalkyl;
[0097] R.sup.14, R.sup.15, R.sup.37, and R.sup.38 are independently
selected from the group consisting of hydrido, hydroxy, halo,
cyano, hydroxyalkyl, alkoxy, alkyl, alkoxyalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl,
haloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,
halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,
carboxy, carboxyalkyl, carboalkoxy, carboxamide, and
carboxamidoalkyl;
[0098] R.sup.14 and R.sup.38 can be independently selected from the
group consisting of acyl, aroyl, and heteroaroyl with the proviso
that acyl is selected from other than formyl;
[0099] .PSI. is selected from the group consisting of NR.sup.5, O,
C(O), C(S), S, S(O), S(O).sub.2, ON(R.sup.5), P(O)(R.sup.8), and
CR.sup.39R.sup.40;
[0100] R.sup.5 is selected from the group consisting of hydrido,
hydroxy, amino, alkyl, alkoxy, alkoxyalkyl, haloalkyl, acyl, aroyl,
and heteroaroyl;
[0101] R.sup.39 and R.sup.40 are independently selected from the
group consisting of hydrido, hydroxy, halo, cyano, hydroxyalkyl,
acyl, aroyl, heteroaroyl, acylamido, alkoxy, alkyl, alkoxyalkyl,
haloalkyl, haloalkoxy, haloalkoxyalkyl, alkylsulfonyl,
haloalkylsulfonyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide,
and carboxamidoalkyl;
[0102] M is selected from the group consisting of N and
R.sup.1--C;
[0103] R.sup.2 and R.sup.1 are independently selected from the
group consisting of Z.sup.0--Q, hydrido, alkyl, alkenyl, and
halo;
[0104] R.sup.1 is optionally selected from the group consisting of
amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy,
hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio,
dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl,
heteroarylamino, nitro, arylamino, aralkylamino, alkanoyl,
alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,
haloalkanoyl, hydroxyhaloalkyl, cyano, and phosphono;
[0105] Z.sup.0 is selected from the group consisting of covalent
single bond, (CR.sup.41R.sup.42).sub.q wherein q is an integer
selected from 1 through 6,
(CH(R.sup.41)).sub.g--W.sup.0--(CH(R.sup.42)).sub.p wherein g and p
are integers independently selected from 0 through 3 and W.sup.0 is
selected from the group consisting of O, S, C(O), C(S), C(O)O,
C(S)O, C(O)S, C(S)S, C(O)N(R.sup.41), (R.sup.41)NC(O),
C(S)N(R.sup.41), (R.sup.41)NC(S), OC(O)N(R.sup.41),
(R.sup.41)NC(O)O, SC(S)N(R.sup.41), (R.sup.41)NC(S)S,
SC(O)N(R.sup.41), (R.sup.41)NC(O)S, OC(S)N(R.sup.41),
(R.sup.41)NC(S)O, N(R.sup.42)C(O)N(R.sup.41),
(R.sup.41)NC(O)N(R.sup.42), N(R.sup.42)C(S)N(R.sup.41),
(R.sup.41)NC(S)N(R.sup.42), S(O), S(O).sub.2,
S(O).sub.2N(R.sup.41), N(R.sup.41)S(O).sub.2, Se, Se(O),
Se(O).sub.2, Se(O).sub.2N(R.sup.41), N(R.sup.41)Se(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
N(R.sup.41), ON(R.sup.41), and SiR.sup.28R.sup.29, and (CH(R
.sup.41)).sub.e--W.sup.22- --(CH(R.sup.42)).sub.h wherein e and h
are integers independently selected from 0 through 2 and W.sup.22
selected from the group consisting of CR.sup.41.dbd.CR.sup.42,
CR.sup.41R.sup.42.dbd.C; vinylidene), ethynylidene (C.ident.C;
1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl,
1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl,
2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,
1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl,
1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl,
2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl,
1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl,
2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl1,
2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and
3,4-tetrahydrofuranyl, with the provisos that R.sup.41 and R.sup.42
are selected from other than halo and cyano when directly bonded to
N and Z.sup.0 is directly bonded to the uracil ring;
[0106] R.sup.41 and R.sup.42 are independently selected from the
group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino,
halo, cyano, aryloxy, hydroxyalkyl, acyl, aroyl, heteroaroyl,
heteroaryloxyalkyl, alkoxy, alkyl, aryl, aralkyl, aryloxyalkyl,
aralkoxyalkylalkoxy, alkoxyalkyl, heteroaryloxyalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,
cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,
halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,
halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,
saturated heterocyclyl, partially saturated heterocyclyl,
heteroaryl, heteroaralkyl, heteroarylthioalkyl,
heteroaralkylthioalkyl, alkylsulfonyl, haloalkylsulfonyl,
arylsulfonyl, arylsulfonylalkyl, aralkylsulfonyl,
cycloalkylsulfonyl, cycloalkylsufonylalkyl,
heteroarylsulfonylalkyl, heteroarylsulfonyl, and
aralkylsulfonylalkyl;
[0107] Q is formula (II): 9
[0108] wherein D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, no more than one of D.sup.1, D.sup.2, J.sup.1,
J.sup.2 and K.sup.1 is O, no more than one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 is S, one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 must be a covalent bond when two of
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are O and S, and no
more than four of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1
are N, with the proviso that R.sup.9, R.sup.10, R.sup.11, R.sup.12,
and R.sup.13 are each independently selected to maintain the
tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, and the divalent nature of oxygen;
[0109] Q is optionally selected from formula (III): 10
[0110] wherein D.sup.3, D.sup.4, J.sup.3, and J.sup.4 are
independently selected from the group consisting of C, N, O, and S,
no more than one of D.sup.3, D.sup.4, J.sup.3, and J.sup.4 is O, no
more than one of D.sup.3, D.sup.4, J.sup.3, and J.sup.4 is S, and
no more than three of D.sup.1, D.sup.2, J.sup.1, and J.sup.2 are N
with the proviso that R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are
each independently selected to maintain the tetravalent nature of
carbon, trivalent nature of nitrogen, the divalent nature of
sulfur, and the divalent nature of oxygen;
[0111] Q is optionally selected from the group consisting of
hydrido, alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio,
alkenyl, alkynyl, saturated heterocyclyl, partially saturated
heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,
cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl,
halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl,
haloalkenyloxyalkyl, halocycloalkoxyalkyl, and
halocycloalkenyloxyalkyl with the proviso that Z.sup.0 is selected
from other than a single covalent bond when Q is hydrido;
[0112] K is (CR.sup.4aR.sup.4b).sub.n wherein n is an integer
selected from 1 through 2;
[0113] R.sup.4a and R.sup.4b are independently selected from the
group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl,
alkyl, alkenyl, alkoxyalkyl, aralkyl, heteroaralkyl,
alkylthioalkyl, haloalkyl, haloalkenyl, and cyanoalkyl;
[0114] E.sup.0 is E.sup.1, when K is (CR.sup.4aR.sup.4b).sub.n,
wherein E.sup.1 is selected from the group consisting of a covalent
single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,
C(O)N(R.sup.7), (R.sup.7)NC(O), C(S)N(R.sup.7), (R.sup.7)NC(S),
OC(O)N(R.sup.7), (R.sup.7)NC(O)O, SC(S)N(R.sup.7), (R.sup.7)NC(S)S,
SC(O)N(R.sup.7), (R.sup.7)NC(O)S, OC(S)N(R.sup.7), (R.sup.7)NC(S)O,
N(R.sup.8)C(O)N(R.sup.7), (R.sup.7)NC(O)N(R.sup.8),
N(R.sup.8)C(S)N(R.sup.7), (R.sup.7)NC(S)N(R.sup.8), S(O),
S(O).sub.2, S(O).sub.2N(R.sup.7), N(R.sup.7)S(O).sub.2,
S(O).sub.2N(R.sup.7)C(O), C(O)N(R.sup.7)S(O).sub.2, P(O)(R.sup.8),
N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7), N(R.sup.7),
ON(R.sup.7), CR.sup.4a.dbd.CR.sup.4b- , ethynylidene (C.ident.C;
1,2-ethynyl), and C.dbd.CR.sup.4aR.sup.4b;
[0115] K is optionally (CH(R.sup.14)).sub.j--T wherein j is
selected from a integer from 0 through 2 and T is selected from the
group consisting of single covalent bond, O, S, and N(R.sup.7) with
the proviso that (CH(R.sup.14)).sub.j is bonded to the uracil
ring;
[0116] E.sup.0 is optionally E.sup.2, when K is
(CH(R.sup.14)).sub.j--T, wherein E.sup.2 is selected from the group
consisting of a covalent single bond, C(O), C(S), C(O)O, C(S)O,
C(O)S, C(S)S, C(O)N(R.sup.7), (R.sup.7)NC(O), C(S)N(R.sup.7),
(R.sup.7)NC(S), (R.sup.7)NC(O)O, (R.sup.7)NC(S)S, (R.sup.7)NC(O)S,
(R.sup.7)NC(S)O, N(R.sup.8)C(O)N(R.sup.7),
(R.sup.7)NC(O)N(R.sup.8), N(R.sup.8)C(S)N(R.sup.7),
(R.sup.7)NC(S)N(R.sup.8), S(O), S(O).sub.2, S(O).sub.2N(R.sup.7),
N(R.sup.7)S(O).sub.2, S(O).sub.2N(H)C(O), C(O)N(H)S(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
and N(R.sup.7);
[0117] K is optionally G--(CH(R.sup.15)).sub.k wherein k is
selected from an integer from 1 through 2 and G is selected from
the group consisting of O, S, and N(R.sup.7) with the proviso that
R.sup.15 is other than hydroxy, cyano, halo, amino, alkylamino,
dialkylamino, and sulfhydryl when k is 1;
[0118] E.sup.0 is optionally E.sup.3 when K is
G--(CH(R.sup.15)).sub.k, wherein E.sup.3 is selected from the group
consisting of a covalent single bond, O, S, C(O), C(S), C(O)O,
C(S)O, C(O)S, C(S)S, C(O)N(R.sup.7), (R.sup.7)NC(O),
C(S)N(R.sup.7), (R.sup.7)NC(S), OC(O)N(R.sup.7), (R.sup.7)NC(O)O,
SC(S)N(R.sup.7), (R.sup.7)NC(S)S, SC(O)N(R.sup.7), (R.sup.7)NC(O)S,
OC(S)N(R.sup.7), (R.sup.7)NC(S)O, N(R.sup.8)C(O)N(R.sup.7),
(R.sup.7)NC(O)N(R.sup.8), N(R.sup.8)C(S)N(R.sup.7),
(R.sup.7)NC(S)N(R.sup.8), S(O), S(O).sub.2, S(O).sub.2N(R.sup.7),
N(R.sup.7)S(O).sub.2, P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8),
P(O)(R.sup.8)N(R.sup.7), N(R.sup.7), ON(R.sup.7),
CR.sup.4a.dbd.CR.sup.4b, ethynylidene (C.ident.C; 1,2-ethynyl), and
C.dbd.CR.sup.4aR.sup.4b;
[0119] Y.sup.0 is formula (IV): 11
[0120] wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is independently selected from the group
consisting of C and N.sup.+, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is O, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 must be a covalent bond when two of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are O and S, no more than three of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 is N when K.sup.2 is N.sup.+, and no
more than four of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are N when
K.sup.2 is carbon with the provisos that R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are each independently selected to maintain
the tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, and the divalent nature of oxygen;
[0121] R.sup.16 and R.sup.17 are optionally independently taken
together to form a linear moiety spacer having from 3 through 6
contiguous atoms connected to form a ring selected from the group
consisting of a cycloalkenyl ring having from 5 through 8
contiguous members, a partially saturated heterocyclyl ring having
from 5 through 8 contiguous members, a heteroaryl having from 5
through 6 contiguous members, and an aryl;
[0122] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, .sup.+NR.sup.20R.sup.21R.sup.22, oxy, alkyl,
aminoalkylenyl, alkylamino, dialkylamino, dialkylsulfoniumalkyl,
acylamino and Q.sup.be, wherein Q.sup.be is hydrido and R.sup.20,
R.sup.21, and R.sup.22 are independently selected from the group
consisting of hydrido, amino, alkyl, hydroxy, alkoxy,
aminoalkylenyl,alkylamino, dialkylamino, and hydroxyalkyl with the
provisos that no more than one of R.sup.20, R.sup.21, and R.sup.22
is hydroxy, alkoxy, alkylamino, amino, and dialkylamino at the same
time and that R.sup.20, R.sup.21, and R.sup.22 must be other than
be hydroxy, alkoxy, alkylamino, amino, and dialkylamino when
K.sup.2 is N.sup.+;
[0123] R.sup.20 and R.sup.21, R.sup.20 and R.sup.22, and R.sup.21
and R.sup.22 are independently optionally selected to form a spacer
pair wherein a spacer pair is taken together to form a linear
moiety having from 4 through 7 contiguous atoms connecting the
points of bonding of said spacer pair members to form a
heterocyclyl ring having 5 through 8 contiguous members with the
proviso that no more than one of the group consisting of spacer
pairs R.sup.20 and R.sup.21, R.sup.20 and R.sup.22, and R.sup.21
and R.sup.22 is used at the same time;
[0124] Q.sup.b is optionally selected from the group consisting of
N(R.sup.26)SO.sub.2N(R.sup.23)(R.sup.24), N(R.sup.26)C(O)OR.sup.5,
N(R.sup.26)C(O)SR.sup.5, N(R.sup.26)C(S)OR.sup.5 and
N(R.sup.26)C(S)SR.sup.5 with the proviso that no more than one of
R.sup.23, R.sup.24, and R.sup.26 is hydroxy, alkoxy, alkylamino,
amino, and dialkylamino when two of the group consisting of
R.sup.23, R.sup.24, and R.sup.26 are bonded to the same atom;
[0125] Q.sup.b is optionally selected from the group consisting of
dialkylsulfonium, trialkylphosphonium,
C(NR.sup.25)NR.sup.23R.sup.24,
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24),
N(R.sup.26)C(O)N(R.sup.23)(- R.sup.24),
N(R.sup.26)C(S)N(R.sup.23)(R.sup.24), C(NR.sup.25)OR.sup.5,
C(O)N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24),
C(S)N(R.sup.26)C(NR.sup- .25)N(R.sup.23)(R.sup.24),
N(R.sup.26)N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R- .sup.24),
ON(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24),
N(R.sup.26)N(R.sup.26)SO.sub.2N(R.sup.23)(R.sup.24),
C(NR.sup.25)SR.sup.5, C(O)NR.sup.23R.sup.24, and
C(O)NR.sup.23R.sup.24 with the provisos that no more than one of
R.sup.23, R.sup.24, and R.sup.26 can be hydroxy, alkoxy,
alkylaminol, amino, or dialkylamino when two of the group
consisting of R.sup.23, R.sup.24, and R.sup.26 are bonded to the
same atom and that said Q.sup.b group is bonded directly to a
carbon atom;
[0126] R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are independently
selected from the group consisting of hydrido, alkyl, hydroxy,
alkoxy, aminoalkylenyl, alkylamino, dialkylamino, amino, and
hydroxyalkyl;
[0127] R.sup.23 and R.sup.24 are optionally taken together to form
a linear spacer moiety having from 4 through 7 contiguous atoms
connecting the points of bonding to form a heterocyclyl ring having
5 through 8 contiguous members;
[0128] Q.sup.s is selected from the group consisting of a single
covalent bond, (CR.sup.37R.sup.38).sub.b--(W.sup.0).sub.az wherein
az is an integer selected from 0 through 1, b is an integer
selected from 1 through 4, and W.sup.0 is selected from the group
consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,
C(O)N(R.sup.14), (R.sup.14)NC(O), C(S)N(R.sup.14), (R.sup.14)NC(S),
OC(O)N(R.sup.14), SC(S)N(R.sup.14), SC(O)N(R.sup.14),
OC(S)N(R.sup.14), N(R.sup.15)C(O)N(R.sup.14),
(R.sup.14)NC(O)N(R.sup.15), N(R.sup.15)C(S)N(R.sup.14),
(R.sup.14)NC(S)N(R.sup.15), S(O), S(O).sub.2,
S(O).sub.2N(R.sup.14), N(R.sup.14)S(O).sub.2, P(O)(R.sup.8),
N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7), N(R.sup.14),
ON(R.sup.14), (CH(R.sup.14)).sub.c--W.sup.1--(CH(R.sup.15)).sub.d
wherein c and d are integers independently selected from 1 through
4, and W.sup.1 is selected from the group consisting of O, S, C(O),
C(S), C(O)O, C(S)O, C(O)S, C(S)S, C(O)N(R.sup.14), (R.sup.14)NC(O),
C(S)N(R.sup.14), (R.sup.14)NC(S), OC(O)N(R.sup.14),
(R.sup.14)NC(O)O, SC(S)N(R.sup.14), (R.sup.14)NC(S)S,
SC(O)N(R.sup.14), (R.sup.14)NC(O)S, OC(S)N(R.sup.14),
(R.sup.14)NC(S)O, N(R.sup.15)C(O)N(R.sup.14),
(R.sup.14)NC(O)N(R.sup.15), N(R.sup.15)C(S)N(R.sup.14),
(R.sup.14)NC(S)N(R.sup.15), S(O), S(O).sub.2,
S(O).sub.2N(R.sup.14), N(R.sup.14)S(O).sub.2, P(O)(R.sup.8),
N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7), N(R.sup.14),
ON(R.sup.14), and
(CH(R.sup.14)).sub.e--W.sup.22--(CH(R.sup.15)).sub.h wherein e and
h are integers independently selected from 0 through 2 and W.sup.22
is selected from the group consisting of CR.sup.41.dbd.CR.sup.42- ,
CR.sup.41R.sup.42.dbd.C; vinylidene), ethynylidene (C.ident.C;
1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl,
1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl,
2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,
1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl,
1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl,
2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl,
1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl,
2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl,
2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and
3,4-tetrahydrofuranyl, with the provisos that R.sup.14 and R.sup.15
are selected from other than halo and cyano when directly bonded to
N and that (CR.sup.37R.sup.38).sub.b, (CH(R.sup.14)).sub.c,
(CH(R.sup.14)).sub.e and are bonded to E.sup.0;
[0129] Y.sup.0 is optionally Q.sup.b--Q.sup.ss wherein Q.sup.ss is
selected from the group consisting of (CR.sup.37R.sup.38).sub.f
wherein f is an integer selected from 1 through 6,
(CH(R.sup.14)).sub.c--W.sup.1--(- CH(R.sup.15)).sub.d wherein c and
d are integers independently selected from 1 through 4, and W.sup.1
is selected from the group consisting of W.sup.1 is selected from
the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S,
C(S)S, C(O)N(R.sup.14), (R.sup.14)NC(O), C(S)N(R.sup.14),
(R.sup.14)NC(S), OC(O)N(R.sup.14), (R.sup.14)NC(O)O,
SC(S)N(R.sup.14), (R.sup.14)NC(S)S, SC(O)N(R.sup.14),
(R.sup.14)NC(O)S, OC(S)N(R.sup.14), (R.sup.14)NC(S)O,
N(R.sup.15)C(O)N(R.sup.14), (R.sup.14)NC(O)N(R.sup.15),
N(R.sup.15)C(S)N(R.sup.14), (R.sup.14)NC(S)N(R.sup.15), S(O),
S(O).sub.2, S(O).sub.2N(R.sup.14), N(R.sup.14)S(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
N(R.sup.14), ON(R.sup.14), and
(CH(R.sup.14)).sub.e--W.sup.2--(CH(R.sup.15)).sub.h wherein e and h
are integers independently selected from 0 through 2 and W.sup.2 is
selected from the group consisting of CR.sup.4a.dbd.CR.sup.4b,
ethynylidene (C.ident.C; 1,2-ethynyl), and C.dbd.CR.sup.4aR.sup.4b
with the provisos that R.sup.14 and R.sup.15 are selected from
other than halo and cyano when directly bonded to N and that
(CR.sup.37R.sup.38).sub.f, (CH(R.sup.14)).sub.c, and
(CH(R.sup.14)).sub.e are bonded to E.sup.0;
[0130] Y.sup.0 is optionally Q.sup.b--Q.sup.sss wherein Q.sup.sss
is (CH(R.sup.38)).sub.r--W.sup.3, r is an integer selected from 1
through 3, W.sup.3 is selected from the group consisting of
1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl,
1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl,
1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl,
2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl,
1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl,
2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl,
2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl,
3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl,
1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,
2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl,
4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl,
2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl,
2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl,
2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl,
2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl,
3,4-tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon
and hyrido containing nitrogen member of the ring of the W.sup.3
other than the points of attachment is optionally substituted with
one or more of the group consisting of R.sup.9, R.sup.10, R.sup.11,
and R.sup.12, with the proviso that (CH(R.sup.38)).sub.r is bonded
to E.sup.0 and Q.sup.b is bonded to lowest numbered substituent
position of each W.sup.3;
[0131] Y.sup.0 is optionally Q.sup.b--Q.sup.sssr wherein Q.sup.sssr
is (CH(R.sup.38)).sub.r--W.sup.4, r is an integer selected from 1
through 3, W.sup.4 is selected from the group consisting of
1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl,
1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,
2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,
1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl,
2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl,
1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl,
2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl,
1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,
2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl,
4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl,
2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl,
2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl,
2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl,
2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl,
3,4-tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon
and hydrido containing nitrogen member of the ring of the W.sup.4
other than the points of attachment is optionally substituted with
one or more of the group consisting of R.sup.9, R.sup.10, R.sup.11,
and R.sup.12, with the provisos that (CH(R.sup.38)).sub.r is bonded
to E.sup.0 and Q.sup.b is bonded to highest number substituent
position of each W.sup.4;
[0132] Y.sup.0 is optionally Q.sup.b--Q.sup.ssss wherein Q.sup.ssss
is (CH(R.sup.38)).sub.r--W.sup.5, r is an integer selected from 1
through 3, W.sup.5 is selected from the group consisting of
1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl,
2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl,
3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl,
2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl,
3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl,
2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl,
2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl,
3,6-benzothiophenyl, 3,7-benzothiophenyl,
2,7-imidazo(1,2-a)pyridinyl, 3,4-imidazo(1,2-a)pyridinyl,
3,5-imidazo(1,2-a)pyridinyl, 3,6-imidazo(1,2-a)pyridinyl,
3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl,
2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl,
1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl,
2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl,
3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl,
2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl,
2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl,
3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl,
1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl,
2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl,
2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl,
2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl,
3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl,
4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl,
1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl,
1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl,
3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl,
4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl,
4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl,
3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl,
4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido
containing nitrogen member of the ring of the W.sup.5 other than
the points of attachment is optionally substituted with one or more
of the group consisting of R.sup.9, R.sup.10, R.sup.11, and
R.sup.12, with the proviso that Q.sup.b is bonded to lowest number
substituent position of each W.sup.5 and that (CH(R.sup.38)).sub.r
is bonded to E.sup.0;
[0133] Y.sup.0 is optionally Q.sup.b--Q.sup.ssssr wherein
Q.sup.ssssr is (CH(R.sup.38)).sub.r--W.sup.6, r is an integer
selected from 1 through 3, W.sup.6 is selected from the group
consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl,
2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl,
3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl,
2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl,
3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl,
3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl,
2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl,
3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl,
2,7-imidazo(1,2-a)pyridinyl, 3,4-imidazo(1,2-a)pyridinyl,
3,5-imidazo(1,2-a)pyridinyl, 3,6-imidazo(1,2-a)pyridinyl,
3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl,
2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl,
1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl,
2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl,
3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl,
2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl,
2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl,
3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl,
1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl,
2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl,
2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl,
2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl,
3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl,
4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl,
1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl,
1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl,
3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl,
4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl,
4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl,
3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl,
4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hydrido
containing nitrogen member of the ring of the W.sup.6 other than
the points of attachment is optionally substituted with one or more
of the group consisting of R.sup.9, R.sup.10, R.sup.11, and
R.sup.12, with the proviso that Q.sup.b is bonded to highest number
substituent position of each W.sup.6 and that (CH(R.sup.38)).sub.r
is bonded to E.sup.0.
[0134] In another embodiment of compounds of Formula I or a
pharmaceutically acceptable salt thereof,
[0135] J.sup.a and J.sup.b are independently selected from the
group consisting of O and S;
[0136] B is formula (V): 12
[0137] wherein D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, no more than one of D.sup.1, D.sup.2, J.sup.1,
J.sup.2 and K.sup.1 is O, no more than one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 is S, one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 must be a covalent bond when two of
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are O and S, and no
more than four of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1
are N;
[0138] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.16,
R.sup.17, R.sup.18, R.sup.19, R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36 are independently selected from the group
consisting of hydrido, acetamido, haloacetamido, amidino,
guanidino, dialkylsulfonium, trialkylphosphonium,
dialkylsulfoniumalkyl, carboxy, heteroaralkylthio, heteroaralkoxy,
cycloalkylamino, acylalkyl, acylalkoxy, aryloylalkoxy,
heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,
heterocyclyl, perhaloaralkyl, aralkylsulfonyl,
aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,
halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,
cycloalkylsulfinylalkyl, cycloalkylsulfonyl,
cycloalkylsulfonylalkyl, heteroarylamino,
N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,
haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl,
heteroaralkoxy, cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl,
cycloalkylalkoxy, cycloalkenyloxyalkyl, cycloalkylenedioxy,
halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxy,
halocycloalkenyloxyalkyl, hydroxy, amino, alkoxyamino, thio, nitro,
lower alkylamino, alkylthio, alkylthioalkyl, arylamino,
aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,
alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl,
arylsulfonylalkyl, heteroarylsulfinylalkyl,
heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,
haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,
alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,
diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,
arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,
heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio,
alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl,
heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl, alkynyl,
alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,
cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower
cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl,
haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,
hydroxyalkyl, alkylenylamino, hydoxyheteroaralkyl, haloalkoxyalkyl,
aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated
heterocyclyl, partially saturated heterocyclyl, heteroaryl,
heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl,
arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy,
alkoxycarboxamido, alkylamidocarbonylamido, arylamidocarbonylamido,
carboalkoxyalkyl, carboalkoxyalkenyl, carboxy, carboaralkoxy,
carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono,
phosphonoalkyl, diaralkoxyphosphono, and
diaralkoxyphosphonoalkyl;
[0139] R.sup.16, R.sup.19, R.sup.32, R.sup.33, R.sup.34, R.sup.35,
and R.sup.36 are independently optionally Q.sup.b with the proviso
that no more than one of R.sup.16 and R.sup.19 is Q.sup.b at the
same time and that Q.sup.b is Q.sup.be;
[0140] B is optionally selected from the group consisting of
hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8
alkenyl, C3-C8 alkynyl, C2-C8 haloalkyl, and C3-C8 haloalkenyl
wherein each member of group B is optionally substituted at any
carbon up to and including 6 atoms from the point of attachment of
B to A with one or more of the group consisting of R.sup.32,
R.sup.33, R.sup.34, R.sup.35, and R.sup.36;
[0141] B is optionally selected from the group consisting of C3-C12
cycloalkyl, C5-C10 cycloalkenyl, and C4-C9 saturated heterocyclyl,
wherein each ring carbon is optionally substituted with R.sup.33, a
ring carbon other than the ring carbon at the point of attachment
of B to A is optionally substituted with oxo provided that no more
than one ring carbon is substituted by oxo at the same time, ring
carbons and a nitrogen adjacent to the carbon atom at the point of
attachment are optionally substituted with R.sup.9 or R.sup.13, a
ring carbon or nitrogen adjacent to the R.sup.9 position and two
atoms from the point of attachment is optionally substituted with
R.sup.10, a ring carbon or nitrogen adjacent to the R.sup.13
position and two atoms from the point of attachment is optionally
substituted with R.sup.12, a ring carbon or nitrogen three atoms
from the point of attachment and adjacent to the R.sup.10 position
is optionally substituted with R.sup.11, a ring carbon or nitrogen
three atoms from the point of attachment and adjacent to the
R.sup.12 position is optionally substituted with R.sup.33, and a
ring carbon or nitrogen four atoms from the point of attachment and
adjacent to the R.sup.11 and R.sup.33 positions is optionally
substituted with R.sup.34;
[0142] A is selected from the group consisting of single covalent
bond, (W.sup.7).sub.rr--(CH(R.sup.15)).sub.pa and
(CH(R.sup.15)).sub.pa--(W.sup- .7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
6, and W.sup.7 is selected from the group consisting of O, S, C(O),
C(O)N(R.sup.7), C(S)N(R.sup.7), (R.sup.7)NC(O), (R.sup.7)NC(S), and
N(R.sup.7) with the proviso that no more than one of the group
consisting of rr and pa can be 0 at the same time;
[0143] R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrido, hydroxy, alkyl, and alkoxyalkyl;
[0144] R.sup.14, R.sup.15, R.sup.37, and R.sup.38 are independently
selected from the group consisting of hydrido, hydroxy, halo,
alkyl, alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl;
[0145] R.sup.14 and R.sup.38 can be independently selected from the
group consisting of aroyl and heteroaroyl;
[0146] .PSI. is selected from the group consisting of NR.sup.5,
C(O), and S(O).sub.2;
[0147] R.sup.5 is selected from the group consisting of hydrido,
hydroxy, alkyl, and alkoxy;
[0148] R.sup.39 and R.sup.40 are independently selected from the
group consisting of hydrido, hydroxy, halo, hydroxyalkyl, alkyl,
alkoxyalkyl, haloalkyl, haloalkoxy, and haloalkoxyalkyl;
[0149] M is selected from the group consisting of N and
R.sup.1--C;
[0150] R.sup.1 is selected from the group consisting of hydrido,
alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio,
amino, aminoalkyl, alkylamino, amidino, guanidino, hydroxy,
hydroxyamino, alkoxy, hydroxyalkyl, alkoxyamino, thiol, alkylthio,
and phosphono;
[0151] R.sup.2 is Z.sup.0--Q;
[0152] Z.sup.0 is selected from the group consisting of covalent
single bond, (CR.sup.41R.sup.42).sub.q wherein q is an integer
selected from 1 through 3,
(CH(R.sup.41)).sub.g--W.sup.0--(CH(R.sup.42)).sub.p wherein g and p
are integers independently selected from 0 through 3 and W.sup.0 is
selected from the group consisting of O, S, C(O), S(O), S(O).sub.2,
N(R.sup.41), and ON(R.sup.41), and
(CH(R.sup.41)).sub.e--W.sup.22--(CH(R.- sup.42)).sub.h wherein e
and h are integers independently selected from 0 through 2 and
W.sup.22 is selected from the group consisting of
CR.sup.41.dbd.CR.sup.42, 1,2-cyclopropyl, 1,2-cyclobutyl,
1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl,
2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl,
3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl,
2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl,
2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl,
1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,
2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso
that Z.sup.0 is directly bonded to the uracil ring;
[0153] R.sup.41 and R.sup.42 are independently selected from the
group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino,
and alkyl;
[0154] Q is selected from the group consisting of hydrido, with the
proviso that Z.sup.0 is other than a covalent single bond, the
formula (II): 13
[0155] wherein D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, no more than one of D.sup.1, D.sup.2, J.sup.1,
J.sup.2 and K.sup.1 is O, no more than one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 is S, one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 must be a covalent bond when two of
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are O and S, and no
more than four of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 is
N, with the proviso that R.sup.9, R.sup.10, R.sup.11, R.sup.12, and
R.sup.13 are each independently selected to maintain the
tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, and the divalent nature of oxygen;
[0156] K is (CR.sup.4aR.sup.4b).sub.n wherein n is an integer
selected from 1 through 2;
[0157] R.sup.4a and R.sup.4b are independently selected from the
group consisting of halo, hydrido, hydroxyalkyl, alkyl,
alkoxyalkyl, alkylthioalkyl, and haloalkyl;
[0158] E.sup.0 is selected from the group consisting of a covalent
single bond, C(O), C(S), C(O)N(R.sup.7), (R.sup.7)NC(O),
S(O).sub.2, (R.sup.7)NS(O).sub.2, and S(O).sub.2N(R.sup.7);
[0159] Y.sup.0 is formula (IV): 14
[0160] wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is C, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is O, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 must be a covalent bond when two of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are O and S, and no more than four of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are N when K.sup.2 is carbon with the
provisos that R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are each
independently selected to maintain the tetravalent nature of
carbon, trivalent nature of nitrogen, the divalent nature of
sulfur, and the divalent nature of oxygen;
[0161] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, .sup.+NR.sup.20R.sup.21R.sup.22, aminoalkylenyl,
and Q.sup.be, wherein Q.sup.be is hydrido and R.sup.20, R.sup.21,
and R.sup.22 are independently selected from the group consisting
of hydrido, alkyl, hydroxy, amino, aminoalkylenyl, dialkylamino,
alkylamino, and hydroxyalkyl with the proviso that no more than one
of R.sup.20 and R.sup.21 is hydroxy, amino, alkylamino, or
dialkylamino at the same time;
[0162] Q.sup.b is optionally selected from the group consisting of
C(NR.sup.25)NR.sup.23R.sup.24,
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.2- 4),
C(O)N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24),
N(R.sup.26)N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), and
ON(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24) with the provisos
that no more than one of R.sup.23, R.sup.24, and R.sup.26 is
hydroxy, alkylamino, amino, or dialkylamino when two of the group
consisting of R.sup.23, R.sup.24, and R.sup.26 are bonded to the
same atom;
[0163] R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are independently
selected from the group consisting of hydrido, alkyl, hydroxy,
amino, alkylenylamino, dialkylamino, alkylamino, and
hydroxyalkyl;
[0164] Q.sup.s is selected from the group consisting of a single
covalent bond, (CR.sup.37R.sup.38).sub.b--(W.sup.0).sub.az wherein
az is an integer selected from 0 through 1, b is an integer
selected from 1 through 5, and W.sup.0 is selected from the group
consisting of O, C(O), S(O), S(O).sub.2, S(O).sub.2N(R.sup.14),
N(R.sup.14)S(O).sub.2, and N(R.sup.14),
(CH(R.sup.14)).sub.c--W.sup.1--(CH(R.sup.15)).sub.d wherein c and d
are integers independently selected from 1 through 4 and W.sup.1 is
selected from the group consisting of O, S, C(O), C(S), C(O)O,
C(S)O, C(O)S, C(S)S, C(O)N(R.sup.14), (R.sup.14)NC(O),
C(S)N(R.sup.14), (R.sup.14)NC(S), OC(O)N(R.sup.14),
(R.sup.14)NC(O)O, SC(S)N(R.sup.14), (R.sup.14)NC(S)S,
SC(O)N(R.sup.14), (R.sup.14)NC(O)S, OC(S)N(R.sup.14),
(R.sup.14)NC(S)O, N(R.sup.15)C(O)N(R.sup.14),
(R.sup.14)NC(O)N(R.sup.15), N(R.sup.15)C(S)N(R.sup.14),
(R.sup.14)NC(S)N(R.sup.15), S(O), S(O).sub.2,
S(O).sub.2N(R.sup.14), N(R.sup.14)S(O).sub.2, P(O)(R.sup.8),
N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7), N(R.sup.14),
ON(R.sup.14), and
(CH(R.sup.14)).sub.e--W.sup.22--(CH(R.sup.15)).sub.h wherein e and
h are integers independently selected from 0 through 2 and W.sup.22
is selected from the group consisting of CR.sup.41.dbd.CR.sup.42- ,
CR.sup.41R.sup.42.dbd.C; vinylidene), ethynylidene (C.ident.C;
1,2-ethynyl), 1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl,
1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl,
2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,
1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl,
1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl,
2,6-piperidinyl, 3,4-piperidinyl, 1,2-pyrrolidinyl,
1,3-pyrrolidinyl, 2,3-pyrrolidinyl, 2,4-pyrrolidinyl,
2,5-pyrrolidinyl, 3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl,
2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl, and
3,4-tetrahydrofuranyl, with the provisos that R.sup.14 and R.sup.15
are selected from other than halo and cyano when directly bonded to
N and that (CR.sup.37R.sup.38).sub.b, (CH(R.sup.14)).sub.c, and
(CH(R.sup.14)).sub.e are bonded to E.sup.0;
[0165] Y.sup.0 is optionally Q.sup.b--Q.sup.SS wherein Q.sup.ss is
selected from the group consisting of (CR.sup.37R.sup.38).sub.f
wherein f is an integer selected from 1 through 4,
(CH(R.sup.14)).sub.c--W.sup.1--(- CH(R.sup.15)).sub.d wherein c and
d are integers independently selected from 1 through 2, and W.sup.1
is selected from the group consisting of W.sup.1 is selected from
the group consisting of O, S, C(O), C(O)N(R.sup.14),
(R.sup.14)NC(O), N(R.sup.15)C(O)N(R.sup.14),
(R.sup.14)NC(O)N(R.sup.15), N(R.sup.14), ON(R.sup.14), and
(CH(R.sup.14)).sub.e--W.sup.2--(CH(R.sup.15)).sub.h wherein e and h
are integers independently selected from 0 through 2 and W.sup.2 is
selected from the group consisting of
CR.sup.4a.dbd.CR.sup.4b,ethynylidene (C.ident.C; 1,2-ethynyl), and
C.dbd.CR.sup.4aR.sup.4b with the provisos that R.sup.14 and
R.sup.15 are selected from other than halo when directly bonded to
N and that (CR.sup.37R.sup.38).sub.f, (CH(R.sup.14)).sub.c, and
(CH(R.sup.14)).sub.e are bonded to E.sup.0;
[0166] Y.sup.0 is optionally Q.sup.b--Q.sup.sss wherein Q.sup.sss
is (CH(R.sup.38)).sub.r--W.sup.3, r is an integer selected from 1
through 2, W.sup.3 is selected from the group consisting of
1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl,
1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl,
1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl,
2,6morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl,
1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl,
2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl,
2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl,
3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl,
1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,
2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl.
4H-2,4pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl,
2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl,
2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl,
2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl,
2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl,
3,4-tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon
and hyrido containing nitrogen member of the ring of the W.sup.3
other than the points of attachment is optionally substituted with
one or more of the group consisting of R.sup.9, R.sup.10, R.sup.11,
and R.sup.12, with the proviso that (CH(R.sup.38)).sub.r is bonded
to E.sup.0 and Q.sup.b is bonded to lowest numbered substituent
position of each W.sup.3;
[0167] Y.sup.0 is optionally Q.sup.b--Q.sup.sssr wherein Q.sup.sssr
is (CH(R.sup.38)).sub.r--W.sup.4, r is an integer selected from 1
through 2, W.sup.4 is selected from the group consisting of
1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl,
1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,
2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,
1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl,
2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl,
1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl,
2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl,
1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,
2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl,
4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyran-2-one-3,4-yl,
2H-pyran-2-one4,5-yl, 4H-pyran-4-one-2,3-yl, 2,3-tetrahydrofuranyl,
2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl,
3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl,
2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl,
2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, and
3,5-tetrahydropyranyl, and each carbon and hyrido containing
nitrogen member of the ring of the W.sup.4 other than the points of
attachment is optionally substituted with one or more of the group
consisting of R.sup.9, R.sup.10, R.sup.11, and R.sup.12, with the
provisos that (CH(R.sup.38)).sub.r is bonded to E.sup.0 and Q.sup.b
is bonded to highest number substituent position of each
W.sup.4;
[0168] Y.sup.0 optionally Q.sup.b--Q.sup.ssss wherein Q.sup.sss is
(CH(R.sup.38)).sub.r--W.sup.5, r is an integer selected from 1
through 2, W.sup.5 is selected from the group consisting of
1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl,
2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl,
3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl,
2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl,
3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl,
2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl,
2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl,
3,6-benzothiophenyl, 3,7-benzothiophenyl,
2,7-imidazo(1,2-a)pyridinyl, 3,4-imidazo(1,2-a)pyridinyl,
3,5-imidazo(1,2-a)pyridinyl, 3,6-imidazo(1,2-a)pyridinyl,
3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl,
2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl,
1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl,
2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl,
3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl,
2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl,
2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl,
3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl,
1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl,
2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl,
2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl,
2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl,
3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl,
4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl,
1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl,
1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl,
3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl,
4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl,
4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl,
3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl,
4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hyrido
containing nitrogen member of the ring of the W.sup.5 other than
the points of attachment is optionally substituted with one or more
of the group consisting of R.sup.9, R.sup.10, R.sup.11, and
R.sup.12, with the proviso that Q.sup.b is bonded to lowest number
substituent position of each W.sup.5 and that (CH(R.sup.38)).sub.r
is bonded to E.sup.0;
[0169] Y.sup.0 is optionally Q.sup.b--Q.sup.ssssr wherein
Q.sup.ssssr is (CH(R.sup.38)).sub.r--W.sup.6, r is an integer
selected from 1 through 2, W.sup.6 is selected from the group
consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl,
2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl,
3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl,
2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl,
3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl,
3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl,
2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl,
3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl,
2,7-imidazo(1,2-a)pyridinyl, 3,4-imidazo(1,2-a)pyridinyl,
3,5-imidazo(1,2-a)pyridinyl, 3,6-imidazo(1,2-a)pyridinyl,
3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl,
2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl,
1,4-isoindolyl, 1,5isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl,
2,5isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl,
3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl,
2,4-benzoxazolyl, 2,5-benzoxazolyl, 2,6-benzoxazolyl,
2,7-benzoxazolyl, 3,4-benzisoxazolyl, 3,5-benzisoxazolyl,
3,6-benzisoxazolyl, 3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl,
1,6-naphthyl, 1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl,
2,5-naphthyl, 2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl,
2,4-quinolinyl, 2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl,
2,8-quinolinyl, 3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl,
3,7-quinolinyl, 3,8-quinolinyl, 4,5-quinotinyl, 4,6-quinolinyl,
4,7-quinolinyl, 4,8-quinolinyl, 1,4-isoquinolinyl,
1,5-isoquinolinyl, 1,6-isoquinolinyl, 1,7-isoquinolinyl,
1,8-isoquinolinyl, 3,4-isoquinolinyl, 3,5-isoquinolinyl,
3,6-isoquinolinyl, 3,7-isoquinolinyl, 3,8-isoquinolinyl,
4,5-isoquinolinyl, 4,6-isoquinolinyl, 4,7-isoquinolinyl,
4,8-isoquinolinyl, 3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl,
3,7-cinnolinyl, 3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl,
4,7-cinnolinyl, and 4,8-cinnolinyl, and each carbon and hyrido
containing nitrogen member of the ring of the W.sup.6 other than
the points of attachment is optionally substituted with one or more
of the group consisting of R.sup.9, R.sup.10, R.sup.11, and
R.sup.12, with the proviso that Q.sup.b is bonded to highest number
substituent position of each W.sup.6 and that (CH(R.sup.38)).sub.r
is bonded to E.sup.0.
[0170] In a preferred embodiment of compounds of Formula I or a
pharmaceutically acceptable salt thereof,
[0171] J.sup.a and J.sup.b are each O;
[0172] B is formula (V): 15
[0173] wherein D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, no more than one of D.sup.1, D.sup.2, J.sup.1,
J.sup.2 and K.sup.1 is O, no more than one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 is S, one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 must be a covalent bond when two of
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are O and S, and no
more than four of D.sup.1,D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are
N;
[0174] R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.32,
R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, amidino ,guanidino, alkylenedioxy, haloalkylthio,
alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, hydroxy, amino,
alkoxyamino, nitro, lower alkylamino, alkylthio, alkylthioalkyl,
alkylsulfinyl, alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl,
cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl,
alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, alkanoyl, haloalkanoyl,
alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy,
hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl,
carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamidoalkyl,
and cyano;
[0175] R.sup.16, R.sup.19, R.sup.32, R.sup.33, R.sup.34, R.sup.35,
and R.sup.36 are independently optionally Q.sup.b with the proviso
that no more than one of R.sup.16 and R.sup.19 is Q.sup.b at the
same time and that Q.sup.b is Q.sup.be;
[0176] B is optionally selected from the group consisting of
hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8
alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of
group B is optionally substituted at any carbon up to and including
6 atoms from the point of attachment of B to A with one or more of
the group consisting of R.sup.32, R.sup.33, R.sup.34, R.sup.35, and
R.sup.36;
[0177] B is optionally selected from the group consisting of C3-C12
cycloalkyl and C4-C9 saturated heterocyclyl, wherein each ring
carbon may be optionally substituted with R.sup.33, a ring carbon
other than the ring carbon at the point of attachment of B to A is
optionally substituted with oxo provided that no more than one ring
carbon is substituted by oxo at the same time, ring carbons and a
nitrogen adjacent to the carbon atom at the point of attachment may
be optionally substituted with R.sup.9 or R.sup.13, a ring carbon
or nitrogen adjacent to the R.sup.9 position and two atoms from the
point of attachment is optionally substituted with R.sup.10, a ring
carbon or nitrogen adjacent to the R.sup.13 position and two atoms
from the point of attachment is optionally substituted with
R.sup.12, a ring carbon or nitrogen three atoms from the point of
attachment and adjacent to the R.sup.10 position is optionally
substituted with R.sup.11, a ring carbon or nitrogen three atoms
from the point of attachment and adjacent to the R.sup.12 position
is optionally substituted with R.sup.33, and a ring carbon or
nitrogen four atoms from the point of attachment and adjacent to
the R.sup.11 and R.sup.33 positions is optionally substituted with
R.sup.34;
[0178] A is selected from the group consisting of single covalent
bond, (W.sup.7).sub.rr--(CH(R.sup.15)).sub.pa and
(CH(R.sup.15)).sub.pa--(W.sup- .7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
6, and W.sup.7 is selected from the group consisting of O, S, C(O),
(R.sup.7)NC(O), (R.sup.7)NC(S), and N(R.sup.7) with the proviso
that no more than one of the group consisting of rr and pa is 0 at
the same time;
[0179] R.sup.7 is selected from the group consisting of hydrido,
hydroxy, and alkyl;
[0180] R.sup.15 is selected from the group consisting of hydrido,
hydroxy, halo, alkyl, and haloalkyl;
[0181] .PSI. is selected from the group consisting of NH and
NOH;
[0182] M is selected from the group consisting of N and
R.sup.1--C;
[0183] R.sup.1 is selected from the group consisting of hydrido,
alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio,
amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino,
alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio;
[0184] R.sup.2 is Z.sup.0--Q;
[0185] Z.sup.0 is selected from the group consisting of covalent
single bond, (CR.sup.41R.sup.42).sub.q wherein q is an integer
selected from 1 through 3,
(CH(R.sup.41)).sub.g--W.sup.0--(CH(R.sup.42)).sub.p wherein g and p
are integers independently selected from 0 through 3 and W.sup.0 is
selected from the group consisting of O, S, C(O), S(O),
N(R.sup.41), and ON(R.sup.41), and
(CH(R.sup.41)).sub.e--W.sup.22--(CH(R.sup.42)).sub.h wherein e and
h are integers independently selected from 0 through 1 and W.sup.22
is selected from the group consisting of CR.sup.41.dbd.CR.sup.42- ,
1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl,
1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,
2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl,
1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl,
1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl,
3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,
2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl,
3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso
that Z.sup.0 is directly bonded to the uracil ring;
[0186] R.sup.41 and R.sup.42 are independently selected from the
group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino,
and alkyl;
[0187] Q is selected from the group consisting of hydrido, with the
proviso that Z.sup.0 is other than a covalent single bond, and the
formula (II): 16
[0188] wherein D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, no more than one of D.sup.1, D.sup.2, J.sup.1,
J.sup.2 and K.sup.1 is O, no more than one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 is S, one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 must be a covalent bond when two of
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are O and S, and no
more than four of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1
are N, with the proviso that R.sup.9, R.sup.10, R.sup.11, R.sup.12,
and R.sup.13 are each independently selected to maintain the
tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, and the divalent nature of oxygen;
[0189] K is (CR.sup.4aR.sup.4b).sub.n wherein n is an integer
selected from 1 through 2;
[0190] R.sup.4a and R.sup.4b are independently selected from the
group consisting of halo, hydrido, hydroxyalkyl, alkyl,
alkoxyalkyl, alkylthioalkyl, and haloalkyl;
[0191] E.sup.0 is E.sup.1, when K is (CR.sup.4aR.sup.4b).sub.n,
wherein E.sup.1 is selected from the group consisting of a covalent
single bond, C(O), C(S), C(O)N(R.sup.7), (R.sup.7)NC(O),
S(O).sub.2, (R.sup.7)NS(O).sub.2, and S(O).sub.2N(R.sup.7);
[0192] Y.sup.0 is formula (IV): 17
[0193] wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is C, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is O, no more than one of D.sup.5,D.sup.6,
J.sup.5,and J.sup.6 is S, one of D.sup.5, D.sup.6, J.sup.5,and
J.sup.6 must be a covalent bond when two of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are O and S, and no more than four of D.sup.5,
D.sup.6, J.sup.5 and J.sup.6 are N with the proviso that R.sup.16,
R.sup.17, R.sup.18, and R.sup.19 are each independently selected to
maintain the tetravalent nature of carbon, trivalent nature of
nitrogen, the divalent nature of sulfur, and the divalent nature of
oxygen;
[0194] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino,
lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, alkylenylamino, haloalkoxyalkyl,
carboalkoxy, and cyano;
[0195] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, aminoalkylenyl, Q.sup.be wherein Q.sup.be is
hydrido, N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), and
C(NR.sup.25)NR.sup.23R.- sup.24, with the provisos that no more
than one of R.sup.20 and R.sup.21 is hydroxy, amino, alkylamino, or
dialkylamino at the same time and that no more than one of R.sup.23
and R.sup.24 is hydroxy, amino, alkylamino, or dialkylamino at the
same time;
[0196] R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are independently selected from the group consisting of
hydrido, alkyl, hydroxy, aminoalkylenyl, amino, dialkylamino,
alkylamino, and hydroxyalkyl;
[0197] Q.sup.s is selected from the group consisting of a single
covalent bond, (CR.sup.37R.sup.38).sub.b wherein b is an integer
selected from 1 through 4, and
(CH(R.sup.14)).sub.c--W.sup.1--(CH(R.sup.15)).sub.d wherein c and d
are integers independently selected from 1 through 3 and W.sup.1 is
selected from the group consisting of C(O)N(R.sup.14),
(R.sup.14)NC(O), S(O), S(O).sub.2, S(O).sub.2N(R.sup.14),
N(R.sup.14)S(O).sub.2, and N(R.sup.14), with the provisos that
R.sup.14 is selected from other than halo when directly bonded to N
and that (CR.sup.37R.sup.38).sub.b, and (CH(R.sup.14)).sub.c are
bonded to E.sup.0;
[0198] R.sup.14 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0199] R.sup.37 and R.sup.38 are independently selected from the
group consisting of hydrido, alkyl, and haloalkyl;
[0200] R.sup.38 is optionally selected from the group consisting of
aroyl and heteroaroyl;
[0201] Y.sup.0 is optionally Q.sup.b--Q.sup.ss wherein Q.sup.ss is
(CH(R.sup.14)).sub.e--W.sup.2--(CH(R.sup.15)).sub.h, wherein e and
h are integers independently selected from 1 through 2 and W.sup.2
is CR.sup.4a.dbd.CR.sup.4b with the proviso that
(CH(R.sup.14)).sub.e is bonded to E.sup.0;
[0202] Y.sup.0 is optionally selected from the group consisting of
Q.sup.b--Q.sup.ssss and Q.sup.b--Q.sup.ssssr wherein Q.sup.ssss is
(CH(R.sup.38)).sub.r--W.sup.5 and Q.sup.ssssr is
(CH(R.sup.38)).sub.r--W.- sup.6, r is an integer selected from 1
through 2, and W.sup.5 and W.sup.6 are independently selected from
the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl,
1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl,
3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl,
2,4benzofuranyl, 2,5-benzofuranyl, 2,6-benzofuranyl,
2,7-benzofuranyl, 3,4-benzofuranyl, 3,5-benzofuranyl,
3,6-benzofuranyl, 3,7-benzofuranyl, 2,4-benzothiophenyl,
2,5-benzothiophenyl, 2,6-benzothiophenyl, 2,7-benzothiophenyl,
3,4-benzothiophenyl, 3,5-benzothiophenyl, 3,6-benzothiophenyl,
3,7-benzothiophenyl, 2,7-imidazo(1,2-a)pyridinyl,
3,4-imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2-a)pyridinyl,
3,6-imidazo(1,2-a)pyridinyl, 3,7-imidazo(1 ,2-a)pyridinyl,
2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl,
3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl,
1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl,
2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl,
3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl,
2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl,
3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl,
3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl,
1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl,
2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl,
2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl,
3,4-quinolinyl, 3,5-quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl,
3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl,
4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl,
1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl,
3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl,
3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl,
4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl,
3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl,
3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and
4,8-cinnolinyl, and each carbon and hyrido containing nitrogen
member of the ring of the W.sup.5 and of the ring of the W.sup.6,
other than the points of attachment of W.sup.5 and W.sup.6, is
optionally substituted with one or more of the group consisting of
R.sup.9, R.sup.10, R.sup.11, and R.sup.12, with the provisos that
Q.sup.b is bonded to lowest number substituent position of each
W.sup.5, Q.sup.b is bonded to highest number substituent position
of each W.sup.6, and (CH(R.sup.38)).sub.r is bonded to E.sup.0.
[0203] In a more preferred embodiment of compounds of Formula I or
a pharmaceutically acceptable salt thereof,
[0204] J.sup.a and J.sup.b are each O;
[0205] B is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.32, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.36, a carbon adjacent to R.sup.32 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.33, a carbon adjacent to R.sup.36 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.35, and any carbon adjacent to both R.sup.33
and R.sup.35 is optionally substituted by R.sup.34;
[0206] R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkylenedioxy,
haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino,
alkanoyl, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl,
aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl,
haloalkoxy, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b;
[0207] B is optionally selected from the group consisting of
hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl, C3-C8
alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of
group B is optionally substituted at any carbon up to and including
6 atoms from the point of attachment of B to A with one or more of
the group consisting of R.sup.32, R.sup.33, R.sup.34, R.sup.35, and
R.sup.36;
[0208] B is optionally selected from the group consisting of C3-C12
cycloalkyl and C4-C9 saturated heterocyclyl, wherein each ring
carbon is optionally optionally substituted with R.sup.33, a ring
carbon other than the ring carbon at the point of attachment of B
to A is optionally substituted with oxo provided that no more than
one ring carbon is substituted by oxo at the same time, ring
carbons and a nitrogen adjacent to the carbon atom at the point of
attachment are optionally substituted with R.sup.9 or R.sup.13, a
ring carbon or nitrogen adjacent to the R.sup.9 position and two
atoms from the point of attachment is optionally substituted with
R.sup.10, a ring carbon or nitrogen adjacent to the R.sup.13
position and two atoms from the point of attachment is optionally
substituted with R.sup.12, a ring carbon or nitrogen three atoms
from the point of attachment and adjacent to the R.sup.10 position
is optionally substituted with R.sup.11, a ring carbon or nitrogen
three atoms from the point of attachment and adjacent to the
R.sup.12 position is optionally substituted with R.sup.33, and a
ring carbon or nitrogen four atoms from the point of attachment and
adjacent to the R.sup.11 and R.sup.33 positions is optionally
substituted with R.sup.34;
[0209] R.sup.9, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl,
amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy,
amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxyalkyl, carboxy, carboxamido, and
cyano;
[0210] A is selected from the group consisting of single covalent
bond and (CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an
integer selected from 0 through 1, pa is an integer selected from 0
through 3, and W.sup.7 is selected from the group consisting of O,
S, C(O), (R.sup.7)NC(O), (R.sup.7)NC(S), and N(R.sup.7);
[0211] R.sup.7 is selected from the group consisting of hydrido,
hydroxy and alkyl;
[0212] R.sup.15 is selected from the group consisting of hydrido,
hydroxy, halo, alkyl, and haloalkyl;
[0213] .PSI. is NH;
[0214] M is selected from the group consisting of N and
R.sup.1--C;
[0215] R.sup.1 is selected from the group consisting of hydrido,
alkyl, cyano, halo, haloalkyl, haloalkoxy, amino, aminoalkyl,
alkylamino, amidino, hydroxy, hydroxyamino, alkoxy, hydroxyalkyl,
alkoxyamino, thiol, and alkylthio;
[0216] R.sup.2 is Z.sup.0--Q;
[0217] Z.sup.0 is selected from the group consisting of covalent
single bond and (CR.sup.41R.sup.42).sub.q wherein q is an integer
selected from 1 through 2,
(CH(R.sup.41)).sub.g--W.sup.0--(CH(R.sup.42)).sub.p wherein g and p
are integers independently selected from 0 through 3 and W.sup.0 is
selected from the group consisting of O, S, and N(R.sup.41), and
(CH(R.sup.41)).sub.e--W.sup.22--(CH(R.sup.42)).sub.h wherein e and
h are integers independently selected from 0 through 1 and W.sup.22
is selected from the group consisting of CR.sup.41.dbd.CR.sup.42,
1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl,
1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,
2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl,
1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl,
1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl,
3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,
2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl,
3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso
that Z.sup.0 is directly bonded to the uracil ring;
[0218] R.sup.41 and R.sup.42 are independently selected from the
group consisting of hydrido, hydroxy, and amino;
[0219] Q is selected from the group consisting of hydrido, with the
proviso that Z.sup.0 is other than a covalent single bond, aryl,
and heteroaryl, wherein a carbon adjacent to the carbon at the
point of attachment is optionally substituted by R.sup.9, the other
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.13, a carbon adjacent to R.sup.9
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.10, a carbon adjacent to R.sup.13
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.12, and any carbon adjacent to both
R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
[0220] K is CHR.sup.4a wherein R.sup.4a is selected from the group
consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl,
alkylthioalkyl, and haloalkyl;
[0221] E.sup.0 is selected from the group consisting of a covalent
single bond, C(O)N(H), (H)NC(O), (R.sup.7)NS(O).sub.2, and
S(O).sub.2N(R.sup.7);
[0222] Y.sup.0 is formula (IV): 18
[0223] wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is C, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is O, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is S, one of D.sup.5 D.sup.6, J.sup.5, and
J.sup.6 must be a covalent bond when two of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are O and S, and no more than four of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are N, with the provisos that
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are each independently
selected to maintain the tetravalent nature of carbon, trivalent
nature of nitrogen, the divalent nature of sulfur, and the divalent
nature of oxygen;
[0224] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, alkoxyamino, lower
alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl,
haloalkanoyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,
aminoalkyl, and cyano;
[0225] R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be;
[0226] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido,
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(- R.sup.24), and
C(NR.sup.25)NR.sup.23R.sup.24, with the provisos that no more than
one of R.sup.20 and R.sup.21 is hydroxy, amino, alkylamino, or
dialkylamino at the same time and that no more than one of R.sup.23
and R.sup.24 is hydroxy, amino, alkylamino, or dialkylamino at the
same time;
[0227] R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are independently selected from the group consisting of
hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;
[0228] Q.sup.s is selected from the group consisting of a single
covalent bond, (CR.sup.37R.sup.38).sub.b wherein b is an integer
selected from 1 through 4, and
(CH(R.sup.14)).sub.c--W.sup.1--(CH(R.sup.15)).sub.d wherein c and d
are integers independently selected from 1 through 3 and W.sup.1 is
selected from the group consisting of C(O)N(R.sup.14),
(R.sup.14)NC(O), S(O), S(O).sub.2, S(O).sub.2N(R.sup.14),
N(R.sup.14)S(O).sub.2, and N(R.sup.14), with the provisos that
R.sup.14 is selected from other than halo when directly bonded to N
and that (CR.sup.37R.sup.38).sub.b, and (CH(R.sup.14)).sub.c are
bonded to E.sup.0;
[0229] R.sup.14 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0230] R.sup.37 and R.sup.38 are independently selected from the
group consisting of hydrido, alkyl, and haloalkyl;
[0231] R.sup.38 is optionally selected from the group consisting of
aroyl and heteroaroyl;
[0232] Y.sup.0 is optionally Q.sup.b--Q.sup.ss wherein Q.sup.ss is
(CH(R.sup.14)).sub.e--W.sup.2--(CH(R.sup.15)).sub.h, wherein e and
h are integers independently selected from 1 through 2 and W.sup.2
is CR.sup.4a.dbd.CH with the proviso that (CH(R.sup.14)).sub.e is
bonded to E.sup.0.
[0233] In an even more preferred embodiment of compounds of Formula
I or a pharmaceutically acceptable salt thereof,
[0234] J.sup.a and J.sup.b are each O;
[0235] B is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.32, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.36, a carbon adjacent to R.sup.32 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.33, a carbon adjacent to R.sup.36 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.35, and any carbon adjacent to both R.sup.33
and R.sup.35 is optionally substituted by R.sup.34;
[0236] R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b;
[0237] A is selected from the group consisting of single covalent
bond and (CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an
integer selected from 0 through 1, pa is an integer selected from 0
through 3, and W.sup.7 is selected from the group consisting of
(R.sup.7)NC(O) and N(R.sup.7);
[0238] R.sup.7 is selected from the group consisting of hydrido,
hydroxy and alkyl
[0239] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl and haloalkyl;
[0240] .PSI. is NH;
[0241] M is selected from the group consisting of N and
R.sup.1--C;
[0242] R.sup.1 is selected from the group consisting of hydrido,
hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy,
alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl,
haloalkoxy, and halo;
[0243] R.sup.2 is Z.sup.0--Q;
[0244] Z.sup.0 is selected from the group consisting of a covalent
single bond, O, S, NH, and CH.sub.2;
[0245] Q is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.13, a carbon adjacent to R.sup.9 and two atoms
from the carbon at the point of attachment is optionally
substituted by R.sup.10, a carbon adjacent to R.sup.13 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.12, and any carbon adjacent to both R.sup.10
and R.sup.12 is optionally substituted by R.sup.11;
[0246] R.sup.9, R.sup.11, and R.sup.13 are independently selected
from the group consisting of hydrido, hydroxy, amino, amidino,
guanidino, lower alkylamino, alkylthio, alkylsulfonamido,
alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl
amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy,
hydroxyalkyl, carboxy, carboxamido, and cyano;
[0247] R.sup.10 and R.sup.12 are independently selected from the
group consisting of hydrido, acetamido, haloacetamido, amidino,
guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower
alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl,
carboalkoxy, carboxy, carboxyalkyl, aminocarbonyl, halo, haloalkyl,
and cyano;
[0248] K is CH.sub.2;
[0249] E.sup.0 is C(O)N(H);
[0250] Y.sup.0 is formula (IV): 19
[0251] wherein D.sup.5, D.sup.6, J.sup.5 and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is C, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is optionally O, no more than one of D.sup.5,
D.sup.6, J.sup.5,and J.sup.6 is optionally S, one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 must be a covalent bond when two of
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are O and S, and no more
than four of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are N;
[0252] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and
cyano;
[0253] R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be;
[0254] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido, and
C(NR.sup.25)NR.sup.23R.sup.24, with the provisos that no more than
one of R.sup.20 and R.sup.21 is hydroxy at the same time and that
no more than one of R.sup.23 and R.sup.24 is hydroxy at the same
time;
[0255] R.sup.20, R.sup.21, R.sup.23, R.sup.24, and R.sup.25 are
independently selected from the group consisting of hydrido, alkyl,
and hydroxy;
[0256] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0257] In another even more preferred embodiment of compounds of
Formula I or a pharmaceutically acceptable salt thereof,
[0258] J.sup.a and J.sup.b are each O;
[0259] B is optionally selected from the group consisting of
hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8
haloalkyl, wherein each member of group B is optionally substituted
at any carbon up to and including 6 atoms from the point of
attachment of B to A with one or more of the group consisting of
R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36;
[0260] R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b;
[0261] A is selected from the group consisting of single covalent
bond and (CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an
integer selected from 0 through 1, pa is an integer selected from 0
through 3, and W.sup.7 is selected from the group consisting of
(R.sup.7)NC(O) and N(R.sup.7);
[0262] R.sup.7 is selected from the group consisting of hydrido,
hydroxy and alkyl;
[0263] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl and haloalkyl;
[0264] .PSI. is NH;
[0265] M is selected from the group consisting of N and
R.sup.1--C;
[0266] R.sup.1 is selected from the group consisting of hydrido,
hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy,
alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl,
haloalkoxy, and halo;
[0267] R.sup.2 is Z.sup.0--Q;
[0268] Z.sup.0 is selected from the group consisting of a covalent
single bond, O, S, NH, and CH.sub.2;
[0269] Q is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.13, a carbon adjacent to R.sup.9 and two atoms
from the carbon at the point of attachment is optionally
substituted by R.sup.10, a carbon adjacent to R.sup.13 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.12, and any carbon adjacent to both R.sup.10
and R.sup.12 is optionally substituted by R.sup.11;
[0270] R.sup.9, R.sup.11, and R.sup.13 are independently selected
from the group consisting of hydrido, hydroxy, amino, amidino,
guanidino, lower alkylamino, alkylthio, alkylsulfonamido,
alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl
amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy,
hydroxyalkyl, carboxy, carboxamido, and cyano;
[0271] R.sup.10 and R.sup.12 are independently selected from the
group consisting of hydrido, acetamido, haloacetamido, amidino,
guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower
alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, alkylenylamino,
carboalkoxy, carboxy, carboxyalkyl, aminocarbonyl, halo haloalkyl,
and cyano;
[0272] K is CH.sub.2;
[0273] E.sup.0 is C(O)N(H);
[0274] Y.sup.0 is formula (IV); 20
[0275] wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is C, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is O, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 must be a covalent bond when two of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are O and S, and no more than four of D.sup.5,
D.sup.6, J.sup.5 and J.sup.6 are N, with the provisos that
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are each independently
selected to maintain the tetravalent nature of carbon, trivalent
nature of nitrogen, the divalent nature of sulfur, and the divalent
nature of oxygen;
[0276] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino,
and cyano;
[0277] R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be;
[0278] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido,
C(NR.sup.25)NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), with the provisos
that no more than one of R.sup.20 and R.sup.21 is hydroxy at the
same time and that no more than one of R.sup.23 and R.sup.24 is
hydroxy at the same time;
[0279] R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are independently selected from the group consisting of
hydrido, alkyl, and hydroxy;
[0280] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0281] In still another even more preferred embodiment of compounds
of Formula I or a pharmaceutically acceptable salt thereof,
[0282] J.sup.a and J.sup.b are each O;
[0283] B is optionally selected from the group consisting of C3-C7
cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring
carbon is optionally substituted with R.sup.33, a ring carbon other
than the ring carbon at the point of attachment of B to A is
optionally substituted with oxo provided that no more than one ring
carbon is substituted by oxo at the same time, ring carbons and a
nitrogen adjacent to the carbon atom at the point of attachment are
optionally substituted with R.sup.9 or R.sup.13, a ring carbon or
nitrogen adjacent to the R.sup.9 position and two atoms from the
point of attachment is optionally substituted with R.sup.10, a ring
carbon or nitrogen adjacent to the R.sup.13 position and two atoms
from the point of attachment is optionally substituted with
R.sup.12, a ring carbon or nitrogen three atoms from the point of
attachment and adjacent to the R.sup.10 position is optionally
substituted with R.sup.11, a ring carbon or nitrogen three atoms
from the point of attachment and adjacent to the R.sup.12 position
is optionally substituted with R.sup.33, and a ring carbon or
nitrogen four atoms from the point of attachment and adjacent to
the R.sup.11 and R.sup.33 positions is optionally substituted with
R.sup.34;
[0284] R.sup.9, R.sup.11, and R.sup.13 are independently selected
from the group consisting of hydrido, hydroxy, amino, amidino,
guanidino, lower alkylamino, alkylthio, alkylsulfonamido,
alkylsulfinyl, alkylsulfonyl, amidosulfonyl, monoalkyl
amidosulfonyl, alkyl, alkoxy, halo, haloalkyl, haloalkoxy,
hydroxyalkyl, carboxy, carboxamido, and cyano;
[0285] R.sup.10 and R.sup.12 are independently selected from the
group consisting of hydrido, acetamido, haloacetamido, amidino,
guanidino, alkyl, alkoxy, hydroxy, amino, alkoxyamino, lower
alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, alkylenylamino,
carboalkoxy, carboxy, carboxyalkyl, aminocarbonyl, halo, haloalkyl,
and cyano;
[0286] R.sup.33 and R.sup.34 are independently selected from the
group consisting of hydrido, acetamido, haloacetamido, amidino,
guanidino, alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino,
alkylthio, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,
carboalkoxy, carboxy, carboxamido, cyano, and Q.sup.b;
[0287] A is selected from the group consisting of single covalent
bond and (CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an
integer selected from 0 through 1, pa is an integer selected from 0
through 3, and W.sup.7 is selected from the group consisting
of(R.sup.7)NC(O) and N(R.sup.7);
[0288] R.sup.7 is selected from the group consisting of hydrido,
hydroxy and alkyl;
[0289] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0290] .PSI. is NH;
[0291] M is selected from the group consisting of N and
R.sup.1--C;
[0292] R.sup.1 is selected from the group consisting of hydrido,
hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy,
alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl,
haloalkoxy, and halo;
[0293] R.sup.2 is Z.sup.0--Q;
[0294] Z.sup.0 is selected from the group consisting of a covalent
single bond, O, S, NH, and CH.sub.2;
[0295] Q is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.13, a carbon adjacent to R.sup.9 and two atoms
from the carbon at the point of attachment is optionally
substituted by R.sup.10, a carbon adjacent to R.sup.13 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.12, and any carbon adjacent to both R.sup.10
and R.sup.12 is optionally substituted by R.sup.11;
[0296] K is CH.sub.2;
[0297] E.sup.0 is C(O)N(H);
[0298] Y.sup.0 is formula (IV): 21
[0299] wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is C, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is O, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6, J.sup.5 and
J.sup.6 must be a covalent bond when two of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are O and S, and no more than four of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are N, with the provisos that
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are each independently
selected to maintain the tetravalent nature of carbon, trivalent
nature of nitrogen, the divalent nature of sulfur, and the divalent
nature of oxygen;
[0300] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino,
and cyano;
[0301] R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be;
[0302] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido, and
C(NR.sup.25)NR.sup.23R.sup.24, with the provisos that no more than
one of R.sup.20 and R.sup.21 is hydroxy at the same time and that
no more than one of R.sup.23 and R.sup.24 is hydroxy at the same
time;
[0303] R.sup.20, R.sup.21, R.sup.23, R.sup.24, and R.sup.25 are
independently selected from the group consisting of hydrido, alkyl,
and hydroxy;
[0304] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0305] In a most preferred embodiment of compounds of Formula I or
a pharmaceutically acceptable salt thereof,
[0306] J.sup.a and J.sup.b are each O;
[0307] B is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.32, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.36, a carbon adjacent to R.sup.32 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.33, a carbon adjacent to R.sup.36 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.35, and any carbon adjacent to both R.sup.33
and R.sup.35 is optionally substituted by R.sup.34;
[0308] R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b;
[0309] A is selected from the group consisting of single covalent
bond and (CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an
integer selected from 0 through 1, pa is an integer selected from 0
through 3, and W.sup.7 is N(R.sup.7);
[0310] R.sup.7 is selected from the group consisting of hydrido and
alkyl;
[0311] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0312] .PSI. is NH;
[0313] M is selected from the group consisting of N and
R.sup.1--C;
[0314] R.sup.1 is selected from the group consisting of hydrido,
hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy,
alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl,
haloalkoxy, and halo;
[0315] R.sup.2 is Z.sup.0--Q;
[0316] Z.sup.0 is a covalent single bond;
[0317] Q is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.13, a carbon adjacent to R.sup.9 and two atoms
from the carbon at the point of attachment is optionally
substituted by R.sup.10, a carbon adjacent to R.sup.13 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.12, and any carbon adjacent to both R.sup.10
and R.sup.12 is optionally substituted by R.sup.11;
[0318] R.sup.9, R.sup.11, and R.sup.13 are independently selected
from the group consisting of hydrido, hydroxy, amino, amidino,
guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and
cyano;
[0319] R.sup.10 and R.sup.12 are independently selected from the
group consisting of hydrido, acetamido, haloacetamido, amidino,
guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino,
lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl,
halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido,
and cyano;
[0320] K is CH.sub.2;
[0321] E.sup.0 is C(O)N(H);
[0322] Y.sup.0 is formula (IV): 22
[0323] wherein D.sup.5, D.sup.6, J.sup.5 and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is C, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is O, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 must be a covalent bond when two of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are O and S, and no more than four of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are N;
[0324] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and
cyano;
[0325] R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be;
[0326] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido, and
C(NR.sup.25)NR.sup.23R.sup.24;
[0327] R.sup.20, R.sup.21, R.sup.23, R.sup.24, and R.sup.25 are
independently selected from the group consisting of hydrido and
alkyl;
[0328] Q.sup.s is CH.sub.2.
[0329] In another most preferred embodiment of compounds of Formula
I or a pharmaceutically acceptable salt thereof,
[0330] J.sup.a and J.sup.b are each O;
[0331] B is optionally selected from the group consisting of
hydrido, C2-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8
haloalkyl, wherein each member of group B is optionally substituted
at any carbon up to and including 6 atoms from the point of
attachment of B to A with one or more of the group consisting of
R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36;
[0332] R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, cyano,and Q.sup.b;
[0333] A is selected from the group consisting of single covalent
bond and (CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an
integer selected from 0 through 1, pa is an integer selected from 0
through 3, and W.sup.7 is N(R.sup.7);
[0334] R.sup.7 is selected from the group consisting of hydrido and
alkyl;
[0335] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0336] .PSI. is NH;
[0337] M is selected from the group consisting of N and
R.sup.1--C;
[0338] R.sup.1 is selected from the group consisting of hydrido,
hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy,
alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl,
haloalkoxy, and halo;
[0339] R.sup.2 is Z.sup.0--Q;
[0340] Z.sup.0 is a covalent single bond;
[0341] Q is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.13, a carbon adjacent to R.sup.9 and two atoms
from the carbon at the point of attachment is optionally
substituted by R.sup.10, a carbon adjacent to R.sup.13 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.12, and any carbon adjacent to both R.sup.10
and R.sup.12 is optionally substituted by R.sup.11;
[0342] R.sup.9, R.sup.11, and R.sup.13 are independently selected
from the group consisting of hydrido, hydroxy, amino, amidino,
guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and
cyano;
[0343] R.sup.10 and R.sup.12 are independently selected from the
group consisting of hydrido, acetamido, haloacetamido, amidino,
guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino,
lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl,
halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido,
and cyano;
[0344] K is CH.sub.2;
[0345] E.sup.0 is C(O)N(H);
[0346] Y.sup.0 is formula (IV): 23
[0347] wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is C, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is O, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 must be a covalent bond when two of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are O and S, and no more than four of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are N, with the provisos that
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are each independently
selected to maintain the tetravalent nature of carbon, trivalent
nature of nitrogen, the divalent nature of sulfur, and the divalent
nature of oxygen;
[0348] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and
cyano;
[0349] R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be;
[0350] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido,
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(- R.sup.24), and
C(NR.sup.25)NR.sup.23R.sup.24;
[0351] R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are independently selected from the group consisting of
hydrido and alkyl;
[0352] Q.sup.s is CH.sub.2.
[0353] In still another most preferred embodiment of compounds of
Formula I or a pharmaceutically acceptable salt thereof,
[0354] J.sup.a and J.sup.b are each O;
[0355] B is optionally selected from the group consisting of C3-C7
cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring
carbon is optionally substituted with R.sup.33, a ring carbon other
than the ring carbon at the point of attachment of B to A is
optionally substituted with oxo provided that no more than one ring
carbon is substituted by oxo at the same time, ring carbons and a
nitrogen adjacent to the carbon atom at the point of attachment are
optionally substituted with R.sup.9 or R.sup.13, a ring carbon or
nitrogen adjacent to the R.sup.9 position and two atoms from the
point of attachment is optionally substituted with R.sup.10, a ring
carbon or nitrogen adjacent to the R.sup.13 position and two atoms
from the point of attachment is optionally substituted with
R.sup.12, a ring carbon or nitrogen three atoms from the point of
attachment and adjacent to the R.sup.10 position is optionally
substituted with R.sup.11, a ring carbon or nitrogen three atoms
from the point of attachment and adjacent to the R.sup.12 position
is optionally substituted with R.sup.33, and a ring carbon or
nitrogen four atoms from the point of attachment and adjacent to
the R.sup.11 and R.sup.33 positions is optionally substituted with
R.sup.34;
[0356] R.sup.9, R.sup.11, and R.sup.13 are independently selected
from the group consisting of hydrido, hydroxy, amino, amidino,
guanidino, lower alkylamino, alkylthio, alkoxy, alkylsulfinyl,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and
cyano;
[0357] R.sup.10 and R.sup.12 are independently selected from the
group consisting of hydrido, acetamido, haloacetamido, amidino,
guanidino, alkyl, alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino,
lower alkylamino, alkylsulfonamido, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl, aminoalkyl,
halo, haloalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxyamido,
and cyano;
[0358] R.sup.33 and R.sup.34 are independently selected from the
group consisting of hydrido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, and cyano;
[0359] R.sup.33 is optionally Q.sup.b;
[0360] A is selected from the group consisting of single covalent
bond and (CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an
integer selected from 0 through 1, pa is an integer selected from 0
through 3, and W.sup.7 is N(R.sup.7);
[0361] R.sup.7 is seleted from the group consisting of hydrido,
hydroxy and alkyl;
[0362] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0363] .PSI. is NH;
[0364] M is selected from the group consisting of N and
R.sup.1--C;
[0365] R.sup.1 is selected from the group consisting of hydrido,
hydroxy, hydroxyamino, amidino, amino, cyano, hydroxyalkyl, alkoxy,
alkyl, alkylamino, aminoalkyl, alkylthio, alkoxyamino, haloalkyl,
haloalkoxy, and halo;
[0366] R.sup.2 is Z.sup.0--Q;
[0367] Z.sup.0 is a covalent single bond;
[0368] Q is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.13, a carbon adjacent to R.sup.9 and two atoms
from the carbon at the point of attachment is optionally
substituted by R.sup.10, a carbon adjacent to R.sup.13 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.12, and any carbon adjacent to both R.sup.10
and R.sup.12 is optionally substituted by R.sup.11;
[0369] K is CH.sub.2;
[0370] E.sup.0 is C(O)N(H);
[0371] Y.sup.0 is formula (IV): 24
[0372] wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is C, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is O, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 must be a covalent bond when two of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are O and S, and no more than four of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are N, with the provisos that
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are each independently
selected to maintain the tetravalent nature of carbon, trivalent
nature of nitrogen, the divalent nature of sulfur, and the divalent
nature of oxygen;
[0373] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkylenylamino,
and cyano;
[0374] R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be;
[0375] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido, and
C(NR.sup.25)NR.sup.23R.sup.24;
[0376] R.sup.20, R.sup.21, R.sup.23, R.sup.24, and R.sup.25 are
independently selected from the group consisting of hydrido and
alkyl;
[0377] Q.sup.s is CH.sub.2.
[0378] In a preferred specific embodiment of Formula I, compounds
have the Formula I-S: 25
[0379] or a pharmaceutically acceptable salt thereof, wherein;
[0380] B is selected from the group consisting of phenyl,
2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,
2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,
1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,4oxadiazol-3-yl,
1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-3-yl, 1,3,4-oxadiazol-5-yl,
3-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 2-thiazolyl,
3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrazinyl, 2-pyrimidinyl, 4pyrimidinyl, 5-pyrimidinyl,
3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yl,
1,2,4triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl,
1,2,3-triazin-4-yl, and 1,2,3-triazin-5-yl, wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.32, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.36, a
carbon adjacent to R.sup.32 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.33, a carbon
adjacent to R.sup.36 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.35, and any carbon
adjacent to both R.sup.33 and R.sup.35 is optionally substituted by
R.sup.34;
[0381] R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
amidino, guanidino, carboxy, methyl, ethyl, isopropyl, propyl,
methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino,
ethoxyamino, acetamido, trifluoroacetamido, nitro, aminomethyl,
1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino,
N-ethylamino, methylthio, ethylthio, isopropylthio,
trifluoromethylthio, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl,
2,2,2-trifluoro-1-trifluoromethyl-1-hydroxyethyl, carboxymethyl,
methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and
Q.sup.b;
[0382] B is selected from the group consisting of hydrido,
trimethylsilyl, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl,
butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, tert-butyl,
isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl,
4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl,
1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl,
1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl,
2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl,
3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl,
3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,
2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl,
1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl,
3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl,
1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,
5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl,
5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl,
1-methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexynyl,
1-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl,
1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl,
1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl,
1-octyl, 2-octenyl, 3-octenyl, 4octenyl, 5-octenyl, 6-octenyl,
7-octenyl, 2-octynyl, 3-octynyl, 4-octynyl, 5-octynyl, 6-octynyl,
2-octyl, 1-methyl-2-heptenyl, 1-methyl-3-heptenyl,
1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl,
1-methyl-2-heptynyl, 1-methyl-3-heptynyl, 1-methyl-4-heptenyl,
1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptenyl,
1-methyl-3-heptynyl, 1-methyl-4heptynyl, 1-methyl-5-heptynyl,
3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethylthexenyl,
1-ethyl-2-hexynyl, 1-ethyl-3-hexynyl, 1-ethyl-4-hexynyl,
1-ethyl-5-hexenyl, 1-pentyl-2-propenyl, 4-octyl,
1-propyl-2-pentenyl, 1-propyl-3-pentenyl, 1-propyl-4-pentenyl,
1-butyl-2-butenyl, 1-propyl-2-pentynyl, 1-propyl-3-pentynyl,
1-butyl-2-butynyl, 1-butyl-3-butenyl, 2,2,2-trifluoroethyl,
2,2-difluoropropyl, 4-trifluoromethyl-5,5,5-trifluoropentyl,
4-trifluoromethylpentyl, 5,5,6,6,6-pentafluorohexyl, and
3,3,3-trifluoropropyl, wherein each member of group B is optionally
substituted at any carbon up to and including 5 atoms from the
point of attachment of B to A with one or more of the group
consisting of R.sup.32, R.sup.33, R.sup.34, R.sup.35, and
R.sup.36;
[0383] B is optionally selected from the group consisting of
cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-1-yl,
azetidin-2-yl, azetidin-3-yl, thiaetan-2-yl, thiaetan-3-yl,
cyclopentyl, cyclohexyl, adamantyl, norbornyl,
3-trifluoromethylnorbornyl, 7-oxabicyclo[2.2.1]hept- an-2-yl,
bicyclo[3.1.0]hexan-6-yl, cycloheptyl, cyclooctyl, 2-morpholinyl,
3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl,
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,
1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl,
4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl,
4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,
2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl,
2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring
carbon is optionally substituted with R.sup.33, ring carbons and a
nitrogen adjacent to the carbon atom at the point of attachment is
optionally substituted with R.sup.9 or R.sup.13, a ring carbon or
nitrogen adjacent to the R.sup.9 position and two atoms from the
point of attachment is optionally substituted with R.sup.10, and a
ring carbon or nitrogen adjacent to the R.sup.13 position and two
atoms from the point of attachment is optionally substituted with
R.sup.12;
[0384] R.sup.9, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are
independently selected from the group consisting of hydrido,
amidino, guanidino, carboxy, carboxymethyl, methyl, ethyl,
isopropyl, propyl, methoxy, ethoxy, isopropoxy, propoxy, hydroxy,
amino, methoxyamino, ethoxyamino, acetamido, trifluoroacetamido,
nitro, aminomethyl, 1-aminoethyl, 2-aminoethyl, N-methylamino,
dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio,
trifluoromethylthio, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, acetyl, propanoyl, trifluoroacetyl,
pentafluoropropanoyl, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl,
2,2,2-trifluoro-1-trifluo- romethyl-1-hydroxyethyl, carboxymethyl,
methoxycarbonyl, ethoxycarbonyl, aminocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
[0385] A is selected from the group consisting of single covalent
bond, O, S, NH, N(CH.sub.3), N(OH), C(O), CH.sub.2, CH.sub.3CH,
CF.sub.3CH, NHC(O), N(CH.sub.3)C(O), C(O)NH, C(O)N(CH.sub.3),
CF.sub.3CC(O), C(O)CCH.sub.3, C(O)CCF.sub.3, CH.sub.2C(O),
(O)CCH.sub.2, CH.sub.2CH.sub.2, CH.sub.2CH.sub.2CH.sub.2,
CH.sub.3CHCH.sub.2, CF.sub.3CHCH.sub.2, CH.sub.3CC(O)CH.sub.2,
CF.sub.3CC(O)CH.sub.2, CH.sub.2C(O)CCH.sub.3,
CH.sub.2C(O)CCF.sub.3, CH.sub.2CH.sub.2C(O), and CH.sub.2(O)
CCH.sub.2;
[0386] A is optionally selected from the group consisting of
CH.sub.2N(CH.sub.3), CH.sub.2N(CH.sub.2CH.sub.3),
CH.sub.2CH.sub.2N(CH.su- b.3), and
CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3) with the proviso that B is
hydrido;
[0387] M is selected from the group consisting of N and
R.sup.1--C;
[0388] R.sup.1 is selected from the group consisting of hydrido,
hydroxy, amino, thiol, amidino, hydroxyamino, aminomethyl,
1-aminoethyl, 2-aminoethyl, methylamino, dimethylamino, cyano,
methyl, ethyl, isopropyl, propyl, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, methoxy, ethoxy, propoxy,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyamino,
ethoxyamino, methylthio, ethylthio, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and bromo;
[0389] R.sup.2 is Z.sup.0--Q;
[0390] Z.sup.0 is selected from the group consisting of covalent
single bond, O, S, NH, CH.sub.2, CH.sub.2CH.sub.2, CH(OH),
CH(NH.sub.2), CH.sub.2CH(OH), CH.sub.2CHNH.sub.2, CH(OH)CH.sub.2,
and CH(NH.sub.2)CH.sub.2;
[0391] Q is selected from the group consisting of phenyl,
2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,
2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,
1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,4-oxadiazol-3-yl,
1,2,4-oxadiazol-5-yl, 1,3,4oxadiazol-3-yl, 1,3,4-oxadiazol-5-yl,
3-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 2-thiazolyl,
3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yl,
1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl,
1,2,3-triazin-4yl, and 1,2,3-triazin-5-yl, wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.9, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.13, a
carbon adjacent to R.sup.9 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.10, a carbon
adjacent to R.sup.13 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.12, and any carbon
adjacent to both R.sup.10 and R.sup.12 is optionally substituted by
R.sup.11;
[0392] K is CHR.sup.4a wherein R.sup.4a is selected from the group
consisting of methyl, ethyl, propyl, isopropyl, hydroxymethyl,
1-hydroxyehtyl, methoxymethyl, triflouromethyl, pentafluoroethyl,
2,2,2-triflouromethyl, methylthiomethyl, and hydrido;
[0393] E.sup.0 is a covalent single bond, C(O)N(H), (H)NC(O), and
S(O).sub.2N(H);
[0394] Y.sup.0 is selected from the group of formulas consisting
of: 26
[0395] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, methyl, ethyl,
isopropyl, propyl, amidino, guanidino, carboxy, methoxy, ethoxy,
isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino,
aminomethyl, 1-aminoethyl, 2-aminoethyl, N-N-methylamino,
dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio,
trifluoromethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl,
ethylsulfonyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
acetyl, propanoyl, trifluoroacetyl, pentafluoropropanoyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, and cyano;
[0396] R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be;
[0397] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido,
C(NR.sup.25)NR.sup.23R.sup.24 and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), with the proviso that
no more than one of R.sup.20 and R.sup.21 is hydroxy,
N-methylamino, and N,N-dimethylamino at the same time and that no
more than one of R.sup.23 and R.sup.24 is hydroxy, N-methylamino,
and N,N-dimethylamino at the same time;
[0398] R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are independently selected from the group consisting of
hydrido, methyl, ethyl, propyl, butyl, isopropyl, hydroxy,
2-aminoethyl, 2-(N-methylamino)ethyl, and
2-(N,N-dimethylamino)ethyl;
[0399] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, CH.sub.2CH.sub.2, CH.sub.3CH, CF.sub.3CH,
CH.sub.3CHCH.sub.2, CF.sub.3CHCH.sub.2, CH.sub.2(CH.sub.3)CH,
CH.dbd.CH, CF.dbd.CH, C(CH.sub.3).dbd.CH, CH.dbd.CHCH.sub.2,
CF.dbd.CHCH.sub.2, C(CH.sub.3).dbd.CHCH.sub.2, CH.sub.2CH.dbd.CH,
CH.sub.2CF.dbd.CH, CH.sub.2C(CH.sub.3).dbd.CH,
CH.sub.2CH.dbd.CHCH.sub.2, CH.sub.2CF.dbd.CHCH.sub.2,
CH.sub.2C(CH.sub.3).dbd.CHCH.sub.2,
CH.sub.2CH.dbd.CHCH.sub.2CH.sub.2,
CH.sub.2CF.dbd.CHCH.sub.2CH.sub.2, and
CH.sub.2C(CH.sub.3).dbd.CHCH.sub.2CH.sub.2.
[0400] In a more preferred specific embodiment of Formula I,
compounds have the Formula I-MPS wherein B is an aromatic: 27
[0401] (I-MPS wherein B is aromatic)
[0402] or a pharmaceutically acceptable salt thereof, wherein;
[0403] B is selected from the group consisting of phenyl,
2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,
2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl,
3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrazinyl, 2-pyrimidinyl, 4pyrimidinyl, 5-pyrimidinyl,
3-pyridazinyl, 4pyridazinyl, and 1,3,5-triazin-2-yl, wherein a
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.32, the other carbon adjacent to
the carbon at the point of attachment is optionally substituted by
R.sup.36, a carbon adjacent to R.sup.32 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.33, a carbon adjacent to R.sup.36 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.35, and any carbon adjacent to both R.sup.33 and R.sup.35 is
optionally substituted by R.sup.34;
[0404] R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy,
hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl,
methoxycarbonyl, ethoxycarbonyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and
Q.sup.b;
[0405] A is selected from the group consisting of single covalent
bond, NH, N(CH.sub.3), N(OH), CH.sub.2, CH.sub.3CH, CF.sub.3CH,
NHC(O), N(CH.sub.3)C(O), C(O)NH, C(O)N(CH.sub.3), CH.sub.2CH.sub.2,
CH.sub.2CH.sub.2CH.sub.2, CH.sub.3CHCH.sub.2, and
CF.sub.3CHCH.sub.2;
[0406] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido, and
C(NR.sup.25)NR.sup.23R.sup.24, with the provisos that no more than
one of R.sup.20 and R.sup.21 is hydroxy at the same time and that
no more than one of R.sup.23 and R.sup.24 is hydroxy at the same
time;
[0407] R.sup.20, R.sup.21, R.sup.23, R.sup.24, and R.sup.25 are
independently selected from the group consisting of hydrido,
methyl, ethyl, propyl, butyl, isopropyl, and hydroxy;
[0408] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0409] In another more preferred specific embodiment of Formula I,
compounds have the Formula I-MPS wherein B is a non-cyclic
substituent: 28
[0410] wherein B is a non-cyclic substituent)
[0411] or a pharmaceutically acceptable salt thereof, wherein;
[0412] B is selected from the group consisting of hydrido, ethyl,
2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl,
3-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl,
2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl, 1-methyl
-3-butenyl, 1-methyl-2-butynyl, 3-pentyl, 1-ethyl-2-propenyl,
2-methylbutyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl,
2-methyl-3-butynyl, 3-methylbutyl, 3-methyl-2-butenyl,
3-methyl-3-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,
5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl
-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl,
1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 3-hexyl,
1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl -2-propenyl,
1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,
5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4heptynyl,
5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl,
1-methyl-4-hexenyl, 1-methyl-5hexenyl, 1-methyl-2-hexynyl,
1-methyl-3-hexynyl, 1-methyl -4-hexynyl, 3-heptyl,
1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl,
1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl,
2,2,2-trifluoroethyl, 2,2-difluoropropyl,
4-trifluoromethyl-5,5,5-trifluo- ropentyl, 4-trifluoromethylpentyl,
5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each
member of group B is optionally substituted at any carbon up to and
including 5 atoms from the point of attachment of B to A with one
or more of the group consisting of R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36;
[0413] R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy,
hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl,
methoxycarbonyl, ethoxycarbonyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and
Q.sup.b;
[0414] A is selected from the group consisting of single covalent
bond, NH, N(CH.sub.3), N(OH), CH.sub.2, CH.sub.3CH, CF.sub.3CH,
NHC(O), N(CH.sub.3)C(O), C(O)NH, C(O)N(CH.sub.3), CH.sub.2CH.sub.2,
CH.sub.2CH.sub.2CH.sub.2, CH.sub.3CHCH.sub.2, and
CF.sub.3CHCH.sub.2;
[0415] A is optionally selected from the group consisting of
CH.sub.2N(CH.sub.3), CH.sub.2N(CH.sub.2CH.sub.3),
CH.sub.2CH.sub.2N(CH.su- b.3), and
CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3) with the proviso that B is
hydrido;
[0416] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be, wherein Q.sup.be is hydrido,
C(NR.sup.25)NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), with the provisos
that no more than one of R.sup.20 and R.sup.21 is hydroxy at the
same time and that no more than one of R.sup.23 and R.sup.24 is
hydroxy at the same time;
[0417] R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are independently selected from the group consisting of
hydrido, methyl, ethyl, propyl, butyl, isopropyl, and hydroxy;
[0418] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0419] In still another more preferred specific embodiment of
Formula I, compounds have the Formula I-MPS wherein B is a
non-aromatic cyclic substituent: 29
[0420] wherein B is a non-aromatic cyclic substituent)
[0421] or a pharmaceutically acceptable salt thereof, wherein;
[0422] B is optionally selected from the group consisting of
cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl,
azetidin-3-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, norbornyl,
7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl,
cycloheptyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl,
1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,
3-pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl,
4H-4pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl,
2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl,
3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and
3-tetrahydrothienyl, wherein each ring carbon is optionally
substituted with R.sup.33, a ring carbon and a nitrogen adjacent to
the carbon atom at the point of attachment are optionally
substituted with R.sup.9 or R.sup.13, a ring carbon or nitrogen
adjacent to the R.sup.9 position and two atoms from the point of
attachment is optionally substituted with R.sup.10, and a ring
carbon or nitrogen adjacent to the R.sup.13 position and two atoms
from the point of attachment is optionally substituted with
R.sup.12;
[0423] A is selected from the group consisting of single covalent
bond, NH, N(CH.sub.3), N(OH), CH.sub.2, CH.sub.3CH, CF.sub.3CH,
NHC(O), N(CH.sub.3)C(O), C(O)NH, C(O)N(CH.sub.3), CH.sub.2CH.sub.2,
CH.sub.2CH.sub.2CH.sub.2, CH.sub.3CHCH.sub.2, and
CF.sub.3CHCH.sub.2;
[0424] R.sup.33 is selected from the group consisting of hydrido,
amidino, guanidino, carboxy, methoxy, ethoxy, isopropoxy, propoxy,
hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl,
methoxycarbonyl, ethoxycarbonyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and
Q.sup.b;
[0425] Q.sup.b is selected from the group consisting of NR.sup.20
R.sup.21, Q.sup.be wherein Q.sup.be is hydrido, and
C(NR.sup.25)NR.sup.23R.sup.24, with the provisos that no more than
one of R.sup.20 and R.sup.21 is hydroxy at the same time and that
no more than one of R.sup.23 and R.sup.24 is hydroxy at the same
time;
[0426] R.sup.20, R.sup.21, R.sup.23, R.sup.24, and R.sup.25 are
independently selected from the group consisting of hydrido,
methyl, ethyl, propyl, butyl, isopropyl, and hydroxy;
[0427] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0428] The more preferred specific embodiment (I-MPS) compounds of
the present invention having the Formula: 30
[0429] or a pharmaceutically acceptable salt thereof, have common
structural units, wherein;
[0430] M is selected from the group consisting of N and
R.sup.1--C;
[0431] R.sup.1 is selected from the group consisting of hydrido,
hydroxy, amino, amidino, hydroxyamino, aminomethyl, 1-aminoethyl,
methylamino, dimethylamino, cyano, methyl, ethyl, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl, methoxy, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, methoxyamino, methylthio,
ethylthio, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro,
chloro, and bromo;
[0432] R.sup.2 is Z.sup.0--Q;
[0433] Z.sup.0 is selected from the group consisting of a covalent
single bond, O, S, NH, and CH.sub.2;
[0434] Q is selected from the group consisting of phenyl,
2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,
2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl,
3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a
carbon or nitrogen adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
or nitrogen adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.13, a carbon or nitrogen adjacent
to R.sup.9 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.10, a carbon adjacent to
R.sup.13 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.12, and any carbon adjacent to
both R.sup.10 and R.sup.12 is optionally substituted by
R.sup.11;
[0435] R.sup.9, R.sup.11, and R.sup.13 are independently selected
from the group consisting of hydrido, amidino, guanidino, carboxy,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino,
N-ethylamino, methylthio, ethylthio, isopropylthio,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
[0436] R.sup.10 and R.sup.12 are independently selected from the
group consisting of hydrido, amidino, guanidino, carboxy,
carboxymethyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,
isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino,
acetamido, trifluoroacetamido, aminomethyl, 1-aminoethyl,
2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl,
ethoxycarbonyl, amidocarbonyl, N-methylamidocarbonyl,
N,N-dimethylamidocarbonyl, fluoro, chloro, bromo, and cyano;
[0437] Y.sup.0 is selected from the group of formulas consisting
of: 31
[0438] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, methyl, ethyl,
isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy,
isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl,
2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethylthio,
methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and
cyano;
[0439] R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
the same time and that Q.sup.b is Q.sup.be.
[0440] In a most preferred specific embodiment of Formula I,
compounds have the Formula I-EMPS wherein B is an aromatic: 32
[0441] (I-EMPS wherein B is aromatic)
[0442] or a pharmaceutically acceptable salt thereof, wherein;
[0443] B is selected from the group consisting of phenyl,
2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,
2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl,
3-isoxazolyl, and 5-isoxazolyl, wherein a carbon adjacent to the
carbon at the point of attachment is optionally substituted by
R.sup.32, the other carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.36, a carbon adjacent
to R.sup.32 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.33, a carbon adjacent
to R.sup.36 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.35, and any carbon
adjacent to both R.sup.33 and R.sup.35 is optionally substituted by
R.sup.34;
[0444] R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino,
N-methylamino, dimethylamino, methylthio, ethylthio,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro,
chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl,
amidocarbonyl, carboxy, cyano, and Q.sup.b;
[0445] A is selected from the group consisting of single covalent
bond, NH, N(CH.sub.3), CH.sub.2, CH.sub.3CH, and
CH.sub.2CH.sub.2;
[0446] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21 and C(NR.sup.25)NR.sup.23R.sup.24, with the
proviso that said Q.sup.b group is bonded directly to a carbon
atom;
[0447] R.sup.20, R.sup.21, R.sup.23, R.sup.24, and R.sup.25 are
independently selected from the group consisting of hydrido,
methyl, and ethyl;
[0448] Q.sup.S is CH.sub.2.
[0449] In another most preferred specific embodiment of Formula I,
compounds have the Formula I-EMPS wherein B is a non-cyclic
substituent: 33
[0450] wherein B is a non-cyclic substituent)
[0451] or a pharmaceutically acceptable salt thereof, wherein;
[0452] B is selected from the group consisting of hydrido, ethyl,
2-propenyl, 2-propynyl, propyl, isopropyl, butyl, 2-butenyl,
2-butynyl, sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl,
1-pentyl, 2-pentenyl, 3-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl,
3-pentyl, 2-methylbutyl, 2-methyl-2-butenyl, 3-methylbutyl,
3-methyl-2-butenyl, 1-hexyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,
2-hexynyl, 3-hexynyl, 4-hexynyl, 2-hexyl, 1-methyl-2-pentenyl,
1-methyl -3-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl,
3-hexyl, 1-ethyl -2-butenyl, 1-heptyl, 2-heptenyl, 3-heptenyl,
4-heptenyl, 5-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl,
5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl -3-hexenyl,
1-methyl-4-hexenyl, 1-methyl-2-hexynyl, 1-methyl-3-hexynyl,
1-methyl-4-hexynyl, 3-heptyl, 1-ethyl-2-pentenyl,
1-ethyl-3-pentenyl, 1-ethyl -2-pentynyl, 1-ethyl-3-pentynyl,
2,2,2-trifluoroethyl, 2,2-difluoropropyl,
4-trifluoromethyl-5,5,5-trifluoropentyl, 4-trifluoromethylpentyl,
5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each
member of group B is optionally substituted at any carbon up to and
including 5 atoms from the point of attachment of B to A with one
or more of the group consisting of R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36;
[0453] R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino,
N-methylamino, dimethylamino, methylthio, ethylthio,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro,
chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl,
amidocarbonyl, carboxy, cyano, and Q.sup.b;
[0454] A is selected from the group consisting of single covalent
bond, NH, N(CH.sub.3), CH.sub.2, CH.sub.3CH, and
CH.sub.2CH.sub.2;
[0455] A is optionally selected from the group consisting of
CH.sub.2N(CH.sub.3), CH.sub.2N(CH.sub.2CH.sub.3),
CH.sub.2CH.sub.2N(CH.su- b.3), and
CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3) with the proviso that B is
hydrido;
[0456] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, C(NR.sup.25)NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.s- up.24), with the proviso
that said Q.sup.b group is bonded directly to a carbon atom;
[0457] R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are independently selected from the group consisting of
hydrido, methyl, and ethyl;
[0458] Q.sup.s is CH.sub.2.
[0459] In still another most preferred specific embodiment of
Formula I, compounds have the Formula I-EMPS wherein B is a
non-aromatic cyclic substituent: 34
[0460] (I-EMPS wherein B is a non-aromatic cyclic substituent)
[0461] or a pharmaceutically acceptable salt thereof, wherein;
[0462] B is optionally selected from the group consisting of
cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-3-yl, thiaetan-3-yl,
cyclopentyl, cyclohexyl, 1-pyrrolidinyl, 2-pyrrolidinyl,
3-pyrrolidinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,
2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring
carbon is optionally substituted with R.sup.33, ring carbons and a
nitrogen adjacent to the carbon atom at the point of attachment are
optionally substituted with R.sup.9 or R.sup.13, a ring carbon or
nitrogen adjacent to the R.sup.9 position and two atoms from the
point of attachment is optionally substituted with R.sup.10, and a
ring carbon or nitrogen adjacent to the R.sup.13 position and two
atoms from the point of attachment is optionally substituted with
R.sup.12;
[0463] R.sup.33 are independently selected from the group
consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy,
ethoxy, hydroxy, carboxy, amino, N-methylamino, dimethylamino,
methylthio, ethylthio, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, hydroxymethyl, amidocarbonyl, cyano, and
Q.sup.b;
[0464] A is selected from the group consisting of single covalent
bond, NH, N(CH.sub.3), CH.sub.2, CH.sub.3CH, and
CH.sub.2CH.sub.2;
[0465] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21 and C(NR.sup.25)NR.sup.23R.sup.24, with the
proviso that said Q.sup.b group is bonded directly to a carbon
atom;
[0466] R.sup.20, R.sup.21, R.sup.23, R.sup.24, and R.sup.25 are
independently selected from the group consisting of hydrido,
methyl, and ethyl;
[0467] Q.sup.s is CH.sub.2.
[0468] The most preferred specific embodiment (I-EMPS) compounds of
the present invention having the Formula: 35
[0469] or a pharmaceutically acceptable salt thereof, have common
structural units, wherein;
[0470] M is selected from the group consisting of N and
R.sup.1--C;
[0471] R.sup.1 is selected from the group consisting of hydrido,
hydroxy, amino, amidino, hydroxyamino, aminomethyl, methylamino,
cyano, methyl, trifluoromethyl, methoxy, hydroxymethyl,
methoxyamino, methylthio, trifluoromethoxy, fluoro, and chloro;
[0472] R.sup.2 is Z.sup.0--Q;
[0473] Z.sup.0 is a covalent single bond;
[0474] Q is selected from the group consisting of phenyl,
2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl,
3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent
to the carbon at the point of attachment is optionally substituted
by R.sup.9, the other carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.13, a carbon adjacent
to R.sup.9 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.10, a carbon adjacent to
R.sup.13 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.12, and any carbon adjacent to
both R.sup.10 and R.sup.12 is optionally substituted by
R.sup.11;
[0475] R.sup.9, R.sup.11, and R.sup.13 are independently selected
from the group consisting of hydrido, methyl, ethyl, methoxy,
ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino,
methylthio, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and
cyano;
[0476] R.sup.10 and R.sup.12 are independently selected from the
group consisting of hydrido, amidino, amidocarbonyl,
N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy,
hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy,
carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl,
N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo,
and cyano;
[0477] Y.sup.0 is selected from the group of formulas consisting
of: 36
[0478] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, methyl, ethyl,
amidino, guanidino, methoxy, hydroxy, amino, aminomethyl,
1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino,
methylthio, ethylthio, trifluoromethylthio, methylsulfinyl,
methylsulfonyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro,
amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and
cyano.
[0479] The compounds of this invention can be used in anticoagulant
therapy for the treatment and prevention of a variety of thrombotic
conditions including coronary artery and cerebrovascular disease.
The compounds of this invention can be used to inhibit serine
protease associated with the coagulation cascade and factors II,
VII, VIII, IX, X, XI, or XII. The compounds of the invention can
inhibit the formation of blood platelet aggregates, inhibit the
formation of fibrin, inhibit thrombus formation, and inhibiting
embolus formation in a mammal, in blood, in blood products, and in
mammalian organs. The compounds also can be used for treating or
preventing unstable angina, refractory angina, myocardial
infarction, transient ischemic attacks, atrial fibrillation,
thrombotic stroke, embolic stroke, deep vein thrombosis,
disseminated intravascular coagulation, ocular build up of fibrin,
and reocclusion or restenosis of recanalized vessels in a mammal.
The compounds can also be used in prophylactic treatment of
subjects who are at risk of developing such disorders. The
compounds can be used to lower the risk of atherosclerosis. The
compounds of Formula (I) would also be useful in prevention of
cerebral vascular accident (CVA) or stroke.
[0480] Besides being useful for human treatment, these compounds
are also useful for veterinary treatment of companion animals,
exotic animals and farm animals, including mammals, rodents, and
the like. More preferred animals include horses, dogs, and
cats.
[0481] In yet another embodiment of the present invention, the
novel compounds are selected from the compounds set forth in
Examples 1 through Example 7.
[0482] The use of generic terms in the description of the compounds
are herein defined for clarity.
[0483] Standard single letter elemental symbols are used to
represent specific types of atoms unless otherwise defined. The
symbol "C" represents a carbon atom. The symbol "O" represents an
oxygen atom. The symbol "N" represents a nitrogen atom. The symbol
"P" represents a phosphorus atom. The symbol "S" represents a
sulfur atom. The symbol "H" represents a hydrido atom. Double
letter elemental symbols are used as defined for the elements of
the periodical table (i.e., Cl represents chlorine, Se represents
selenium, etc.).
[0484] As utilized herein, the term "alkyl", either alone or within
other terms such as "haloalkyl" and "alkylthio", means an acyclic
alkyl radical containing from 1 to about 10, preferably from 3 to
about 8 carbon atoms and more preferably 3 to about 6 carbon atoms.
Said alkyl radicals may be optionally substituted with groups as
defined below. Examples of such radicals include methyl, ethyl,
chloroethyl, hydroxyethyl, n-propyl, oxopropyl, isopropyl, n-butyl,
cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl,
iso-amyl, hexyl, octyl and the like.
[0485] The term "alkenyl" refers to an unsaturated, acyclic
hydrocarbon radical in so much as it contains at least one double
bond. Such alkenyl radicals contain from about 2 to about 10 carbon
atoms, preferably from about 3 to about 8 carbon atoms and more
preferably 3 to about 6 carbon atoms. Said alkenyl radicals may be
optionally substituted with groups as defined below. Examples of
suitable alkenyl radicals include propenyl, 2-chloropropenyl,
buten-1-yl, isobutenyl, penten-1-yl, 2-2-methylbuten-1-yl,
3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl,
and octen-1-yl, and the like.
[0486] The term "alkynyl" refers to an unsaturated, acyclic
hydrocarbon radical in so much as it contains one or more triple
bonds, such radicals containing about 2 to about 10 carbon atoms,
preferably having from about 3 to about 8 carbon atoms and more
preferably having 3 to about 6 carbon atoms. Said alkynyl radicals
may be optionally substituted with groups as defined below.
Examples of suitable alkynyl radicals include ethynyl, propynyl,
hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl,
4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl,
hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
[0487] The term "hydrido" denotes a single hydrogen atom (H). This
hydrido radical may be attached, for example, to an oxygen atom to
form a "hydroxyl" radical, one hydrido radical may be attached to a
carbon atom to form a "methine" radical --CH.dbd., or two hydrido
radicals may be attached to a carbon atom to form a "methylene"
(--CH.sub.2--) radical.
[0488] The term "carbon" radical denotes a carbon atom without any
covalent bonds and capable of forming four covalent bonds.
[0489] The term "cyano" radical denotes a carbon radical having
three of four covalent bonds shared by a nitrogen atom.
[0490] The term "hydroxyalkyl" embraces radicals wherein any one or
more of the alkyl carbon atoms is substituted with a hydroxyl as
defined above. Specifically embraced are monohydroxyalkyl,
dihydroxyalkyl and polyhydroxyalkyl radicals.
[0491] The term "alkanoyl" embraces radicals wherein one or more of
the terminal alkyl carbon atoms are substituted with one or more
carbonyl radicals as defined below. Specifically embraced are
monocarbonylalkyl and dicarbonylalkyl radicals. Examples of
monocarbonylalkyl radicals include formyl, acetyl, and pentanoyl.
Examples of dicarbonylalkyl radicals include oxalyl, malonyl, and
succinyl.
[0492] The term "alkylene" radical denotes linear or branched
radicals having from 1 to about 10 carbon atoms and having
attachment points for two or more covalent bonds. Examples of such
radicals are methylene, ethylene, methylethylene, and
isopropylidene.
[0493] The term "alkenylene" radical denotes linear or branched
radicals having from 2 to about 10 carbon atoms, at least one
double bond, and having attachment points for two or more covalent
bonds. Examples of such radicals are 1,1-vinylidene
(CH.sub.2.dbd.C), 1,2-vinylidene (--CH.dbd.CH--), and
1,4-butadienyl (--CH.dbd.CH--CH.dbd.CH--).
[0494] The term "halo" means halogens such as fluorine, chlorine,
bromine or iodine atoms.
[0495] The term "haloalkyl" embraces radicals wherein any one or
more of the alkyl carbon atoms is substituted with halo as defined
above. Specifically embraced are monohaloalkyl, dihaloalkyl and
polyhaloalkyl radicals. A monohaloalkyl radical, for one example,
may have either a bromo, chloro or a fluoro atom within the
radical. Dihalo radicals may have two or more of the same halo
atoms or a combination of different halo radicals and polyhaloalkyl
radicals may have more than two of the same halo atoms or a
combination of different halo radicals. More preferred haloalkyl
radicals are "lower haloalkyl" radicals having one to about six
carbon atoms. Examples of such haloalkyl radicals include
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,
dichloromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl,
heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl and
dichloropropyl.
[0496] The term "hydroxyhaloalkyl" embraces radicals wherein any
one or more of the haloalkyl carbon atoms is substituted with
hydroxy as defined above. Examples of "hydroxyhaloalkyl" radicals
include hexafluorohydroxypropyl.
[0497] The term "haloalkylene radical" denotes alkylene radicals
wherein any one or more of the alkylene carbon atoms is substituted
with halo as defined above. Dihalo alkylene radicals may have two
or more of the same halo atoms or a combination of different halo
radicals and polyhaloalkylene radicals may have more than two of
the same halo atoms or a combination of different halo radicals.
More preferred haloalkylene radicals are "lower haloalkylene"
radicals having one to about six carbon atoms. Examples of
"haloalkylene" radicals include difluoromethylene,
tetrafluoroethylene, tetrachloroethylene, alkyl substituted
monofluoromethylene, and aryl substituted trifluoromethylene.
[0498] The term "haloalkenyl" denotes linear or branched radicals
having from 1 to about 10 carbon atoms and having one or more
double bonds wherein any one or more of the alkenyl carbon atoms is
substituted with halo as defined above. Dihaloalkenyl radicals may
have two or more of the same halo atoms or a combination of
different halo radicals and polyhaloalkenyl radicals may have more
than two of the same halo atoms or a combination of different halo
radicals.
[0499] The terms "alkoxy" and "alkoxyalkyl" embrace linear or
branched oxy-containing radicals each having alkyl portions of one
to about ten carbon atoms, such as methoxy radical. The term
"alkoxyalkyl" also embraces alkyl radicals having one or more
alkoxy radicals attached to the alkyl radical, that is, to form
monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxy
radicals are "lower alkoxy" radicals having one to six carbon
atoms. Examples of such radicals include methoxy, ethoxy, propoxy,
butoxy, isopropoxy and tert-butoxy alkyls. The "alkoxy" radicals
may be further substituted with one or more halo atoms, such as
fluoro, chloro or bromo, to provide "haloalkoxy" and
"haloalkoxyalkyl" radicals. Examples of such haloalkoxy radicals
include fluoromethoxy, chloromethoxy, trifluoromethoxy,
difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy,
pentafluoroethoxy, and fluoropropoxy. Examples of such
haloalkoxyalkyl radicals include fluoromethoxymethyl,
chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl,
and trifluoroethoxymethyl.
[0500] The terms "alkenyloxy" and "alkenyloxyalkyl" embrace linear
or branched oxy-containing radicals each having alkenyl portions of
two to about ten carbon atoms, such as ethenyloxy or propenyloxy
radical. The term "alkenyloxyalkyl" also embraces alkenyl radicals
having one or more alkenyloxy radicals attached to the alkyl
radical, that is, to form monoalkenyloxyalkyl and dialkenyloxyalkyl
radicals. More preferred alkenyloxy radicals are "lower alkenyloxy"
radicals having two to six carbon atoms. Examples of such radicals
include ethenyloxy, propenyloxy, butenyloxy, and isopropenyloxy
alkyls. The "alkenyloxy" radicals may be further substituted with
one or more halo atoms, such as fluoro, chloro or bromo, to provide
"haloalkenyloxy" radicals. Examples of such radicals include
trifluoroethenyloxy, fluoroethenyloxy, difluoroethenyhloxy, and
fluoropropenyloxy.
[0501] The term "haloalkoxyalkyl" also embraces alkyl radicals
having one or more haloalkoxy radicals attached to the alkyl
radical, that is, to form monohaloalkoxyalkyl and dihaloalkoxyalkyl
radicals. The term "haloalkenyloxy" also embraces oxygen radicals
having one or more haloalkenyloxy radicals attached to the oxygen
radical, that is, to form monohaloalkenyloxy and dihaloalkenyloxy
radicals. The term "haloalkenyloxyalkyl" also embraces alkyl
radicals having one or more haloalkenyloxy radicals attached to the
alkyl radical, that is, to form monohaloalkenyloxyalkyl and
dihaloalkenyloxyalkyl radicals.
[0502] The term "alkylenedioxy" radicals denotes alkylene radicals
having at least two oxygens bonded to a single alkylene group.
Examples of "alkylenedioxy" radicals include methylenedioxy,
ethylenedioxy, alkylsubstituted methylenedioxy, and arylsubstituted
methylenedioxy. The term "haloalkylenedioxy" radicals denotes
haloalkylene radicals having at least two oxy groups bonded to a
single haloalkyl group. Examples of "haloalkylenedioxy" radicals
include difluoromethylenedioxy, tetrafluoroethylenedioxy,
tetrachloroethylenedioxy, alkylsubstituted
monofluoromethylenedioxy, and arylsubstituted
monofluoromethylenedioxy.
[0503] The term "aryl", alone or in combination, means a
carbocyclic aromatic system containing one, two or three rings
wherein such rings may be attached together in a pendant manner or
may be fused. The term "fused" means that a second ring is present
(ie, attached or formed) by having two adjacent atoms in common
(ie, shared) with the first ring. The term "fused" is equivalent to
the term "condensed". The term "aryl" embraces aromatic radicals
such as phenyl, naphthyl, tetrahydronaphthyl, indane and
biphenyl.
[0504] The term "perhaloaryl" embraces aromatic radicals such as
phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl wherein
the aryl radical is substituted with 3 or more halo radicals as
defined below.
[0505] The term "heterocyclyl" embraces saturated and partially
saturated heteroatom-containing ring-shaped radicals having from 4
through 15 ring members, herein referred to as "C4-C15
heterocyclyl", selected from carbon, nitrogen, sulfur and oxygen,
wherein at least one ring atom is a heteroatom. Heterocyclyl
radicals may contain one, two or three rings wherein such rings may
be attached in a pendant manner or may be fused. Examples of
saturated heterocyclic radicals include saturated 3 to 6-membered
heteromonocylic group containing 1 to 4 nitrogen atoms[e.g.
pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.];
saturated 3 to 6-membered heteromonocyclic group containing 1 to 2
oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.];
saturated 3 to 6-membered heteromonocyclic group containing 1 to 2
sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.].
Examples of partially saturated heterocyclyl radicals include
dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
Non-limiting examples of heterocyclic radicals include
2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl,
2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl,
1,4-dithianyl, thiomorpholinyl, and the like.
[0506] The term "heteroaryl" embraces fully unsaturated
heteroatom-containing ring-shaped aromatic radicals having from 5
through 15 ring members selected from carbon, nitrogen, sulfur and
oxygen, wherein at least one ring atom is a heteroatom. Heteroaryl
radicals may contain one, two or three rings wherein such rings may
be attached in a pendant manner or may be fused. Examples of
"heteroaryl" radicals, include unsaturated 5 to 6 membered
heteromonocyclyl group containing 1 to 4 nitrogen atoms, for
example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl
[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl,
etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.;
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen
atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.],
etc.; unsaturated 3 to 6-membered heteromonocyclic group containing
an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.;
unsaturated 5 to 6-membered heteromonocyclic group containing a
sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated
5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen
atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,
oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,5-oxadiazolyl, etc.] etc.; unsaturated condensed heterocyclic
group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms
[e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to
6-membered heteromonocyclic group containing 1 to 2 sulfur atoms
and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl
[e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl,
etc.] etc.; unsaturated condensed heterocyclic group containing 1
to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,
benzothiadiazolyl, etc.] and the like. The term also embraces
radicals where heterocyclic radicals are fused with aryl radicals.
Examples of such fused bicyclic radicals include benzofuran,
benzothiophene, and the like. Said "heterocyclyl" group may have 1
to 3 substituents as defined below. Preferred heterocyclic radicals
include five to twelve membered fused or unfused radicals.
Non-limiting examples of heteroaryl radicals include pyrrolyl,
pyridinyl, pyridyloxy, pyrazolyl, triazolyl, pyrimidinyl,
pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl,
furanyl, tetrazolyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl,
pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,
1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyrazinyl, piperazinyl,
1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl,
benzimidazoyl, quinolinyl, tetraazolyl, and the like.
[0507] The term "sulfonyl", whether used alone or linked to other
terms such as alkylsulfonyl, denotes respectively divalent radicals
--SO.sub.2--. "Alkylsulfonyl", embraces alkyl radicals attached to
a sulfonyl radical, where alkyl is defined as above.
"Alkylsulfonylalkyl", embraces alkylsulfonyl radicals attached to
an alkyl radical, where alkyl is defined as above.
"Haloalkylsulfonyl", embraces haloalkyl radicals attached to a
sulfonyl radical, where haloalkyl is defined as above.
"Haloalkylsulfonylalkyl", embraces haloalkylsulfonyl radicals
attached to an alkyl radical, where alkyl is defined as above. The
term "aminosulfonyl" denotes an amino radical attached to a
sulfonyl radical.
[0508] The term "sulfinyl", whether used alone or linked to other
terms such as alkylsulfinyl, denotes respectively divalent radicals
--S(O)--. "Alkylsulfinyl", embraces alkyl radicals attached to a
sulfinyl radical, where alkyl is defined as above.
"Alkylsulfinylalkyl", embraces alkylsulfinyl radicals attached to
an alkyl radical, where alkyl is defined as above.
"Haloalkylsulfinyl", embraces haloalkyl radicals attached to a
sulfinyl radical, where haloalkyl is defined as above.
"Haloalkylsulfinylalkyl", embraces haloalkylsulfinyl radicals
attached to an alkyl radical, where alkyl is defined as above.
[0509] The term "aralkyl" embraces aryl-substituted alkyl radicals.
Preferable aralkyl radicals are "lower aralkyl" radicals having
aryl radicals attached to alkyl radicals having one to six carbon
atoms. Examples of such radicals include benzyl, diphenylmethyl,
triphenylmethyl, phenylethyl and diphenylethyl. The terms benzyl
and phenylmethyl are interchangeable.
[0510] The term "heteroaralkyl" embraces heteroaryl-substituted
alkyl radicals wherein the heteroaralkyl radical may be
additionally substituted with three or more substituents as defined
above for aralkyl radicals. The term "perhaloaralkyl" embraces
aryl-substituted alkyl radicals wherein the aralkyl radical is
substituted with three or more halo radicals as defined above.
[0511] The term "aralkylsulfinyl", embraces aralkyl radicals
attached to a sulfinyl radical, where aralkyl is defined as above.
"Aralkylsulfinylalkyl", embraces aralkylsulfinyl radicals attached
to an alkyl radical, where alkyl is defined as above.
[0512] The term "aralkylsulfonyl", embraces aralkyl radicals
attached to a sulfonyl radical, where aralkyl is defined as above.
"Aralkylsulfonylalkyl", embraces aralkylsulfonyl radicals attached
to an alkyl radical, where alkyl is defined as above.
[0513] The term "cycloalkyl" embraces radicals having three to 15
carbon atoms. More preferred cycloalkyl radicals are "lower
cycloalkyl" radicals having three to seven carbon atoms. Examples
include radicals such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl. The term cycloalkyl embraces radicals
having seven to 15 carbon atoms and having two to four rings.
Examples include radicals such as norbornyl (i.e.,
bicyclo[2.2.1]heptyl) and adamantyl. The term "cycloalkylalkyl"
embraces cycloalkyl-substituted alkyl radicals. Preferable
cycloalkylalkyl radicals are "lower cycloalkylalkyl" radicals
having cycloalkyl radicals attached to alkyl radicals having one to
six carbon atoms. Examples of such radicals include
cyclohexylhexyl. The term "cycloalkenyl" embraces radicals having
three to ten carbon atoms and one or more carbon-carbon double
bonds. Preferred cycloalkenyl radicals are "lower cycloalkenyl"
radicals having three to seven carbon atoms. Examples include
radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and
cycloheptenyl. The term "halocycloalkyl" embraces radicals wherein
any one or more of the cycloalkyl carbon atoms is substituted with
halo as defined above. Specifically embraced are
monohalocycloalkyl, dihalocycloalkyl and polyhalocycloalkyl
radicals. A monohalocycloalkyl radical, for one example, may have
either a bromo, chloro or a fluoro atom within the radical. Dihalo
radicals may have two or more of the same halo atoms or a
combination of different halo radicals and polyhalocycloalkyl
radicals may have more than two of the same halo atoms or a
combination of different halo radicals. More preferred
halocycloalkyl radicals are "lower halocycloalkyl" radicals having
three to about eight carbon atoms. Examples of such halocycloalkyl
radicals include fluorocyclopropyl, difluorocyclobutyl,
trifluorocyclopentyl, tetrafluorocyclohexyl, and
dichlorocyclopropyl. The term "halocycloalkenyl" embraces radicals
wherein any one or more of the cycloalkenyl carbon atoms is
substituted with halo as defined above. Specifically embraced are
monohalocycloalkenyl, dihalocycloalkenyl and polyhalocycloalkenyl
radicals.
[0514] The term "cycloalkoxy" embraces cycloalkyl radicals attached
to an oxy radical. Examples of such radicals includes cyclohexoxy
and cyclopentoxy. The term "cycloalkoxyalkyl" also embraces alkyl
radicals having one or more cycloalkoxy radicals attached to the
alkyl radical, that is, to form monocycloalkoxyalkyl and
dicycloalkoxyalkyl radicals. Examples of such radicals include
cyclohexoxyethyl. The "cycloalkoxy" radicals may be further
substituted with one or more halo atoms, such as fluoro, chloro or
bromo, to provide "halocycloalkoxy" and "halocycloalkoxyalkyl"
radicals.
[0515] The term "cycloalkylalkoxy" embraces cycloalkyl radicals
attached to an alkoxy radical. Examples of such radicals includes
cyclohexylmethoxy and cyclopentylmethoxy.
[0516] The term "cycloalkenyloxy" embraces cycloalkenyl radicals
attached to an oxy radical. Examples of such radicals includes
cyclohexenyloxy and cyclopentenyloxy. The term
"cycloalkenyloxyalkyl" also embraces alkyl radicals having one or
more cycloalkenyloxy radicals attached to the alkyl radical, that
is, to form monocycloalkenyloxyalkyl and dicycloalkenyloxyalkyl
radicals. Examples of such radicals include cyclohexenyloxyethyl.
The "cycloalkenyloxy" radicals may be further substituted with one
or more halo atoms, such as fluoro, chloro or bromo, to provide
"halocycloalkenyloxy" and "halocycloalkenyloxyalkyl" radicals.
[0517] The term "cycloalkylenedioxy" radicals denotes cycloalkylene
radicals having at least two oxygens bonded to a single
cycloalkylene group. Examples of "alkylenedioxy" radicals include
1,2-dioxycyclohexylene.
[0518] The term "cycloalkylsulfinyl", embraces cycloalkyl radicals
attached to a sulfinyl radical, where cycloalkyl is defined as
above. "Cycloalkylsulfinylalkyl", embraces cycloalkylsulfinyl
radicals attached to an alkyl radical, where alkyl is defined as
above. The term "Cycloalkylsulfonyl", embraces cycloalkyl radicals
attached to a sulfonyl radical, where cycloalkyl is defined as
above. "Cycloalkylsulfonylalkyl", embraces cycloalkylsulfonyl
radicals attached to an alkyl radical, where alkyl is defined as
above.
[0519] The term "cycloalkylalkanoyl" embraces radicals wherein one
or more of the cycloalkyl carbon atoms are substituted with one or
more carbonyl radicals as defined below. Specifically embraced are
monocarbonylcycloalkyl and dicarbonylcycloalkyl radicals. Examples
of monocarbonylcycloalkyl radicals include cyclohexylcarbonyl,
cyclohexylacetyl, and cyclopentylcarbonyl. Examples of
dicarbonylcycloalkyl radicals include
1,2-dicarbonylcyclohexane.
[0520] The term "alkylthio" embraces radicals containing a linear
or branched alkyl radical, of one to ten carbon atoms, attached to
a divalent sulfur atom. More preferred alkylthio radicals are
"lower alkylthio" radicals having one to six carbon atoms. An
example of "lower alkylthio" is methylthio (CH.sub.3--S--). The
"alkylthio" radicals may be further substituted with one or more
halo atoms, such as fluoro, chloro or bromo, to provide
"haloalkylthio" radicals. Examples of such radicals include
fluoromethylthio, chloromethylthio, trifluoromethylthio,
difluoromethylthio, trifluoroethylthio, fluoroethylthio,
tetrafluoroethylthio, pentafluoroethylthio, and
fluoropropylthio.
[0521] The term "alkyl aryl amino" embraces radicals containing a
linear or branched alkyl radical, of one to ten carbon atoms, and
one aryl radical both attached to an amino radical. Examples
include N-methyl-4-methoxyaniline, N-ethyl-4-methoxyaniline, and
N-methyl-4-trifluoromethoxyaniline.
[0522] The terms alkylamino denotes "monoalkylamino" and
"dialkylamino" containing one or two alkyl radicals, respectively,
attached to an amino radical.
[0523] The terms arylamino denotes "monoarylamino" and
"diarylamino" containing one or two aryl radicals, respectively,
attached to an amino radical. Examples of such radicals include
N-phenylamino and N-naphthylamino.
[0524] The term "aralkylamino", embraces aralkyl radicals attached
to an amino radical, where aralkyl is defined as above. The term
aralkylamino denotes "monoarakylamino" and "diaralkylamino"
containing one or two aralkyl radicals, respectively, attached to
an amino radical. The term aralkylamino further denotes
"monoaralkyl monoalkylamino" containing one aralkyl radical and one
alkyl radical attached to an amino radical.
[0525] The term "arylsulfinyl" embraces radicals containing an aryl
radical, as defined above, attached to a divalent S(O) atom. The
term "arylsulfinylalkyl" denotes arylsulfinyl radicals attached to
a linear or branched alkyl radical, of one to ten carbon atoms.
[0526] The term "arylsulfonyl", embraces aryl radicals attached to
a sulfonyl radical, where aryl is defined as above.
"arylsulfonylalkyl", embraces arylsulfonyl radicals attached to an
alkyl radical, where alkyl is defined as above. The term
"heteroarylsulfinyl" embraces radicals containing an heteroaryl
radical, as defined above, attached to a divalent S(O) atom. The
term "heteroarylsulfinylalkyl" denotes heteroarylsulfinyl radicals
attached to a linear or branched alkyl radical, of one to ten
carbon atoms. The term "Heteroarylsulfonyl", embraces heteroaryl
radicals attached to a sulfonyl radical, where heteroaryl is
defined as above. "Heteroarylsulfonylalkyl", embraces
heteroarylsulfonyl radicals attached to an alkyl radical, where
alkyl is defined as above.
[0527] The term "aryloxy" embraces aryl radicals, as defined above,
attached to an oxygen atom. Examples of such radicals include
phenoxy, 4-chloro-3-ethylphenoxy, 4-chloro-3-methylphenoxy,
3-chloro4-ethylphenoxy, 3,4-dichlorophenoxy, 4methylphenoxy,
3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy,
4-fluorophenoxy, 3,4dimethylphenoxy, 5-bromo-2-fluorophenoxy,
4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy,
5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy,
3-cyclopropylphenoxy, 3-ethylphenoxy, 3-pentafluoroethylphenoxy,
3-(1,1,2,2-tetrafluoroethoxy)-phenoxy, and 4-tert
-butylphenoxy.
[0528] The term "aroyl" embraces aryl radicals, as defined above,
attached to an carbonyl radical as defined above. Examples of such
radicals include benzoyl and toluoyl.
[0529] The term "aralkanoyl" embraces aralkyl radicals, as defined
herein, attached to an carbonyl radical as defined above. Examples
of such radicals include, for example, phenylacetyl.
[0530] The term "aralkoxy" embraces oxy-containing aralkyl radicals
attached through an oxygen atom to other radicals. More preferred
aralkoxy radicals are "lower aralkoxy" radicals having phenyl
radicals attached to lower alkoxy radical as described above.
Examples of such radicals include benzyloxy, 1-phenylethoxy,
3-trifluoromethoxybenzyloxy, 3-trifluoromethylbenzyloxy,
3,5-difluorobenyloxy, 3-bromobenzyloxy, 4-propylbenzyloxy,
2-fluoro-3-trifluoromethylbenzyloxy, and 2-phenylethoxy.
[0531] The term "aryloxyalkyl" embraces aryloxy radicals, as
defined above, attached to an alkyl group. Examples of such
radicals include phenoxymethyl.
[0532] The term "haloaryloxyalkyl" embraces aryloxyalkyl radicals,
as defined above, wherein one to five halo radicals are attached to
an aryloxy group.
[0533] The term "heteroaroyl" embraces heteroaryl radicals, as
defined above, attached to an carbonyl radical as defined above.
Examples of such radicals include furoyl and nicotinyl.
[0534] The term "heteroaralkanoyl" embraces heteroaralkyl radicals,
as defined herein, attached to an carbonyl radical as defined
above. Examples of such radicals include, for example,
pyridylacetyl and furylbutyryl.
[0535] The term "heteroaralkoxy" embraces oxy-containing
heteroaralkyl radicals attached through an oxygen atom to other
radicals. More preferred heteroaralkoxy radicals are "lower
heteroaralkoxy" radicals having heteroaryl radicals attached to
lower alkoxy radical as described above.
[0536] The term "haloheteroaryloxyalkyl" embraces
heteroaryloxyalkyl radicals, as defined above, wherein one to four
halo radicals are attached to an heteroaryloxy group.
[0537] The term "heteroarylamino" embraces heterocyclyl radicals,
as defined above, attached to an amino group. Examples of such
radicals include pyridylamino.
[0538] The term "heteroarylaminoalkyl" embraces heteroarylamino
radicals, as defined above, attached to an alkyl group. Examples of
such radicals include pyridylmethylamino.
[0539] The term "heteroaryloxy" embraces heterocyclyl radicals, as
defined above, attached to an oxy group. Examples of such radicals
include 2-thiophenyloxy, 2-pyrimidyloxy, 2-pyridyloxy,
3-pyridyloxy, and 4-pyridyloxy.
[0540] The term "heteroaryloxyalkyl" embraces heteroaryloxy
radicals, as defined above, attached to an alkyl group. Examples of
such radicals include 2-pyridyloxymethyl, 3-pyridyloxyethyl, and
4-pyridyloxymethyl.
[0541] The term "arylthio" embraces aryl radicals, as defined
above, attached to an sulfur atom. Examples of such radicals
include phenylthio.
[0542] The term "arylthioalkyl" embraces arylthio radicals, as
defined above, attached to an alkyl group. Examples of such
radicals include phenylthiomethyl.
[0543] The term "alkylthioalkyl" embraces alkylthio radicals, as
defined above, attached to an alkyl group. Examples of such
radicals include methylthiomethyl. The term "alkoxyalkyl" embraces
alkoxy radicals, as defined above, attached to an alkyl group.
Examples of such radicals include methoxymethyl.
[0544] The term "carbonyl" denotes a carbon radical having two of
the four covalent bonds shared with an oxygen atom. The term
"carboxy" embraces a hydroxyl radical, as defined above, attached
to one of two unshared bonds in a carbonyl group. The term
"carboxamide" embraces amino, monoalkylamino, dialkylamino,
monocycloalkylamino, alkylcycloalkylamino, and dicycloalkylamino
radicals, attached to one of two unshared bonds in a carbonyl
group. The term "carboxamidoalkyl" embraces carboxamide radicals,
as defined above, attached to an alkyl group. The term
"carboxyalkyl" embraces a carboxy radical, as defined above,
attached to an alkyl group. The term "carboalkoxy" embraces alkoxy
radicals, as defined above, attached to one of two unshared bonds
in a carbonyl group. The term "carboaralkoxy" embraces aralkoxy
radicals, as defined above, attached to one of two unshared bonds
in a carbonyl group. The term "monocarboalkoxyalkyl" embraces one
carboalkoxy radical, as defined above, attached to an alkyl group.
The term "dicarboalkoxyalkyl" embraces two carboalkoxy radicals, as
defined above, attached to an alkylene group. The term
"monocyanoalkyl" embraces one cyano radical, as defined above,
attached to an alkyl group. The term "dicyanoalkylene" embraces two
cyano radicals, as defined above, attached to an alkyl group. The
term "carboalkoxycyanoalkyl" embraces one cyano radical, as defined
above, attached to an carboalkoxyalkyl group.
[0545] The term "acyl", alone or in combination, means a carbonyl
or thionocarbonyl group bonded to a radical selected from, for
example, hydrido, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy,
alkoxyalkyl, haloalkoxy, aryl, heterocyclyl, heteroaryl,
alkylsulfinylalkyl, alkylsulfonylalkyl, aralkyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, alkylthio, arylthio, amino,
alkylamino, dialkylamino, aralkoxy, arylthio, and alkylthioalkyl.
Examples of "acyl" are formyl, acetyl, benzoyl, trifluoroacetyl,
phthaloyl, malonyl, nicotinyl, and the like. The term
"haloalkanoyl" embraces one or more halo radicals, as defined
herein, attached to an alkanoyl radical as defined above. Examples
of such radicals include, for example, chloroacetyl,
trifluoroacetyl, bromopropanoyl, and heptafluorobutanoyl.
[0546] The term "phosphono" embraces a pentavalent phosphorus
attached with two covalent bonds to an oxygen radical. The term
"dialkoxyphosphono" denotes two alkoxy radicals, as defined above,
attached to a phosphono radical with two covalent bonds. The term
"diaralkoxyphosphono" denotes two aralkoxy radicals, as defined
above, attached to a phosphono radical with two covalent bonds. The
term "dialkoxyphosphonoalkyl" denotes dialkoxyphosphono radicals,
as defined above, attached to an alkyl radical. The term
"diaralkoxyphosphonoalkyl" denotes diaralkoxyphosphono radicals, as
defined above, attached to an alkyl radical.
[0547] The term "amino" denotes a nitrogen atom containing two
substituents such as hydrido, hydroxy or alkyl and having one
covalent bond available for bonding to a single atom such as
carbon. Examples of such amino radicals include, for example,
--NH.sub.2, --NHCH.sub.3, --NHOH, and --NHOCH.sub.3. The term
"imino" denotes a nitrogen atom containing one substituent such as
hydrido, hydroxy or alkyl and having two covalent bonds available
for bonding to a single atom such as carbon. Examples of such imino
radicals include, for example, .dbd.NH, .dbd.NCH.sub.3, .dbd.NOH,
and .dbd.NOCH.sub.3. The term "imino carbonyl" denotes a carbon
radical having two of the four covalent bond sites shared with an
imino group. Examples of such imino carbonyl radicals include, for
example, C.dbd.NH, C.dbd.NCH.sub.3, C.dbd.NOH, and
C.dbd.NOCH.sub.3. The term "amidino" embraces a substituted or
unsubstituted amino group bonded to one of two available bonds of
an iminocarbonyl radical. Examples of such amidino radicals
include, for example, NH.sub.2--C.dbd.NH,
NH.sub.2--C.dbd.NCH.sub.3, NH.sub.2--C.dbd.NOCH.sub.3 and
CH.sub.3NH--C.dbd.NOH. The term "guanidino" denotes an amidino
group bonded to an amino group as defined above where said amino
group can be bonded to a third group. Examples of such guanidino
radicals include, for example, NH.sub.2--C(NH)--NH--,
NH.sub.2--C(NCH.sub.3)--NH--, NH.sub.2--C(NOCH.sub.3)--NH--, and
CH.sub.3NH--C(NOH)--NH--.
[0548] The term "sulfonium" denotes a positively charged trivalent
sulfur atom where said sulfur is substituted with three carbon
based groups such as alkyl, alkenyl, aralkyl, or aryl. The term
"dialkyl sulfonium" denotes a sulfonium group where said sulfur is
substituted with two alkyl groups. Examples of such
dialkylsulfonium radicals include, for example,
(CH.sub.3).sub.2S.sup.+--. The term "dialkyl sulfonium alkyl"
denotes a dialkyl sulfonium group where said group is bonded to one
bond of an alkylene group as defined above. Examples of such
dialkylsulfoniumalkyl radicals include
(CH.sub.3).sub.2S.sup.+--CH.sub.2CH.sub.2--.
[0549] The term "phosphonium" denotes a positively charged
tetravalent phosphorus atom where said phosphorus is substituted
with four carbon based groups such as alkyl, alkenyl, aralkyl, or
aryl. The term "trialkyl phosphonium" denotes a phosphonium group
where said phosphorus is substituted with three alkyl groups.
Examples of such trialkylphosphonium radicals include, for example,
(CH.sub.3).sub.3P.sup.+.
[0550] Said "alkyl", "alkenyl", "alkynyl", "alkanoyl", "alkylene",
"alkenylene", "hydroxyalkyl", "haloalkyl", "haloalkylene",
"haloalkenyl", "alkoxy", "alkenyloxy", "alkenyloxyalkyl",
"alkoxyalkyl", "aryl", "perhaloaryl", "haloalkoxy",
"haloalkoxyalkyl", "haloalkenyloxy", "haloalkenyloxyalkyl",
"alkylenedioxy", "haloalkylenedioxy", "heterocyclyl", "heteroaryl",
"hydroxyhaloalkyl", "alkylsulfonyl", "haloalkylsulfonyl",
"alkylsulfonylalkyl", "haloalkylsulfonylalkyl", "alkylsulfinyl",
"alkylsulfinylalkyl", "haloalkylsulfinylalkyl", "aralkyl",
"heteroaralkyl", "perhaloaralkyl", "aralkylsulfonyl",
"aralkylsulfonylalkyl", "aralkylsulfinyl", "aralkylsulfinylalkyl",
"cycloalkyl", "cycloalkylalkanoyl", "cycloalkylalkyl",
"cycloalkenyl", "halocycloalkyl", "halocycloalkenyl",
"cycloalkylsulfinyl", "cycloalkylsulfinylalkyl",
"cycloalkylsulfonyl", "cycloalkylsulfonylalkyl- ", "cycloalkoxy",
"cycloalkoxyalkyl", "cycloalkylalkoxy", "cycloalkenyloxy",
"cycloalkenyloxyalkyl", "cycloalkylenedioxy", "halocycloalkoxy",
"halocycloalkoxyalkyl", "halocycloalkenyloxy",
"halocycloalkenyloxyalkyl", "alkylthio", "haloalkylthio",
"alkylsulfinyl", "amino", "oxy", "thio", "alkylamino", "arylamino",
"aralkylamino", "arylsulfinyl", "arylsulfinylalkyl",
"arylsulfonyl", "arylsulfonylalkyl", "heteroarylsulfinyl",
"heteroarylsulfinylalkyl", "heteroarylsulfonyl",
"heteroarylsulfonylalkyl", "heteroarylamino",
"heteroarylaminoalkyl", "heteroaryloxy", "heteroaryloxylalkyl",
"aryloxy", "aroyl", "aralkanoyl", "aralkoxy", "aryloxyalkyl",
"haloaryloxyalkyl", "heteroaroyl", "heteroaralkanoyl",
"heteroaralkoxy", "heteroaralkoxyalkyl", "arylthio",
"arylthioalkyl", "alkoxyalkyl", "acyl", "amidino", "guanidino",
"dialkylsulfonium", "trialkylphosphonium", and
"dialkylsulfoniumalkyl" groups defined above may optionally have 1
or more non-hydrido substituents such as amidino, guanidino,
dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl,
perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,
aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl,
halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl,
cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino,
N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,
heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy,
alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy,
cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,
cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,
halocycloalkoxyalkyl, halocycloalkenyloxy,
halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower
alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino,
arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl,
alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,
heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,
alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,
alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl,
arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl
amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio,
heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl,
heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl,
alkenyl, alkynyl, alkenyloxy, alkenyloxyalkyl, alkylenedioxy,
haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl, cycloalkenyl,
lower cycloalkylalkyl, lower cycloalkenylalkyl, halo, haloalkyl,
haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyaralkyl,
hydroxyalkyl, aminoalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl,
aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated
heterocyclyl, partially saturated heterocyclyl, heteroaryl,
heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl,
arylalkenyl, heteroarylalkenyl, carboxyalkyl, carboalkoxy,
alkoxycarbonyl, carboaralkoxy, carboxamido, carboxamidoalkyl,
cyano, carbohaloalkoxy, phosphono, phosphonoalkyl,
diaralkoxyphosphono, and diaralkoxyphosphonoalkyl.
[0551] The term "spacer" can include a covalent bond and a linear
moiety having a backbone of 1 to 7 contiguous atoms. The spacer may
have 1 to 7 atoms of a univalent or multi-valent chain. Univalent
chains may be constituted by a radical selected from .dbd.C(H)--,
.dbd.C(R.sup.2a)--, --O--, --S--, --S(O)--, --S(O).sub.2--, --NH--,
--N(R.sup.2a)--, --N.dbd., --CH(OH)--, .dbd.C(OH)--,
--CH(OR.sup.2a)--, .dbd.C(OR.sup.2a)--, and --C(O)-- wherein
R.sup.2a is selected from alkyl, alkenyl, alkynyl, aryl,
heteroaryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl,
arylthioalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, haloalkenyl,
haloalkoxyalkyl, perhaloaralkyl, heteroarylalkyl,
heteroaryloxyalkyl, heteroarylthioalkyl, and heteroarylalkenyl.
Multi-valent chains may consist of a straight chain of 1 or 2 or 3
or 4 or 5 or 6 or 7 atoms or a straight chain of 1 or 2 or 3 or 4
or 5 or 6 atoms with a side chain. The chain may be constituted of
one or more radicals selected from: lower alkylene, lower alkenyl,
--O--, --O--CH.sub.2--, --S--CH.sub.2--, --CH.sub.2CH.sub.2--,
ethenyl, --CH.dbd.CH(OH)--, --OCH.sub.2O--, --O(CH.sub.2).sub.2O--,
--NHCH.sub.2--, --OCH(R.sup.2a)O--, --O(CH.sub.2CHR.sup.2a)O--,
--OCF.sub.2O--, --O(CF.sub.2).sub.2O--, --S--, --S(O)--,
--S(O).sub.2--, --N(H)--, --N(H)O--, --N(R.sup.2a)O--,
--N(R.sup.2a)--, --C(O)--, --C(O)NH--, --C(O)NR.sup.2a--, --N.dbd.,
--OCH.sub.2--, --SCH.sub.2--, S(O)CH.sub.2--, --CH.sub.2C(O)--,
--CH(OH)--, .dbd.C(OH)--, --CH(OR.sup.2a)--, .dbd.C(OR.sup.2a)--,
S(O).sub.2CH.sub.2--, and --NR.sup.2aCH.sub.2-- and many other
radicals defined above or generally known or ascertained by one of
skill-in-the art. Side chains may include substituents such as 1 or
more non-hydrido substituents such as amidino, guanidino,
dialkylsulfonium, trialkylphosphonium, dialkylsulfoniumalkyl,
perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,
aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl,
halocycloalkenyl, cycloalkylsulfinyl, cycloalkylsulfinylalkyl,
cycloalkylsulfonyl, cycloalkylsulfonylalkyl, heteroarylamino,
N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl,
heteroaryloxy, heteroaryloxylalkyl, haloalkylthio, alkanoyloxy,
alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy,
cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,
cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,
halocycloalkoxyalkyl, halocycloalkenyloxy,
halocycloalkenyloxyalkyl, hydroxy, amino, thio, nitro, lower
alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino,
arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl,
alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,
heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,
alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,
alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, monoarylamidosulfonyl,
arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl
amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio,
heteroarylsulfinyl, heteroarylsulfonyl, alkanoyl, alkenoyl, aroyl,
heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl,
alkenyl, alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy,
haloalkylenedioxy, cycloalkyl, cycloalkenyl, lower cycloalkylalkyl,
lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,
hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, aminoalkyl,
hydoxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy,
aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated
heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl,
arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl,
carboxyalkyl, carboalkoxy, carboaralkoxy, carboxamido,
carboxamidoalkyl, cyano, carbohaloalkoxy, phosphono,
phosphonoalkyl, diaralkoxyphosphono, and
diaralkoxyphosphonoalkyl.
[0552] Compounds of the present invention can exist in tautomeric,
geometric or stereoisomeric forms. The present invention
contemplates all such compounds, including cis- and trans-geometric
isomers, E- and Z-geometric isomers, R- and S-enantiomers,
diastereomers, d-isomers, 1-isomers, the racemic mixtures thereof
and other mixtures thereof, as falling within the scope of the
invention. Pharmaceutically acceptable sales of such tautomeric,
geometric or stereoisomeric forms are also included within the
invention.
[0553] The terms "cis" and "trans" denote a form of geometric
isomerism in which two carbon atoms connected by a double bond will
each have a hydrogen atom on the same side of the double bond
("cis") or on opposite sides of the double bond ("trans").
[0554] Some of the compounds described contain alkenyl groups, and
are meant to include both cis and trans or "E" and "Z" geometric
forms.
[0555] Some of the compounds described contain one or more
stereocenters and are meant to include R, S, and mixtures of R and
S forms for each stereocenter present.
[0556] Some of the compounds described herein may contain one or
more ketonic or aldehydic carbonyl groups or combinations thereof
alone or as part of a heterocyclic ring system. Such carbonyl
groups may exist in part or principally in the "keto" form and in
part or principally as one or more "enol" forms of each aldehyde
and ketone group present. Compounds of the present invention having
aldehydic or ketonic carbonyl groups are meant to include both
"keto" and "enol" tautomeric forms.
[0557] Some of the compounds described herein may contain one or
more amide carbonyl groups or combinations thereof alone or as part
of a heterocyclic ring system. Such carbonyl groups may exist in
part or principally in the "keto" form and in part or principally
as one or more "enol" forms of each amide group present. Compounds
of the present invention having amidic carbonyl groups are meant to
include both "keto" and "enol" tautomeric forms. Said amide
carbonyl groups may be both oxo (C.dbd.O) and thiono (C.dbd.S) in
type.
[0558] Some of the compounds described herein may contain one or
more imine or enamine groups or combinations thereof. Such groups
may exist in part or principally in the "imine" form and in part or
principally as one or more "enamine" forms of each group present.
Compounds of the present invention having said imine or enamine
groups are meant to include both "imine" and "enamine" tautomeric
forms.
[0559] The present invention also comprises a treatment and
prophylaxis in anticoagulant therapy for the treatment and
prevention of a variety of thrombotic conditions including coronary
artery and cerebrovascular disease in a subject, comprising
administering to the subject having such disorder a
therapeutically-effective amount of a compound of Formula (I):
37
[0560] or a pharmaceutically-acceptable salt thereof.
[0561] As a further embodiment, compounds of the present invention
of Formula (I) or a pharmaceutically-acceptable salt thereof as
defined above, comprise a treatment and prophylaxis of coronary
artery disease, cerebrovascular disease and other coagulation
cascade related disorders in a subject, comprising administering to
the subject having such disorder a therapeutically-effective amount
of compounds of formula (I) of the present invention or a
pharmaceutically-acceptable salt thereof.
[0562] Compounds of the present invention of Formula (I) or a
pharmaceutically-acceptable salt thereof can also be used whenever
inhibition of blood coagulation is required such as to prevent
coagulation of stored whole blood and to prevent coagulation in
other biological samples for testing or storage. Thus coagulation
inhibitors of the present inhibition can be added to or contacted
with stored whole blood and any medium containing or suspected of
containing plasma coagulation factors and in which it is desired
that blood coagulation be inhibited, e.g. when contacting the
mammal's blood with material selected from the group consisting of
vascular grafts, stents, orthopedic prothesis, cardiac prosthesis,
and extracorporeal circulation systems.
[0563] Compounds of Formula (I) are capable of inhibiting activity
of serine proteases related to the coagulation cascade, and thus
could be used in the manufacture of a medicament, a method for the
prophylactic or therapeutic treatment of diseases mediated by
coagulation cascade serine proteases, such as inhibiting the
formation of blood platelet aggregates, inhibiting the formation of
fibrin, inhibiting thrombus formation, and inhibiting embolus
formation in a mammal, in blood, in blood products, and in
mammalian organs. The compounds also can be used for treating or
preventing unstable angina, refractory angina, myocardial
infarction, transient ischemic attacks, atrial fibrillation,
thrombotic stroke, embolic stroke, deep vein thrombosis,
disseminated intravascular coagulation, ocular build up of fibrin,
and reocclusion or restenosis of recanalized vessels in a mammal.
The compounds also can be used to study the mechanism of action of
coagulation cascade serine proteases to enable the design of better
inhibitors and development of better assay methods. The compounds
of Formula (I) would be also useful in prevention of cerebral
vascular accident (CVA) or stroke.
[0564] Also included in the family of compounds of Formula (I) are
the pharmaceutically-acceptable salts thereof. The term
"pharmaceutically-acceptable salt" embraces salts commonly used to
form alkali metal salts and to form addition salts of free acids or
free bases. The nature of the salt is not critical, provided that
it is pharmaceutically acceptable. Suitable
pharmaceutically-acceptable acid addition salts of compounds of
Formula (I) may be prepared from inorganic acid or from an organic
acid. Examples of such inorganic acids are hydrochloric,
hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric
acid. Appropriate organic acids may be selected from aliphatic,
cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and
sulfonic classes of organic acids, examples of which are formic,
acetic, propionic, succinic, glycolic, gluconic, lactic, malic,
tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic,
aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic,
p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic,
stearic, cyclohexylaminosulfonic, algenic, galacturonic acid.
Suitable pharmaceutically-acceptable base addition salts of
compounds of Formula (I) include metallic salts made from aluminum,
calcium, lithium, magnesium, potassium, sodium and zinc or organic
salts made from N,N'-dibenzylethyleneldiamine, choline,
chloroprocaine, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine) and procain. All of these salts may be prepared
by conventional means from the corresponding compound of Formula
(I) by reacting, for example, the appropriate acid or base with the
compound of Formula (I).
[0565] The present invention also comprises a pharmaceutical
composition comprising a therapeutically-effective amount of a
compound of Formulas (I) in association with at least one
pharmaceutically-acceptable carrier, adjuvant or diluent.
Pharmaceutical compositions of the present invention can comprise
the active compounds of Formula (I) in association with one or more
non-toxic, pharmaceutically-acceptable carriers and/or diluents
and/or adjuvants (collectively referred to herein as "carrier"
materials) and, if desired, other active ingredients. The active
compounds of the present invention may be administered by any
suitable route, preferably in the form of a pharmaceutical
composition adapted to such a route, and in a dose effective for
the treatment intended.
[0566] The active compounds and composition may, for example, be
administered orally, intravascularly, intraperitoneally,
subcutaneously, intramuscularly, oculary, or topically. For
treating ocular build up of fibrin, the compounds may be
administered intraocularly or topically as well as orally or
parenterally.
[0567] The compounds can be administered in the form of a depot
injection or implant preparation which may be formulated in such a
manner as to permit a sustained release of the active ingredient.
The active ingredient can be compressed into pellets or small
cylinders and implanted subcutaneously or intramusculary as depot
injections or implants. Implants may employ inert materials such as
biodegradable polymers or synthetic silicones, for example,
Silastic, silicone rubber or other silicon containing polymers.
[0568] The compounds can also be administered in the form of
liposome delivery systems, such as small unilamellar vesicles,
large unilamellar vesicles and multilamellar vesicles. Liposomes
can be formed from a variety of phospholipids, such as cholesterol,
stearylamine or phosphatidylcholines.
[0569] The compounds may also be delivered by the use of monoclonal
antibodies as individual carriers to which the compound molecules
are coupled. The compounds may also be coupled with soluble
polymers as targetable drug carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer,
polyhydroxy-propylmethacrylamide-phenol,
polyhydroxyethyl-aspartamide-phenol, or
ployethyleneoxide-polylysine substituted with palmitoyl residues.
Furthermore, the compounds may be coupled to a class of
biodegradable polymers useful in achieving controlled release of a
drug, for example, polylactic acid, polyglycolic acid, copolymers
of polylactic and polyglycolic acid, polyepsilon caprolactone,
polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacrylates and cross linked or
amphitpathic block copolymers of hydrogels.
[0570] For oral administration, the pharmaceutical composition may
be in the form of, for example, tablets, capsules (each of which
includes sustained release or timed release formulations), pills,
powders, granules, elixers, tinctures, suspensions, liquids
including syrups, and emulsions. The pharmaceutical composition is
preferably made in the form of a dosage unit containing a
particular amount of the active ingredient. Examples of such dosage
units are tablets or capsules. The active ingredient may also be
administered by injection as a composition wherein, for example,
saline, dextrose or water may be used as a suitable carrier.
[0571] The amount of therapeutically active compounds which are
administered and the dosage regimen for treating a disease
condition with the compounds and/or compositions of this invention
depends on a variety of factors, including the age, weight, sex and
medical condition of the subject, the severity of the disease, the
route and frequency of administration, and the particular compound
employed, and thus may vary widely.
[0572] The pharmaceutical compositions may contain active
ingredients in the range of about 0.1 to 2000 mg, and preferably in
the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100
mg/kg body weight, and preferably between about 0.5 and about 20
mg/kg body weight, may be appropriate. The daily dose can be
administered in one to four doses per day.
[0573] The compounds may be formulated in topical ointment or
cream, or as a suppository, containing the active ingredients in a
total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to
20% w/w and most preferably 0.4 to 15% w/w. When formulated in an
ointment, the active ingredients may be employed with either
paraffinic or a water-miscible ointment base.
[0574] Alternatively, the active ingredients may be formulated in a
cream with an oil-in-water cream base. If desired, the aqueous
phase of the cream base may include, for example at least 30% w/w
of a polyhydric alcohol such as propylene glycol, butane-1,3-diol,
mannitol, sorbitol, glycerol, polyethylene glycol and mixtures
thereof. The topical formulation may desirably include a compound
which enhances absorption or penetration of the active ingredient
through the skin or other affected areas. Examples of such dermal
penetration enhancers include dimethylsulfoxide and related
analogs. The compounds of this invention can also be administered
by a transdermal device. Preferably topical administration will be
accomplished using a patch either of the reservoir and porous
membrane type or of a solid matrix variety. In either case, the
active agent is delivered continuously from the reservoir or
microcapsules through a membrane into the active agent permeable
adhesive, which is in contact with the skin or mucosa of the
recipient. If the active agent is absorbed through the skin, a
controlled and predetermined flow of the active agent is
administered to the recipient. In the case of microcapsules, the
encapsulating agent may also function as the membrane.
[0575] The oily phase of the emulsions of this invention may be
constituted from known ingredients in a known manner. While the
phase may comprise merely an emulsifier, it may comprise a mixture
of at least one emulsifier with a fat or an oil or with both a fat
and an oil. Preferably, a hydrophilic emulsifier is included
together with a lipophilic emulsifier which acts as a stabilizer.
It is also preferred to include both an oil and a fat. Together,
the emulsifier(s) with or without stabilizer(s) make-up the
so-called emulsifying wax, and the wax together with the oil and
fat make up the so-called emulsifying ointment base which forms the
oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
present invention include Tween 60, Span 80, cetostearyl alcohol,
myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate,
among others.
[0576] The choice of suitable oils or fats for the formulation is
based on achieving the desired cosmetic properties, since the
solubility of the active compound in most oils likely to be used in
pharmaceutical emulsion formulations is very low. Thus, the cream
should preferably be a non-greasy, non-staining and washable
product with suitable consistency to avoid leakage from tubes or
other containers. Straight or branched chain, mono- or dibasic
alkyl esters such as diisoadipate, isocetyl stearate, propylene
glycol diester of coconut fatty acids, isopropyl myristate, decyl
oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate
or a blend of branched chain esters may be used. These may be used
alone or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used.
[0577] For therapeutic purposes, the active compounds of the
present invention are ordinarily combined with one or more
adjuvants appropriate to the indicated route of administration. If
administered per os, the compounds may be admixed with lactose,
sucrose, starch powder, cellulose esters of alkanoic acids,
cellulose alkyl esters, talc, stearic acid, magnesium stearate,
magnesium oxide, sodium and calcium salts of phosphoric and
sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted
or encapsulated for convenient administration. Such capsules or
tablets may contain a controlled-release formulation as may be
provided in a dispersion of active compound in hydroxypropylmethyl
cellulose. Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules having one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration. The compounds may be dissolved in water,
polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, and/or various buffers. Other adjuvants and modes of
administration are well and widely known in the pharmaceutical
art.
[0578] In practicing the methods of the present invention for the
treatment and prevention of a variety of thrombotic conditions
including coronary artery and cerebrovascular disease, the
compounds and pharmaceutical compositions of the present invention
are administered alone or in combination with one another, or in
combination with other therapeutics or in vivo diagnostic agents.
The coagulation cascade inhibitors of the present invention can
also be co-administered with suitable anti-platelet agreggation
agents, including, but not limited to ticlopidine or clopidrogel,
fibrinogen receptor antagonists (e.g. to treat or prevent unstable
angina or to prevent reocculsion after angioplasty and restenosis),
anti-coagulants such as aspirin, warfarin or heparins, thrombolytic
agents such as plasminogen activators or streptokinase to achieve
synergistic effects in the treatment of various pathologies, lipid
lowering agents including antihypercholesterolemics (e.g. HMG CoA
reductase inhibitors such as mevastatin, lovastatin, simvastatin,
pravastatin, and fluvastatin, HMG CoA synthatase inhibitors, etc.),
anti-diabetic drugs, or other cardiovascular agents (loop
diuretics, thiazide type diuretics, nitrates, aldosterone
antagonistics (i.e., spironolactone and epoxymexlerenone),
angiotensin converting enzyme (e.g. ACE) inhibitors, angiotensin II
receptor antagonists, beta-blockers, antiarrythmics,
anti-hypertension agents, and calcium channel blockers) to treat or
prevent atheriosclerosis. For example, patients suffering from
coronary artery disease, and patients subjected to angioplasty
procedures, would benefit from coadministration of fibrinogen
receptor antagonists and coagulation cascade inhibitors of the
present invention. Also, coagulation cascade inhibitors could
enhance the efficiency of tissue plasminogen activator-mediated
thrombolytic reperfusion.
[0579] Typical doses of coagulation cascade inhibitors of the
present invention with other suitable anti-platelet agents,
anticoagulation agents, cardiovascular therapeutic agents, or
thrombolytic agents may be the same as those doses of coagulation
cascade inhibitors administered without coadministration of
additional anti-platelet agents, anticoagulation agents,
cardiovascular therapeutic agents, or thrombolytic agents, or may
be substantially less than those doses of coagulation cascade
inhibitors administered without coadministration of additional
anti-platelet agents, anticoagulation agents, cardiovascular
therapeutic agents, or thrombolytic agents, depending on a
patient's therapeutic needs.
[0580] All mentioned references are incorporated by reference as if
here written.
[0581] Although this invention has been described with respect to
specific embodiments, the details of these embodiments are not to
be construed as limitations. The following examples are provided to
illustrate the present invention and are not intended to limit the
scope thereof. Without further elaboration, it is believed that one
skilled in the art can, using the preceding descriptions, utilize
the present invention to its fullest extent. Therefore the
following preferred specific embodiments are to be construed as
merely illustrative and not limitative of the remainder of the
disclosure in any way whatsoever. Compounds containing multiple
variations of the structural modifications illustrated in the
schemes or the following Examples are also contemplated. Those
skilled in the art will readily understand that known variations of
the conditions and processes of the following preparative
procedures can be used to prepare these compounds.
[0582] One skilled in the art may use these generic methods to
prepare the following specific examples, which have been or may be
properly characterized by .sup.1H NMR, mass spectrometry, elemental
composition, and similar procedures. These compounds also may be
formed in vivo. The following examples contain detailed
descriptions of the methods of preparation of compounds of Formula
(I). These detailed descriptions fall within the scope and are
presented for illustrative purposes only and are not intended as a
restriction on the scope of the invention. All parts are by weight
and temperatures are Degrees centigrade unless otherwise
indicated.
[0583] The following general synthetic sequences are useful in
making the present invention. Abbreviations used in the schemes and
tables include: "AA" represents amino acids, "AcCN" represents
acetonitrile, "AcOH" represents acetic acid, "BINAP" represents
2,2'-bis(diphenylphosphino)-1,- 1'-binaphthyl, "BnOH" represents
benzyl alcohol, "BnCHO" represents 2-phenylethanal, "BnSO.sub.2Cl"
represents benzylsulfonyl chloride, "Boc" represents
tert-butyloxycarbonyl, "BOP" represents
benzotriazol-1-yl-oxy-tris-(dimethylamino), "bu" represents butyl,
"dba" represents dibenzylidene-acetone, "DCC" represents
1,3-dicyclohexylcarbodiimide, "DCM" represents dichloromethane or
methylene chloride, "DIBAH" or "DIBAL" represents
diisobutylaluminum hydride, "DMF" represents dimethylformamide,
"DMSO" represents dimethylsulfoxide, "DPPA" represents
diphenylphosphoryl azide", "EDC" represents
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, "Ex.
No." represents Example Number, "Fmoc" represents
9-fluorenylmethoxycarbonyl, "HOBt" represents
hydroxybenzoltriazole", "LDA" represents lithium diisopropylamide,
"MW" represents molecular weight, "NMM" represents
N-methylmorpholine, "Ph" represents phenyl or aryl, "PHTH"
represents a phthaloyl group, "pnZ" represents
4-nitrobenzyloxy-carbonyl, "PTC" represents a phase transfer
catalyst , "py" represents pyridine, "RNH.sub.2" represents a
primary organic amine, "SEM" represents
2-(trimethylsilyl)ethoxy-methyl chloride, "p-TsOH" represents
paratoluenesulfonic acid, "TBAF" represents tetrabutylammonium
fluoride, "TBTU" represents
2-(1H-benzotriozole-1-yl)-1,1,3,3-tetramethyl uronium
tetrafluoroborate, "TEA" represents triethylamine, "TFA" represents
trifluoroacetic acid, "THF" represents tetrahydrofuran, "TMS"
represents trimethylsilyl, "TMSCN" represents trimethylsilyl
cyanide, and "Cbz" or "Z" represents benzyloxycarbonyl.
GENERAL SYNTHETIC PROCEDURES AND SPECIFIC EXAMPLES
[0584] The general synthetic approach to substituted uracils (i.e.,
pyrimidinediones) is shown in Scheme 1 below. Several N-1
substituted pyrimidinediones have been previously prepared,
disclosed, and are useful intermediates for the preparation of the
compounds of this invention. Stirring a solution of such a N-1
substituted pyrimidinedione and an .alpha.-haloacetate in
dimethylsulfoxide, in the presence of potassium carbonate results
in alkylation of the N-3 nitrogen. Reduction of the nitro
functional group to the primary amine is easily accomplished with
catalytic palladium on carbon in an atmosphere of hydrogen. The
primary amine can then be reacted with a variety of raw materials
including, but not limited to, acid chlorides, acid anhydrides,
sulfonyl chlorides, alkyl and aromatic halides, aldehydes, and
ketones. The acetate ester can then be hydrolyzed to the acid with
lithium hydroxide. The acid can then be coupled with a wide range
of desired amines under standard peptide coupling conditions to
give an amide. The amines used in the process of this invention are
typically multi-functional and are reacted in protected form.
Removal of these protecting groups provides the compounds of the
present invention. 38
[0585] This general uracil (i.e., pyrimidinedione) synthetic scheme
is exemplified in Examples 1 and 2 below. 39
[0586] EX-1A) A solution of 1-benzyl-5-nitro-2,4(1H,3H)
pyrimidinedione (6.14 g, 24.82 mmol) prepared as described by
Vampa, G. and Pecorari P. Boll. Chim. Farm. 1987, 126,467-469 was
dissolved in 100 mL dimethylsulfoxide and potassium dicarbonate
(3.78 g, 27.34 mmol) was added in one portion with stirring. After
approximately 10 minutes a solution of methyl bromoacetate (2.50
mL, 26.40 mmol) in 20 mL dimethylsulfoxide was added drop wise over
a 10 minute period. The reaction mixture was then heated to
40.degree. C. and allowed to stir for 18 hours. The reaction
mixture was diluted with water (500 mL). The aqueous solution was
extracted with ethyl acetate (4.times.100 mL). The combined organic
solutions were washed with water (1.times.150 mL), brine
(2.times.150 mL). The organic solution was dried (MgSO.sub.4),
filtered, and concentrated to give an oil. The crude oil was
purified by MPLC (20% ethyl acetate/hexanes) to give pure
1-Benzyl-3-methoxycarbonyl-methyl-5-n-
itro-2,4(1H,3H)pyrimidinedione (EX-1A) as a white solid in 81%
yield: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.73 (s, 1H)
7.38-7.30 (m, 5H), 5.06 (s, 2H), 4.69 (s, 2H), 3.72 (s, 3H); HRMS
(ES) calcd for C.sub.14H.sub.13N.sub.3O.sub.6 319.0804, found
319.0797.
[0587] EX-1B) A solution of
1-Benzyl-3-methoxycarbonylmethyl-5-nitro-2,4(1- H,3H)
pyrimidinedione (EX-1A; 6.30 g, 19.74 mmol) in 100.0 mL methanol
was degassed with hydrogen gas. The solution was then added 5% Pd/C
(0.737 g) and allowed to stir under an atmosphere of hydrogen at
room temperature for 24 hours. The crude reaction was filtered
through a pad of Celite 545 and concentrated under reduced
pressure. The oil was purified by MPLC (60% Ethyl acetate/hexanes)
to give pure 5-amino-1-Benzyl-3-methoxycarbon-
ylmethyl-2,4(1H,3H)-pyrimidinedione (EX-1B) in 63% yield as a tan
solid: .sup.1H NMR (300 MHz, DMSO) .delta. 7.41-7.28 (m, 5H), 6.93
(s, 1H), 4.93 (s, 2H), 4.66 (s, 2H), 4.32 (s, 2H),3.69 (s,3H); HRMS
(ES) calcd for C.sub.14H.sub.16N.sub.3O.sub.4 290.1141, found
290.1138.
[0588] EX-1C) A solution of
5-amino-1-Benzyl-3-methoxycarbonylmethyl-2,4(1- H,3H)
pyrimidinedione (EX-1B; 3.12 g, 10.77 mmol) in 18.0 mL of
tetrahydrofuran and dimethylformamide (1:1, 0.62M) was added
N-methyl morpholine (3.60 mL, 32.74 mmol) in one portion at room
temperature. The resulting mixture was cooled to 0.degree. C. in an
ice bath and was allowed to stir for 15 minutes. A solution of
benzylsulfonyl chloride (2.26 g, 11.86 mmol) in 18.0 mL
tetrahydrofuran was added drop wise over a 30 minute period. After
the addition was complete the reaction was stirred for 3 hours at
0.degree. C. The reaction mixture was diluted with ethyl acetate
(250.0 mL) and washed with 1N HCl ((2.times.50 mL), saturated
NaHCO3 (2.times.50 mL), and brine (2.times.50 mL). The organic
solution was dried (MgSO.sub.4), filtered and concentrated.
Trituration with ethyl acetate and hexanes gave pure
1-Benzyl3-methoxycarbonylmethyl--
5-[[(phenylmethyl)sulfonyl]amino]-2,4(1H,3H)pyrimidinedione (EX-1C)
in 74% yield as a white solid: .sup.1H NMR (300 MHz, DMSO) .delta.
9.16 (s, 1H), 8.02 (s, 1H), 7.43-7.37 (m, 10H), 5.01 (s, 2H), 4.65
(s, 2H), 4.45 (s, 2H), 3.69 (s, 3H); HRMS (ES) calcd for
C.sub.21H.sub.22N.sub.3O.sub.6S 444.1229, found 444.1242.
[0589] EX-1D) A suspension of
1-benzyl-3-methoxycarbonylmethyl-5-[[(phenyl- methyl)
sulfonyl]amino]-2,4(1H,3H)pyrimidinedione (EX-1C; 3.28 g, 7.40
mmol) in 94.0 mL tetrahydrofuran and methanol (1:1, 0.078 M) was
added 30.0 mL of 0.1 M lithium hydroxide in water. The suspension
quickly clears and becomes homogeneous. The reaction was stirred
for 1 hour, and the volatiles were removed under reduced pressure.
The remaining aqueous solution was cooled in an ice bath and
acidified to a pH of 1 with 1.0 N HCl which resulted in a white
precipitate forming. The precipitate was collected by filtration,
washed with 1.0 N HCl and water, and dried under vacuum to give
pure 1-Benzyl3-methylene-carboxy-5-[[(phenylmethyl)
sulfonyl]amino]-2,4(1H,3H)pyrimidinedione (EX -1D) in 99% yield:
.sup.1H NMR (300 MHz, DMSO) .delta. 9.14 (br s, 1H), 7.98 (s, 1H),
7.44-7.35 (m, 10H), 5.00 (s, 2H), 4.51 (s, 2H), 4.45 (s, 2H); HRMS
(ES) calcd for C.sub.20H.sub.19N.sub.3O.sub.6S 429.0995, found
429.0981.
[0590] EX-1E) A solution of
1-Benzyl-3-methylenecarboxy-5-[[(phenylmethyl)-
-sulfonyl]amino]-2,4(1H,3H)pyrimidinedione (EX-1D; 531.6 mg, 1.238
mmol) in 12.4 mL tetrahydrofuran and dimethylformamide (1:1, 0.1 M)
was added N,N-diisopropylethylamine (1.10 mL, 6.315 mmol),
N-hydroxybenzotriazole (499.6 mg, 3.697 mmol), and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimi- de hydrochloride
(717.2 mg, 3.741 mmol). The resulting mixture was allowed to stir
for 30 minutes. The reaction mixture was then added amine (623.3
mg, 2.500 mmol) in one portion. The resulting mixture was allowed
to stir over night. The reaction mixture was diluted with ethyl
acetate (50 mL) and washed with 5% citric acid (1.times.25 mL),
saturated NaHCO.sub.3 (1.times.25 mL), and brine (1.times.25 mL).
The organic solution was dried (MgSO.sub.4), filtered and
concentrated. The crude reaction was purified by MPLC (75% ethyl
acetate/hexanes) to give the product EX-1E:
[0591] .sup.1H NMR (300 MHz, DMSO) .delta. 9.13 (br s, 1H), 8.77
(t, J=5.3 Hz, 1H), 7.98 (s, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.45-7.35
(m, 13H), 5.01 (s, 2H), 4.56 (s, 2H), 4.56 (s, 2H), 4.44 (s, 2H),
4.38 (d, J=5.4 Hz, 2H), 1.47 (s, 9H); HRMS (ES) calcd for
C.sub.33H.sub.37N.sub.6O.sub.7S 661.2444, found 661.2448.
[0592] A flask of protected pyrimidinedione (EX-1E) (238.5 mg,
0.3610 mmol) was added 4.0 ml of 4 M HCl in dioxane. The resulting
solution was allowed to stir overnight (approximately 18 hours).
The solution was concentrated and the crude product was triturated
from ethyl ether. The resulting white solid was collected by
filtration, washed with ethyl ether and dried to give pure product:
.sup.1H NMR (300 MHz, DMSO) .delta. 9.44 (s, 2H), 9.29 (s, 2H),
9.14 (s, 1H), 9.01-8.99 (m, 1H), 7.99 (s, 1H), 7.81 (d, J=7.9 Hz,
1H), 7.51-7.37 (m, 14H), 5.01 (s, 2H), 4.57 (s, 2H), 4.45-4.41 (m,
2H), 3.58 (s, 2H); HRMS (ES) calcd for
C.sub.28H.sub.29N.sub.6O.sub.5S 561.1920, found 561.1917. 40
[0593] (EX-2A) A solution of
1-Benzyl-3-methylenecarboxy-5-[[(phenyl-methy-
l)sulfonyl]amino]-2,4(1H,3H)pyrimidinedione (439.8 mg, 1.024 mmol)
in 10.0 mL tetrahydrofuran and dimethylformamide (1:1, 0.1 M) was
added N,N-diisopropylethylamine (1.80 mL, 10.30 mmol),
N-hydroxybenzotriazole (169.3 mg, 1.253 mmol), and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimi- de hydrochloride
(238.2 mg, 1.243 mmol). The resulting mixture was allowed to stir
for 10 minutes. The reaction mixture was then added amine (648.3
mg, 1.231 mmol) in one portion. The resulting mixture was allowed
to stir over night. The reaction mixture was diluted with ethyl
acetate (100 mL) and washed with 5% citric acid (1.times.50 mL),
saturated NaHCO.sub.3 (1.times.50 mL), and brine (1.times.50 mL).
The organic solution was dried (MgSO.sub.4), filtered and
concentrated. The crude reaction was purified by MPLC (75% ethyl
acetate/hexanes) to give the product EX-2A: .sup.1H NMR (300 MHz,
DMSO) .delta. 9.09 (s, 1H), 8.78 (d, J=7.1 Hz, 1H), 8.28 (d, J=3.0
Hz, 1H), 8.19 (d, J=3.0 Hz, 1H), 7.94 (s, 1H), 7.43-7.31 (m, 10H),
6.68(s, 1H), 5.44-5.43 (m, 1H), 4.97 (s, 2H), 4.56 (d, J=4.2 Hz,
2H), 4.41 (s, 2H), 3.80 (s, 3H), 3.08 (br d, J=5.4 Hz, 3H), 2.91
(s, 1H), 2.75 (s, 1H), 2.59(s, 3H), 2.52 (s, 3H), 2.06 (s, 3H),
1.92-1.80 (m, 1H), 1.61-1.51 (m, 3H), 1.37-1.33 (m 1H); HRMS (EI)
calcd for C.sub.39H.sub.45N.sub.8O.sub.9S.sub.3 865.2472, found
865.2484.
[0594] A solution of EX-2A (281.3 mg, 0.3252 mmol) in 3.0 mL
trifluoroacetic acid (0.1 M) was added thioanisole (0.115 mL,
0.9796 mmol) at room temperature with stirring. The resulting
mixture was allowed to stir 6 hours. The reaction mixture was
concentrated under reduced pressure. The crude product was purified
by trituration from ethyl ether. A light yellow powder was
collected by filtration, washed with ethyl ether to give pure
product 2: .sup.1H NMR (300 MHz, DMSO) .delta. 9.07 (s, 1H), 8.82
(d, J=7.0 Hz, 1H), 8.30 (d, J=3.0 Hz, 1H), 8.21 (d, J=3.0 Hz, 1H),
7.95 (s, 1H), 7.55-7.20 (m, 10H), 5.49-5.48 (m, 1H), 4.97 (s, 2H),
4.63-4.51 (m, 2H), 4.42 (s, 2H), 3.13 (br d, J=6.0 Hz, 2H), 2.49
(s, 3H), 1.91 (br s, 1H), 1.67-1.58 (m, 4H); LRMS (EI), (MH+)
653.2.
[0595] Using the procedures exemplified in Examples 1 and 2 and the
attached Scheme 1, the following compounds can be prepared. 41
[0596] Following Steps A and B exemplified in Example 1 and
replacing benzyl bromide with 3-(N-Boc-amino)benzyl bromide
(Murakami, Y.; Hagishita, S.; Okada, T.; Kii, M.; Hashizume, H.;
Yagami, T.; Fujimoto, M.; Bioorg. Med. Chem. 1999, 7, 1703-1714.),
alkylated intermediate, methyl
3-[1-[3-(N-Boc-amino)benzyl]-5-amino-2,4-dioxopyrimidinyl]acetate
(EX-3A) can be prepared.
[0597] To a solution of 1 eq. of ester EX-3A and 1 eq. of
cyclobutanone in tetrahydrofuran is added 1 eq. of sodium
cyanoborohydride, and the mixture is stirred for several hours. The
solvent is evaporated off to afford the crude product. The crude
product is purified by silica gel chromatagraphy to afford purified
methyl 2-[3-[1-[3-(N-Boc-amino)benzyl]--
5-(N-cyclobutyl)amino-2,4-dioxopyrimidinyl]]-acetate (EX-3B).
[0598] Following the remaining procedure exemplified in Example 1,
the indicated compound of Example 3 can be obtained. 42
[0599] A solution of 1 eq. of the appropriate amide and 1 eq. of
3-nitropnenylisocyanate in DMF is heated to 100.degree. C. for
several hours. The solvent is evaporated off to afford the crude
product. The crude product is purified by silica gel chromatagraphy
to afford purified product
1-[3-Nitrophenyl]-5-nitro-2,4-dioxopyrimidine (EX-4A)
[0600] A solution of 1 eq. of uracil EX-4A in dimethylsulfoxide is
added to 1.1 eq. of potassium dicarbonate in one portion with
stirring. After approximately 10 minutes a solution containing 1.1
eq. of methyl bromoacetate in dimethylsulfoxide is added dropwise
over a 10 minute period. The reaction mixture is heated to
40.degree. C. and allowed to stir for 18 hours. The reaction
mixture is diluted with water. The aqueous solution is extracted
with ethyl acetate and the combined organic solution is washed with
water and brine. The organic solution is dried over MgSO.sub.4,
filtered, and concentrated to give a crude product. The crude
product is purified by silica gel chromatagraphy to afford purified
methyl
2-[3-[1-[3-nitrophenyl]-5-nitro-2,4-dioxopyrimidinyl]]acetate
(EX-4B).
[0601] A suspension of methyl ester EX-4B in tetrahydrofuran and
methanol is added excess lithium hydroxide in water. The reaction
is stirred for 1 hour, and the volatiles are removed under reduced
pressure. The remaining aqueous solution is cooled in an ice bath
and acidified to a pH of 1 with 1.0 N HCl which results in a white
precipitate forming. The precipitate is collected by filtration,
washed with 1.0 N HCl and water, and dried under vacuum to give
pure acid, 2-[3-[1-[3-nitrophenyl]-5-nitro-2,4-dioxo-
pyrimidinyl]]acetic acid (EX-4C).
[0602] A solution of acid EX-4C in dimethylformamide (0.1 M) is
added to 5 eq N,N-diisopropylethylamine, 1 eq
N-hydroxybenzotriazole mmol), and 1 eq
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The
resulting mixture is allowed to stir for 30 minutes. To the
reaction mixture is then added 1 eq. of
4-(N-Boc-amidino)benzylamine in one portion. The resulting mixture
is allowed to stir over night. The reaction mixture is diluted with
ethyl acetate and washed with 5% citric acid, saturated
NaHCO.sub.3, and brine. The organic solution is dried (MgSO.sub.4),
filtered and concentrated. Purification by MPLC pure,
N-[4-(N-Boc-amidinobenzyl)]-2-[3-[1-[3-nitrophenyl]-5nitro-2,4-dioxopyrim-
idinyl]]acetamide (EX-4D).
[0603] A solution of bis-nitro compound EX-4D in methanol is
treated with 5 molar percent of 10% Pd/C under an atmosphere of
hydrogen (balloon pressure). The suspension is allowed to stir over
night. Filtration through Celite 545 followed by removal of the
solvent affords pure,
N-[4-(N-Boc-amidinobenzyl)]-2-[3-[1-[3-aminophenyl]-5-amino-2,4-dioxopyri-
midinyl]]acetamide (EX-4E).
[0604] A solution of bis-amine EX-4E and 1 eq. of cyclobutanone in
tetrahydrofuran is treated with 1 eq of sodium cyanoborohydride
followed by a catalytic amount of hydrochloric acid. The reaction
mixture is allowed to stir at room temperature for several hour.
The reaction is quenched with the cautious addition of water. The
aqueous solution is extracted with ethyl acetate. The organic
solutions are washed with water and brine. The organic solution is
dried (MgSO.sub.4), filtered and concentrated. Purifaction by MPLC
affords pure, N-[4-(N-Boc-amidinobenzyl-
)]-2-[3-[1-[3-aminophenyl]-5-(N-cyclobutyl-amino)-2,4-dioxopyrimidinyl]]ac-
etamide (EX-4F).
[0605] A solution of N-Boc amidine EX-4F in methanol is treated
with 3 eq of 4 M HCl in dioxane. The solution is stirred for five
hours. Removal of the solvents under vacuum followed by trituration
with ethyl ether affords pure product.
[0606] A wide variety of methylene analogs of pyrimidinediones
wherein a methylene is present as a replacement for the carbonyl of
the acetamide at the N-2 position of the pyrimidinedione can be
prepared using the procedure detailed below 43
[0607] EX-5A) A solution of 1 eq. of phenyl isocyanate and 1 eq. of
3-ethoxy-2-nitro-propenamide in DMF is heated to 100.degree. C. for
several hours. The solvent is evaporated off to afford the crude
product. The crude product is purified by silica gel chromatagraphy
to afford purified product EX-5A.
[0608] EX-5B) To a solution of 1 eq. of EX-5A in dimethylsulfoxide
is added to 1.1 eq. of potassium dicarbonate in one portion with
stirring. After approximately 10 minutes, a solution containing 1.1
eq. of methyl bromoacetate in dimethylsulfoxide is added dropwise
over a 10 minute period. The reaction mixture is heated to
40.degree. C. and allowed to stir for 18 hours. The reaction
mixture is diluted with water. The aqueous solution is extracted
with ethyl acetate and the combined organic solution is washed with
water and brine. The organic solution is dried over MgSO.sub.4,
filtered, and concentrated to give a crude product. The crude
product is purified by silica gel chromatagraphy to afford purified
product methyl 2-[3-[5-nitro-2,4-dixoxo-1-phenylpyrimidyl]]acetate
(EX-5B).
[0609] EX-5C) Diisobutylaluminum hydride (1.05 equiv.) is added
over a period of 15 min to a cooled solution -78.degree. C. of 1
eq. of EX-5B in tetrahydrofuran . After stirring for 1 h at
-78.degree. C., the reaction is slowly quenched at -78.degree. C.
with cold methanol. The mixture is slowly poured into ice-cold 1N
HCl, and the aqueous mixture is extracted with ethyl acetate. The
combined organic layers are washed with brine, dried with
MgSO.sub.4, filtered, and the solvents are removed under reduced
pressure. The crude product is purified by column chromatagraphy to
afford purified aldehyde product EX-5C.
[0610] EX-5D) A suspension of 1.0 eq. of the aldehyde,
2-[3-[5-nitro-2,4-dixoxo-1-phenylpyrimidyl]]ethanal (EX-5C) and 1.0
eq. of the amine, 4-(N-Boc-amidino)benzylamine in dichloromethane,
and catalytic acetic acid is added 1.2 eq. of sodium
triacetoxyborohydride. The suspension quickly clears and becomes
homogeneous. The reaction is stirred for several hours. The
solution is cooled in an ice bath and is made alkaline with 1.0 N
NaOH. The reaction mixture is diluted with dichloromethane and
washed with brine. The organic solution is dried (MgSO.sub.4),
filtered and concentrated to give the crude product. The crude
product is purified by silica gel chromatagraphy to afford purified
product
2-[3-2-[2-[2-(4-(N-Boc-amidino)benzyl)amino]ethyl-5-nitro-2,4-dio-
xo-1-phenylpyrimidine (EX-5D):
[0611] EX-5E) A solution of 1 eq. of EX-5D in methanol is degassed
with hydrogen gas. To the solution is added a catalytic amount of
5% Pd/C, and the reaction mixture is allowed to stir under an
atmosphere of hydrogen at room temperature for 24 hours. The crude
reaction is filtered through a pad of Celite 545 and concentrated
under reduced pressure. The crude product is purified by silica gel
chromatagraphy to afford purified product amine,
2-[3-2-[2-[2-(4-(N-Boc-amidino)benzyl)amino]ethyl-5-amino--
2,4-dioxo-1-phenylpyrimidine (EX-5E).
[0612] EX-5F) To a suspension of 1.0 eq. of EX-5E and 1.0 eq. of
the phenylacetaldehyde in dichloromethane and catalytic acetic acid
is added 1.2 eq. of sodium triacetoxyborohydride. The suspension
quickly clears and becomes homogeneous. The reaction is stirred for
several hours. The solution is cooled in an ice bath and basified
with 1.0 N NaOH. The reaction mixture is diluted with
dichloromethane and washed with brine. The organic solution is
dried (MgSO.sub.4), filtered and concentrated to give the crude
product. The crude product is purified by silica gel chromatagraphy
to afford purified 2-[3-2-[2-[2-(4-(N-Boc-amidino)benzyl)a-
mino]ethyl-5-(N-(2-phenylethyl)amino)-2,4-dioxo-1-phenylpyrimidine
(EX-5F).
[0613] To a flask of 1 eq. of EX-5F is added 4 M HCl in dioxane.
The resulting solution is allowed to stir overnight. The solution
is concentrated and the crude product is triturated from ethyl
ether to afford purified product as the dihydrochloride salt.
[0614] Sulfonyl analogs of pyrimidinediones wherein a sulfonyl is
present as a replacement for the carbonyl of the acetamide at the
N-2 position of the pyrimidinedione can be prepared as detailed
below in the specific Example 6. 44
[0615] EX-6A) A solution of 1 eq. of EX-5A in dimethylsulfoxide is
added to 1.1 eq. of potassium dicarbonate in one portion with
stirring. After approximately 10 minutes, a solution containing 1.1
eq. of sodium bromomethylsulfonate in dimethylsulfoxide is added
dropwise over a 10 minute period. The reaction mixture is heated to
40.degree. C. and allowed to stir for 18 hours. The reaction
mixture is diluted with water. The aqueous solution is extracted
with ethyl acetate. The combined organic solutions are washed with
water and brine. The organic solution is dried over MgSO.sub.4,
filtered, and concentrated to give a crude product. The crude
product is purified by silica gel chromatagraphy to afford purified
product, 3-[5-nitro-2,4-dixoxo-1-phenylpyrimidyl]methanes- ulfonic
acid (EX-6A).
[0616] EX-6B) A solution of 1 eq. of EX-6A in methanol is degassed
with hydrogen gas. To the solution is added a catalytic amount of
5% Pd/C, and the reaction mixture is allowed to stir under an
atmosphere of hydrogen at room temperature for 24 hours. The crude
reaction is filtered through a pad of Celite 545 and concentrated
under reduced pressure. The crude product is purified by silica gel
chromatagraphy to afford purified product,
3-[5-amino-2,4-dixoxo-1-phenylpyrimidyl]methanesulfonic acid (EX
-6B).
[0617] EX-6C) To a suspension of 1.0 eq. of EX-6B and 1.0 eq. of
the phenylacetaldehyde in dichloromethane and catalytic acetic acid
is added 1.2 eq. of sodium triacetoxyborohydride. The reaction is
stirred for several hours. The solution is cooled in an ice bath
and basified with 1.0 N NaOH. The reaction mixture is diluted with
dichloromethane and washed with brine. The organic solution is
dried (MgSO.sub.4), filtered and concentrated to give the crude
product. The crude product is purified by silica gel chromatagraphy
to afford purified product,
3-[5-[N-(2-phenylethyl)amino]-2,4-dixoxo-1-phenylpyrimidyl]methanesulfoni-
c acid (EX-6C).
[0618] EX-6D) A solution of 1 eq. of EX-6C in dichloromethane with
several drops of dimethylformamide is cooled to 0.degree. C.
Thionyl chloride (1.1 equiv.) is added dropwise, and the solution
is slowly warmed to room temperature. After completion of the
reaction, the volatile components are removed under reduced
pressure, and the sulfonyl chloride product is immediately used.
The sulfonyl chloride is dissolved into dichloromethane, and 1 eq.
of the appropriate amine, 4-(N-Boc-amidino)benzylamine, in DMF is
added with 5 eq. of N-methylmorpholine to the sulfonyl chloride
solution. After completion of the reaction, polyaldehyde and/or
polyamine resin (10 equiv.) are added to remove any unreacted
starting materials. The resins are filtered, rinsed with DMF/DCM
(1:1), and the solvents are removed under reduced pressure to give
pure N-[4-(N-Boc-amidino)benzyl]-3-[5-[N-(2-phenylethyl)-
amino]-2,4-dixoxo-1-phenylpyrimidyl]methanesulfonamide (EX-6D).
[0619] A flask of 1 eq. of EX-6D is added to 4 M HCl in dioxane.
The resulting solution is allowed to stir overnight. The solution
is concentrated and the crude product was triturated from ethyl
ether to afford purified product of Example 6.
[0620] Triazinedione (aza analogs) of uracils (i.e.,pyrimidinones)
wherein a nitrogen is present as a replacement for the carbon at
the 5-position of the pyrimidinedione can be prepared as detailed
below with the specific Example 7. 45
[0621] EX-7A) A mixture of aniline (1; 50 mmol), concentrated HCl
(10 mL), and water (50 mL) is cooled to 5.degree. C. Separately, a
solution of sodium nitrite (50 mmol) in water (7.2 mL) is cooled to
5.degree. C. and added to the aniline hydrochloride slurry with the
addition tube beneath the liquid surface. The temperature is
maintained at 5.degree. C. during the addition and for 1 hour
thereafter. This solution of diazotized aniline (EX-7A) is used in
the next step.
[0622] EX-7B) A mixture of cyanoacetylurethane (59 mmol), pyridine
(656 mL), ice (216 g) and water (40 mL) is held at 5.degree. C.
while the slurry of EX-67A is added over 15 min with stirring.
After an additional hour of stirring at 5.degree. C., the orange
solid, N-ethoxycarbonyl-2-cyano-2-(N-phenylhydrazo)acetamide (EX-7B
is isolated by filtration.
[0623] EX-7C) A mixture of EX-7B (95 mmol), sodium acetate (110
mmol) and acetic acid (140 mL) is refluxed for 75 min. The
resulting clear solution is concentrated at reduced pressure, and
the solid that separates is removed by filtration and washed with
water. Compound, 6-cyano-2-phenyl-3,5-dioxo-1,2,4-triazine (EX-7C),
is recrystallized from 95% ethanol.
[0624] EX-7D) A mixture of compound EX-7C (50 mmol), 6 N HCl (190
mL) and dioxane (500 mL) is refluxed for 12 h. On cooling the
crystallized product,
6-(2-phenyl-3,5-dioxo-1,2,4-triazinyl)carboxylic acid (EX-7D) is
separated by filtration and recrystallized from methanol-water.
[0625] EX-7E) The acid EX-7D (8.4 mmol) is dissolved in dry
tert-butyl alcohol (127 mL) and DPPA (9.3 mmol), and triethyl amine
(9.3 mmol) is added. The solution is refluxed for 24 h thereafter.
At this time the solution is concentrated in vacuo. The residue is
dissolved in methylene chloride (150 mL) and washed with 0.5 N
citric acid (150 mL), 1 N NaHCO.sub.3 (150 mL) and water (150 mL).
The methylene chloride solution is then dried (sodium sulfate).
Filtration and concentration gives the Boc-protected compound
EX-7E. This material can be purified by chromatagraphy if
necessary.
[0626] EX-7F) A solution of compound EX-7E (50 mmol) in DMF (150
mL) is treated with potassium carbonate (55 mmol) in one portion
with stirring. After approximately 10 min, a solution of methyl
bromoacetate (50 mmol) in DMF (100 mL) is added dropwise. The
reaction mixture is heated to 40.degree. C. and allowed to stir for
18 h. Typical aqueous workup and chromatographic purification
provides pure methyl 2-(2-phenyl-3,5-dioxo-6-
-(N-Boc-amino)-1,2,4-triazinyl)acetate (EX-7F).
[0627] EX-7G) A solution of compound EX-7F (50 mmol) is dissolved
in methylene chloride (400 mL) and is treated with TFA (100 mL).
The resulting solution is stirred at room temperature for 4 h
thereafter. Concentration and trituration with ether affords TFA
salt of methyl
2-(2-phenyl-3,5-dioxo-6-amino-1,2,4-triazinyl)acetate (EX-7G).
[0628] EX-7H) A solution of compound EX-7G in tetrahydrofuran and
methylene chloride (1:1, 0.3 M) is treated with 1 eq. of
phenylacetaldehyde and 0.9 eq. of triethyl amine. The solution will
be cooled to 0.degree. C. and treated with 1 eq. of sodium
triacetoxyborohydride. After stirring for 5 minutes, the ice bath
is removed, and the reaction mixture is allowed to warm to room
temperature and stir there for 2 h. The reaction is quenched by the
addition of 1 N NaOH, and the mixture is stirred for 5 min. Typical
aqueous workup is followed by chromatographic purification to
provide pure product, methyl
2-(2-phenyl-3,5-dioxo-6-(N-(2-phenylethyl)amino)-1,2,4-triazinyl)acetate
(EX-7H).
[0629] EX-7I) A solution of compound EX-7H (50 mmol) in THF (250
mL) is treated with LiOH (50 mmol). After the hydrolysis is
complete, the volatiles are removed under reduced pressure. The
remaining aqueous solution is cooled in an ice bath and acidified
to pH 1 with 1.0 N HCl. The aqueous mixture is extracted with
EtOAc. The EtOAc solution is dried (sodium sulfate), filtered and
concentrated to afford pure
2-(2-phenyl-3,5-dioxo-6-(N-(2-phenylethyl)amino)-1,2,4-triazinyl)acetic
acid EX-7I).
[0630] EX-7J) A solution of compound EX-7I (50 mmol) in DMF (250
mL) is treated with N-hydroxybenzotriazole (60 mmol) and EDC
hydrochloride (60 mmol). The mixture is stirred at room temperature
for 30 min and treated with 4-(N-Cbz-amidinobenxylamine (50 mmol).
The resulting mixture is allowed to stir overnight. Typical aqueous
workup is followed by chromatographic purification to afford pure
product,
N-(4-Cbz-amidinobenzyl)-2-(2-phenyl-3,5-dioxo-6-(N-(2-phenylethyl)amino)--
1,2,4-triazinyl)acetamide (EX-7J).
[0631] A solution of compound EX-7J (50 mmol) in methanol (300 mL)
and 4M HCl-dioxane (100 mL) is degassed with hydrogen. 5% Pd(C)
(0.5 g) is added, and the solution is stirred under an atmosphere
of hydrogen at room temp for 24 h. The reaction mixture is filtered
through a pad of celite 545 and concentrated under reduced
pressure. Purification by reverse phase chromatagraphy affords pure
product of Example 7.
[0632] Using these methods and ordinary skill in the art of
synthetic numerous novel compounds of the present invention have
been or can be prepared.
[0633] Formula (I) compounds of this invention possessing hydroxyl,
thiol, and amine functional groups can be converted to a wide
variety derivatives. Alternatively, derivatized Formula (I)
compounds can be obtained by first derivatizing one or more
intermediates in the processes of preparation before further
transforming the derivatized intermediate to compounds of Formula
(I). A hydroxyl group in the form of an alcohol or phenol can be
readily converted to esters of carboxylic, sulfonic, carbamic,
phosphonic, and phosphoric acids. Acylation to form a carboxylic
acid ester is readily effected using a suitable acylating reagent
such as an aliphatic acid anhydride or acid chloride. The
corresponding aryl and heteroaryl acid anhydrides and acid
chlorides can also be used. Such reactions are generally carried
out using an amine catalyst such as pyridine in an inert solvent.
Similarly, carbamic acid esters (urethanes) can be obtained by
reacting a hydroxyl group with isocyanates and carbamoyl chlorides.
Sulfonate, phosphonate, and phosphate esters can be prepared using
the corresponding acid chloride and similar reagents. Compounds of
Formula (I) that have at least one thiol group present can be
converted to the corresponding thioesters derivatives analogous to
those of alcohols and phenols using the same reagents and
comparable reaction conditions. Compounds of Formula (I) that have
at least one primary or secondary amine group present can be
converted to the corresponding amide derivatives. Amides of
carboxylic acids can be prepared using the appropriate acid
chloride or anhydrides with reaction conditions analogous to those
used with alcohols and phenols. Ureas of the corresponding primary
or secondary amine can be prepared using isocyanates directly and
carbamoyl chlorides in the presence of an acid scavenger such as
triethylamine or pyridine. Sulfonamides can be prepared from the
corresponding sulfonyl chloride in the presence of aqueous sodium
hydroxide or a tertiary amine. Suitable procedures and methods for
preparing these derivatives can be found in House's Modern
Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and
Curtin in The Systematic Identification of Organic Compounds, 5th
Edition, John Wiley & Sons, and Fieser and Fieser in Reagents
for Organic Synthesis, Volume 1, John Wiley & Sons. Reagents of
a wide variety that can be used to derivatize hydroxyl, thiol, and
amines of compounds of Formula (I) are available from commercial
sources or the references cited above, which are incorporated
herein by reference.
[0634] Formula (I) compounds of this invention possessing hydroxyl,
thiol, and amine functional groups can be alkylated to a wide
variety of derivatives. Alternatively, alkylated Formula (I)
compounds can be obtained by first alkylating one or more
intermediates in the processes of preparation before further
transforming the alkylated intermediate to compounds of Formula
(I). A hydroxyl group of compounds of Formula (I) can be readily
converted to ethers. Alkylation to form an ether is readily
effected using a suitable alkylating reagent such as an alkyl
bromide, alkyl iodide or alkyl sulfonate. The corresponding
aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and
heteroaralkyloxyalkyl bromides, iodides, and sulfonates can also be
used. Such reactions are generally carried out using an alkoxide
forming reagent such as sodium hydride, potassium t-butoxide,
sodium amide, lithium amide, and n-butyl lithium using an inert
polar solvent such as DMF, DMSO, THF, and similar, comparable
solvents. amine catalyst such as pyridine in an inert solvent.
Compounds of Formula (I) that have at least one thiol group present
can be converted to the corresponding thioether derivatives
analogous to those of alcohols and phenols using the same reagents
and comparable reaction conditions. Compounds of Formula (I) that
have at least one primary, secondary or tertiary amine group
present can be converted to the corresponding secondary, tertiary
or quaternary ammonium derivative. Quaternary ammonium derivatives
can be prepared using the appropriate bromides, iodides, and
sulfonates analogous to those used with alcohols and phenols.
Conditions involve reaction of the amine by warming it with the
alkylating reagent with a stoichiometric amount of the amine (i.e.,
one equivalent with a tertiary amine, two with a secondary, and
three with a primary). With primary and secondary amines, two and
one equivalents, respectively, of an acid scavenger are used
concurrently. Secondary or tertiary amines can be prepared from the
corresponding primary or secondary amine. A primary amine can be
dialkylated by reductive amination using an aldehyde, such as
formaldehyde, and sodium cyanoborohydride in the presence of
glacial acetic acid. A primary amine can be monoalkylated by first
mono-protecting the amine with a ready cleaved protecting group,
such as trifluoroacetyl. An alkylating agent, such as
dimethylsulfate, in the presence of a non-nucleophilic base, such
as Barton's base (2-tert-butyl-1,1,3,3-tetramethylguanidine), gives
the monomethylated protected amine. Removal of the protecting group
using aqueous potassium hydroxide gives the desired monoalkylated
amine. Additional suitable procedures and methods for preparing
these derivatives can be found in House's Modern Synthetic
Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and Curtin in The
Systematic Identification of Organic Compounds, 5th Edition, John
Wiley & Sons, and Fieser and Fieser in Reagents for Organic
Synthesis published by John Wiley & Sons. Perfluoroalkyl
derivatives can be prepared as described by DesMarteau in J. Chem.
Soc. Chem. Commun. 2241 (1998). Reagents of a wide variety that can
be used to derivatize hydroxyl, thiol, and amines of compounds of
Formula (I) are available from commercial sources or the references
cited above, which are incorporated herein by reference.
Assays for Biological Activity
TF-VIIa Assay
[0635] In this assay 100 nM recombinant soluble tissue factor and 2
nM recombinant human factor VIIa are added to a 96-well assay plate
containing 0.4 mM of the substrate,
N-Methylsulfonyl-D-phe-gly-arg-p-nitr- oaniline and either
inhibitor or buffer (5 mM CaCl.sub.2, 50 mM Tris-HCl, pH 8.0, 100
mM NaCl, 0.1% BSA). The reaction, in a final volume of 100 ul is
measured immediately at 405 nm to determine background absorbance.
The plate is incubated at room temperature for 60 min, at which
time the rate of hydrolysis of the substrate is measured by
monitoring the reaction at 405 nm for the release of
p-nitroaniline. Percent inhibition of TF-VIIa activity is
calculated from OD.sub.405 nm value from the experimental and
control sample.
Xa Assay
[0636] 0.3 nM human factor Xa and 0.15 mM
N-.alpha.-Benzyloxycarbonyl-D-ar-
ginyl-L-glycyl-L-arginine-p-nitroaniline-dihydrochloride (S-2765)
are added to a 96-well assay plate containing either inhibitor or
buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA). The
reaction, in a final volume of 100 ul is measured immediately at
405 nm to determine background absorbance. The plate is incubated
at room temperature for 60 min, at which time the rate of
hydrolysis of the substrate is measured by monitoring the reaction
at 405 nm for the release of p-nitroaniline. Percent inhibition of
Xa activity is calculated from OD.sub.405 nm value from the
experimental and control sample.
Thrombin Assay
[0637] 0.28 nM human thrombin and 0.06 mM
H-D-Phenylalanyl-L-pipecolyl-L-a- rginine-p-nitroaniline
dihydrochloride are added to a 96-well assay plate containing
either inhibitor or buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCl,
0.1% BSA). The reaction, in a final volume of 100 ul is measured
immediately at 405 nm to determine background absorbance. The plate
is incubated at room temperature for 60 min, at which time the rate
of hydrolysis of the substrate is measured by monitoring the
reaction at 405 nm for the release of p-nitroaniline. Percent
inhibition of thrombin activity is calculated from OD.sub.405 nm
value from the experimental and control sample.
Trypsin Assay
[0638] 5 ug/ml trypsin, type IX from porcine pancreas and 0.375 mM
N-.alpha.-Benzoyl-L-arginine-p-nitroanilide (L-BAPNA) are added to
a 96-well assay plate containing either inhibitor or buffer (50 mM
Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA). The reactions, in a final
volume of 100 ul are measured immediately at 405 nm to determine
background absorbance. The plate is incubated at room temperature
for 60 min, at which time the rate of hydrolysis of the substrate
is measured by monitoring the reaction at 405 nm for the release of
p-nitroaniline. Percent inhibition of trypsin activity is
calculated from OD.sub.405 nm value from the experimental and
control sample.
[0639] Recombinant soluble TF, consisting of amino acids 1-219 of
the mature protein sequence was expressed in E. coli and purified
using a Mono Q Sepharose FPLC. Recombinant human VIIa was purchased
from American Diagnostica, Greenwich, Conn. and chromogenic
substrate N-Methylsulfonyl-D-phe-gly-arg-p-nitroaniline was
prepared by American Peptide Company, Inc., Sunnyvale, Calif.
Factor Xa was obtained from Enzyme Research Laboratories, South
Bend, Ind., thrombin from Calbiochem, La Jolla, Calif., and trypsin
and L-BAPNA from Sigma, St. Louis, Mo. The chromogenic substrates
S-2765 and S-2238 were purchased from Chromogenix, Sweden.
[0640] The biological activity of the compounds of Examples 1
through 7 as determined by the bioassay procedures is summarized in
the Table 1.
1TABLE 1 Inhibitory Activity of Uracils toward Factor Xa, TF-VIIA,
Thrombin II, and Trypsin II. Example TF-VIIA Thrombin II Factor Xa
Trpysin II Number IC50 (uM) IC50 (uM) IC50 (uM) IC50 (uM) 1 >100
13.0 25.6 0.4 2 12.9 0.3 0.2 0.2
* * * * *