U.S. patent application number 10/680873 was filed with the patent office on 2005-03-10 for substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade.
This patent application is currently assigned to Pharmacia Corporation. Invention is credited to Hamme, Ashton T. II, Jones, Darin E., Neumann, William L., Rueppel, Melvin L., South, Michael S..
Application Number | 20050054643 10/680873 |
Document ID | / |
Family ID | 29586273 |
Filed Date | 2005-03-10 |
United States Patent
Application |
20050054643 |
Kind Code |
A1 |
South, Michael S. ; et
al. |
March 10, 2005 |
Substituted polycyclic aryl and heteroaryl pyrimidinones useful for
selective inhibition of the coagulation cascade
Abstract
The invention relates to substituted polycyclic aryl and
heteroaryl pyrimidinone 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) ; Hamme, Ashton T. II; (St. Louis, MO)
; Neumann, William L.; (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: |
29586273 |
Appl. No.: |
10/680873 |
Filed: |
October 7, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10680873 |
Oct 7, 2003 |
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09574739 |
May 18, 2000 |
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6750342 |
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60134794 |
May 19, 1999 |
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Current U.S.
Class: |
514/242 |
Current CPC
Class: |
C07D 239/47 20130101;
C07D 417/12 20130101; C07D 253/07 20130101; C07D 401/04
20130101 |
Class at
Publication: |
514/242 |
International
Class: |
A61K 031/53 |
Claims
1-11. (canceled).
12. A composition for inhibiting thrombotic conditions in blood
comprising a pharmaceutically acceptable carrier and a compound
having the Formula: 66or a pharmaceutically acceptable salt
thereof, wherein; B is: 67R.sup.32, R.sup.33, R.sup.34, R.sup.35,
and R.sup.36 are independently selected from the group consisting
of hydrogen, 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 hydrogen and alkyl; R.sup.15 is selected from the
group consisting of hydrogen, halo, alkyl, and haloalkyl; M is
R.sup.1--C; R.sup.1 is selected from the group consisting of
hydrogen, 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) a ring carbon in a
first alpha position relative to the ring carbon at the point of
attachment is optionally substituted by R.sup.9, (b) a ring carbon
in a second alpha position relative to the ring carbon at the point
of attachment is optionally substituted by R.sup.13, (c) a ring
carbon, in a first beta position relative to the ring carbon at the
point of attachment and in an alpha position relative to the ring
atom optionally substituted by R.sup.9, is optionally substituted
by R.sup.10, (d) a ring carbon, in a second beta position relative
to the ring carbon at the point of attachment and in an alpha
position relative to the ring atom optionally substituted by
R.sup.13, is optionally substituted by R.sup.12, and (e) a ring
carbon, if present, in the gamma position relative to the ring
carbon at the point of attachment and in an alpha position relative
to each of the ring atoms optionally substituted by R.sup.10 and
R.sup.12, respectively, 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 hydrogen, 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 hydrogen, 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): 68wherein 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, 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
hydrogen, amidino, guanidino, carboxy, haloalkylthio, alkoxy,
hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Q.sup.b is
selected from the group consisting of NR.sup.20R.sup.21, hydrogen,
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 hydrogen and alkyl; and Q.sup.s is CH.sub.2.
13. The composition as recited in claim 12, or a pharmaceutically
acceptable salt thereof, wherein; R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36 are independently selected from the group
consisting of hydrogen, 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
R.sup.1--C; R.sup.1 is selected from the group consisting of
hydrogen, 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
and 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl,
3-isoxazolyl, 2-pyridyl, and 3-pyridyl heteroaryl rings, wherein
(a) a ring carbon in a first alpha position relative to the ring
carbon at the point of attachment is optionally substituted by
R.sup.9, (b) a ring carbon in a second alpha position relative to
the ring carbon at the point of attachment is optionally
substituted by R.sup.13, (c) a ring carbon, in a first beta
position relative to the ring carbon at the point of attachment and
in an alpha position relative to the ring atom optionally
substituted by R.sup.9, is optionally substituted by R.sup.10, (d)
a ring carbon, in a second beta position relative to the ring
carbon at the point of attachment and in an alpha position relative
to the ring atom optionally substituted by R.sup.13, is optionally
substituted by R.sup.12, and (e) a ring carbon, if present, in the
gamma position relative to the ring carbon at the point of
attachment and in an alpha position relative to each of the ring
atoms optionally substituted by R.sup.10 and R.sup.12,
respectively, 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 hydrogen, 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 hydrogen, 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: 69R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrogen, 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; R.sup.20, R.sup.21, R.sup.23,
R.sup.24, and R.sup.25 are independently selected from the group
consisting of hydrogen, methyl, and ethyl; and Q.sup.s is
CH.sub.2.
14. The composition 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, and phenyl; 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 R.sup.1--C; R.sup.1 is selected from the group consisting of
hydrogen, hydroxy, amino, methyl, trifluoromethyl, 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,
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-carboxymethyl phenyl, 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: 70R.sup.16 and R.sup.19 are independently
selected from the group consisting of hydrogen, 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 hydrogen, fluoro, chloro, hydroxy,
hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is selected from
the group consisting of hydrogen 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 hydrogen and methyl; and Q.sup.s is
CH.sub.2.
15. The composition 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, and phenyl; 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 R.sup.1--C; R.sup.1 is selected from
the group consisting of hydrogen, 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; and Y.sup.0 is
selected from the group consisting of 5-amidino-2-thienylmethyl,
4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and
3-fluoro-4-amdinobenzyl.
16. The composition as recited in claim 12, where said compound, or
a pharmaceutically acceptable salt thereof, is selected from the
group consisting of: 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-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-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 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-aminophenyl, B is 3-chlorophenyl, A is CH.sub.2CH.sub.2,
Y.sup.0 is 4-amidinobenzyl, and M is CCl; R.sup.2 is 3-aminophenyl,
B is phenyl, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M is
CCl; 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 CCl; 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 CCl; 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
CCl; R.sup.2 is phenyl, B is 3-aminophenyl, A is C(O)NH, Y.sup.0 is
4-amidinobenzyl, and M is CCl; R.sup.2 is phenyl, B is
3-amidinophenyl, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M
is CCl; 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 CCl; 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 CCl; R.sup.2 is phenyl, B is
4-amidinophenyl, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and M
is CCl; 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 CCl; R.sup.2
is phenyl, B is phenyl, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and M is CCl; 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 CCl; 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-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-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; and 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.
17-19. (canceled).
20. A composition for inhibiting thrombotic conditions in blood
comprising a pharmaceutically acceptable carrier and a compound
having the Formula: 71or a pharmaceutically acceptable salt
thereof, wherein; B is selected from the group consisting of
hydrogen, 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 hydrogen, 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 hydrogen and alkyl; R.sup.15 is
selected from the group consisting of hydrogen, halo, alkyl, and
haloalkyl; M is R.sup.1--C; R.sup.1 is selected from the group
consisting of hydrogen, 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) a ring
carbon in a first alpha position relative to the ring carbon at the
point of attachment is optionally substituted by R.sup.9, (b) a
ring carbon in a second alpha position relative to the ring carbon
at the point of attachment is optionally substituted by R.sup.13,
(c) a ring carbon, in a first beta position relative to the ring
carbon at the point of attachment and in an alpha position relative
to the ring atom optionally substituted by R.sup.9, is optionally
substituted by R.sup.10, (d) a ring carbon, in a second beta
position relative to the ring carbon at the point of attachment and
in an alpha position relative to the ring atom optionally
substituted by R.sup.13, is optionally substituted by R.sup.12, and
(e) a ring carbon, if present, in the gamma position relative to
the ring carbon at the point of attachment and in an alpha position
relative to each of the ring atoms optionally substituted by
R.sup.10 and R.sup.12, respectively, 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 hydrogen, 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
hydrogen, 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): 72wherein 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, 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
hydrogen, amidino, guanidino, carboxy, haloalkylthio, alkoxy,
hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Q.sup.b is
selected from the group consisting of NR.sup.20R.sup.21, hydrogen,
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 hydrogen and alkyl; and Q.sup.s is
CH.sub.2.
21. The composition as recited in claim 20, or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of hydrogen, 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.3,
R.sup.35, and R.sup.36; R.sup.32, R.sup.33, R.sup.3, R.sup.35, and
R.sup.36 are independently selected from the group consisting of
hydrogen, 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: (i) single covalent bond,
NH, N(CH.sub.3), CH.sub.2, CH.sub.3CH, and CH.sub.2CH.sub.2; and
(ii) 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
hydrogen; M is R.sup.1--C; R.sup.1 is selected from the group
consisting of hydrogen, 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
and 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl,
3-isoxazolyl, 2-pyridyl, and 3-pyridyl heteroaryl rings, wherein
(a) a ring carbon in a first alpha position relative to the ring
carbon at the point of attachment is optionally substituted by
R.sup.9, (b) a ring carbon in a second alpha position relative to
the ring carbon at the point of attachment is optionally
substituted by R.sup.13, (c) a ring carbon, in a first beta
position relative to the ring carbon at the point of attachment and
in an alpha position relative to the ring atom optionally
substituted by R.sup.9, is optionally substituted by R.sup.10, (d)
a ring carbon, in a second beta position relative to the ring
carbon at the point of attachment and in an alpha position relative
to the ring atom optionally substituted by R.sup.13, is optionally
substituted by R.sup.12, and (e) a ring carbon, if present, in the
gamma position relative to the ring carbon at the point of
attachment and in an alpha position relative to each of the ring
atoms optionally substituted by R.sup.10 and R.sup.12,
respectively, 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 hydrogen, 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 hydrogen, 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: 73R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrogen, 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.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 hydrogen, methyl, and ethyl;
and Q.sup.s is CH.sub.2.
22. The composition as recited in claim 21, or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of hydrogen, 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 hydrogen, 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: 74R.sup.16 and R.sup.19 are independently
selected from the group consisting of hydrogen, 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 hydrogen, fluoro, chloro, hydroxy,
hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is selected from
the group consisting of hydrogen and C(NR.sup.25)NR.sup.2R.sup.24;
R.sup.23, R.sup.24, and R.sup.25 are independently selected from
the group consisting of hydrogen and methyl; and Q.sup.s is
CH.sub.2.
23. The composition as recited in claim 22, or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of hydrogen, 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
R.sup.1--C; R.sup.1 is selected from the group consisting of
hydrogen, 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; and
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. The composition as recited in claim 20, where said compound, or
a pharmaceutically acceptable salt thereof, is selected from the
group consisting of: 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; 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
hydrogen, 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; and 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.
25-27. (canceled).
28. A composition for inhibiting thrombotic conditions in blood
comprising a pharmaceutically acceptable carrier and a compound
having the Formula: 75B is selected from the group consisting of
C3-C7 cycloalkyl and C4 saturated heterocyclyl, wherein (a) each
ring carbon is optionally substituted with R.sup.33, (b) a ring
carbon, other than the ring carbon at the point of attachment, is
optionally substituted with oxo provided that no more than one ring
carbon is substituted by oxo at the same time, (c) a ring carbon or
nitrogen in a first alpha position relative to the ring carbon at
the point of attachment is optionally substituted by R.sup.9, (d) a
ring carbon or nitrogen in a second alpha position relative to the
ring carbon at the point of attachment is optionally substituted by
R.sup.13, (e) a ring carbon or nitrogen, if present, in a first
beta position relative to the ring carbon at the point of
attachment and in an alpha position relative to the ring atom
optionally substituted by R.sup.9, is optionally substituted by
R.sup.10, (f) a ring carbon or nitrogen, if present, in a second
beta position relative to the ring carbon at the point of
attachment and in an alpha position relative to the ring atom
optionally substituted by R.sup.13, is optionally substituted by
R.sup.12, (g) a ring carbon or nitrogen, if present, in a first
gamma position relative to the ring carbon at the point of
attachment and in an alpha position relative to the ring atom
optionally substituted by R.sup.10, is optionally substituted by
R.sup.11, and (h) a ring carbon or nitrogen, if present, in a
second gamma position relative to the carbon at the point of
attachment and in an alpha position relative to the ring atom
optionally substituted by R.sup.12, is optionally substituted by
R.sup.33; R.sup.9, R.sup.11, and R.sup.13 are independently
selected from the group consisting of hydrogen, 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 hydrogen,
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 hydrogen, 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 hydrogen and alkyl; R.sup.15 is selected from the
group consisting of hydrogen, halo, alkyl, and haloalkyl; M is
R.sup.1--C; R.sup.1 is selected from the group consisting of
hydrido hydrogen, 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) a ring carbon in a
first alpha position relative to the ring carbon at the point of
attachment is optionally substituted by R.sup.9, (b) a ring carbon
in a second alpha position relative to the ring carbon at the point
of attachment is optionally substituted by R.sup.13, (c) a ring
carbon, in a first beta position relative to the ring carbon at the
point of attachment and in an alpha position relative to the ring
atom optionally substituted by R.sup.9, is optionally substituted
by R.sup.10, (d) a ring carbon, in a second beta position relative
to the ring carbon at the point of attachment and in an alpha
position relative to the ring atom optionally substituted by
R.sup.13, is optionally substituted by R.sup.12, and (e) a ring
carbon, if present, in the gamma position relative to the ring
carbon at the point of attachment and in an alpha position relative
to each of the ring atoms optionally substituted by R.sup.10 and
R.sup.12, respectively, 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 hydrogen, 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 hydrogen, 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): 76wherein 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, 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
hydrogen, amidino, guanidino, carboxy, haloalkylthio, alkoxy,
hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; Q.sup.b is
selected from the group consisting of NR.sup.20R.sup.21, hydrogen,
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 hydrogen and alkyl; and Q.sup.s is CH.sub.2.
29. The composition 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, 2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3-yl,
azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and
bicyclo[3.1.0]hexan-6-yl, wherein (a) each ring carbon is
optionally substituted with R.sup.33, (b) a ring carbon or nitrogen
in a first alpha position relative to the ring carbon at the point
of attachment is optionally substituted by R.sup.9, (c) a ring
carbon or nitrogen in a second alpha position relative to the ring
carbon at the point of attachment is optionally substituted by
R.sup.13, (d) a ring carbon or nitrogen, if present, in a first
beta position relative to the ring carbon at the point of
attachment and in an alpha position relative to the ring atom
optionally substituted by R.sup.9, is optionally substituted by
R.sup.10, and (e) a ring carbon or nitrogen, if present, in a
second beta position relative to the ring carbon at the point of
attachment and in an alpha position relative to the ring atom
optionally substituted by R.sup.13, is optionally substituted by
R.sup.12; R.sup.9, R.sup.11, and R.sup.13 are independently
selected from the group consisting of hydrogen, methyl, ethyl,
methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-di methylamino,
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 hydrogen, 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 are independently selected from the group
consisting of hydrogen, 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 R.sup.1--C; R.sup.1 is selected from
the group consisting of hydrogen, 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 and 2-thienyl, 2-furyl, 2-pyrrolyl,
2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl
heteroaryl rings, wherein (a) a ring carbon in a first alpha
position relative to the ring carbon at the point of attachment is
optionally substituted by R.sup.9, (b) a ring carbon in a second
alpha position relative to the ring carbon at the point of
attachment is optionally substituted by R.sup.13, (c) a ring
carbon, in a first beta position relative to the ring carbon at the
point of attachment and in an alpha position relative to the ring
atom optionally substituted by R.sup.9, is optionally substituted
by R.sup.10, (d) a ring carbon, in a second beta position relative
to the ring carbon at the point of attachment and in an alpha
position relative to the ring atom optionally substituted by
R.sup.13, is optionally substituted by R.sup.12, and (e) a ring
carbon, if present, in the gamma position relative to the ring
carbon at the point of attachment and in an alpha position relative
to each of the ring atoms optionally substituted by R.sup.10 and
R.sup.12, respectively, is optionally substituted by R.sup.11;
Y.sup.0 is selected from the group consisting of: 77R.sup.16,
R.sup.17, R.sup.18, and R.sup.19 are independently selected from
the group consisting of hydrogen, 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; R.sup.20, R.sup.21, R.sup.23,
R.sup.24, and R.sup.25 are independently selected from the group
consisting of hydrogen, methyl, and ethyl; and Q.sup.s is
CH.sub.2.
30. The composition as recited in claim 29, or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3-yl, azetidin-1-yl,
azetidin-2-yl, and azetidin-3-yl; 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 R.sup.1--C;
R.sup.1 is selected from the group consisting of hydrogen, hydroxy,
amino, methyl, trifluoromethyl, fluoro, and chloro; R.sup.2 is
selected from the group consisting of 3-aminophenyl,
2,6-dichlorophenyl, 2-hydroxyphenyl, 5-amino-2-thienyl, and
3-thienyl; Y.sup.0 is selected from the group consisting of:
78R.sup.16 and R.sup.19 are independently selected from the group
consisting of hydrogen, 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 hydrogen, fluoro, chloro, hydroxy, hydroxymethyl,
amino, carboxy, and cyano; Q.sup.b is selected from the group
consisting of hydrogen 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 hydrogen and methyl; and Q.sup.s is CH.sub.2.
31. The composition as recited in claim 30, or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
2-(2R)-bicyclo[2.2.1]-heptyl, oxetan-3-yl, azetidin-1-yl,
azetidin-2-yl, and azetidin-3-yl; 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 R.sup.1--C; R.sup.1 is selected
from the group consisting of hydrogen, 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; and Y.sup.0 is selected from the group consisting of
5-amidino-2-thienylmethyl, 4-amidinobenzyl,
2-fluoro-4-amidinobenzyl, and 3-fluoro-4-amdinobenzyl.
32. The composition as recited in claim 28, where said compound, or
a pharmaceutically acceptable salt thereof, is selected from the
group consisting of: 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.sup.0 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
4-amidino-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 2-hydroxyphenyl, B is cyclobutyl, A is
single bond, 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
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 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 5-amino-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 2-hydroxyphenyl, B is cyclobutyl, A is single bond, 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; and R.sup.2 is 2,6-dichlorophenyl, B
is cyclobutyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and M
is CF.
33-39. (canceled).
40. A method for inhibiting thrombotic conditions in blood
comprising adding to blood a therapeutically effective amount of a
composition of any one of claims 12-16, 20-24, or 28-32.
41. A method for inhibiting formation of blood platelet aggregates
in blood comprising adding to blood a therapeutically effective
amount of a composition of any one of claims 12-16, 20-24, or
28-32.
42. A method for inhibiting thrombus formation in blood comprising
adding to blood a therapeutically effective amount of a composition
of any one of claims 12-16, 20-24, or 28-32.
43. 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 any
one of claims 12-16, 20-24, or 28-32.
44. 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 any one of claims 12-16,
20-24, or 28-32.
45. A method for treating or preventing cardiogenic thromboembolism
in a mammal comprising administering to the mammal a
therapeutically effective amount of a composition of any one of
claims 12-16, 20-24, or 28-32.
46. A method for treating or preventing thromboembolic stroke in
humans and other mammals comprising administering to the mammal a
therapeutically effective amount of a composition of any one of
claims 12-16, 20-24, or 28-32.
47. 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 any one of claims 12-16, 20-24, or
28-32.
48. 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 any one of
claims 12-16, 20-24, or 28-32.
49. A method for inhibiting thrombus formation in blood comprising
adding to blood a therapeutically effective amount of a compound of
any one of claims 12-16, 20-24, or 28-32 with a therapeutically
effective amount of fibrinogen receptor antagonist.
50 (canceled).
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
pyrimidinone 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
pyrimidinone compounds that act as an inhibitor of a coagulation
factor present in the coagulation cascade or clotting process. In
PCT Patent Application WO 98/47876, Van Boeckel et al. describe
peptidic 6-alkylpyridones and 2-alkylpyrimidinones as
anti-thrombotic compounds. In PCT Patent Application WO 98/16547,
Zhu and Scarborough describe
3-(N-heterocyclylamino)4,5,6-substituted-pyridonylacetamides and
2,4-substituted-5-(N-heterocyclylamino)-pyrimidinonyl-acetamides
containing amide substituents and having activity against mammalian
factor Xa. In U.S. Pat. No. 5,656,645, Tamura et al. describe
4,5,6-substituted-3-aminopyridonyl-acetamides,
1,6-substituted-5-aminoura- cinylacetamides, and
2,4-substituted-5-aminopyrimidinonyl-acetamides containing amide
substituents having a formyl function and having activity against
thrombin. In U.S. Pat. No. 5,658,930, Tamura et al. again describe
4,5,6-substituted-3-aminopyridonyl-acetamides,
1,6-substituted-5-aminouracinylacetamides, and
2,4-substituted-5-aminopyr- imidinonyl-acetamides containing amide
substituents having a formyl function and having activity against
thrombin. In PCT Patent Applications 96/18644 and 97/46207, Tamura
et al. further describe
4,5,6-substituted-3-aminopyridonylacetamides,
1,6-substituted-5-aminourac- inyl-acetamides, and
2,4-substituted-5-amino-pyrimidinonylacetamides containing amide
substituents having a formyl function and having activity against
thrombin. In PCT Patent Application WO 98/09949, Suzuki et al.
describe 2-heterocyclylacetamido derivatives of 1,2-diketones and
report that they inhibit proteases, especially chymase
inhibitors.
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
pyrimidinones, 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 is selected from the group consisting of O and S;
[0012] J 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 a chain length of 1 to 4 atoms linked to the point of
bonding of a substituent selected from the group consisting of
R.sup.4a, R.sup.4b, R.sup.39, R.sup.40, R.sup.5, R.sup.14, and
R.sup.15 to form a heterocyclyl ring having 5 through 8 contiguous
members;
[0013] J 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 a chain length of 1 to 4 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;
[0014] J 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 a chain length of 1 to 4 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;
[0015] B is formula (V): 3
[0016] 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,
[0017] 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;
[0018] 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;
[0019] 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;
[0020] 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;
[0021] B is optionally formula (VI): 4
[0022] 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.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;
[0023] B is optionally selected from the group consisting of
hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkenyl, C3-C8
alkylenyl, 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;
[0024] 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 carbon and nitrogen atoms
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 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 atom 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 atom 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 atom 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;
[0025] 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;
[0026] 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;
[0027] R.sup.14, R.sup.15, R.sup.37, R.sup.38, R.sup.39, 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 and 2-oxoacyl;
[0028] 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;
[0029] 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;
[0030] 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;
[0031] .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;
[0032] 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;
[0033] 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;
[0034] M is selected from the group consisting of N and
R.sup.1--C;
[0035] R.sup.2 and R.sup.1 are independently selected from the
group consisting of Z.sup.0-Q, hydrido, alkyl, alkenyl, and
halo;
[0036] 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;
[0037] 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;
[0038] 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;
[0039] 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;
[0040] 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), 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.2-(C- H(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.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.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 pyrimidinone ring;
[0041] 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;
[0042] 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;
[0043] Q is formula (II): 5
[0044] 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;
[0045] Q is optionally selected from formula (III): 6
[0046] 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;
[0047] 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 is selected from
other than a single covalent bond when Q is hydrido;
[0048] K is (CR.sup.4aR.sup.4b).sub.n wherein n is an integer
selected from 1 through 4;
[0049] 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 pyrimidinone
nitrogen;
[0050] 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 pyrimidinone nitrogen;
[0051] 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.ident.C; 1,2-ethynyl), and
C.dbd.CR.sup.4aR.sup.4b;
[0052] 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 pyrimidinone ring;
[0053] 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);
[0054] 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;
[0055] 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.ident.C; 1,2-ethynyl), and
C.dbd.CR.sup.4aR.sup.4b;
[0056] Y.sup.0 is formula (IV): 7
[0057] 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;
[0058] 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;
[0059] 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;
[0060] 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.+;
[0061] 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;
[0062] 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;
[0063] 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,
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;
[0064] 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;
[0065] 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;
[0066] 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.2S(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.28Si(R.sup.29)R.sup.28,
Si(R.sup.29)R.sup.28OSi(R.sup.2- 9)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;
[0067] 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;
[0068] 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;
[0069] 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;
[0070] 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;
[0071] 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;
[0072] 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;
[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 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;
[0074] 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.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.sub.0;
[0075] 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;
[0076] 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;
[0077] 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;
[0078] 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;
[0079] 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;
[0080] 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;
[0081] 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;
[0082] 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;
[0083] 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, 2,4-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.
[0084] In an embodiment of compounds of Formula I or a
pharmaceutically acceptable salt thereof,
[0085] J is selected from the group consisting of O and S;
[0086] J 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 a chain length of 1 to 4 atoms linked to the point of
bonding of a substituent selected from the group consisting of
R.sup.4a, R.sup.4b, R.sup.39, R.sup.40, R.sup.5, R.sup.14, and
R.sup.15 to form a heterocyclyl ring having 5 through 8 contiguous
members;
[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.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 carbon and nitrogen atoms
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 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 atom 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 atom 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 atom 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 and 2-oxoacyl;
[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
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.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 pyrimidinone 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 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 pyrimidinone
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 is 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
carbon and nitrogen atoms 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 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 atom 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
atom 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 atom 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) 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.noteq.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 pyrimidinone 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,
2,6-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;
[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-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.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 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 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, 1,5-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.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 is O;
[0172] B is the Formula: 15
[0173] 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, 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;
[0174] 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;
[0175] R.sup.16, R.sup.19, R.sup.32R.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 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;
[0177] B is selected from the group consisting of C3-C12 cycloalkyl
and C4-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 may be 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 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 may be
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
may be 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 may be 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 may be 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 may be 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 pyrimidinone 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.su- p.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,
2,4-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 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 is O;
[0205] B is the Formula: 18
[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, 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 selected from the group consisting of C3-C12 cycloalkyl
and C4-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 may be 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 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 may be
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
may be substituted with R.sup.12, a ring carbon three atoms from
the point of attachment and adjacent to the R.sup.10 position may
be substituted with R.sup.11, a ring carbon three atoms from the
point of attachment and adjacent to the R.sup.12 position may be
substituted with R.sup.33, and a ring carbon four atoms from the
point of attachment and adjacent to the R.sup.11 and R.sup.33
positions may be 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] 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;
[0211] 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);
[0212] R.sup.7 is selected from the group consisting of hydrido,
hydroxy and alkyl;
[0213] R.sup.15 is selected from the group consisting of hydrido,
hydroxy, halo, alkyl, and haloalkyl;
[0214] .PSI. is NH;
[0215] M is selected from the group consisting of N and
R.sup.1--C;
[0216] 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;
[0217] R.sup.2 is Z.sup.0-Q;
[0218] 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,%
tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso that
Z.sup.0 is directly bonded to the pyrimidinone ring;
[0219] R.sup.41 and R.sup.42 are independently selected from the
group consisting of hydrido, hydroxy, and amino;
[0220] 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;
[0221] K is CHR.sup.4a wherein R.sup.4a is selected from the group
consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl,
alkylthioalkyl, and haloalkyl;
[0222] 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);
[0223] Y.sup.0 is formula (IV): 19
[0224] 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;
[0225] 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;
[0226] 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;
[0227] 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;
[0228] 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;
[0229] 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;
[0230] R.sup.14 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0231] R.sup.37 and R.sup.38 are independently selected from the
group consisting of hydrido, alkyl, and haloalkyl;
[0232] R.sup.38 is optionally selected from the group consisting of
aroyl and heteroaroyl;
[0233] 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.
[0234] In an even more preferred embodiment of compounds of Formula
I or a pharmaceutically acceptable salt thereof,
[0235] J is O;
[0236] B is the Formula: 20
[0237] 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;
[0238] 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);
[0239] R.sup.7 is selected from the group consisting of hydrido,
hydroxy and alkyl;
[0240] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0241] .PSI. is NH;
[0242] M is selected from the group consisting of N and
R.sup.1--C;
[0243] 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;
[0244] R.sup.2 is Z.sup.0-Q;
[0245] Z.sup.0 is selected from the group consisting of a covalent
single bond, O, S, NH, and CH.sub.2;
[0246] 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;
[0247] 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;
[0248] 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;
[0249] K is CH.sub.2;
[0250] E.sup.0 is C(O)N(H);
[0251] Y.sup.0 is formula (IV): 21
[0252] 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;
[0253] 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;
[0254] 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;
[0255] 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;
[0256] 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;
[0257] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0258] In another even more preferred embodiment of compounds of
Formula I or a pharmaceutically acceptable salt thereof,
[0259] J is O;
[0260] 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;
[0261] 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;
[0262] 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);
[0263] R.sup.7 is selected from the group consisting of hydrido,
hydroxy and alkyl;
[0264] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0265] .PSI. is NH;
[0266] M is selected from the group consisting of N and
R.sup.1--C;
[0267] 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;
[0268] R.sup.2 is Z.sup.0-Q;
[0269] Z.sup.0 is selected from the group consisting of covalent
single bond, O, S, NH, and CH.sub.2;
[0270] 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;
[0271] 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;
[0272] 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, amidocarbonyl, halo, haloalkyl,
and cyano;
[0273] K is CH.sub.2;
[0274] E.sup.0 is C(O)N(H);
[0275] Y.sup.0 is formula (IV): 22
[0276] 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;
[0277] 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;
[0278] 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;
[0279] 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;
[0280] 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;
[0281] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0282] In still another even more preferred embodiment of compounds
of Formula I or a pharmaceutically acceptable salt thereof,
[0283] J is O;
[0284] B is selected from the group consisting of C3-C7 cycloalkyl
and C4-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 may be 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 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 may be
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
may be substituted with R.sup.12, a ring carbon three atoms from
the point of attachment and adjacent to the R.sup.10 position may
be substituted with R.sup.11, a ring carbon three atoms from the
point of attachment and adjacent to the R.sup.12 position may be
substituted with R.sup.33, and a ring carbon four atoms from the
point of attachment and adjacent to the R.sup.11 and R.sup.33
positions may be substituted with R.sup.34;
[0285] 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;
[0286] 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, amidocarbonyl, halo, haloalkyl,
and cyano;
[0287] 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;
[0288] 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);
[0289] R.sup.7 is selected from the group consisting of hydrido,
hydroxy and alkyl;
[0290] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0291] .PSI. is NH;
[0292] M is selected from the group consisting of N and
R.sup.1--C;
[0293] 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;
[0294] R.sup.2 is Z.sup.0-Q;
[0295] Z.sup.0 is selected from the group consisting of covalent
single bond, O, S, NH, and CH.sub.2;
[0296] 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;
[0297] K is CH.sub.2;
[0298] E.sup.0 is C(O)N(H);
[0299] Y.sup.0 is formula (IV): 23
[0300] 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;
[0301] 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;
[0302] 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;
[0303] 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;
[0304] 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;
[0305] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0306] In a most preferred embodiment of compounds of Formula I or
a pharmaceutically acceptable salt thereof,
[0307] J is O;
[0308] B is the Formula: 24
[0309] 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;
[0310] 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);
[0311] R.sup.7 is selected from the group consisting of hydrido and
alkyl;
[0312] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0313] .PSI. is NH;
[0314] M is selected from the group consisting of N and
R.sup.1--C;
[0315] 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;
[0316] R.sup.2 is Z.sup.0-Q;
[0317] Z.sup.0 is a covalent single bond;
[0318] 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;
[0319] 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;
[0320] 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;
[0321] K is CH.sub.2;
[0322] E.sup.0 is C(O)N(H);
[0323] Y.sup.0 is formula (IV): 25
[0324] 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;
[0325] 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;
[0326] 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;
[0327] 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;
[0328] 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;
[0329] Q.sup.s is CH.sub.2.
[0330] In another most preferred embodiment of compounds of Formula
I or a pharmaceutically acceptable salt thereof,
[0331] J is O;
[0332] 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.34, R.sup.35, and R.sup.36;
[0333] 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;
[0334] 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);
[0335] R.sup.7 is selected from the group consisting of hydrido and
alkyl;
[0336] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0337] .PSI. is NH;
[0338] M is selected from the group consisting of N and
R.sup.1--C;
[0339] 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;
[0340] R.sup.2 is Z.sup.0-Q;
[0341] Z.sup.0 is a covalent single bond;
[0342] 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;
[0343] 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;
[0344] 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;
[0345] K is CH.sub.2;
[0346] E.sup.0 is C(O)N(H);
[0347] Y.sup.0 is formula (IV): 26
[0348] 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;
[0349] 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;
[0350] 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;
[0351] 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;
[0352] 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;
[0353] Q.sup.s is CH.sub.2.
[0354] In still another most preferred embodiment of compounds of
Formula I or a pharmaceutically acceptable salt thereof,
[0355] J is O;
[0356] B is selected from the group consisting of C3-C7 cycloalkyl
and C4-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 may be optionally substituted
with oxo provided that no more than one ring carbon is substituted
by oxo at the same time, ring carbons and nitrogens adjacent to the
carbon 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 may be
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
may be substituted with R.sup.12, a ring carbon three atoms from
the point of attachment and adjacent to the R.sup.10 position may
be substituted with R.sup.11, a ring carbon three atoms from the
point of attachment and adjacent to the R.sup.12 position may be
substituted with R.sup.33, and a ring carbon four atoms from the
point of attachment and adjacent to the R.sup.11 and R.sup.33
positions may be substituted with R.sup.34;
[0357] 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;
[0358] 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;
[0359] 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;
[0360] R.sup.33 is optionally Q.sup.b;
[0361] 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);
[0362] R.sup.7 is selected from the group consisting of hydrido,
hydroxy and alkyl;
[0363] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0364] .PSI. is NH;
[0365] M is selected from the group consisting of N and
R.sup.1--C;
[0366] 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;
[0367] R.sup.2 is Z.sup.0-Q;
[0368] Z.sup.0 is a covalent single bond;
[0369] 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;
[0370] K is CH.sub.2;
[0371] E.sup.0 is C(O)N(H);
[0372] Y.sup.0 is formula (IV): 27
[0373] 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;
[0374] 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;
[0375] 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;
[0376] 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;
[0377] 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;
[0378] Q.sup.s is CH.sub.2.
[0379] In a preferred specific embodiment of Formula 1, compounds
have the Formula I-S: 28
[0380] or a pharmaceutically acceptable salt thereof, wherein;
[0381] B is the Formula: 29
[0382] 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, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and
Q.sup.b;
[0383] 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, S-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, 4-octenyl, 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-S-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptenyl,
1-methyl-3-heptynyl, 1-methyl-4-heptynyl, 1-methyl-S-heptynyl,
3-octyl, 1-ethyl-2-hexenyl, 1-ethyl-3-hexenyl, 1-ethyl-4-hexenyl,
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-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;
[0384] 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, bicyclo[3.1.0]hexan-6-y- l,
cycloheptyl, and cyclooctyl, wherein each ring carbon is optionally
substituted with R.sup.33, ring carbons or 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 a 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 a nitrogen adjacent to the R.sup.13 position and two
atoms from the point of attachment is optionally substituted with
R.sup.12;
[0385] 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, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
[0386] 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;
[0387] 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;
[0388] M is selected from the group consisting of N and
R.sup.1--C;
[0389] 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;
[0390] R.sup.2 is Z.sup.0-Q;
[0391] 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;
[0392] 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, 1,3,4-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, 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-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.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;
[0393] K is CHR.sup.4a wherein R.sup.4a is selected from the group
consisting of methyl, ethyl, propyl, isopropyl, hydroxymethyl,
1-hydroxyethyl, methoxymethyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoromethyl, methylthiomethyl, and hydrido;
[0394] E.sup.0 is a covalent single bond, C(O)N(H), (H)NC(O), and
S(O).sub.2N(H);
[0395] Y.sup.0 is selected from the group of formulas consisting
of: 30
[0396] 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;
[0397] 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;
[0398] 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-methyl amino,
and N,N-dimethylamino at the same time;
[0399] 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;
[0400] 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.
[0401] In a more preferred specific embodiment of Formula I,
compounds have the Formula I-MPS wherein B is an aromatic: 31
[0402] or a pharmaceutically acceptable salt thereof, wherein;
[0403] B is the Formula: 32
[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: 33
[0410] or a pharmaceutically acceptable salt thereof, wherein;
[0411] 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, 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,
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;
[0412] 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;
[0413] 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;
[0414] 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;
[0415] 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;
[0416] 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;
[0417] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0418] In still another more preferred specific embodiment of
Formula I, compounds have the Formula I-MPS wherein B is a
non-aromatic cyclic substituent: 34
[0419] or a pharmaceutically acceptable salt thereof, wherein;
[0420] 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,
bicyclo[3.1.0]hexan-6-yl, and cycloheptyl, wherein each ring carbon
is optionally substituted with R.sup.33, ring carbons or 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;
[0421] 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;
[0422] R.sup.33 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, isopropyl thio,
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;
[0423] 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;
[0424] 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;
[0425] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0426] The more preferred specific embodiment (I-MPS) compounds of
the present invention having the Formula: 35
[0427] or a pharmaceutically acceptable salt thereof, have common
structural units, wherein;
[0428] M is selected from the group consisting of N and
R.sup.1--C;
[0429] 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;
[0430] R.sup.2 is Z.sup.0-Q;
[0431] Z.sup.0 is selected from the group consisting of covalent
single bond, O, S, NH, and CH.sub.2;
[0432] 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;
[0433] 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;
[0434] 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;
[0435] Y.sup.0 is selected from the group of formulas consisting
of: 36
[0436] 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;
[0437] 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.
[0438] In a most preferred specific embodiment of Formula I,
compounds have the Formula I-EMPS wherein B is an aromatic: 37
[0439] or a pharmaceutically acceptable salt thereof, wherein;
[0440] B is the Formula: 38
[0441] 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;
[0442] 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;
[0443] 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;
[0444] 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;
[0445] Q.sup.s is CH.sub.2.
[0446] In another most preferred specific embodiment of Formula I,
compounds have the Formula I-EMPS wherein B is a non-cyclic
substituent: 39
[0447] or a pharmaceutically acceptable salt thereof, wherein;
[0448] 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;
[0449] 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;
[0450] 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;
[0451] 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;
[0452] 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;
[0453] 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;
[0454] Q.sup.s is CH.sub.2.
[0455] In still another most preferred specific embodiment of
Formula I, compounds have the Formula I-EMPS wherein B is a
non-aromatic cyclic substituent: 40
[0456] or a pharmaceutically acceptable salt thereof, wherein;
[0457] B is optionally selected from the group consisting of
cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-3-yl, thiaetan-3-yl,
cyclopentyl, and cyclohexyl, wherein each ring carbon is optionally
substituted with R.sup.33, ring carbons or 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;
[0458] 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;
[0459] 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;
[0460] 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;
[0461] 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;
[0462] Q.sup.s is CH.sub.2.
[0463] The most preferred specific embodiment (I-EMPS) compounds of
the present invention having the Formula: 41
[0464] or a pharmaceutically acceptable salt thereof, have common
structural units, wherein;
[0465] M is selected from the group consisting of N and
R.sup.1--C;
[0466] 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;
[0467] R.sup.2 is Z.sup.0-Q;
[0468] Z.sup.0 is a covalent single bond;
[0469] 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;
[0470] 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;
[0471] 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;
[0472] Y.sup.0 is selected from the group of formulas consisting
of: 42
[0473] 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.
[0474] 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.
[0475] 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.
[0476] In yet another embodiment of the present invention, the
novel compounds are selected from the compounds set forth in
Examples 1 through Example 19 and Tables 1.
[0477] The use of generic terms in the description of the compounds
are herein defined for clarity.
[0478] 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.).
[0479] 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.
[0480] 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.
[0481] 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.
[0482] 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.
[0483] The term "carbon" radical denotes a carbon atom without any
covalent bonds and capable of forming four covalent bonds.
[0484] The term "cyano" radical denotes a carbon radical having
three of four covalent bonds shared by a nitrogen atom.
[0485] 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.
[0486] 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.
[0487] 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.
[0488] 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--).
[0489] The term "halo" means halogens such as fluorine, chlorine,
bromine or iodine atoms.
[0490] 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.
[0491] 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.
[0492] 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.
[0493] 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.
[0494] 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.
[0495] 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.
[0496] 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.
[0497] 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.
[0498] 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.
[0499] 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.
[0500] 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.
[0501] 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.
[0502] 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.
[0503] 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.
[0504] 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.
[0505] 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.
[0506] 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.
[0507] 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.
[0508] 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.
Exmaples incude 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.
[0509] 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.
[0510] The term "cycloalkylalkoxy" embraces cycloalkyl radicals
attached to an alkoxy radical. Examples of such radicals includes
cyclohexylmethoxy and cyclopentylmethoxy.
[0511] 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.
[0512] 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.
[0513] 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.
[0514] 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.
[0515] 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 fluoropropyl
thio.
[0516] 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.
[0517] The terms alkylamino denotes "monoalkylamino" and
"dialkylamino" containing one or two alkyl radicals, respectively,
attached to an amino radical.
[0518] 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.
[0519] The term "aralkylamino", embraces aralkyl radicals attached
to an amino radical, where aralkyl is defined as above. The term
aralkylamino denotes "monoaralkylamino" 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.
[0520] 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.
[0521] 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.
[0522] 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-chloroethylphenoxy, 3,4-dichlorophenoxy, 4-methylphenoxy,
3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy,
4-fluorophenoxy, 3,4-dimethylphenoxy, 5-bromo-2-fluorophenoxy,
4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenox- y,
5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy,
3-cyclopropylphenoxy, 3-ethylphenoxy, 3-pentafluoroethylphenoxy,
3-(1,1,2,2-tetrafluoroethoxy)-phenoxy, and 4-tert-butylphenoxy.
[0523] 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.
[0524] 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.
[0525] 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.
[0526] The term "aryloxyalkyl" embraces aryloxy radicals, as
defined above, attached to an alkyl group. Examples of such
radicals include phenoxymethyl.
[0527] The term "haloaryloxyalkyl" embraces aryloxyalkyl radicals,
as defined above, wherein one to five halo radicals are attached to
an aryloxy group.
[0528] 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.
[0529] 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.
[0530] 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.
[0531] The term "haloheteroaryloxyalkyl" embraces
heteroaryloxyalkyl radicals, as defined above, wherein one to four
halo radicals are attached to an heteroaryloxy group.
[0532] The term "heteroarylamino" embraces heterocyclyl radicals,
as defined above, attached to an amino group. Examples of such
radicals include pyridylamino.
[0533] The term "heteroarylaminoalkyl" embraces heteroarylamino
radicals, as defined above, attached to an alkyl group. Examples of
such radicals include pyridylmethylamino.
[0534] 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.
[0535] 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.
[0536] The term "arylthio" embraces aryl radicals, as defined
above, attached to an sulfur atom. Examples of such radicals
include phenylthio.
[0537] The term "arylthioalkyl" embraces arylthio radicals, as
defined above, attached to an alkyl group. Examples of such
radicals include phenylthiomethyl.
[0538] 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.
[0539] 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.
[0540] 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.
[0541] 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.
[0542] 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--.
[0543] 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--.
[0544] 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.+.
[0545] 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, alkenyloxyalky, 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.
[0546] 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.
[0547] 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, l-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.
[0548] 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").
[0549] Some of the compounds described contain alkenyl groups, and
are meant to include both cis and trans or "E" and "Z" geometric
forms.
[0550] 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.
[0551] 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.
[0552] 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.
[0553] 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.
[0554] 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):
43
[0555] or a pharmaceutically-acceptable salt thereof.
[0556] 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.
[0557] 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.
[0558] 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.
[0559] 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).
[0560] 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.
[0561] 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.
[0562] 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.
[0563] 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.
[0564] The compounds may also be delivered by the use of monoclonal
antibodies as individual carriers to which the compound molecules
are coupled.
[0565] The compounds may also be coupled with soluble polymers as
targetable drug carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer,
polyhydroxy-propyl-methacrylamide-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.
[0566] 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.
[0567] 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.
[0568] 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.
[0569] 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.
[0570] 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.
[0571] 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.
[0572] 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.
[0573] 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.
[0574] 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.
[0575] 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.
[0576] All mentioned references are incorporated by reference as if
here written.
[0577] 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.
[0578] 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.
[0579] 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 dibenzylideneacetone, "DCC" represents
1,3-dicyclohexylcarbodi- imide, "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 diisopropylaride,
"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
[0580] The compounds of the present invention can be synthesized,
for example, according to the following procedures and Schemes
given below.
[0581] A general synthetic approach to a wide variety of
R.sup.2-substituted pyrimidinones is shown in Schemes 1 through
Scheme 5 below. Treatment of a solution of ethyl benzimidate
hydrochloride in methanol with aminoacetaldehyde dimethyl acetal
provided the substituted benzamidine. Cyclization of the
benzamidine with dimethyl methoxymethylene-malonate resulted in the
formation of the pyrimidinone heterocyclic core with the required
functional groups for further manipulation. Demethylation of the
ester with lithium iodide followed by Curtius rearrangement of the
resulting acid installed the crucial nitrogen at C-5 as a protected
carbamate. Hydrolysis of the dimethyl acetal and oxidation of the
resulting aldehyde with sodium chlorite gave the glycine unit at
N-3. Protection of the acid as a t-butyl ester followed by
deprotection of carbamate by hydrogenation gave the free amine at
C-5. Treatment of this amine with a sulfonyl chloride or with an
aldehyde under reductive amination conditions gave the sulfonamide
or secondary amine, respectively. The protected acids were then
unmasked with HCl. These acids are then coupled under standard
peptide coupling conditions with various amines. These amines are
typically multifunctional, and are used in some protected form.
Removal of these protecting groups provides the compounds for
evaluation. These synthetic schemes and procedures are exemplified
below. 44 45 46 47 48
[0582] Synthetic Scheme 1 through Scheme 5 are exemplified in the
following examples.
EXAMPLE 1
[0583] 49
[0584] (EX-1A) A solution of ethyl benzimidate hydrochloride (92.25
g, 496.9 mmol) in 300.0 mL dry methanol (1.68 M) was cooled to ca
0.degree. C. and added a solution of aminoacetaldehyde dimethyl
acetal (73.10 mL, 670.9 mmol) in dry methanol (75.0 mL, 9.0 M) drop
wise at such a rate the temperature was kept below 5.degree. C. The
resulting solution was allowed to stir for 3 days with the
temperature being maintained below 5.degree. C. The reaction
mixture was then concentrated under reduced pressure to give a
yellow oil. The residue was dissolved in 1 N NaOH (750 mL) and
extracted with dichloromethane (4.times.250 mL). The organic
solutions were combined, dried (MgSO.sub.4), and concentrated to
give 108.13 g crude N-(2,2-dimethoxyethyl)benzamidine as a yellow
oil. The crude N-(2,2-dimethoxyethyl)benzamidine (108.13 g, 519.2
mmol) in dry methanol (125.0 mL, 4.2 M) was added dimethyl
methoxymethylenemalonate (94.13 g, 540.5 mmol) in one portion at
room temperature. The resulting mixture was heated to approximately
100.degree. C., where the solvent was slowly distilled off over a
two hour period. The resulting dark brown solution was allowed to
cool to room temperature and was diluted ethyl acetate (1 L). The
organic solution was washed with saturated NH.sub.4Cl (2.times.500
mL) and brine (1.times.500 ml). The organic solution was dried
(MgSO.sub.4), filtered and concentrated. Purification of the crude
product by MPLC (25% ethyl acetate/hexane) gave pure methyl
1-(2,2-dimethoxyethyl-2-phenylpyrimidin-6(1H)-one-5-carboxylate
(EX-1A) in 73% yield as a tan oil: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.73 (s, 1H), 7.59-7.49 (m, 5H), 4.86 (t, J=5.5
Hz, 1H), 4.16 (d, J=5.4 Hz, 2H), 3.95 (s, 3H), 3.32 (s, 6H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 165.9, 164.6, 159.3,
158.2, 134.6, 130.9, 128.93, 128.78, 114.9, 101.4, 56.0, 55.1,
52.7, 49.1; HRMS (ES) calcd for C.sub.16H.sub.19N.sub.2O.sub.5
319.1294, found 319.1288.
[0585] (EX-1B) A solution of methyl
1-(2,2-dimethoxyethyl-2-phenylpyrimidi- n-6(1H)-one-5-carboxylate
(93.00 g, 292.2 mmol) in 420.0 mL dry pyridine (0.70 M) was added
lithium iodide (98.00 mL, 732.2 mmol) in one portion with stirring
at room temperature, upon which an exotherm occurs. The resulting
light brown suspension was heated to reflux for 2 hours. The dark
brown reaction was allowed to cool to room temperature and the
volatiles were removed under reduced pressure. The resulting oil
was diluted with 1 N HCl (500 mL). The aqueous solution was
extracted with dichloromethane/methanol (4:1, 4.times.250 mL). The
combined organic solutions were washed with 6 N HCl (2.times.250
mL), dried (MgSO.sub.4), filtered and concentrated. The crude
product was purified by crystallization (ethyl acetate/hexane) to
give pure
1-(2,2-dimethoxyethyl-2-phenylpyrimidin-6(1H)-one-5-carboxylate
(EX-1B) in 63% yield as a white solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 12.99 (s, 1H), 8.97 (s, 1H), 7.63-7.51 (m, 5H),
4.78 (dd, J=4.3, 5.5 Hz, 1H), 4.28 (d, J=5.4 Hz, 2H), 3.30 (s, 6H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 165.8, 165.1, 164.1,
159.1, 133.6, 131.5, 129.1, 129.0, 112.6, 101.0, 55.8, 49.2; HRMS
(ES) calcd for C.sub.15H.sub.17N.sub.2O.sub.5 305.1137, found
305.1113.
[0586] (EX-1C) A suspension of
1-(2,2-dimethoxyethyl-2-phenylpyrimidin-6(1- H)-one-5-carboxylate
(65.93 g, 216.67 mmol) in 800 mL 1,4-dioxane (0.27 M) was added
triethylamine (50.0 mL, 358.7 mmol) followed by diphenylphosphoryl
azide (51.40 mL, 238.5 mmol) in one portion at room temperature.
The resulting solution was slowly heated to reflux for 2 hours. The
reaction mixture was then added benzyl alcohol (45.00 mL, 434.8
mmol) and refluxing was maintained for approximately 14 hours. The
black solution was allowed to cool to room temperature, and the
volatiles were removed under vacuum. The resulting residue was
diluted with ethyl acetate (1.5 L). The organic solution was washed
with saturated NH.sub.4Cl (2.times.500 mL), 1 N NaOH (1.times.500
mL), and brine (1.times.500 ml). The organic solution was dried
(MgSO.sub.4), filtered and concentrated to give the crude product.
Purification by MPLC (15%-30% ethyl acetate/hexane) afforded pure
[5-[(benzyloxycarbonyl)amino]-2-pheny-
l-6-oxo-1,6-dihydro-1-pyrimidinyl]acetaldehyde dimethyl acetal
(EX-1C) as light brown solid in 46% yield: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.72 (br s, 1H), 7.53-7.32 (m, 11H), 5.20 (s,
2H), 4.68 (t, J=5.6 Hz, 1H), 4.12 (d, J=5.6 Hz, 2H), 3.22 (s, 6H);
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta. 158.3, 153.7, 153.2,
135.9, 134.9, 134.7, 130.1, 129.1, 128.9, 128.8, 128.71, 128.66,
128.4, 125.1, 101.3, 67.7, 55.4, 48.6; HRMS (EI) calcd for
C.sub.22H.sub.24N.sub.3O.sub.5 410.1716, found 410.1741.
[0587] (EX-1D) A solution of
[5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo--
1,6-dihydro-1-pyrimidinyl]acetaldehyde dimethyl acetal (17.24 g,
42.11 mmol) in 103.0 mL tetrahydrofuran was added 35.0 mL 1 N HCl.
The resulting biphasic mixture was allowed to heated to reflux for
12 hours. The reaction mixture was allowed to cool to room
temperature and the volatiles were removed under vacuum. The
resulting residue was diluted with water (200 mL) and the pH was
adjusted to 7 by addition of solid NaHCO3. The resulting emulsion
was extracted with dichloromethane (4.times.150 mL). The combined
organic solutions were washed with water (1.times.200 mL), dried
(MgSO.sub.4), filtered, and concentrated to give 15.74 g crude
[5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1--
pyrimidinyl]acetaldehyde.
[0588] A solution of crude
[5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,-
6-dihydro-1-pyrimidinyl]acetaldehyde (15.30 g, 42.11 mmol) in 198.0
mL of tetrahydrofuran, t-butyl alcohol, and 2-methyl-2-butene
(1:1:1.3, 0.21 M) was cooled to 0.degree. C. The solution was then
slowly added a solution of sodium chlorite (29.94 g, 331.1 mmol)
and sodium dihydrogenphosphate monohydrate (35.42 g, 256.7 mmol) in
102.0 mL of water (3.2 M based on sodium chlorite). The resulting
gold colored, biphasic solution was stirred for 10 minutes and the
cold bath was removed. The reaction was stirred for 1 hour at room
temperature. The volatiles were removed under reduced pressure. The
resulting solution was diluted with water (200 mL) and the pH was
adjusted to 3 by addition of sat NaHCO3 and 1 N HCl. The aqueous
solution was extracted by tetrahydrofuran, dichloromethane (1:2,
4.times.180 mL). The combined organic solutions were dried (MgSO4),
filtered, and concentrated to give the crude product. Purification
by trituration with ethyl ether gave an 88% yield of
[5-[(benzyloxycarbonyl)-
amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid as a
white solid: .sup.1H NMR (300 MHz, d-DMSO) .delta. 13.34 (br s,
1H), 9.03 (s, 1H), 7.57-7.34 (m, 10H), 5.23 (s, 2H), 4.56 (s, 2H);
.sup.13C NMR (75 MHz, d-DMSO) .delta. 169.4, 158.0, 154.6, 154.3,
137.1, 134.8, 130.9, 129.4, 129.1, 128.78, 128.72, 128.50, 125.5,
67.0, 48.8; HRMS (EI) calcd for C.sub.20H.sub.18N.sub.3O.sub.5
380.1246, found 380.1246.
[0589] (EX-1E) A suspension of
[5-[(benzyloxycarbonyl)amino]-2-phenyl-6-ox-
o-1,6-dihydro-1-pyrimidinyl]acetic acid (5.2503 g, 13.84 mmol) in
70.0 mL chloroform (0.2 M) was cooled in an ice bath to
approximately 0.degree. C. The cold suspension was then added
oxalyl chloride (6.00 mL, 68.78 mmol) drop wise via syringe. After
vigorous gas evolution, a golden homogeneous solution resulted.
After stirring for 5 minutes, the cold bath was removed and the
solution was stirred for an additional 2 hours at room temperature.
The solvent was removed under reduced pressure and placed on the
high vacuum system to remove residual solvents for 10 minutes. The
resulting yellow solid was diluted with 70.0 mL chloroform (0.2 M)
and added pyridine (1.70 mL, 21.02 mmol) and 2-methyl-2-propanol
(3.50 ml, 36.60 mmol). The resulting tan colored solution was
stirred for 1 hour at room temperature, and then heated to reflux
for 12 hours. The reaction mixture was cooled to room temperature
and diluted with chloroform (300 mL). The organic solution was
washed with water (1.times.100 mL), saturated NaHCO.sub.3
(1.times.100 mL), and brine (1.times.100 mL). The organic solution
was dried (MgSO.sub.4), filtered and concentrated. The crude
reaction was purified by MPLC (25% ethyl acetate/hexanes) to give
the product in 49% yield: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.81 (br s, 1H), 7.57-7.38 (m, 11H), 5.27 (s, 2H), 4.57 (s, 2H),
1.47 (s, 9H); .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 166.4,
158.0, 153.2, 135.9, 135.0, 134.4, 130.6, 129.1, 128.9, 128.7,
128.5, 128.4, 125.4, 83.4, 67.7, 49.1, 28.2; HRMS (EI) calcd for
C.sub.24H.sub.26N.sub.3O.sub.5 436.1872, found 436.1876.
[0590] (EX-1F) A solution of
[5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimid- inyl]acetic acid
t-butyl ester (1.8647 g, 4.282 mmol) in 21.0 mL methanol (0.2 M)
was added 211.3 mg 10% Pd/C in one portion. The resulting mixture
was stirred under an atmosphere of hydrogen gas (balloon) at room
temperature for approximately 16 hours. The crude reaction mixture
was filtered through a pad of Celite 545 and the solvent was
removed under reduced pressure. The crude product was triturated
from ethyl ether to give pure product [5-amino-2-phenyl-6
oxo-1,6-dihydro-1-pyrimidinyl]aceti- c acid t-butyl ester (EX-1F)
in 99% yield: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41-7.39
(m, 6H), 4.48 (s, 2H), 4.06 (br s, 2H), 1.39 (s, 9H); .sup.13C NMR
(100 MHz, CDCl.sub.3) .delta. 166.8, 158.6, 149.3, 134.9, 132.9,
130.0, 128.9, 128.5, 127.7, 82.9, 48.7, 28.1; HRMS (EI) calcd for
C.sub.16H.sub.20N.sub.3O.sub.3 302.1505, found 302.1491.
[0591] (EX-1G) A solution of
[5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimid- inyl]acetic acid
t-butyl ester (1.0300 g, 3.418 mmol) in 5.5 mL tetrahydrofuran and
2.0 mL dimethylformamide (0.45 M) was added N-methylmorpholine
(1.20 mL, 10.91 mmol) in one portion. The solution was cooled to
0.degree. C. in an ice bath. After stirring for 10 minutes, a
solution of 718.2 mg a-toluenesulfonyl chloride (3.767 mmol) in 5.5
mL tetrahydrofuran (0.68 M) was added drop wise over a 5 minute
period. The reaction mixture was stirred for 2 hours at 0.degree.
C. The reaction mixture was diluted with ethyl acetate (150 mL).
The organic solution was washed with 1 N HCl (2.times.25 mL),
saturated NaHCO.sub.3 (2.times.25 mL), and brine (1.times.50 mL).
The organic solution was dried (MgSO.sub.4), filtered and
concentrated under reduced pressure. The resulting yellow solid was
triturated with ethyl ether, filtered, and dried under vacuum to
afford pure product (EX-1G) as a white solid in 74% yield: .sup.1H
NMR (400 MHz, d-DMSO) .delta. 9.34 (s, 1H), 7.76 (s, 1H), 7.55-7.28
(m, 10H), 4.59 (s, 2H), 4.49 (s, 2H), 1.32 (s, 9H); .sup.13C NMR
(100 MHz, d-DMSO) .delta. 167.0, 158.8, 156.5, 142.1, 134.5, 131.7,
131.0, 130.1, 129.4, 129.0, 128.94, 128.58, 124.8, 83.0, 59.6,
49.2, 28.1; HRMS (EI) calcd for C.sub.23H.sub.26N.sub.3O.sub.5S
456.1593, found 456.1597.
[0592] (EX-1H) A solution of (EX-1G) (1.0643 g, 2.336 mmol) in 9.0
mL 4M HCl in dioxane (0.1 M) was stirred for 12 hours at room
temperature. The crude reaction was concentrated under reduced
pressure. The resulting residue was triturated with ethyl ether to
afford pure product (EX-1H) in 87% yield as a white solid: .sup.1H
NMR (400 MHz, d-DMSO) .delta. 9.32 (s, 1H), 7.74 (s, 1H), 7.51-7.30
(m, 10H), 4.58 (s, 2H), 4.48 (s, 2H); .sup.13C NMR (100 MHz,
d-DMSO) .delta. 169.2, 158.7, 156.6, 141.9, 134.5, 131.7, 131.0,
130.1, 129.4, 129.0, 128.90, 128.56, 124.8, 59.6, 48.9; HRMS (EI)
calcd for C.sub.19H.sub.18N.sub.3O.sub.5S 400.0967, found
400.0959.
[0593] (EX-1I) A solution of acid (EX-1H) (406.8 mg, 1.018 mmol) in
10.0 mL dimethylformamide (0.10 M) was added
N,N-diisopropylethylamine (0.900 mL, 5.167 mmol),
N-hydroxybenzotriazole (167.7 mg, 1.241 mmol), and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
(236.1 mg, 1.232 mmol). The resulting mixture was allowed to stir
for 30 minutes at room temperature after which the mixture had
become homogeneous. The reaction mixture was then added
4-(Cbz-amidino)benzylamine (324.6 mg, 1.126 mmol) in one portion at
room temperature. The resulting mixture was then allowed to stir
for 18 hours. The reaction mixture was diluted with ethyl acetate
(50 mL). The organic solution was 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 mixture was purified
trituration with ethyl ether to afford pure product (EX-1I) in as a
white solid: .sup.1H NMR (300 MHz, d-DMSO) .delta. 9.36-9.18 (br m,
3H), 8.82-8.78 (m, 1H), 7.98 (d, J=8.3 Hz, 2H), 7.84, (s, 1H),
7.56-7.32 (m, 16H), 5.15 (s, 2H). 4.65 (s, 2H), 4.58 (s, 2H), 4.40
(d, J=5.4 Hz, 2H); HRMS (EI) calcd for
C.sub.35H.sub.33N.sub.6O.sub.6S.sub.2 665.2182, found 665.2177.
[0594] A solution of Cbz-amidine (EX-1I) (237.7 mg, 357.6 mmol) in
3.5 mL methanol and 4 M HCl in dioxane (4:1, 0.1 M) was added 42.1
mg 10% Pd/C in one portion. The resulting mixture was stirred under
an atmosphere of hydrogen gas (balloon) at room temperature for
approximately 16 hours. The crude reaction mixture was filtered
through a pad of Celite 545 and the solvent was removed under
reduced pressure. Purification of the crude product by HPLC
(gradient, 5%-95% acetonitrile/water with 0.1% trifluoroacetic
acid) afforded pure product as a white solid: .sup.1H NMR (300 MHz,
d-DMSO) .delta. 9.31-9.28 (m, 4H), 8.88 (br s, 1H), 7.81-7.77 (m,
3H), 7.60-7.54 (m, 5H), 7.43-7.37 (m, 7H), 4.65 (s, 2H), 4.58 (s,
2H), 4.42-4.41 (m, 2H); HRMS (EI) calcd for
C.sub.27H.sub.27O.sub.4S 531.1815, found 531.1794.
EXAMPLE 2
[0595] 50
[0596] By following the method of Example 1, the title compound was
prepared: .sup.1H NMR (300 MHz, d-DMSO) .delta. 9.40-9.33 (m, 4H),
8.86 (s, 1H), 7.82 (s, 2H), 7.72-7.37 (m, 15H), 4.65-4.59 (m, 4H),
4.41-4.40 (m, 2H); HRMS (EI) calcd for
C.sub.27H.sub.27N.sub.6O.sub.4S 531.1815, found 531.1794.
EXAMPLE 3
[0597] 51
[0598] (EX-3A) A solution of
[5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrimid- inyl]acetic acid
t-butyl ester (EX-1F) (613.7 mg, 2.037 mmol) in 7.0 mL
tetrahydrofuran and dichloromethane (1:1, 0.3 M) was added 25.0 mL
acetic acid and phenylacetaldehyde (0.475 mL, 4.060 mmol). The
solution was cooled to 0.degree. C. in an ice bath and added sodium
triacetoxyborohydride (1.9131 g, 9.027 mmol) in one portion. After
stirring for 5 minutes, the ice bath was removed and the reaction
mixture was allowed to stir at room temperature for 2 hours. The
reaction was quenched by the addition of 1 N NaOH (5 mL), and the
mixture was stirred for 5 minutes. The reaction mixture was diluted
0.5 N NaOH (100 mL). The aqueous solution was extracted with ethyl
acetate (3.times.25 mL). The combined organic solutions were washed
with 0.5 N NaOH (1.times.25 mL) and brine (1.times.25 mL). The
solution was dried (MgSO.sub.4), filtered and concentrated under
reduced pressure. Purification by MPLC (25% ethyl acetate/hexanes)
afforded EX-3A as a yellow oil in 74% yield: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.43-7.40 (m, 4H), 7.31-7.26 (m, 2H), 7.23-7.16
(m, 5H), 4.70 (br s, 1H), 4.49 (s, 2H), 3.38-3.34 (m, 2H),
2.96-2.92 (m, 2H), 1.40 (s, 9H); HRMS (EI) calcd for
C.sub.24H.sub.28N.sub.3O.sub.3 406.2131, found 406-2125.
[0599] A solution of EX-3A (521.3 mg, 1.286 mmol) in 13.0 mL 4M HCl
in dioxane (0.1 M) was stirred for 12 hours at room temperature.
The crude reaction was concentrated under reduced pressure. The
resulting residue was triturated with ethyl ether to afford pure
product EX-3B in quantitative yield as a yellow solid: .sup.1H NMR
(300 MHz, d-DMSO) .delta. 7.66-7.57 (m, 5H), 7.33-7.23 (m, 6H),
4.57 (s, 2H), 3.443.35 (m, 2H), 2.97-2.92 (m, 2H); .sup.13C NMR (75
MHz, d-DMSO) .delta. 168.8, 157.0, 148.0, 139.9, 135.0, 132.2,
129.69, 129.48, 129.07, 126.9, 48.8, 44.5, 34.5; HRMS (EI) calcd
for C.sub.20H.sub.20N.sub.3O.sub.3 350.1505, found 350.1520.
[0600] A solution of EX-3B (497.8 mg, 1.290 mmol) in 13.0 mL
dimethylformamide (0.10 M) was added N,N-diisopropylethylamine
(1.800 mL, 10.33 mmol), N-hydroxybenzotriazole (212.8 mg, 1.575
mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (302.5 mg, 1.578 mmol). The resulting mixture was
allowed to stir for 30 minutes at room temperature after which the
mixture had become homogeneous. The reaction mixture was then added
4-(Cbz-amidino)benzylamine (410.9 mg, 1.425 mmol) in one portion at
room temperature. The resulting mixture was then allowed to stir
for 18 hours. The reaction mixture was diluted with ethyl acetate
(50 mL). The organic solution was 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 mixture was purified
trituration with ethyl ether to afford pure product EX-3C in as a
white solid: .sup.1H NMR (400 MHz, d-DMSO) .delta. 9.08 (br s, 2H),
8.62 (t, J=5.8 Hz, 1H), 7.90 (d, J=8.3 Hz, 2H), 7.44-7.15 (m, 17H),
5.35 (t, J=5.9 Hz, 1H), 5.07 (s, 2H), 4.44 (s, 2H), 4.29 (d, J=5.4
Hz, 2H), 3.31-3.26 (m, 2H), 2.88-2.85 (m, 2H); HRMS (EI) calcd for
C.sub.36H.sub.35N.sub.6O.sub.4 615.2720, found 615.2688.
[0601] A solution of EX-3C (222.6 mg, 362.1 mmol) in 4.0 mL
methanol and 4 M HCl in dioxane (3:1, 0.1 M) was added 53.0 mg 10%
Pd/C in one portion. The resulting mixture was stirred under an
atmosphere of hydrogen gas (balloon) at room temperature for
approximately 16 hours. The crude reaction mixture was filtered
through a pad of Celite 545 and the solvent was removed under
reduced pressure. Purification of the crude product by trituration
from ethyl ether afforded pure product as a yellow solid: .sup.1H
NMR (300 MHz, d-DMSO) .delta. 9.62-9.30 (br m, 5H). 7.88 (br m,
2H), 7.58-6.86 (br m, 15H), 4.59 (br s, 2H), 4.36 (br s, 2H), 3.38
(br s, 2H), 2.91 (br s, 2H); HRMS (EI) calcd for
C.sub.28H.sub.29N.sub.6O.sub.2 481.2352, found 481.2348.
[0602] Pyrimidinones having, for example, a directly bonded 2-aryl,
2-heteroaryl, or 2-heteroatom linking/bonding an organic group
through the heteroatom to the pyrimidinone ring can be prepared
using Scheme 6 and Scheme 7 below. The heteroatom is typically a
sulfur, nitrogen, oxygen, or another suitable heteroatom. Use of
the general procedure in Scheme 6 to prepare specific heteroatom
substituted pyrimidinones is disclosed in Examples 4 and 5. 52
EXAMPLE 4
[0603] 53
[0604] (EX-4A) A solution of 5-nitro-2,4(1H,3H)pyrimidinedione in
dimethylsulfoxide (0.2 M) is added 1.1 equivalents potassium
carbonate in one portion with stirring. After approximately 10
minutes, a solution of 1 equivalent 2-(trimethylsilyl)ethoxy-methyl
chloride in dimethylsulfoxide is added drop wise. The reaction
mixture is then heated to 40.degree. C. and allowed to stir for 18
hours. Typical aqueous work up followed by chromatographic
purification provides pure product EX-4A.
[0605] EX-4B) A solution of 5-nitro-1-SEM-2,4(1H,3H)
pyrimidinedione (EX-4A) in dimethylsulfoxide (0.2 M) is added 1.1
equivalents potassium carbonate in one portion with stirring. After
approximately 10 minutes a solution of 1 equivalent methyl
bromoacetate in dimethylsulfoxide is added drop wise. The reaction
mixture is then heated to 40.degree. C. and allowed to stir for 18
hours. Typical aqueous work up followed by chromatographic
purification provides pure product EX-4B.
[0606] EX-4C) A solution of 5-nitro-1-SEM-3-methoxycarbonylmethyl
(EX-4B) 2,4(1H,3H)pyrimidinedione in methanol is degassed with
hydrogen gas. To the solution is then added 5% Pd/C which is
stirred 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. Purification by column
chromatography gives pure
5-amino-1-SEM-3-methoxycarbonylmethyl-2,4(1H,3H)pyrimidinedione
EX-4C.
[0607] EX-4D) To a solution of
5-amino-1-SEM-3-methoxycarbonylmethyl-2,4(1- H,3H)pyrimidinedione
(EX-4C) in tetrahydrofuran and dichloromethane (1:1, 0.3 M) is
added a catalytic amount of acetic acid and 1 equivalent
phenylacetaldehyde. The solution is cooled to 0.degree. C. in an
ice bath and 1 equivalent sodium triacetoxyborohydride is added in
one portion. After stirring for 5 minutes, the ice bath is removed,
and the reaction mixture is allowed to stir at room temperature for
2 hours. The reaction is quenched by the addition of 1 N NaOH, and
the mixture is stirred for 5 minutes. Typical aqueous work up,
followed by chromatographic purification provides pure product
EX-4D.
[0608] EX-4E) To a solution of
1-SEM-3-methoxycarbonylmethyl-%(2-phenyleth-
yl)amino-2,4(1H,3H)pyrimidinedione (EX-4D) in tetrahydrofuran and
methanol (1:1, 0.2 M) is added 1 equivalent of lithium hydroxide in
water. After the reaction is complete, 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. Extraction
with organic solvent and removal of the solvent under reduced
pressure gives pure product EX-4E.
[0609] EX-4F) To a solution of
1-SEM-3-methylenecarboxy-5-(2-phenylethyl)a-
mino-2,4(1H,3H)pyrimidinedione dimethylformamide (0.1 M) are added
5 equivalents of N,N-diisopropylethylamine, 1 equivalent of
N-hydroxybenzotriazole, and 1 equivalent of
1-[3-(dimethylamino)propyl]-3- -ethylcarbodiimide hydrochloride.
The resulting mixture is stirred for 30 minutes. The reaction
mixture is then treated with 1 equivalent of the appropriate amine
and allowed to stir over night. Typical aqueous work up followed by
chromatographic purification gives pure product EX-4F.
[0610] EX-4G) To a solution of
1-SEM-3-methylenecarbamide-5-(2-phenylethyl-
)amino-2,4(1H,3H)pyrimidinedione in tetrahydrofuran (0.3M) is added
2 equivalents of tetrabutylammonium fluoride in tetrahydrofuran.
The resulting solution is refluxed for several hours. Typical
aqueous work up is followed by chromatographic purification to give
pure product EX-4G.
[0611] EX-4H) To a solution of
3-methylenecarboxamide-5-(2-phenylethyl)ami-
no-2,4(1H,3H)pyrimidinedione (EX-4G) in N,N-dimethylaniline (0.3M)
is added 1 equivalent of phosphorus oxychloride. The resulting
solution is refluxed for several hours. Typical aqueous work up is
followed by chromatographic purification to give pure product
EX-4H.
[0612] EX-4I) To a solution of
2-chloro-3-methylenecarboxamide-5-(2-phenyl-
ethyl)amino-2,4(1H,3H)pyrimidinedione (EX-4H) in dioxane (03M) is
added 2 equivalents of phenylthiol. The resulting solution is
refluxed for several hours. Typical aqueous work up is followed by
chromatographic purification to give pure product EX-4I.
[0613] A solution of
2-thiophenyl-3-methylenecarboxamide-5-(2-phenylethyl)-
amino-2,4(1H,3H)pyrimidinedione (EX-4I) in methanol and 4M HCl
dioxane (3:1, 0.1 M) is degassed with hydrogen gas. To the solution
is then added 5% Pd/C which is stirred 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. Purification by column chromatography gives pure
product.
EXAMPLE 5
[0614] 54
[0615] EX-5A) To a degassed solution of
2-chloro-3-methylenecarboxamide-5--
(2-phenylethyl)amino-2,4(1H,3H)pyrimidinedione and 1 equivalent of
3-pyridineboronic acid in 1-propanol (0.5M) is added 1.2
equivalents of 2.0 M sodium carbonate followed by 1 mol % of
tetrakis(triphenylphosphine- )palladium. The resulting mixture is
heated to reflux for several hours. After cooling to room
temperature, typical aqueous work up is followed by chromatographic
purification to give pure product EX-5A.
[0616] A solution of
2-(3-pyridinyl)-3-methylenecarboxamide-5-(2-phenyleth-
yl)amino-2,4(1H,3H)pyrimidinedione (EX-5A) in methanol and 4M HCl
dioxane (3:1, 0.1 M) is degassed with hydrogen gas. To the solution
is then added 5% Pd/C, and the solution is stirred 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. Purification by column chromatography gives
pure product.
[0617] Pyrimidinones having, for example, a directly bonded 2-aryl,
2-heteroaryl, or 2-heteroatom linking/bonding an organic group
through the heteroatom to the pyrimidinone ring can also be
prepared using Scheme 7 below. In this reaction scheme, the aryl is
introduced by forming a carbon-carbon bond. Heteroatom suitable for
forming heterolinked aryl pyrimidinones include sulfur, nitrogen,
oxygen, or another suitable heteroatom. Use of the general
procedure in Scheme 7 to prepare specific heteroatom substituted
pyrimidinones is disclosed in Examples 6 and 7. 55
EXAMPLE 6
[0618] 56
[0619] (EX-6A) 2-Thiouracil (66.7 g, 520.5 mmol) was dissolved in a
sodium hydroxide solution (41.6 g of solid NaOH in 365 mL of
water). The mixture was then treated with methyl iodide (37 mL, 583
mmol), and the resulting reaction mixture was allowed to stir for
16 h at room temperature. The solution was then acidified with
glacial acetic acid (30 mL). The white precipitate was collected by
suction filtration, and the solid was washed several times with
cold water and dried to afford 74 g of EX-6A as a white crystalline
solid in quantitative yield.
[0620] (EX-6B) A solution of EX-6A (74.0 g, 520.5 mmol) in glacial
acetic acid (2275 mL) was cooled to 0.degree. C. with an ice bath
and treated with Br.sub.2. The reaction mixture was allowed to warm
to room temperature, and to stir for 16 h. A yellow precipitate
formed which was filtered and washed with ether three times. 97.2 g
of EX-6B was isolated in 62% yield.
[0621] (EX-6C) A mixture of calcium hydride in THF was cooled to
0.degree. C. and treated with neat EX-6B followed by neat t-butyl
bromoacetate. The reaction mixture was allowed to stir at 0.degree.
C. for 1 h. The reaction mixture was then allowed to stir for 2 h
after the mixture was allowed to warm to room temperature. The
reaction mixture was heated to reflux temperature for 16 h. After
the reaction mixture was cooled to room temperature, the mixture
was slowly poured into a 1 L ice water slurry. The quenched mixture
was extracted with dichloromethane (3.times.500 mL). The organic
layers were combined and washed with water and brine. After the
organic layer was dried over MgSO.sub.4 and filtered, the volatile
components were removed in vacuo to afford 28.81 g (90%) of EX-6C
as an off white solid as a mixture of N-alkylated and O-alkylated
isomers (9:1). N-alkylated isomer. .sup.1H NMR (300 MHz,
CDCl.sub.3) d 8.07 (s, 1H), 4.75 (s, 2H), 2.57 (s, 3H), 1.47 (s,
9H); .sup.13C NMR (75 MHz, CDCl.sub.3) d 165.1, 162.7, 158.4,
152.5, 108.3, 83.7, 46.8, 28.2 (3C), 15.5; HRMS (EI) calcd for
C.sub.11H.sub.15BrN.sub.- 2O.sub.3S 335.0065, found 335.0077.
[0622] (EX-6D) In an argon-filled glove box a 12-ounce
Fischer-Porter bottle containing a magnetic stir bar was charged
with EX-6C (5.00 g, 15.0 mmol), Pd(OAc).sub.2 (168 mg, 0.75 mmol, 5
mole %), rac-BINAP (654 mg, 1.05 mmol, 7 mole %), Cs.sub.2CO.sub.3
(6.84 g, 21.0 mmol), and anhydrous, degassed toluene (65.0 ml). To
this mixture was added isopropyl amine (3.00 ml, 35.2 mmol). The
bottle was capped with a pressure head fitted with a pressure gauge
and removed from the glove box. The closed-system was heated in an
oil bath at 118-120.degree. C. with magnetic stirring for 16 h
thereafter. A head-space pressure of .about.10 psi was developed
during the reaction. The Fischer-Porter bottle containing the
reaction mixture was removed from the oil bath, allowed to cool for
30 min, vented to an argon-flow system and sampled by syringe. LCMS
analysis showed 35% product with 65% starting material remaining.
Under a blanket of argon, the pressure head was removed and the
reaction mixture was treated with Pd(OAc).sub.2 (337 mg, 1.5 mmol,
10 mole %), rac-BINAP (1.00 g, 1.6 mmol, 11 mole %),
Cs.sub.2CO.sub.3 (10.0 g, 30.7 mmol), and isopropyl amine (6.00 ml,
70.4 mmol). The bottle was capped with the pressure head and again
heated to 118-120.degree. C. with magnetic stirring for 16 h. The
sampling procedure was repeated and LCMS revealed that the reaction
was complete. The reaction mixture was allowed to cool to RT and
filtered through a medium frit sintered-glass funnel. The solids
were washed thoroughly with toluene and discarded. The filtrate was
concentrated and purified by flash chromatography (Merck 230-400
mesh SiO.sub.2, 10% ethyl acetate in hexanes) to afford 3.80 g (81%
yield) of (EX-6D) as a tan solid: .sup.1H NMR (300 MHz, CDCl.sub.3)
d 7.05 (s, 1H), 4.74 (s, 2H), 3.44 (septet, J=6.3 Hz, 1H), 2.53 (s,
3H), 1.47 (s, 9H), 1.21 (d, J=6.3 Hz, 6H); .sup.13C NMR (75 MHz,
CDCl.sub.3) d 165.7 (s), 158.7 (s), 147.4 (s), 130.5 (s), 123.6
(d), 82.9 (s), 45.9 (t), 44.1 (d), 28.0 (q), 22.1 (q), 14.8 (q);
HRMS (ESI) calcd for C.sub.14H.sub.24N.sub.3SO.sub.3
[M+H].sup.+=314.1538, found 314.1539.
[0623] (EX-6E) In an argon-filled glove box a 3-ounce
Fischer-Porter bottle containing a magnetic stir bar was charged
with EX-6D (1.00 g, 3.20 mmol), 3-nitrophenyl boronic acid (634 mg,
3.80 mmol), Cu(I)-2-thiophenecarboxylate (1.21 g, 6.37 mmol), and
Pd(PPh3).sub.4 (100 mg, 0.86 mmol, 2.7 mol %). THF (25 ml) was
added and the bottle was capped with a pressure head fitted with a
pressure gauge and removed from the glove box. The closed-system
was heated in an oil bath at 70.degree. C. with magnetic stirring
for 16 h thereafter. The reaction mixture was allowed to cool to
RT, vented and diluted with ether (200 ml). The mixture was
filtered through a medium frit sintered glass funnel. The green
solid was washed with ether (100 ml) and discarded. The filtrate
was concentrated and purified by flash chromatography (Merck
230-400 mesh SiO.sub.2, 10% ethyl acetate in hexanes to 30%) to
afford 961 mg (78% yield) of EX-6E as a yellow foam: .sup.1H NMR
(300 MHz, CDCl.sub.3) d 8.39 (s, 1H), 8.31 (d, J=8.1 Hz, 1H), 7.86
(d, J=7.8 Hz, 1H), 7.64 (t, J=8.1 Hz, 1H), 7.15 (bs, 1H), 4.51 (s,
2H), 3.58 (septet, J=6.0 Hz, 1H), 1.46 (s, 9H), 1.27 (d, J=6.3 Hz,
6H); HRMS (ESI) calcd for C.sub.19H.sub.25N.sub.4O.sub.5
[M+H].sup.+=389.1815, found 389.1825.
[0624] (EX-6F) A 250-mL round-bottom flask fitted with a magnetic
stir bar was charged with EX-6E (755 mg, 1.9 mmol) and
trifluoroacetic acid (30 mL). This mixture was stirred at RT under
an argon-flow atmosphere for 30 min and concentrated on a rotary
evaporator. The residue was triturated with ether (50 mL) and
coevaporated with heptane (2.times.50 mL) to afford 801 mg (95%
yield) of EX-6F as a clear yellow glass: .sup.1H NMR (300 MHz,
DMSO-d.sub.6) d 8.34-8.26 (m, 2H), 7.89 (d, J=7.8 Hz, 1H), 7.76 (t,
J=7.9 Hz, 1H), 7.20 (s, 1H), 4.51 (s, 2H), 3.57 (septet, J=6.6 Hz,
1H), 1.17 (d, J=6.6 Hz, 6H); HRMS (ESI) calcd for
C.sub.15H.sub.17N.sub.4- O.sub.5 [M+H].sup.+ of free base=333.1223,
found 333.1199.
[0625] Prepared from EX-6F according to the procedure described for
the CBZ-protected precursor to afford the product: .sup.1H NMR (300
MHz, CDCl.sub.3) d 9.34 (bs, 1H), 8.32 (s, 1H), 8.14 (d, J=8.0 Hz,
1H), 7.81 (t, J=7.8 Hz, 2H), 7.53 (d, J=7.8 Hz, 2H), 7.47 (t, J=7.8
Hz, 1H), 7.39-7.25 (m, 5H), 7.08 (s, 1H), 7.00 (d, J=7.8 Hz, 2H),
5.12 (s, 2H), 4.61 (d, J=7.8 Hz, 1H), 4.35 (s, 2H), 4.21 (m, 1H),
3.50 (d of septets, 8 lines J=6.3 Hz, 1H), 1.22 (d, J=6.3 Hz, 6H);
C NMR (75 MHz, CDCl.sub.3) d 168.5 (s), 167.4 (s), 164.0 (s), 158.6
(s), 148.2 (s), 143.8 (s), 142.6 (s), 136.6 (s), 136.2 (s), 135.0
(d), 133.4 (s), 133.2 (s), 129.9 (d), 128.7 (d), 128.3 (d), 127.8
(d), 127.5 (d), 124.4 (d), 124.1 (d), 121.8 (d), 67.4 (t), 49.9
(t), 44.1 (d), 43.2 (t), 22.4 (q); HRMS (ESI) calcd for
C.sub.31H.sub.32N.sub.7O.sub.6 [M+H].sup.+: 598.2463, found
598.2414.
[0626] Prepared from EX-6G according to the method described for
SC-81703 to afford the product: .sup.1H NMR (300 MHz, CD.sub.3OD) d
9.25 (bs, 1H), 8.97 (m, 1H), 8.78 (bs, 1H), 7.93-7.14 (complex m,
9H), 4.77 (s, 2H), 4.51 (s, 3H), 3.66 (m, 1H), 1.30 (d, J=6.3 Hz,
6H); HRMS (ESI) calcd for C.sub.23H.sub.28N.sub.7O.sub.2
[M+H].sup.+=598 of free base 434.2304, found 434.2318.
EXAMPLE 7
[0627] 57
[0628] (EX-7A) Prepared from EX-6D using the same procedure
described for EX-6E with the only exception that Cs.sub.2CO.sub.3
base was used. As such, EX-6D (213 mg, 0.68 mmol),
pyridine-3-boronic acid 1,3-propanediol cyclic ester (166 mg, 1.02
mmol) and Cs.sub.2CO.sub.3 (771 mg, 2.37 mmol) afforded 143 mg of
EX-7A (61% yield) after flash chromatography (Merck 230-400 mesh
SiO.sub.2, 2% MeOH in CHCl.sub.3) as a slightly yellow glass:
.sup.1H NMR (300 MHz, CDCl.sub.3) d 8.79-8.66 (m, 2H), 7.90-7.26
(complex m, 3H), 7.16 (s, 1H), 4.53 (s, 2H), 3.57 (septet, J=6.3
Hz, 1H), 1.44 (s, 9H), 1.27 (d, J=6.3 Hz, 6H); HRMS (ESI) calcd for
C.sub.18H.sub.25N.sub.4O.sub.3 [M+H].sup.+=345.1927, found
345.1928.
[0629] (EX-7B) Prepared from EX-7A (143 mg, 0.41 mmol) using the
same procedure described for EX-6F to afford 212 mg (100% yield) of
EX-7B as a yellow foam: .sup.1H NMR (300 MHz, CDCl.sub.3) d
8.72-8.64 (m, 2H), 7.95-7.89 (m, 1H), 7.62-7.52 (complex m, 2H),
7.42-7.37 (m, 1H), 7.20 (s, 1H), 4.52 (s, 2H), 3.57 (septet, J=6.3
Hz, 1H), 1.18 (d, J=6.3 Hz, 6H); HRMS (ESI) calcd for
C.sub.14H.sub.7N.sub.4O.sub.3 [M+H].sup.+ 1289.1301, found
289.1296.
[0630] (EX-7C) Prepared from EX-7B using the same procedure
described for the CBZ-protected materail to afford EX-7C; HRMS
(ESI) calcd for C.sub.30H.sub.32N.sub.7O.sub.4
[M+H].sup.+=554.2516, found 554.2523.
[0631] Prepared from EX-7C using the same procedure described for
Example 6 to afford the product.
EXAMPLE 8
[0632] 58
[0633] By following the method of Example 6, the title compound was
prepared: HRMS (ESI) calcd for C.sub.24H.sub.27N.sub.7O.sub.2
[M+H].sup.+ 446.2304, found 446.2309.
[0634] Methylene analogs of pyrimidinones wherein a methylene is
present as a replacement for the carbonyl of the acetamide at the
N-3 position of the pyrimidinone can be prepared using Scheme 8 "A
General Methylene Pyrimidinone Preparation" as detailed below along
with the specific Example 9. 59
EXAMPLE 9
[0635] 60
[0636] EX-9A) To a solution of
[[5[(benzyloxycarbonyl)amino]-2-phenyl-6-ox-
o-1,6-dihydro-1-pyrimidinyl]acetaldehyde in tetrahydrofuran and
dichloromethane (1:1, 0.3 M) is added a catalytic amount of acetic
acid and 1 equivalent of the appropriate amine. The solution is
cooled to 0.degree. C. in an ice bath, and 1 equivalent sodium
triacetoxyborohydride is added in one portion. After stirring for 5
minutes, the ice bath is removed, and the reaction mixture is
allowed to stir at room temperature for 2 hours. The reaction is
quenched by the addition of 1 N NaOH, and the mixture is stirred
for 5 minutes. Typical aqueous work up is followed by
chromatographic purification to provide pure product EX-9A.
[0637] EX-9B) To a solution of
[5[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-
-1,6-dihydro-1-pyrimidinyl]acetamide (EX-9A) in methanol (0.2 M) is
added 10% Pd/C in one portion. The resulting mixture is stirred
under an atmosphere of hydrogen gas (balloon) at room temperature
for approximately 16 hours. The crude reaction mixture is filtered
through a pad of Celite 545, and the solvent is removed under
reduced pressure. Trituration of the residue from ethyl ether gives
pure product EX-9B.
[0638] EX-9C) To a solution of
[5-amino-2-phenyl-6-oxo-1,6-dihydro-1-pyrim- idinyl]acetamide
(EX-9B) in tetrahydrofuran and dichloromethane (1:1, 0.3 M) is
added a catalytic amount of acetic acid and 1 equivalent
phenylacetaldehyde. The solution is cooled to 0.degree. C. in an
ice bath, and 1 equivalent sodium triacetoxyborohydride is added in
one portion. After stirring for 5 minutes, the ice bath is removed,
and the reaction mixture is allowed to stir at room temperature for
2 hours. The reaction is quenched by the addition of 1 N NaOH, and
the mixture is stirred for 5 minutes. Typical aqueous work up is
followed by chromatographic purification to provide pure product
EX-9C.
[0639] A solution of
[5-(2-phenylethyl)amino-2-phenyl-6-oxo-1,6-dihydro-1--
pyrimidinyl]acetamide in 4M HCl dioxane (0.2 M) is stirred for
several hours. After the reaction is complete, the volatiles are
removed under reduced pressure. The residue is purified by
trituration with ethyl ether to afford pure product 5.
[0640] Sulfonyl analogs of pyrimidinones wherein a sulfonyl is
present as a replacement for the carbonyl of the acetamide at the
N-3 position of the pyrimidinone can be prepared using procedures
generally based on those disclosed in Schemes 1-5 by substituting
an appropriate aminomethanesulfonamide of an
N-Boc-amidino-protected amine in place of the
1,1-dimethoxyethylamine. For example, the
N-(4-amidinobenzyl).sub.2-a- minomethanesulfonamide can be used.
Using this approach, sulfonyl analogs in Examples 10 and 11 can be
prepared.
EXAMPLE 10
[0641] 61
EXAMPLE 11
[0642] 62
[0643] Triazinone analogs of pyrimidinones wherein a nitrogen is
present as a replacement for the carbon at the 4-position of the
pyrimidinone can be prepared using Scheme 9 "A General 4Aza
Pyrimidinone Preparation" as detailed below along with the specific
Example 12. 63
EXAMPLE 12
[0644] 64
[0645] EX-12) A solution of glycine t-butyl ester hydrochloride (1
mmol) in dichloromethane is treated with benzoyl chloride (1 mmol)
and triethyl amine (2 mmol). The reaction mixture is allowed to
stir at room temperature for 16 h. The mixture is washed with water
and extracted with dichloromethane. The combined organic layers are
dried over MgSO.sub.4. After removing the volatiles in vacuo pure
product EX-12A is isolated.
[0646] EX-12B) A mixture of N-benzoylglycine t-butyl ester (1 mmol;
EX-12A), Lawesson's reagent (0.5 mmol) and toluene are heated to
80.degree. C. for 16 h. The reaction mixture is concentrated under
reduced pressure. Purification via column chromatography on silica
gel gives pure product EX-12B.
[0647] EX-12C) A mixture of N-thiobenzoylolycine t-butyl ester (1
mmol; EX12B) in dichloromethane is treated with trimethyloxonium
tetrafluoroborate (1.1 mmol) at -78.degree. C. After stirring the
reaction mixture for 2 h, the mixture is washed with NaHCO.sub.3
(aq) and extracted with dichloromethane. The combined organic
layers are dried over MgSO.sub.4 and filtered. After concentration
of the volatile organic components, the desired product EX-12C is
isolated.
[0648] EX-12D) A solution of N-thiomethylbenzylglycine t-butyl
ester (1 mmol; EX-12C) in methanol is treated with hydrazine (1
mmol). The volatile materials are removed in vacuo, and the desired
compound EX-12D is isolated without further purification.
[0649] EX-12E) A mixture of compound EX-12D (1 mmol) and ethyl
thiooxamate (1 mmol) in methanol is heated to reflux temperature
for 4 h. A precipitation of colorless crystals occurs, and the
crystals of the desired product EX-12E are isolated by suction
filtration.
[0650] A solution of compound EX-12E (1 mmol) and pyridine (5 mmol)
in acetonitrile is treated with a solution of a-toluenesulfonyl
chloride (3 mmol) in acetonitrile. The reaction mixture is stirred
at -10.degree. C. to 0.degree. C. for 3 h. A white precipitate
forms after the reaction is complete. The crystals of the desired
product EX-12F are isolated by suction filtration.
[0651] EX-12G) Trifluoroacetic acid is added to a mixture of
compound EX-12F (1 mmol) in anisole at 0.degree. C. The reaction
mixture is allowed to stir at 0.degree. C. for 1 h. The reaction
mixture is extracted with an organic solvent. Removal of the
organic solvent under reduced pressure gives pure product
EX-12G.
[0652] EX-12H) Compound EX-12G (1 mmol), EDC (1.3 mmol), and HOBt
(1.3 mmol) are mixed in DMF, and the mixture is stirred at 200C for
15 minutes. To this mixture is added a solution of benzyl-[[(4
aminomethylphenyl)iminomethyl]amino]carbamate hydrogen chloride
salt (1.3 mmol) and DIEA (1.3 mmol) in DMF. Typical aqueous work-up
is followed by chromatographic purification to provide the desired
product EX-12H.
[0653] Compound EX-12H (1 mmol), p-toluene sulfonic acid mono
hydrate (1 mmol) and 10% Pd on activated carbon (0.1 mmol) are
mixed with methanol. The mixture is stirred for 2 h under hydrogen
atmosphere which is introduced and maintained through a rubber
balloon. After filtering off the catalyst and removing the
methanol, the desired product is isolated.
[0654] 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 comounds 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 derivative 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.
[0655] 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 comounds 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 derivative 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.
[0656] The results of the aforementioned synthetic approaches to
the preparation pyrimidinones by derivatization of a nucleophilic
substituent such as may be present in B, R.sup.1, R.sup.2 and
Y.sup.0 are shown in Table 1 for the specific Examples 13 through
19. The specific examples recited below should be considered a
being merely illustrative of the wide variety possible and not as
limiting to one of ordinary skill in the art.
1TABLE 1 Structures of Pyrimidinones Prepared by General
Derivatization Procedures 65 Ex. MW No. R.sup.2 B--A-- Y.sup.O (m/z
+ 1) 13 phenyl methoxyacetyl 4-amidinobenzyl 449.47 14 phenyl
4-methylbenzoyl 4-amidinobenzyl 495.54 15 phenyl 4-nitrobenzoyl
4-amidinobenzyl 526.52 16 phenyl isobutyryl 4-amidinobenzyl 447.50
17 phenyl 2,4,6-trimethylbenzoyl 4-amidinobenzyl 523.60 18 phenyl
benzoyl 4-amidinobenzyl 481.52 19 phenyl acetyl 4-amidobenzyl
419.45
Assays for Biological Activity
TF-VIIa Assay
[0657] 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.405nm value from the experimental and
control sample.
Xa Assay
[0658] 0.3 nM human factor Xa and 0.15 mM
N-.alpha.-Benzyloxycarbonyl-D-ar-
ginyl-1-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.405nm value from the
experimental and control sample.
Thrombin Assay
[0659] 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.405nm
value from the experimental and control sample.
Trypsin Assay
[0660] 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.405nm value from the experimental and
control sample.
[0661] 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.
[0662] The biological activity of the compounds of Examples 1
through 19 as determined by the bioassay procedures is summarized
in the Table 2.
2TABLE 2 Inhibitory Activity of Pyrimidinones 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 15.4 22.4 -- 0.5 2 >30 >30 -- >30 3 1.0 1.0 -- 0.6 4 --
-- -- -- 5 -- -- -- -- 6 0.05 43% @ 30 uM 33% @ 30 uM <0.04 7
0.7 11.3 33% @ 30 uM 0.04 8 0.08 42% @ 30 uM 15% @ 30 uM 0.04 9 --
-- -- -- 10 -- -- -- -- 11 -- -- -- -- 12 -- -- -- -- 13 -- -- --
-- 14 -- -- -- -- 15 -- -- -- -- 16 -- -- -- -- 17 -- -- -- -- 18
-- -- -- -- 19 -- -- -- --
* * * * *