U.S. patent application number 10/691958 was filed with the patent office on 2004-05-27 for substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade.
This patent application is currently assigned to Pharmacia Corporation. Invention is credited to Case, Brenda, Dice, Tom, Fenton, Rick, Franklin, Gary W., Hayes, Michael J., Huang, Horng-Chih, Huang, Wei, Jones, Darin E., Kusturin, Carrie, Lindmark, Richard, Long, Scott A., Mahoney, Matthew W., Neumann, William L., Parlow, John J., Reitz, David B., Rueppel, Melvin L., South, Michael S., Trujillo, John I., Wang, Ching-Cheng, Wood, Rhonda, Zeng, Qingping.
Application Number | 20040102448 10/691958 |
Document ID | / |
Family ID | 24297484 |
Filed Date | 2004-05-27 |
United States Patent
Application |
20040102448 |
Kind Code |
A1 |
South, Michael S. ; et
al. |
May 27, 2004 |
Substituted polycyclic aryl and heteroaryl pyrazinones useful for
selective inhibition of the coagulation cascade
Abstract
The invention relates to substituted polycyclic aryl and
heteroaryl pyrazinone 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 dirombotic conditions including coronary
artery and cerebrovascular diseases.
Inventors: |
South, Michael S.; (St.
Louis, MO) ; Parlow, John J.; (Arnold, MO) ;
Jones, Darin E.; (Ballwin, MO) ; Case, Brenda;
(St. Louis, MO) ; Dice, Tom; (St. Charles, MO)
; Lindmark, Richard; (Kirkwood, MO) ; Hayes,
Michael J.; (St. Louis, MO) ; Rueppel, Melvin L.;
(St. Louis, MO) ; Huang, Horng-Chih;
(Chesterfield, MO) ; Huang, Wei; (Wildwood,
MO) ; Long, Scott A.; (Ballwin, MO) ; Mahoney,
Matthew W.; (St. Peters, MO) ; Neumann, William
L.; (Ballwin, MO) ; Reitz, David B.;
(Chesterfield, MO) ; Trujillo, John I.; (St.
Peters, MO) ; Wang, Ching-Cheng; (Wildwood, MO)
; Wood, Rhonda; (Maryland Heights, MO) ; Zeng,
Qingping; (Thousand Oaks, CA) ; Fenton, Rick;
(Collinsville, IL) ; Franklin, Gary W.; (Godfrey,
IL) ; Kusturin, Carrie; (Edwardsville, IL) |
Correspondence
Address: |
SENNIGER POWERS LEAVITT AND ROEDEL
ONE METROPOLITAN SQUARE
16TH FLOOR
ST LOUIS
MO
63102
US
|
Assignee: |
Pharmacia Corporation
|
Family ID: |
24297484 |
Appl. No.: |
10/691958 |
Filed: |
October 23, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10691958 |
Oct 23, 2003 |
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09574752 |
May 18, 2000 |
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6664255 |
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60134958 |
May 19, 1999 |
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Current U.S.
Class: |
514/252.1 ;
514/255.05; 544/405; 544/408 |
Current CPC
Class: |
A61P 9/10 20180101; C07D
409/04 20130101; C07D 409/12 20130101; C07D 401/12 20130101; C07K
5/06191 20130101; A61P 9/00 20180101; C07D 403/12 20130101; A61P
35/00 20180101; C07D 417/12 20130101; C07D 413/12 20130101; A61P
7/02 20180101; A61P 9/04 20180101; C07D 405/04 20130101; A61P 43/00
20180101; C07D 241/20 20130101; C07K 5/06139 20130101; A61K 38/00
20130101 |
Class at
Publication: |
514/252.1 ;
514/255.05; 544/405; 544/408 |
International
Class: |
A61K 031/4965; A61K
031/497; C07D 43/02 |
Claims
What we claim is:
1. A compound having the Formula: 119or a pharmaceutically
acceptable salt thereof, wherein: B is formula (V): 120 wherein
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 independently
selected from the group consisting of C, N, O, S and a covalent
bond with the provisos that no more than one is a covalent bond, no
more than one of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 is
O, no more than one of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and
K.sup.1 is S, one of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1
must be a covalent bond when two of D.sup.1, D.sup.2, J.sup.1,
J.sup.2 and K.sup.1 are O and S, and no more than four of D.sup.1,
D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are N; R.sup.9, R.sup.10,
R.sup.11, R.sup.12, R.sup.13, R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36, are independently selected from the group
consisting of hydrido, acetamido, haloacetamido, amidino,
guanidino, alkylenedioxy, haloalkylthio, alkanoyloxy, alkoxy,
alkoxyalkyl, haloalkoxylalkyl, hydroxy, amino, alkoxyamino, nitro,
lower alkylamino, akylthio, alkylthioalkyl, alkylsulfinyl,
alkylsulfonyl, alkylsulfonylalkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, heteroaryl, heterocyclyl, alkylsulfonamido,
alkylaminosulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkanoyl, haloalkanoyl, alkyl, alkenyl, halo,
haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl, hydroxyalkyl,
aminoalkyl, haloalkoxyalkyl, carboxyalkyl, carboalkoxy, carboxy,
carboxamido, carboxamidoalkyl, and cyano; R.sup.16, R.sup.19,
R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; B is optionally selected from the group
consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl,
C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each
member of group B is optionally substituted at any carbon up to and
including 6 atoms from the point of attachment of B to A with one
or more of the group consisting of R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36; B is optionally selected from the group
consisting of C3-C12 cycloalkyl and C4-C9 saturated heterocyclyl,
wherein each ring carbon is optionally substituted with R.sup.33, a
ring carbon other than the ring carbon at the point of attachment
of B to A is optionally substituted with oxo provided that no more
than one ring carbon is substituted by oxo at the same time, ring
carbons and a nitrogen adjacent to the carbon atom at the point of
attachment are optionally substituted with R.sup.9 or R.sup.13, a
ring carbon or nitrogen atom adjacent to the R.sup.9 position and
two atoms from the point of attachment is optionally substituted
with R.sup.10, a ring carbon or nitrogen adjacent to the R.sup.13
position and two atoms from the point of attachment is optionally
substituted with R.sup.12, a ring carbon or nitrogen three atoms
from the point of attachment and adjacent to the R.sup.10 position
is optionally substituted with R.sup.11, a ring carbon or nitrogen
three atoms from the point of attachment and adjacent to the
R.sup.12 position is optionally substituted with R.sup.33, and a
ring carbon or nitrogen four atoms from the point of attachment and
adjacent to the R.sup.11 and R.sup.33 positions is optionally
substituted with R.sup.34; A is selected from the group consisting
of single covalent bond, (W.sup.7).sub.rr--(CH(R.sup.15)).sub.pa
and (CH(R.sup.15)).sub.pa--- (W.sup.7).sub.rr wherein rr is an
integer selected from 0 through 1, pa is an integer selected from 0
through 6, and W.sup.7 is selected from the group consisting of O,
S, C(O), (R.sup.7)NC(O), (R.sup.7)NC(S), and N(R.sup.7) with the
proviso that no more than one of the group consisting of rr and pa
is 0 at the same time; R.sup.7 is selected from the group
consisting of hydrido, hydroxy, and alkyl; R.sup.15 is selected
from the group consisting of hydrido, hydroxy, halo, alkyl, and
haloalkyl; .PSI. is selected from the group consisting of NH and
NOH; R.sup.1 is selected from the group consisting of hydrido,
alkyl, alkenyl, cyano, halo, haloalkyl, haloalkoxy, haloalkylthio,
amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino,
alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R.sup.2 is
Z.sup.0--Q; Z.sup.0 is selected from the group consisting of
covalent single bond, (CR.sup.41R.sup.42).sub.q wherein q is an
integer selected from 1 through 3,
(CH(R.sup.41)).sub.g--W.sup.0--(- CH(R.sup.42)).sub.p wherein g and
p are integers independently selected from 0 through 3 and W.sup.0
is selected from the group consisting of O, S, C(O), S(O),
N(R.sup.41), and ON(R.sup.41), and (CH(R.sup.41)).sub.e--W-
.sup.22--(CH(R.sup.42)).sub.h wherein e and h are integers
independently selected from 0 through 1 and W.sup.22 is selected
from the group consisting of CR.sup.41.dbd.CR.sup.42,
1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl,
1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,
2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl,
1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl,
1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl,
3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,
2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl,
3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso
that Z.sup.0 is directly bonded to the pyrazinone ring; R.sup.41
and R.sup.42 are independently selected from the group consisting
of amidino, hydroxyamino, hydrido, hydroxy, amino, and alkyl; Q is
selected from the group consisting of hydrido, with the proviso
that Z.sup.0 is other than a covalent single bond, and the formula
(II): 121 wherein D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1
are independently selected from the group consisting of C, N, O, S
and a covalent bond with the provisos that no more than one is a
covalent bond, no more than one of D.sup.1, D.sup.2, J.sup.1,
J.sup.2 and K.sup.1 is O, no more than one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 is S, one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 must be a covalent bond when two of
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are O and S, and no
more than four of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1
are N, with the proviso that R.sup.9, R.sup.10, R.sup.11, R.sup.12,
and R.sup.13 are each independently selected to maintain the
tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, and the divalent nature of oxygen; K is
(CR.sup.4aR.sup.4b).sub.n wherein n is an integer selected from 1
through 2; R.sup.4a and R.sup.4b are independently selected from
the group consisting of halo, hydrido, hydroxyalkyl, alkyl,
alkoxyalkyl, alkylthioalkyl, and haloalkyl; E.sup.0 is E.sup.1 when
K is (CR.sup.4aR.sup.4b).sub.n, wherein E.sup.1 is selected from
the group consisting of a covalent single bond, C(O), C(S),
C(O)N(R.sup.7), (R.sup.7)NC(O), S(O).sub.2, (R.sup.7)NS(O).sub.2,
and S(O).sub.2N(R.sup.7); Y.sup.0 is formula (IV): 122 wherein
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are independently selected
from the group consisting of C, N, O, S and a covalent bond with
the provisos that no more than one is a covalent bond, K.sup.2 is
C, no more than one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is O,
no more than one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is S,
one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 must be a covalent
bond when two of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are O and
S, and no more than four of D.sup.5, D.sup.6, J.sup.5, and J.sup.6
are N; R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, nitro, alkoxyamino,
lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl,
alkanoyl, haloalkanoyl, alkyl, alkenyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, alkylamino, haloalkoxyalkyl, carboalkoxy,
and cyano; Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21 aminoalkylenyl, Q.sup.be wherein Q.sup.be is
hydrido, N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), and
C(NR.sup.25)NR.sup.23R.- sup.24, with the provisos that no more
than one of R.sup.20 and R.sup.21 is hydroxy, amino, alkylamino, or
dialkylamino at the same time and that no more than one of R.sup.23
and R.sup.24 is hydroxy, amino, alkylamino, or dialkylamino at the
same time; R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are independently selected from the group consisting of
hydrido, alkyl, hydroxy, aminoalkylenyl, amino, dialkyl amino,
alkylamino, and hydroxyalkyl; Q.sup.s is selected from the group
consisting of a single covalent bond, (CR.sup.37R.sup.38).sub.b
wherein b is an integer selected from 1 through 4, and
(CH(R.sup.14)).sub.c--W.sup.- 1--(CH(R.sup.15)).sub.d wherein c and
d are integers independently selected from 1 through 3 and W.sup.1
is selected from the group consisting of C(O)N(R.sup.14),
(R.sup.14)NC(O), S(O), S(O).sub.2, S(O).sub.2N(R.sup.14),
N(R.sup.14)S(O).sub.2, and N(R.sup.14), with the provisos that
R.sup.14 is selected from other than halo when directly bonded to N
and that (CR.sup.37R.sup.38).sub.b, and (CH(R.sup.14)).sub.c are
bonded to E.sup.0; R.sup.14 is selected from the group consisting
of hydrido, halo, alkyl, and haloalkyl; R.sup.37 and R.sup.38 are
independently selected from the group consisting of hydrido, alkyl,
and haloalkyl; R.sup.38 is optionally selected from the group
consisting of aroyl and heteroaroyl; Y.sup.0 is optionally
Q.sup.b--Q.sup.ss wherein Q.sup.ss is
(CH(R.sup.14)).sub.e--W.sup.2--(CH(R.sup.15)).sub.h wherein e and h
are integers independently selected from 1 through 2 and W.sup.2 is
CR.sup.4a.dbd.CR.sup.4b with the proviso that (CH(R.sup.14)).sub.e
is bonded to E.sup.0; Y.sup.0 is optionally selected from the group
consisting of Q.sup.b--Q.sup.ssss and Q.sup.b--Q.sup.ssssr wherein
Q.sup.ssss is (CH(R.sup.38)).sub.r--W.sup.5 and Q.sup.ssssr is
(CH(R.sup.38)).sub.r--W.sup.6, r is an integer selected from 1
through 2, and W.sup.5 and W.sup.6 are independently selected from
the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl,
1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl,
3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl,
2,4-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,
3,5-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
is bonded to lowest number substituent position of each W.sup.5,
Q.sup.b is bonded to highest number substituent position of each
W.sup.6, and (CH(R.sup.38)).sub.r is bonded to E.sup.0.
2. The compound as recited in claim 1 having the Formula: 123or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of aryl and heteroaryl wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.32 the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.36, a
carbon adjacent to R.sup.32 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.33, a carbon
adjacent to R.sup.36 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.35, and any carbon
adjacent to both R.sup.33 and R.sup.35 is substituted by R.sup.34;
R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkylenedioxy,
haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino,
haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl,
cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl,
haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b; B is optionally selected from the
group consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8
alkylenyl, C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl,
wherein each member of group B is optionally substituted at any
carbon up to and including 6 atoms from the point of attachment of
B to A with one or more of the group consisting of R.sup.32,
R.sup.33, R.sup.34, R.sup.35,and R.sup.36; B is optionally selected
from the group consisting of C3-C12 cycloalkyl and C4-C9 saturated
heterocyclyl, wherein each ring carbon is optionally substituted
with R.sup.33, a ring carbon other than the ring carbon at the
point of attachment of B to A is optionally substituted with oxo
provided that no more than one ring carbon is substituted by oxo at
the same time, ring carbons and a nitrogen adjacent to the carbon
atom at the point of attachment are optionally substituted with
R.sup.9 or R.sup.13, a ring carbon or nitrogen atom adjacent to the
R.sup.9 position and two atoms from the point of attachment is
optionally substituted with R.sup.10, a ring carbon or nitrogen
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; R.sup.9, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl,
amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy,
amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and
cyano; A is selected from the group consisting of single covalent
bond and (CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an
integer selected from 0 through 1, pa is an integer selected from 0
through 3, and W.sup.7 is selected from the group consisting of O,
S, C(O), (R.sup.7)NC(O), (R.sup.7)NC(S), and N(R.sup.7); R.sup.7 is
selected from the group consisting of hydrido, hydroxy and alkyl;
R.sup.15 is selected from the group consisting of hydrido, hydroxy,
halo, alkyl, and haloalkyl; R.sup.1 is selected from the group
consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy,
amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino,
alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R.sup.2 is
Z.sup.0--Q; Z.sup.0 is selected from the group consisting of
covalent single bond and (CR.sup.41R.sup.42).sub.q wherein q is an
integer selected from 1 through 2,
(CH(R.sup.41)).sub.g--W.sup.0--(CH(R.s- up.42)).sub.p wherein g and
p are integers independently selected from 0 through 3 and W.sup.0
is selected from the group consisting of O, S, and N(R.sup.41), and
(CH(R.sup.41)).sub.e--W.sup.22(CH(R.sup.42)).sub.h wherein e and h
are integers independently selected from 0 through 1 and W.sup.22
is selected from the group consisting of CR.sup.41.dbd.CR.sup.42- ,
1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl,
1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,
2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl,
1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl,
1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl,
3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,
2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl,
3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso
that Z.sup.0 is directly bonded to the pyrazinone ring; R.sup.41
and R.sup.42 are independently selected from the group consisting
of hydrido, hydroxy, and amino; Q is selected from the group
consisting of hydrido, with the proviso that Z.sup.0 is other than
a covalent single bond, aryl, and heteroaryl, wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.9, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.13, a
carbon adjacent to R.sup.9 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.10, a carbon
adjacent to R.sup.13 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.12, and any carbon
adjacent to both R.sup.10 and R.sup.12 is optionally substituted by
R.sup.11; K is CHR.sup.4a wherein R.sup.4a is selected from the
group consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl,
alkylthioalkyl, and haloalkyl; E.sup.0 is selected from the group
consisting of a covalent single bond, C(O)N(H), (H)NC(O),
(R.sup.7)NS(O).sub.2, and S(O).sub.2N(R.sup.7); Y.sup.0 is formula
(IV): 124 wherein D.sup.5, D.sup.6, J.sup.5 and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one can be a
covalent bond, K.sup.2 is C, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 can be O, no more than one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 can be S, one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 must be a covalent bond when two of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are O and S, and no more than four of
D.sup.5, D.sup.6, J.sup.5 and J.sup.6 can be N, with the provisos
that R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are each
independently selected to maintain the tetravalent nature of
carbon, trivalent nature of nitrogen, the divalent nature of
sulfur, and the divalent nature of oxygen; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,
alkoxy, hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R.sup.16 and R.sup.19 are optionally Q.sup.b with the proviso that
no more than one of R.sup.16 and R.sup.19 is Q.sup.b at the same
time and that Q.sup.b is Q.sup.be; Q.sup.b is selected from the
group consisting of NR.sup.20, R.sup.21, Q.sup.be wherein Q.sup.be
is hydrido, N(R.sup.26)C(NR.sup.25)N(- R.sup.23)(R.sup.24), and
C(NR.sup.25)NR.sup.23R.sup.24, with the provisos that no more than
one of R.sup.20 and R.sup.21 is hydroxy, amino, alkylamino, or
dialkylamino at the same time and that no more than one of R.sup.23
and R.sup.24 is hydroxy, amino, alkylamino, or dialkylamino at the
same time; R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are independently selected from the group consisting of
hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;
Q.sup.s is selected from the group consisting of a single covalent
bond, (CR.sup.37R.sup.38).sub.b wherein b is an integer selected
from 1 through 4, and
(CH(R.sup.14)).sub.c--W.sup.1--(CH(R.sup.15)).sub.d wherein c and d
are integers independently selected from 1 through 3 and W.sup.1 is
selected from the group consisting of C(O)N(R.sup.14),
(R.sup.14)NC(O), S(O), S(O).sub.2, S(O).sub.2N(R.sup.14),
N(R.sup.14)S(O).sub.2, and N(R.sup.14), with the provisos that
R.sup.14 is selected from other than halo when directly bonded to N
and that (CR.sup.37R.sup.38).sub.b, and (CH(R.sup.14)).sub.c are
bonded to E.sup.0; R.sup.14 is selected from the group consisting
of hydrido, halo, alkyl, and haloalkyl; R.sup.37 and R.sup.38 are
independently selected from the group consisting of hydrido, alkyl,
and haloalkyl; R.sup.38 is optionally selected from the group
consisting of aroyl and heteroaroyl; Y.sup.0 is optionally
Q.sup.b--Q.sup.ss wherein Q.sup.ss is
(CH(R.sup.14)).sub.e--W.sup.2--(CH(- R.sup.15)).sub.h, wherein e
and h are integers independently selected from 1 through 2 and
W.sup.2 is CR.sup.4a.dbd.CH with the proviso that
(CH(R.sup.14)).sub.e is bonded to E.sup.0.
3. The compound as recited in claim 2 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of hydrido, trialkylsilyl, C2-C8 alkyl, C3-C8 alkylenyl,
C3-C8 alkenyl, C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each
member of group B is optionally substituted at any carbon up to and
including 6 atoms from the point of attachment of B to A with one
or more of the group consisting of R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and
R.sup.36 are independently selected from the group consisting of
hydrido, acetamido, haloacetamido, amidino, guanidino, alkoxy,
hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,
amidosulfonyl, monoalkyl amidosulfonyl, dialkyl amidosulfonyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy,
carboxy, carboxamido, cyano, and Q.sup.b; A is
(CH(R.sup.15)).sub.pa--W.sup.7 wherein pa is an integer selected
from 1 through 3 and W.sup.7 is selected from the group consisting
of O, S, and N(R.sup.7) wherein R.sup.7 is selected from the group
consisting of hydrido and alkyl; R.sup.15 is selected from the
group consisting of hydrido, hydroxy, halo, alkyl, and haloalkyl
with the proviso that R.sup.15 is other than hydroxy and halo when
R.sup.15 is on the carbon bonded directly to W.sup.7; R.sup.1 is
selected from the group consisting of hydrido, alkyl, cyano, halo,
and haloalkyl; R.sup.2 is Z.sup.0--Q; Z.sup.0 is selected from the
group consisting of covalent single bond and
(CR.sup.41R.sup.42).sub.q wherein q is an integer selected from 1
through 2; R.sup.41 and R.sup.42 are independently selected from
the group consisting of hydrido, hydroxy, and amino; Q is selected
from the group consisting of aryl and heteroaryl, wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.9, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.13, a
carbon adjacent to R.sup.9 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.10, a carbon
adjacent to R.sup.13 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.12, and any carbon
adjacent to both R.sup.10 and R.sup.12 is optionally substituted by
R.sup.11; R.sup.9, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl,
amidino, guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy,
amino, lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and
cyano; K is CHR.sup.4a wherein R.sup.4a is selected from the group
consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl,
alkylthioalkyl, and haloalkyl; E.sup.0 is selected from the group
consisting of a covalent single bond, C(O)N(H), (H)NC(O),
(R.sup.7)NS(O).sub.2, and S(O).sub.2N(R.sup.7); Y.sup.0 is formula
(IV); 125 wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is C, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is O, no more than one of D.sup.5, D.sup.6,
J.sup.5 and J.sup.6 is S, one of D.sup.5, D.sup.6, J.sup.5 and
J.sup.6 must be a covalent bond when two of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are O and S, and no more than four of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are N; R.sup.16, R.sup.17, R.sup.18,
and R.sup.19 are independently selected from the group consisting
of hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy,
hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, alkylamino, and cyano;
R.sup.16 and R.sup.19 are optionally Q.sup.b with the proviso that
no more than one of R.sup.16 and R.sup.19 is Q.sup.b at the same
time and that Q.sup.b is Q.sup.be; Q.sup.b is selected from the
group consisting of NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is
hydrido, N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), and
C(NR.sup.25)NR.sup.23R.- sup.24, with the provisos that no more
than one of R.sup.20 and R.sup.21 is hydroxy, amino, alkylamino, or
dialkylamino at the same time and that no more than one of R.sup.23
and R.sup.24 is hydroxy, amino, alkylamino, or dialkylamino at the
same time; R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and
R.sup.26 are independently selected from the group consisting of
hydrido, alkyl, hydroxy, amino, alkylamino and dialkylamino;
Q.sup.s is selected from the group consisting of a single covalent
bond, (CR.sup.37R.sup.38).sub.b wherein b is an integer selected
from 1 through 3, and (CH(R.sup.14)).sub.c--W.sup.1--(CH(R.sup.15)
wherein c and d are integers independently selected from 1 through
2 and W.sup.1 is selected from the group consisting of
C(O)N(R.sup.14), (R.sup.14)NC(O), S(O), S(O).sub.2,
S(O).sub.2N(R.sup.14), N(R.sup.14)S(O).sub.2, and N(R.sup.14), with
the provisos that R.sup.14 is selected from other than halo when
directly bonded to N and that (CR.sup.37R.sup.38).sub.b, and
(CH(R.sup.14)).sub.c are bonded to E.sup.0; R.sup.14 is selected
from the group consisting of hydrido, halo, alkyl, and haloalkyl;
R.sup.37 and R.sup.38 are independently selected from the group
consisting of hydrido, alkyl, and haloalkyl; R.sup.38 is optionally
selected from the group consisting of aroyl and heteroaroyl;
Y.sup.0 is optionally Q.sup.b--Q.sup.ss wherein Q.sup.ss is
(CH(R.sup.14)).sub.e--W.sup.2--(CH(R.sup.15)).sub.h, wherein e and
h are integers independently selected from 1 through 2 and W.sup.2
is CR.sup.4a.dbd.CH with the proviso that (CH(R.sup.14)).sub.e is
bonded to E.sup.0.
4. The compound as recited in claim 3 having the Formula; 126or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of hydrido, trialkylsilyl, C2-C4 alkyl,
C3-C5 alkylenyl, C3-C4 alkenyl, C3-C4 alkynyl, and C2-C4 haloalkyl,
wherein each member of group B is optionally substituted at any
carbon up to and including 3 atoms from the point of attachment of
B to A with one or more of the group consisting of R.sup.32,
R.sup.33, and R.sup.34; R.sup.32, R.sup.33, 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, and cyano; A is (CH(R.sup.15)).sub.pa--N(R.sup.7)
wherein pa is an integer selected from 1 through 2 and R.sup.7 is
selected from the group consisting of hydrido and alkyl; R.sup.15
is selected from the group consisting of hydrido, halo, alkyl, and
haloalkyl; R.sup.1 is selected from the group consisting of
hydrido, alkyl, cyano, halo, and haloalkyl; R.sup.2 is Z.sup.0--Q;
Z.sup.0 is selected from the group consisting of covalent single
bond and CH.sub.2; Q is selected from the group consisting of aryl
and heteroaryl, wherein a carbon adjacent to the carbon at the
point of attachment is optionally substituted by R.sup.9, the other
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.13, a carbon adjacent to R.sup.9
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.10, a carbon adjacent to R.sup.13
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.12, and any carbon adjacent to both
R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
R.sup.9, R.sup.11, and R.sup.13 are independently selected from the
group consisting of hydrido, hydroxy, amino, amidino, guanidino,
lower alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl,
alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy,
carboxamido, and cyano; R.sup.10 and R.sup.12 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino,
alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl,
halo, haloalkyl, and cyano; Y.sup.0 is formula (IV): 127wherein
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;
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and
cyano; R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be; Q.sup.b is selected
from the group consisting of NR.sup.20R.sup.21, Q.sup.be wherein
Q.sup.be is hydrido, C(NR.sup.25)NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.su- p.23)(R.sup.24), with the provisos
that no more than one of R.sup.20 and R.sup.21 is hydroxy at the
same time and that no more than one of R.sup.23 and R.sup.24 is
hydroxy at the same time; R.sup.20, R.sup.21, R.sup.23, R.sup.24,
R.sup.25, and R.sup.26 are independently selected from the group
consisting of hydrido, alkyl, and hydroxy; Q.sup.s is selected from
the group consisting of a single covalent bond, CH.sub.2, and
CH.sub.2CH.sub.2.
5. The compound as recited in claim 4 having the Formula or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of ethyl, 2-propenyl, 2-propynyl, propyl,
isopropyl, trimethylene, tetramethylene, butyl, 2-butenyl,
3-butenyl, 2-butynyl, sec-butyl, tert-butyl, isobutyl,
2-methylpropenyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and
2,2-difluoropropyl, wherein each member of group B is optionally
substituted at any carbon up to and including 3 atoms from the
point of attachment of B to A with one or more of the group
consisting of R.sup.32, R.sup.33, and R.sup.34; R.sup.32, R.sup.33,
and R.sup.34 are independently selected from the group consisting
of hydrido, amidino, guanidino, carboxy, methoxy, ethoxy,
isopropoxy, propoxy, hydroxy, amino, methoxyamino, ethoxyamino,
acetamido, trifluoroacetamido, N-methylamino, dimethylamino,
N-ethylamino, methylthio, ethylthio, isopropylthio,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,
amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl,
and cyano; A is selected from the group consisting of single
covalent bond, NH, and N(CH.sub.3); R.sup.1 is selected from the
group consisting of hydrido, methyl, ethyl, propyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, fluoro, chloro, and bromo; R.sup.2 is
Z.sup.0--Q; Z.sup.0 is selected from the group consisting of a
covalent single bond and CH.sub.2; Q is selected from the group
consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl,
2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4imidazolyl, 3-pyrazolyl,
4pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl,
3-pyridyl, 4pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4pyridazinyl, and 1,3,5-triazin-2-yl,
wherein a carbon adjacent to the carbon at the point of attachment
is optionally substituted by R.sup.9, the other carbon adjacent to
the carbon at the point of attachment is optionally substituted by
R.sup.13, a carbon adjacent to R.sup.9 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.10, a carbon adjacent to R.sup.13 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.12, and any carbon adjacent to both R.sup.10 and R.sup.12 is
optionally substituted by R.sup.11; R.sup.9, R.sup.11, and R.sup.13
are independently selected from the group consisting of hydrido,
amidino, guanidino, carboxy, methyl, ethyl, propyl, isopropyl,
methoxy, ethoxy, isopropoxy, propoxy, hydroxy, amino,
N-methylamino, N,N-dimethylamino, N-ethylamino, methylthio,
ethylthio, isopropylthio, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R.sup.10 and R.sup.12 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,
amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl,
fluoro, chloro, bromo, and cyano; Y.sup.0 is selected from the
group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzen-
e, 2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
2-Q.sup.b-4-Q.sup.s-3-R.sup.16-6-R.sup.18pyrazine,
3-Q.sup.b-2-Q.sup.s-2-R.sup.18-5-R.sup.18-4-R.sup.19 pridazine,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18pyrimidine,
5-Q.sup.b-2-Q.sup.s-3-R.sup.16-6-R.sup.19pyrimidine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-4-R.s- up.16-2-R.sup.19furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19 pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R.sup.19imidazole,
2-Q.sup.b-4-Q.sup.s-5-R.sup.17im- idazole,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16isoxazole, 5-Q.sup.b-3-Q.sup.s-4-R.-
sup.16isoxazole, 2-Q.sup.b-5-Q.sup.s-4-R.sup.16pyrazole,
4-Q.sup.b-2-Q.sup.s-5-R.sup.19thiazole, and
2-Q.sup.b-5-Q.sup.s-4-R.sup.1- 7thiazole; 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-1hydroxyethyl, and cyano; R.sup.16 and R.sup.19 are
optionally Q.sup.b with the proviso that no more than one of
R.sup.16 and R.sup.19 is Q.sup.b at the same time and that Q.sup.b
is Q.sup.be; Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido,
C(NR.sup.25)NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.s- up.24), with the provisos
that no more than one of R.sup.20, R.sup.21, R.sup.23, and R.sup.24
can be hydroxy, when any two of the group consisting of R.sup.20,
R.sup.21, R.sup.23, and R.sup.24 are bonded to the same atom and
that said Q.sup.b group is bonded directly to a carbon atom;
R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are
independently selected from the group consisting of hydrido,
methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; Q.sup.s is
selected from the group consisting of a single covalent bond,
CH.sub.2, and CH.sub.2CH.sub.2.
6. The compound as recited in claim 4 having the Formula: 128or a
pharmaceutically acceptable salt thereof, wherein: A is selected
from the group consisting of CH.sub.2N(CH.sub.3),
CH.sub.2N(CH.sub.2CH.sub.3), CH.sub.2CH.sub.2N(CH.sub.3), and
CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3); R.sup.1 is selected from the
group consisting of hydrido, methyl, ethyl, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, and bromo;
R.sup.2 is Z.sup.0--Q; Z.sup.0 is selected from the group
consisting of covalent single bond and CH.sub.2; Q is selected from
the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl,
3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl,
3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl,
4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and
1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the
point of attachment is optionally substituted by R.sup.9, the other
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.13, a carbon adjacent to R.sup.9
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.10, a carbon adjacent to R.sup.13
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.12, and any carbon adjacent to both
R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
R.sup.9, R.sup.11, and R.sup.13 are independently selected from the
group consisting of hydrido, amidino, guanidino, carboxy, methyl,
ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy,
hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R.sup.10 and R.sup.12 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,
amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl,
fluoro, chloro, bromo, and cyano; Y.sup.0 is selected from the
group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzen-
e, 2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
2-Q.sup.b-4-Q.sup.s-3-R.sup.16-6-R.sup.18pyrazine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.18-5-R.sup.18-4-R.sup.19pyridazine,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18pyrimidine,
5-Q.sup.b-2-Q.sup.s-3-R.sup.16-6-R.sup.19pyrimidine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.s- up.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R- .sup.19imidazole,
2-Q.sup.b-4-Q.sup.s-5-R.sup.17imidazole,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16isoxazole,
5-Q.sup.b-3-Q.sup.s-4-R.sup.16is- oxazole,
2-Q.sup.b-5-Q.sup.s-4-R.sup.16pyrazole, 4-Q.sup.b-2-Q.sup.s-5-R.s-
up.19thiazole, and 2-Q.sup.b-5-Q.sup.s-4-R.sup.17thiazole;
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, methyl, ethyl,
isopropyl, propyl, amidino, guanidino, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-N-methylamino, dimethylamino, N-ethylamino, methylthio,
ethylthio, isopropylthio, trifluoromethylthio, methylsulfinyl,
ethylsulfinyl, methylsulfonyl, ethylsulfonyl, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and
cyano; Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, C(NR.sup.25)NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), with the provisos
that no more than one of R.sup.20, R.sup.21, R.sup.23, and R.sup.24
can be hydroxy, when any two of the group consisting of R.sup.20,
R.sup.21, R.sup.23, and R.sup.24 are bonded to the same atom and
that said Q.sup.b group is bonded directly to a carbon atom;
R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are
independently selected from the group consisting of hydrido,
methyl, ethyl, propyl, butyl, isopropyl, and hydroxy; Q.sup.s is
selected from the group consisting of a single covalent bond,
CH.sub.2, and CH.sub.2CH.sub.2.
7. The compound as recited in claim 6 or a pharmaceutically
acceptable salt thereof, wherein; A is selected from the group
consisting of CH.sub.2N(CH.sub.3), CH.sub.2N(CH.sub.2CH.sub.3),
CH.sub.2CH.sub.2N(CH.su- b.3), and
CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3); R.sup.1 is selected from the
group consisting of hydrido, methyl, ethyl, propyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro,
chloro, and bromo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is selected from
the group consisting of covalent single bond and CH.sub.2; Q is
selected from the group consisting of 5amino-3-amidocarbonylphenyl,
5amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl,
5amino-3-methoxycarbonylphenyl, 3-amidinophenyl,
3-amino-2-methylphenyl, 5amino-2-methylthiophenyl, 3-aminophenyl,
benzyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl,
3-carboxy-5-aminophenyl, 3-chlorophenyl, 2-chlorophenyl,
3-cyanophenyl, 3dimethylaminophenyl, 2-fluorophenyl,
3-fluorophenyl, 2-hydroxyphenyl, 3hydroxyphenyl,
3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3methoxyphenyl,
3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl,
3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl,
4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl,
3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 5amino-2-thienyl,
5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4pyridyl,
2-thienyl, and 3-thienyl; Y.sup.0 is selected from the group
consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.s is CH.sub.2.
8. A compound as recited in claim 7 or a pharmaceutically
acceptable salt thereof where said compound is selected from the
group consisting of:
6-[3-aminophenyl]-chloro-N-[[4-iminomethylphenyl]methyl]-3-[N,N-dimethylh-
ydrazino]-2-oxo-1(2H)-pyrazineacetamide;
6-[3-aminophenyl]-5chloro-3-[N-et-
hyl-N-methylhydrazino]-N-[[4-iminomethylphenyl]methyl]-2-oxo-1(2H)-pyrazin-
eacetamide;
6-[3-aminophenyl]-chloro-3-[N,N-diethylhydrazino]-N-[[4-iminom-
ethylphenyl]methyl]-2-oxo-1(2H)-pyrazineacetamide;
6-[3-aminophenyl]-3-[N--
(azetidin-1-yl)amino]-chloro-N-[[4-iminomethylphenyl]methyl]-2-oxo-1(2H)-p-
yrazineacetamide.
9. The compound as recited in claim 2 having the Formula: 129or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of aryl and heteroaryl wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.32, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.36, a
carbon adjacent to R.sup.32 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.33, a carbon
adjacent to R.sup.36 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.35 and any carbon
adjacent to both R.sup.33 and R.sup.35 is optionally substituted by
R.sup.34; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b; A is selected from the group
consisting of single covalent bond and
(CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
3, and W.sup.7 is selected from the group consisting of
(R.sup.7)NC(O) and N(R.sup.7); R.sup.7 is selected from the group
consisting of hydrido, hydroxy and alkyl; R.sup.15 is selected from
the group consisting of hydrido, halo, alkyl, and haloalkyl;
R.sup.1 is selected from the group consisting of hydrido, alkyl,
cyano, haloalkyl, and halo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is
selected from the group consisting of covalent single bond and
CH.sub.2; Q is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.13, a carbon adjacent to R.sup.9 and two atoms
from the carbon at the point of attachment is optionally
substituted by R.sup.10, a carbon adjacent to R.sup.13 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.12, and any carbon adjacent to both R.sup.10
and R.sup.12 is optionally substituted by R.sup.11; R.sup.9,
R.sup.11, and R.sup.13 are independently selected from the group
consisting of hydrido, hydroxy, amino, amidino, guanidino, lower
alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl,
alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy,
carboxamido, and cyano; R.sup.10 and R.sup.12 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino,
alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl,
halo, haloalkyl, and cyano; Y.sup.0 is formula (IV): 130 wherein
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are independently selected
from the group consisting of C, N, O, S and a covalent bond with
the provisos that no more than one is a covalent bond, K.sup.2 is
C, no more than one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is O,
no more than one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is S,
one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 must be a covalent
bond when two of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are O and
S, and no more than four of D.sup.5, D.sup.6, J.sup.5, and J.sup.6
are N; R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and
cyano; R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be; Q.sup.b is selected
from the group consisting of NR.sup.20R.sup.21, Q.sup.be wherein
Q.sup.be is hydrido, and C(NR.sup.25)NR.sup.23R.sup.24, with the
provisos that no more than one of R.sup.20 and R.sup.21 is hydroxy
at the same time and that no more than one of R.sup.23 and R.sup.24
is hydroxy at the same time; R.sup.20, R.sup.21, R.sup.23,
R.sup.24, and R.sup.25 are independently selected from the group
consisting of hydrido, alkyl, and hydroxy; Q.sup.s is selected from
the group consisting of a single covalent bond, CH.sub.2, and
CH.sub.2CH.sub.2.
10. The compound as recited in claim 9 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl,
2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4imidazolyl, 3-pyrazolyl,
4pyrazolyl, 2-thiazolyl, 3-isoxazoly, 5-isoxazolyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyrazinyl 2-pyrimidinyl, 4pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4pyridazinyl, and 1,3,5-triazin-2-yl,
wherein a carbon adjacent to the carbon at the point of attachment
is optionally substituted by R.sup.32, the other carbon adjacent to
the carbon at the point of attachment is optionally substituted by
R.sup.36, a carbon adjacent to R.sup.32 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.33, a carbon adjacent to R.sup.36 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.35, and any carbon adjacent to both R.sup.33 and R.sup.35 is
optionally substituted by R.sup.34; 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,
1,1,2,2tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl,
methoxycarbonyl, ethoxycarbonyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and
Q.sup.b; A is selected from the group consisting of single covalent
bond, NH, N(CH.sub.3), N(OH), CH.sub.2, CH.sub.3CH, CF.sub.3CH,
NHC(O), N(CH.sub.3)C(O), C(O)NH, C(O)N(CH.sub.3), CH.sub.2CH.sub.2,
CH.sub.2CH.sub.2CH.sub.2, CH.sub.3CHCH.sub.2, and
CF.sub.3CHCH.sub.2; R.sup.1 is selected from the group consisting
of hydrido, methyl, ethyl, propyl, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, fluoro, chloro, and bromo; R.sup.2 is
Z.sup.0--Q; Z.sup.0 is selected from the group consisting of
covalent single bond and CH.sub.2; Q is selected from the group
consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl,
2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4imidazolyl, 3-pyrazolyl,
4pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl,
3-pyridyl, 4pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and
1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the
point of attachment is optionally substituted by R.sup.9, the other
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.13, a carbon adjacent to R.sup.9
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.10, a carbon adjacent to R.sup.13
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.12, and any carbon adjacent to both
R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
R.sup.9, R.sup.11, and R.sup.13 are independently selected from the
group consisting of hydrido, amidino, guanidino, carboxy, methyl,
ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy,
hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
2hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R.sup.10 and R.sup.12 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,
amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl,
fluoro, chloro, bromo, and cyano; Y.sup.0 is selected from the
group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzen-
e, 2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
2-Q.sup.b-4-Q.sup.s-3-R.sup.16-6-R.sup.18pyrazine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.18-5-R.sup.18-4-R.sup.19pyridazine,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18pyrimidine,
5-Q.sup.b-2-Q.sup.s-3-R.sup.16-6-R.sup.19pyrimidine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
2-Q.sup.b-5-Q.sup.s-4-R.sup.16-4-R.sup.17thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.s- up.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R- .sup.19imidazole,
2-Q.sup.b-4-Q.sup.s-5-R.sup.17imidazole,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16isoxazole,
5-Q.sup.b-3-Q.sup.s-3-R.sup.16is- oxazole,
2-Q.sup.b-5-Q.sup.s-4-R.sup.16pyrazole, 4-Q.sup.b-2-Q.sup.s-5-R.s-
up.19thiazole, and 2-Q.sup.b-5-Q.sup.s-4-R.sup.17thiazole;
R.sup.16, R.sup.17, R.sup.18 and R.sup.19 are independently
selected from the group consisting of hydrido, methyl, ethyl,
isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy,
isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl,
2-aminomethyl, N-methylamino, dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethylthio,
methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and
cyano; R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be; Q.sup.b is selected
from the group consisting of Q.sup.be wherein Q.sup.be is hydrido
and C(NR.sup.25)NR.sup.23R.sup.24, with the proviso that no more
than one of R.sup.23 and R.sup.24 is hydroxy at the same time;
R.sup.23, R.sup.24,and R.sup.25 are independently selected from the
group consisting of hydrido, methyl, ethyl, and hydroxy; Q.sup.sis
selected from the group consisting of a single covalent bond,
CH.sub.2 and CH.sub.2CH.sub.2.
11. The compound as recited in claim 10 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl,
4-amidinophenyl, 3-carboxyphenyl, 3carboxy-5-hydroxyphenyl,
3-chlorophenyl, 4chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl,
3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl,
4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl,
3-trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl,
3-pyridyl, 5-chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl,
2-thienyl, 3-thienyl, and 3-trifluoromethyl-2-pyridyl; A is
selected from the group consisting of CH.sub.2, CH.sub.3CH,
CF.sub.3CH, NHC(O), CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2;
R.sup.1 is selected from the group consisting of hydrido, methyl,
ethyl, propyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, fluoro, chloro, and bromo; R.sup.2 is
Z.sup.0--Q; Z.sup.0 is selected from the group consisting of
covalent single bond and CH.sub.2; Q is selected from the group
consisting of 5-amino-3-amidocarbonylphenyl,
5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl,
5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl,
3-amino-2-methylphenyl, 5amino-2-methylthiophenyl, 3-aminophenyl,
benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl,
3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl,
3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl,
3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl,
3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl,
2,5difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl,
3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl,
3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl,
4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl,
3-trifluoromethylphenyl, 2-trifluoromethylphenyl,
5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl,
4-pyridyl, 2-thienyl, and 3-thienyl; p1 Y.sup.0 is selected from
the group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.s is CH.sub.2.
12. The compound as recited in claim 9 having the Formula: 131or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of aryl and heteroaryl wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.32, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.36, a
carbon adjacent to R.sup.32 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.23, a carbon
adjacent to R.sup.36 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.35, and any carbon
adjacent to both R.sup.33 and R.sup.35 is optionally substituted by
R.sup.34; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b; A is selected from the group
consisting of single covalent bond and
(CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
3, and W.sup.7 is N(R.sup.7); R.sup.7 is selected from the group
consisting of hydrido and alkyl; R.sup.15 is selected from the
group consisting of hydrido, halo, alkyl, and haloalkyl; R.sup.1 is
selected from the group consisting of hydrido, cyano, haloalkyl,
and halo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is a covalent single bond;
Q is selected from the group consisting of aryl and heteroaryl
wherein a carbon adjacent to the carbon at the point of attachment
is optionally substituted by R.sup.9, the other carbon adjacent to
the carbon at the point of attachment is optionally substituted by
R.sup.13, a carbon adjacent to R.sup.9 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.10, a carbon adjacent to R.sup.13 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.12, and any carbon adjacent to both R.sup.10 and R.sup.12 is
optionally substituted by R.sup.11; R.sup.9, R.sup.11, and R.sup.13
are independently selected from the group consisting of hydrido,
hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio,
alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl,
monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy,
hydroxyalkyl, carboxy, carboxamido, and cyano; R.sup.10 and
R.sup.12 are independently selected from the group consisting of
hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl,
alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl,
carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano;
Y.sup.0 is formula (IV): 132 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, Do more than one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 must be a covalent bond when two of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are O and S, and no more than four of
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are N; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,
alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; Q.sup.bis selected from the group consisting
of NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido, and
C(NR.sup.25)NR.sup.23R.sup.24; R.sup.20, R.sup.21, R.sup.23,
R.sup.24, and R.sup.25 are independently selected from the group
consisting of hydrido and alkyl; Q.sup.s is CH.sub.2.
13. The compound as recited in claim 12 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl,
2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl,
4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and 5-isoxazolyl, wherein a
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.32, the other carbon adjacent to
the carbon at the point of attachment is optionally substituted by
R.sup.36, a carbon adjacent to R.sup.32 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.33, a carbon adjacent to R.sup.36 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.35, and any carbon adjacent to both R.sup.33 and R.sup.35 is
optionally substituted by R.sup.34; R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36 are independently selected from the group
consisting of hydrido, amidino, guanidino, methyl, ethyl, methoxy,
ethoxy, hydroxy, amino, N-methylamino, dimethylamino, methylthio,
ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,
hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q.sup.b; A is
selected from the group consisting of single covalent bond, NH,
N(CH.sub.3), CH.sub.2, CH.sub.3CH, and CH.sub.2CH.sub.2; R.sup.1 is
selected from the group consisting of hydrido, trifluoromethyl,
pentafluoroethyl, fluoro, and chloro; R.sup.2 is selected from the
group consisting of phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl,
2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and 3-pyridyl,
wherein a carbon adjacent to the carbon at the point of attachment
is optionally substituted by R.sup.9, the other carbon adjacent to
the carbon at the point of attachment is optionally substituted by
R.sup.13, a carbon adjacent to R.sup.9 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.10, a carbon adjacent to R.sup.13 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.12, and any carbon adjacent to both R.sup.10 and R.sup.12 is
optionally substituted by R.sup.11; R.sup.9, R.sup.11, and R.sup.13
are independently selected from the group consisting of hydrido,
methyl, ethyl, methoxy, ethoxy, hydroxy, amino, N-methylamino,
N,N-dimethylamino, methylthio, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and
cyano; R.sup.10 and R.sup.12 are independently selected from the
group consisting of hydrido, amidino, amidocarbonyl,
N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy,
hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy,
carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl,
N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo,
and cyano; Y.sup.0 is selected from the group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.s- up.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-R.sup.18-4-R.sup.16-2-R.sup.19p- yrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R.sup.19thiazole, and
2-Q.sup.b-5-Q.sup.s-4-R.sup.1- 7thiazole; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy,
hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, methylthio, ethylthio,
trifluoromethylthio, methylsulfinyl, methylsulfonyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
trifluoromethoxy, fluoro, chloro, amidosulfonyl,
N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano, Q.sup.b
is selected from the group consisting of NR.sup.20R.sup.21 and
C(NR.sup.25)NR.sup.23R.sup.24, with the proviso that said Q.sup.b
group is bonded directly to a carbon atom; R.sup.20, R.sup.21,
R.sup.23, R.sup.24, and R.sup.25 are independently selected from
the group consisting of hydrido, methyl, and ethyl; Q.sup.s is
CH.sub.2.
14. The compound as recited in claim 13 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of 2-aminophenyl, 3aminophenyl, 3-amidinophenyl,
4-amidinophenyl, 3-carboxyphenyl, 3carboxy-5-hydroxyphenyl,
3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl,
3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl,
4hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl,
4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl,
3-trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl,
5-chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl,
3-thienyl, and 3-trifluoromethyl-2-pyridyl; A is selected from the
group consisting of CH.sub.2, CH.sub.3CH, CF.sub.3CH, NHC(O),
CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2; R.sup.1 is selected
from the croup consisting of hydrido, trifluoromethyl,
pentafluoroethyl, fluoro, and chloro; R.sup.2 is selected from the
group consisting of 5amino-3-amidocarbonylphenyl,
5-amino-2-fluorophenyl, 3-amino-5hydroxymethylphenyl,
5-amino3-methoxycarbonylphenyl, 3-aminophenyl,
3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl,
benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl,
3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl,
3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl,
3-chlorophenyl, 2-chlorophenyl, 3-cyanophenyl,
3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl,
2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl,
3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl,
3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl,
4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl,
3-trifluoromethylphenyl, 2-trifluoromethylphenyl,
5-amino-2-thienyl, 5-amino-3-thienyl, 3-bromo2-thienyl, 3-pyridyl,
4-pyridyl, 2-thienyl, and 3-thienyl; Y.sup.0 is selected from the
group consisting of: 1-Q.sup.b-4-Q.sup.s-2-R.sup.16--
3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-- R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-1-R- .sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.s is CH.sub.2.
15. The compound as recited in claim 14 or a pharmaceutically
acceptable salt thereof, wherein: B is selected from the group
consisting of 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl,
3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl,
4-methylphenyl, phenyl, 2-imidazoyl, 3-pyridyl, 4-pyridyl, and
3-trifluoromethyl-2-pyridy- l; A is selected from the group
consisting of CH.sub.2, NHC(O), CH.sub.2CH.sub.2, and
CH.sub.2CH.sub.2CH.sub.2; R.sup.1 is selected from the group
consisting of hydrido 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-methyl phenyl,
3-methylphenyl, phenyl, 3-trifluoroacetamidophenyl,
3-bromo-2-thienyl, 2-thienyl, and 3-thienyl; Y.sup.0 is selected
from the group consisting of 5-amidino-2-thienylmethy- l,
4-amidinobenzyl, 2-fluoro-4-amidinobenzyl, and
3-fluoro-4-amdinobenzyl.
16. A compound as recited in claim 9 where said compound is
selected from the group having the Formula: 133or a
pharmaceutically acceptable salt thereof, wherein: R.sup.2 is
3-aminophenyl, B is 3-chlorophenyl, A is CH.sub.2CH.sub.2, Y.sup.0
is 4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-aminophenyl, B is phenyl, A is CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is phenyl, B is
3-chlorophenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B is 2-imidazoyl,
A is CH.sub.2CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and
R.sup.1 is chloro; R.sup.2 is 3-dimethylaminophenyl, B is phenyl, A
is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is
chloro; R.sup.2 is 2-methylphenyl, B is phenyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is
chloro; R.sup.2 is phenyl, B is 3-aminophenyl, A is C(O)NH, Y.sup.0
is 4-amidinobenzyl, and R.sup.1 is hydrido; R.sup.2 is phenyl, B is
3-amidinophenyl, A is CH.sub.2, Y.sup.0 .sup.0is 4-amidinobenzyl,
and R.sup.1 is chloro; 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
R.sup.1 is chloro; R.sup.2 is 3-thienyl, B is phenyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is
chloro; R.sup.2 is 3-methylsulfonamidophenyl, B is phenyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is
chloro; R.sup.2 is phenyl, B is 4-amidinophenyl, A is CH.sub.2,
Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-methylaminophenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is hydrido; R.sup.2 is phenyl, B is
phenyl, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is
chloro; R.sup.2 is phenyl, B is 4-pyridyl, A is CH.sub.2CH.sub.2,
Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is
phenyl, B is 3-pyridyl, A is CH.sub.2CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is 3-chlorophenyl,
B is 4-pyridyl, A is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl,
and R.sup.1 is chloro; R.sup.2 is 3-methylphenyl, B is 4-phenyl, A
is CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is
hydrido; R.sup.2 is 3-thienyl, B is 3-chlorophenyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is
chloro.
17. The compound as recited in claim 2 having the Formula: 134or a
pharmaceutically acceptable salt thereof, wherein: B is selected
from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl,
C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B
is optionally substituted at any carbon up to and including 6 atoms
from the point of attachment of B to A with one or more of the
group consisting of R.sup.32, R.sup.33, R.sup.34, R.sup.35, and
R.sup.36; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b; A is selected from the group
consisting of single covalent bond and
(CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
3, and W.sup.7 is selected from the group consisting of
(R.sup.7)NC(O) and N(R.sup.7); R.sup.7 is selected from the group
consisting of hydrido, hydroxy and alkyl; R.sup.15 is selected from
the croup consisting of hydrido, halo, alkyl, and haloalkyl;
R.sup.1 is selected from the group consisting of hydrido, alkyl,
cyano, haloalkyl, and halo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is
selected from the group consisting of covalent single bond and
CH.sub.2; Q is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.13, a carbon adjacent to R.sup.9 and two atoms
from the carbon at the point of attachment is optionally
substituted by R.sup.10, a carbon adjacent to R.sup.13 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.12, and any carbon adjacent to both R.sup.10
and R.sup.12 is optionally substituted by R.sup.11; R.sup.9,
R.sup.11, and R.sup.13 are independently selected from the group
consisting of hydrido, hydroxy, amino, amidino, guanidino, lower
alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl,
alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy,
carboxamido, and cyano; R.sup.10 and R.sup.12 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino,
alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl,
halo, haloalkyl, and cyano; Y.sup.0 is formula (IV): 135 wherein
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are independently selected
from the group consisting of C, N, O, S and a covalent bond with
the provisos that no more than one is a covalent bond, K.sup.2 is
C, no more than one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is O,
no more than one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 is S,
one of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 must be a covalent
bond when two of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are O and
S, and no more than four of D.sup.5, D.sup.6, J.sup.5, and J.sup.6
are N; R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, haloalkylthio, alkoxy, hydroxy, amino, lower alkylamino,
alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl,
alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and
cyano; R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be; Q.sup.b is selected
from the group consisting of NR.sup.20R.sup.21, Q.sup.be wherein
Q.sup.be is hydrido, C(NR.sup.25)NR.sup.23R.sup.24 and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), with the provisos
that DO more than one of R.sup.20 and R.sup.21 is hydroxy at the
same time and that no more than none of R.sup.23 and R.sup.24 is
hydroxy at the same time; R.sup.20, R.sup.21, R.sup.23, R.sup.24,
R.sup.25, and R.sup.26 are independently selected from the group
consisting of hydrido, alkyl, and hydroxy; Q.sup.s is selected from
the group consisting of a single covalent bond, CH.sub.2, and
CH.sub.2CH.sub.2.
18. The compound as recited in claim 17 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of hydrido, ethyl, 2-propynyl, 2-propenyl, propyl,
isopropyl, butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl,
tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl,
3-pentenyl, 4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl,
1-methyl-2-butenyl, 1-methyl-3-butenyl, 1-methyl-2-butenyl,
3-pentyl, 1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl,
2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methyl butyl,
3methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl,
3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexenyl, 3-hexenyl, 4hexenyl,
2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl,
1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl,
3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl,
1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,
5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl,
5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl,
1-methyl4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexenyl,
1-methyl-3-hexenyl, 1-methyl-4-hexenyl, 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; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and
R.sup.36 are independently selected from the group consisting of
hydrido, amidino, guanidino , carboxy, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, N-methylamino, dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxye- thyl,
methoxycarbonyl, ethoxycarbonyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and
Q.sup.b; A is selected from the croup 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.sup.2CH.sub.2,
CH.sub.2CH.sub.2CH.sub.2, CH.sub.3CHCH.sub.2, and
CF.sub.3CHCH.sub.2; R.sup.1 is selected from the group consisting
of hydrido, methyl, ethyl, propyl, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, fluoro, chloro, and bromo; R.sup.2 is
Z.sup.0--Q; Z.sup.0 is selected from the group consisting of
covalent single bond and CH.sub.2; Q is selected from the group
consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl,
2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl,
4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl,
3-pyridyl, 4pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and
1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the
point of attachment is optionally substituted by R.sup.9, the other
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.13, a carbon adjacent to R.sup.9
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.10, a carbon adjacent to R.sup.13
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.12, and any carbon adjacent to both
R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
R.sup.9, R.sup.11, and R.sup.13 are independently selected from the
group consisting of hydrido, amidino, guanidino, carboxy, methyl,
ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, propoxy,
hydroxy, amino, N-methylamino, N,N-dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxye- thyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R.sup.10 and R.sup.12 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,
amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl,
fluoro, chloro, bromo, and cyano; Y.sup.0 is selected from the
group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzen-
e, 2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
2-Q.sup.b-4-Q.sup.s-3-R.sup.16-6-R.sup.18pyrazine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.18-5-R.sup.18-4-R.sup.19pyridazine,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18pyrimidine,
5-Q.sup.b-2-Q.sup.s-3-R.sup.16-6-R.sup.19pyrimidine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene,
3-Q.sup.b-5-4-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R- .sup.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R- .sup.19imidazole,
2-Q.sup.b-4-Q.sup.s-5-R.sup.17imidazole,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16isoxazole,
5-Q.sup.b-3-Q.sup.s-4-R.sup.16is- oxazole,
2-Q.sup.b-5-Q.sup.s-4-R.sup.16pyazole, 4-Q.sup.b-2-Q.sup.s-5-R.su-
p.19thiazole, and 2-Q.sup.b-5-Q.sup.s-4-R.sup.17thiazole; R.sup.16,
R.sup.17, R.sup.18, and R.sup.19 are independently selected from
the group consisting of hydrido, methyl, ethyl, isopropyl, propyl,
carboxy, amidino, guanidino, methoxy, ethoxy, isopropoxy, propoxy,
hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, N-ethylamino, methylthio, ethylthio,
isopropylthio, trifluoromethylthio, methylsulfinyl, ethylsulfinyl,
methylsulfonyl, ethylsulfonyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, and cyano; R.sup.16and R.sup.19 are
optionally Q.sup.b with the proviso that no more than one of
R.sup.16 and R.sup.19 is Q.sup.b at the same time and that Q.sup.b
is Q.sup.be; Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be, wherein Q.sup.be is hydrido,
C(NR.sup.25)NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), with the provisos
that no more than one of R.sup.20 and R.sup.21 is hydroxy at the
same time and that no more than one of R.sup.23 and R.sup.24 is
hydroxy at the same time; R.sup.20, R.sup.21, R.sup.23, R.sup.24,
R.sup.25, and R.sup.26 are independently selected from the group
consisting of hydrido, methyl, ethyl, propyl, butyl, isopropyl, and
hydroxy; Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
19. The compound as recited in claim 18 or a pharmaceutically
acceptable salt thereof, wherein: B is selected from the group
consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl,
isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl,
isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl,
6-amidocarbonylhexyl, 4methyl-2-pentyl, 3-hydroxypropyl,
3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl,
3-methyl-2-butyl, 2-dimethylaminophenyl, 2-cyanoethyl,
6hydroxyhexyl, 2-hydroxyethyl, 2-amidinophenyl, 2-guanidinoethyl,
3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl,
4hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl,
2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and
4-animobutyl; A is selected from the group consisting of single
covalent bond, CH.sub.2, NHC(O), CH.sub.2CH.sub.2,
CH.sub.2CH.sub.2CH.sub.2, and CH.sub.3CHCH.sub.2; R.sup.1 is
selected from the group consisting of hydrido, methyl, ethyl,
propyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
fluoro, chloro, and bromo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is
selected from the group consisting of covalent single bond and
CH.sub.2; Q is selected from the group consisting of
5-amino-3-amidocarbonylphenyl, 5-amino-2-fluorophenyl,
3-amino-5-hydroxymethylphenyl, 5-amino-3-methoxycarbonylphenyl,
3-amidinophenyl, 3-amino-2-methylphenyl,
5-amino-2-methylthiophenyl, 3-aminophenyl, benzyl, 3-carboxyphenyl,
3-carboxy-5-aminophenyl, 3-carboxy-5-hydroxyphenyl,
3-carboxymethyl-5-aminophenyl, 3-carboxymethyl-5-hydroxyphenyl,
3-carboxymethylphenyl, 3-chlorophenyl, 2-chlorophenyl,
2,6-dichlorophenyl, 3-cyanophenyl, 3-dimethylaminophenyl,
2-fluorophenyl, 3-fluorophenyl, 2,5-difluorophenyl,
2-hydroxyphenyl, 3-hydroxyphenyl, 3-methanesulfonylyaminophenyl,
2-methoxyphenyl, 3-methoxyphenyl, 3methoxyaminophenyl,
3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl,
2-methylphenyl, 3-methylphenyl, 4methylphenyl, phenyl,
3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl,
2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl,
3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y.sup.0 is selected from the group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-1-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.s is CH.sub.2.
20. The compound as recited in claim 17 having the Formula: 136or a
pharmaceutically acceptable salt thereof, wherein: B is selected
from the group consisting of hydrido, C2-C8 alkyl, C3-C8 alkenyl,
C3-C8 alkynyl, and C2-C8 haloalkyl, wherein each member of group B
is optionally substituted at any carbon up to and including 6 atoms
from the point of attachment of B to A with one or more of the
group consisting of R.sup.32, R.sup.33, R.sup.34, R.sup.35, and
R.sup.36; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkoxy, hydroxy,
amino, alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b; A is selected from the group
consisting of single covalent bond and
(CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
3, and W.sup.7 is N(R.sup.7); R.sup.7 is selected from the group
consisting of hydrido and alkyl; R.sup.15 is selected from the
group consisting of hydrido, halo, alkyl, and haloalky; R.sup.1 is
selected from the group consisting of hydrido, cyano, haloalkyl,
and halo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is a covalent single bond;
Q is selected from the group consisting of aryl and heteroaryl
wherein a carbon adjacent to the carbon at the point of attachment
is optionally substituted by R.sup.9, the other carbon adjacent to
the carbon at the point of attachment is optionally substituted by
R.sup.13, a carbon adjacent to R.sup.9 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.10, a carbon adjacent to R.sup.13 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.12, and any carbon adjacent to both R.sup.10 and R.sup.12 is
optionally substituted by R.sup.11; R.sup.9, R.sup.11, and R.sup.13
are independently selected from the group consisting of hydrido,
hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio,
alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl,
monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy,
hydroxyalkyl, carboxy, carboxamido, and cyano; R.sup.10 and
R.sup.12 are independently selected from the group consisting of
hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl,
alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl,
carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano;
Y.sup.0 is formula (IV): 137wherein D.sup.5, D.sup.6, J.sup.5 and
J.sup.6 are independently selected from the group consisting of C,
N, O, S and a covalent bond with the provisos that no more than one
is a covalent bond, K.sup.2 is C, no more than one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 is O, no more than one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 must be a covalent bond when two of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are O and S, and no more than four of
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are N; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,
alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; Q.sup.b is selected from the group consisting
of NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido,
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(- R.sup.24), and
C(NR.sup.25)NR.sup.23R.sup.24; R.sup.20, R.sup.21, R.sup.23,
R.sup.24, R.sup.25, and R.sup.26 are independently selected from
the group consisting of hydrido and alkyl; Q.sup.s is CH.sub.2.
21. The compound as recited in claim 17 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl,
isopropyl, butyl, 2-butenyl, 2-butynyl, sec-butyl, tert-butyl,
isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl,
2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl, 2-methylbutyl,
2-methyl-2-butenyl, 3-methylbutyl, 3-methyl-2-butenyl, 1-hexyl,
2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,
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-methyl3-hexenyl,
1-methyl-4-hexenyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl,
1-methyl-3-hexenyl, 3-heptyl, 1-ethyl-2-pentenyl,
1-ethyl-3-pentenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl,
2,2,2-trifluoroethyl, 2,2-difluoropropyl,
4-trifluoromethyl-5,5,5-trifluo- ropentyl, 4-trifluoromethylpentyl,
5,5,6,6,6-pentafluorohexyl, and 3,3,3-trifluoropropyl, wherein each
member of group B is optionally substituted at any carbon up to and
including 5 atoms from the point of attachment of B to A with one
or more of the group consisting of R.sup.32, R.sup.33, R.sup.34,
R.sup.35, and R.sup.36; R.sup.32, R.sup.33, R.sup.34, R.sup.35, and
R.sup.36 are independently selected from the group consisting of
hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy,
hydroxy, amino, N-methylamino, dimethylamino, methylthio,
ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,
hydroxymethyl, amidocarbonyl, carboxy, cyano, and Q.sup.b; A is
selected from the group consisting of single covalent bond, NH,
N(CH.sub.3), CH.sub.2, CH.sub.3CH, and CH.sub.2CH.sub.2; A is
optionally selected from the group consisting of
CH.sub.2N(CH.sub.3), CH.sub.2N(CH.sub.2CH.sub.3),
CH.sub.2CH.sub.2N(CH.sub.3), and
CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3) with the proviso that B is
hydrido; R.sup.1 is selected from the group consisting of hydrido,
trifluoromethyl, pentafluoroethyl, fluoro, and chloro, R.sup.2 is
selected from the group consisting of phenyl, 2-thienyl, 2-furyl,
2-pyrrolyl, 2-imidazolyl, 2-thiazolyl, 3-isoxazolyl, 2-pyridyl, and
3-pyridyl, wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.9, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.13, a carbon adjacent to R.sup.9 and two atoms
from the carbon at the point of attachment is optionally
substituted by R.sup.10, a carbon adjacent to R.sup.13 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.12, and any carbon adjacent to both R.sup.10
and R.sup.12 is optionally substituted by R.sup.11; R.sup.9,
R.sup.11, and R.sup.13 are independently selected from the group
consisting of hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy,
amino, N-methylamino, N,N-dimethylamino, methylthio,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro,
chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
amidocarbonyl, N-methylamidocarbonyl, carboxy, and cyano; R.sup.10
and R.sup.12 are independently selected from the group consisting
of hydrido, amidino, amidocarbonyl, N-methylamidocarbonyl,
guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, carboxy, carboxymethyl, amino,
acetamido, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
methoxycarbonyl, fluoro, chloro, bromo, and cyano; Y.sup.0 is
selected from the group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.s- up.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R- .sup.19thiazole, and
2-Q.sup.b-5-Q.sup.s-4-R.sup.17thiazole; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy,
hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, methylthio, ethylthio,
trifluoromethylthio, methylsulfinyl, methylsulfonyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
trifluoromethoxy, fluoro, chloro, amidosulfonyl,
N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano; Q.sup.b
is selected from the group consisting of NR.sup.20R.sup.21,
C(NR.sup.25)NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.s- up.24), with the proviso
that said Q.sup.b group is bonded directly to a carbon atom;
R.sup.20, R.sup.21, R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are
independently selected from the group consisting of hydrido,
methyl, and ethyl; Q.sup.s is CH.sub.2.
22. The compound as recited in claim 21 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of hydrido,ethyl, 2-propenyl, 2-propynyl, propyl,
isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl,
isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl,
6-amidocarbonylhexyl, 4methyl-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-amidinophenyl, 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
4aminobutyl; A is selected from the group consisting of single
covalent bond, CH.sub.2, CH.sub.3CH, and CH.sub.2CH.sub.2; R.sup.1
is selected from the group consisting of hydrido, 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-methyl phenyl,
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-methanesulfonylyaminophenyl,
2-methoxy,phenyl, 3-methoxyphenyl, 3-methoxyaminophenyl,
3-methoxycarbonylphenyl, 2-methylaminophenyl, 3-methylaminophenyl,
2-methylphenyl, 3-methylphenyl, 4-methylphenyl, phenyl,
3-trifluoroacetamidophenyl, 3-trifluoromethylphenyl,
2-trifluoromethylphenyl, 5-amino-2-thienyl, 5-amino-3-thienyl,
3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl, 2-thienyl, and 3-thienyl;
Y.sup.0 is selected from the group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R-
.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.s- up.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.su- p.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophen- e, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.s is CH.sub.2.
23. The compound as recited in claim 22 or a pharmaceutically
acceptable salt thereof, wherein: B is selected from the group
consisting of hydrido,ethyl, 2-propenyl, 2-propynyl, propyl,
isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl,
isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl,
6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl,
3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl,
3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl,
6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinophenyl, 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; R.sup.1
is selected from the group consisting of hydrido and chloro;
R.sup.2is selected from the group consisting of
5-amino-2-fluorophenyl, 3-amino-2-methylphenyl,
5-amino-2-methylthiophenyl, 3-aminophenyl, 3-carboxyphenyl,
3-cyanophenyl, 3-methoxycarbonylphenyl, phenyl, and 3-pyridyl;
Y.sup.0 is selected from the group consisting of
5-amidino-2-thienylmethyl, 4-amidinobenzyl,
2-fluoro4-amidinobenzyl, and 3-fluoro-4-amidinobenzyl.
24. A compound as recited in claim 17 where said compound is
selected from the group having the Formula: 138or a
pharmaceutically acceptable salt thereof, wherein: R.sup.2 is
3-aminophenyl, B is 2,2,2-trifluoroethyl, A is single bond, Y.sup.0
is 4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-aminophenyl, B is (S)-2-butyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is
5-amino-2-fluorophenyl, B is isopropyl, A is single bond, Y.sup.0
is 4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is
2-methyl-3-aminophenyl, B is isopropyl, A is single bond, Y.sup.0
is 4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-aminophenyl, B is ethyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B
is ethyl, A is single bond, Y.sup.0 is 4-amidino-2-fluorobenzyl,
and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B is 2-propenyl, A
is single bond, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is chloro;
R.sup.2 is 3-aminophenyl, B is isopropyl, A is single bond, Y.sup.0
is 4-amidino-2-fluorobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-aminophenyl, B is isopropyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B
is 2-butyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and
R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B is (R)-2-butyl, A is
single bond, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is chloro;
R.sup.2 is 3-aminophenyl, B is 2-propynyl, A is single bond,
Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-aminophenyl, B is 3-pentyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is hydrido; R.sup.2 is 3-aminophenyl,
B is hydrido, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and
R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B is ethyl, A is
CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is chloro;
R.sup.2 is 3-aminophenyl, B is 2-methypropyl, A is single bond,
Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-aminophenyl, B is 2-propyl, A is CH.sub.3CH, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B
is propyl, A is single bond, Y.sup.0 is 4-amidino-2-fluorobenzyl,
and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B is
6-amidocarbonylhexyl, A is single bond, Y.sup.0is 4-amidinobenzyl,
and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B is tert-butyl, A
is single bond, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is hydrido;
R.sup.2 is 3-aminophenyl, B is tert-butyl, A is single bond,
Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-aminophenyl, B is 3-hydroxypropyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B
is 2-methylpropyl, A is single bond, Y.sup.0 is
4-amidino-2-fluorobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-aminophenyl, B is butyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B
is 3-methoxy-2-propyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B
is 3-methoxy-2-propyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B
is 2-methoxy-2-ethyl, A is single bond, Y.sup.0 is 4-amidinobenzyl,
and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B is 2-propyl, A
is single bond, Y.sup.0 is 5-amidino-2-thienylmethyl, and R.sup.1
is chloro; R.sup.2 is 3-aminophenyl, B is 2-propyl, A is single
bond, Y.sup.0 is 4-amidino-3-2-fluorobenzyl, and R.sup.1 is
hydrido; R.sup.2 is 3-carboxyphenyl, B is 2-propyl, A is single
bond, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is hydrido; R.sup.2
is 3-aminophenyl, B is 2-propyl, A is single bond, Y.sup.0 is
4-amidino-3-fluorobenzyl, and R.sup.1 is chloro.
25. The compound as recited in claim 2 having the Formula: 139or a
pharmaceutically acceptable salt thereof, wherein: B is selected
from the group consisting of C3-C7 cycloalkyl and C4-C6 saturated
heterocyclyl, wherein each ring carbon is optionally substituted
with R.sup.33, a ring carbon other than the ring carbon at the
point of attachment of B to A is optionally substituted with oxo
provided that no more than one ring carbon is substituted by oxo at
the same time, ring carbons and a nitrogen adjacent to the carbon
atom at the point of attachment are optionally substituted with
R.sup.9 or R.sup.13, a ring carbon or nitrogen adjacent to the
R.sup.9 position and two atoms from the point of attachment is
optionally substituted with R.sup.10, a ring carbon or nitrogen
adjacent to the R.sup.13 position and two atoms from the point of
attachment is optionally substituted with R.sup.12, a ring carbon
or nitrogen three atoms from the point of attachment and adjacent
to the R.sup.10 position is optionally substituted with R.sup.11, a
ring carbon or nitrogen three atoms from the point of attachment
and adjacent to the R.sup.12 position is optionally substituted
with R.sup.33, and a ring carbon or nitrogen four atoms from the
point of attachment and adjacent to the R.sup.11 and R.sup.33
positions is optionally substituted with R.sup.34; R.sup.9,
R.sup.11, and R.sup.13 are independently selected from the group
consisting of hydrido, hydroxy, amino, amidino, guanidino, lower
alkylamino, alkylthio, alkylsulfonamido, alkylsulfinyl,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, alkyl,
alkoxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, carboxy,
carboxamido, and cyano; R.sup.10 and R.sup.12 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, amidino, guanidino, alkyl, alkoxy, hydroxy, amino,
alkoxyamino, lower alkylamino, alkylsulfonamido, amidosulfonyl,
monoalkyl amidosulfonyl, dialkyl amidosulfonyl, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, amidocarbonyl,
halo, haloalkyl, and cyano; R.sup.33 and R.sup.34 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, amidino, guanidino, alkoxy, hydroxy, amino,
alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, cyano,
and Q.sup.b; A is selected from the group consisting of single
covalent bond and (CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein
rr is an integer selected from 0 through 1, pa is an integer
selected from 0 through 3, and W.sup.7 is selected from the group
consisting of (R.sup.7)NC(O) and N(R.sup.7); R.sup.7is selected
from the group consisting of hydrido, hydroxy and alkyl; R.sup.15
is selected from the group consisting of hydrido, halo, alkyl, and
haloalkyl; R.sup.1 is selected from the group consisting of
hydrido, alkyl, cyano, haloalkyl, and halo; R.sup.2 is Z.sup.0--Q;
Z.sup.0 is selected from the group consisting of covalent single
bond and CH.sub.2; Q is selected from the group consisting of aryl
and heteroaryl wherein a carbon adjacent to the carbon at the point
of attachment is optionally substituted by R.sup.9, the other
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.13, a carbon adjacent to R.sup.9
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.10, a carbon adjacent to R.sup.13
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.12, and any carbon adjacent to both
R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
Y.sup.0 is formula (IV): 140 wherein D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 are independently selected from the group consisting of C,
N, O, S and a covalent bond with the provisos that no more than one
is a covalent bond, K.sup.2 is C, no more than one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 is O, no more than one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 must be a covalent bond when two of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are O and S, and no more than four of
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are N; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,
alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; Q.sup.b is selected from the group consisting
of NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido, and
C(NR.sup.25)NR.sup.23R.sup.24, with the provisos that no more than
one of R.sup.20 and R.sup.21 is hydroxy at the same time and that
no more than one of R.sup.23 and R.sup.24 is hydroxy at the same
time; R.sup.20, R.sup.21, R.sup.23, R.sup.24, and R.sup.25 are
independently selected from the group consisting of hydrido, alkyl,
and hydroxy; Q.sup.s is selected from the group consisting of a
single covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
26. The compound as recited in claim 25 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl,
azetidin-2-yl, azetidin-3-yl, thiaetan-3-yl, cyclopentyl,
cyclohexyl, norbornyl, 7-oxabicyclo[2,2,1]heptan-2-yl,
bicyclo[3,1,0]hexan-6-yl, cycloheptyl, 2-morpholinyl,
3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl,
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,
1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl,
4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl, 4H-pyran-4-one-2-yl,
4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,
2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl,
2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring
carbon is optionally substituted with R.sup.33, ring carbons and a
nitrogen adjacent to the carbon atom at the point of attachment are
optionally substituted with R.sup.9 or R.sup.13, a ring carbon or
nitrogen adjacent to the R.sup.9 position and two atoms from the
point of attachment is optionally substituted with R.sup.10, and a
ring carbon or nitrogen adjacent to the R.sup.13 position and two
atoms from the point of attachment is optionally substituted with
R.sup.12; R.sup.9, R.sup.11, and R.sup.13 are independently
selected from the group consisting of hydrido, amidino, guanidino,
carboxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy,
isopropoxy, propoxy, hydroxy, amino, N-methylamino,
N,N-dimethylamino, N-ethylamino, methylthio, ethylthlio,
isopropylthio, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo,
methanesulfonamido, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, and cyano;
R.sup.10 and R.sup.12 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, carboxymethyl,
methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy,
propoxy, hydroxy, amino, methoxyamino, ethoxyamino, acetamido,
trifluoroacetamido, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, N-ethylamino, methanesulfonamido,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,
2,2,2-trifluoro-1-hydroxyethyl, methoxycarbonyl, ethoxycarbonyl,
amidocarbonyl, N-methylamidocarbonyl, N,N-dimethylamidocarbonyl,
fluoro, chloro, bromo, and cyano; R.sup.33 is selected from the
group consisting of hydrido, amidino, guanidino, carboxy, methoxy,
ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino,
ethoxyamino, acetamido, trifluoroacetamido, N-methylamino,
dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl,
methoxycarbonyl, ethoxycarbonyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and
Q.sup.b; A is selected from the group consisting of single covalent
bond, NH, N(CH.sub.3), N(OH), CH.sub.2, CH.sub.3CH, CF.sub.3CH,
NHC(O), N(CH.sub.3)C(O), C(O)NH, C(O)N(CH.sub.3), CH.sub.2CH.sub.2,
CH.sub.2CH.sub.2CH.sub.2, CH.sub.3CHCH.sub.2, and
CF.sub.3CHCH.sub.2; R.sup.1 is selected from the group consisting
of hydrido, methyl, ethyl, propyl, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, fluoro, chloro, and bromo; R.sup.2 is
Z.sup.0--Q; Z.sup.0 is selected from the group consisting of
covalent single bond and CH.sub.2: Q is selected from the group
consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl,
2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl,
4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, 5-isoxazolyl, 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, and
1,3,5-triazin-2-yl, wherein a carbon adjacent to the carbon at the
point of attachment is optionally substituted by R.sup.9, the other
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.13, a carbon adjacent to R.sup.9
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.10, a carbon adjacent to R.sup.13
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.12, and any carbon adjacent to both
R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
Y.sup.0 is selected from the group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
2-Q.sup.b-4-Q.sup.s-3-R.sup.16-6-R.sup.18pyrazine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.18-5-R.sup.18-4-R.sup.19pyridazine,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18pyrimidine,
5-Q.sup.b-2-Q.sup.s-3-R.sup.16-6-R.sup.19pyrimidine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.s- up.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R- .sup.19imidazole,
2-Q.sup.b-4-Q.sup.s-5-R.sup.17imidazole,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16isoxazole,
5-Q.sup.b-3-Q.sup.s-4-R.sup.16is- oxazole,
2-Q.sup.b-5-Q.sup.s-4-R.sup.16pyrazole, 4-Q.sup.b-2-Q.sup.s-5-R.s-
up.19thiazole, and 2-Q.sup.b-5-Q.sup.s-4-R.sup.17thiazole;
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, methyl, ethyl,
isopropyl, propyl, carboxy, amidino, guanidino, methoxy, ethoxy,
isopropoxy, propoxy, hydroxy, amino, aminomethyl, 1-aminoethyl,
2-aminoethyl, N-methylamino, dimethylamino, N-ethylamino,
methylthio, ethylthio, isopropylthio, trifluoromethylthio,
methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl ,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl, and
cyano; R.sup.16 and R.sup.19 are optionally Q.sup.b with the
proviso that no more than one of R.sup.16 and R.sup.19 is Q.sup.b
at the same time and that Q.sup.b is Q.sup.be; Q.sup.b is selected
from the croup consisting of Q.sup.be wherein Q.sup.be is hydrido
and C(NR.sup.25)NR.sup.23R.sup.24, with the proviso that no more
than one of R.sup.23 and R.sup.24 is hydroxy at the same time;
R.sup.23, R.sup.24, and R.sup.25 are independently selected from
the group consisting of hydrido, methyl, ethyl, and hydroxy;
Q.sup.s is selected from the group consisting of a single covalent
bond, CH.sub.2 and CH.sub.2CH.sub.2.
27. The compound as recited in claim 26 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclo[2,2,1]-heptyl,
1-pyrrolidinyl, 1-piperidinyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl,
azetidin-1-yl, azetidin-2-yl, azetidin-3-yl,
7-oxabicyclo[2,2,1]heptan-2-yl, bicyclo[3,1,0]hexan-6-yl,
2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 1-piperazinyl,
2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,
4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl, 4H-4-pyranyl,
4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl,
3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl,
4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl;
A is selected from the group consisting of single covalent bond,
CH.sub.2, NHC(O), CH.sub.2CH.sub.2, and CH.sub.2CH.sub.2CH.sub.2;
R.sup.1 is selected from the group consisting of hydrido, methyl,
ethyl, propyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, fluoro, chloro, and bromo; R.sup.2 is
Z.sup.0--Q; Z.sup.0 is selected from the group consisting of
covalent single bond and CH.sub.2; Q is selected from the group
consisting of 5-amino-3-amidocarbonylphenyl,
5-amino-2-fluorophenyl, 3-amino-5-hydroxymethylphenyl,
5-amino-3-methoxycarbonylphenyl, 3-amidinophenyl,
3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl, 3-aminophenyl,
benzyl, 3-carboxyphenyl, 3-carboxy-5-aminophenyl,
3-carboxy-5-hydroxyphenyl, 3-carboxymethyl-5-aminophenyl,
3-carboxymethyl-5-hydroxyphenyl, 3-carboxymethylphenyl,
3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 3-cyanophenyl,
3-dimethylaminophenyl, 2-fluorophenyl, 3-fluorophenyl,
2,5-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
3-methanesulfonylaminophenyl, 2-methoxyphenyl, 3-methoxyphenyl,
3-methoxyaminophenyl, 3-methoxycarbonylphenyl, 2-methylaminophenyl,
3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl,
4-methylphenyl, phenyl, 3-trifluoroacetamidophenyl,
3-trifuoromethylphenyl, 2-trifluoromethylphenyl, 5-amino-2-thienyl,
5-amino-3-thienyl, 3-bromo-2-thienyl, 3-pyridyl, 4-pyridyl,
2-thienyl, and 3-thienyl; Y.sup.0 is selected from the group
consisting of: 1-Q.sup.b-4-Q.sup.s-2-R-
.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.s- up.17-4-R.sup.18-2-R.sup.19pyridine,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.su- p.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophen- e, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.s is CH.sub.2.
28. The compound as recited in claim 25 having the Formula: 141or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting, of C3-C7 cycloalkyl and C4-C6 saturated
heterocyclyl, wherein each ring carbon is optionally substituted
with R.sup.33, a ring carbon other than the ring carbon at the
point of attachment of B to A is optionally substituted with oxo
provided that no more than one ring carbon is substituted by oxo at
the same time, ring carbons and a nitrogen adjacent to the carbon
atom at the point of attachment are optionally substituted with
R.sup.9 or R.sup.13, a ring carbon or nitrogen adjacent to the
R.sup.9 position and two atoms from the point of attachment is
optionally substituted with R.sup.10, a ring carbon or nitrogen
adjacent to the R.sup.13 position and two atoms from the point of
attachment is optionally substituted with R.sup.12, a ring carbon
or nitrogen three atoms from the point of attachment and adjacent
to the R.sup.10 position is optionally substituted with R.sup.11, a
ring carbon or nitrogen three atoms from the point of attachment
and adjacent to the R.sup.12 position is optionally substituted
with R.sup.33, and a ring carbon or nitrogen four atoms from the
point of attachment and adjacent to the R.sup.11 and R.sup.33
positions is optionally substituted with R.sup.34; R.sup.9,
R.sup.11, and R.sup.13 are independently selected from the group
consisting of hydrido, hydroxy, amino, amidino, guanidino, lower
alkylamino, alkylthio, alkoxy, alkylsulfinyl, alkylsulfonyl,
amidosulfonyl, monoalkyl amidosulfonyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, carboxy, carboxamido, and cyano; R.sup.10
and R.sup.12 are independently selected from the group consisting
of hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl,
alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl,
carboalkoxy, carboxy, carboxyalkyl, carboxyamido, and cyano;
R.sup.33 and R.sup.34 are independently selected from the group
consisting of hydrido, amidino, guanidino, alkoxy, hydroxy, amino,
alkoxyamino, lower alkylamino, alkylthio, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, carboalkoxy, carboxy, carboxamido, and
cyano; R.sup.33 is optionally Q.sup.b; A is selected from the group
consisting of single covalent bond and
(CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an integer
selected from 0 through 1, pa is an integer selected from 0 through
3, and W.sup.7 is N(R.sup.7); R.sup.7 is selected from the group
consisting of hydrido and alkyl; R.sup.15 is selected from the
group consisting of hydrido, halo, alkyl, and haloalkyl; R.sup.1 is
selected from the group consisting of hydrido, cyano, haloalkyl,
and halo; R.sup.2 is Z.sup.0--Q; Z.sup.0 is a covalent single bond:
Q is selected from the group consisting of aryl and heteroaryl
wherein a carbon adjacent to the carbon at the point of attachment
is optionally substituted by R.sup.9, the other carbon adjacent to
the carbon at the point of attachment is optionally substituted by
R.sup.13, a carbon adjacent to R.sup.9 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.10, a carbon adjacent to R.sup.13 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.12, and any carbon adjacent to both R.sup.10 and R.sup.12 is
optionally substituted by R.sup.11; R.sup.9, R.sup.11, and R.sup.13
are independently selected from the group consisting of hydrido,
hydroxy, amino, amidino, guanidino, lower alkylamino, alkylthio,
alkoxy, alkylsulfinyl, alkylsulfonyl, amidosulfonyl,
monoalkylamidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy,
hydroxyalkyl, carboxy, carboxamido, and cyano; R.sup.10 and
R.sup.12 are independently selected from the group consisting of
hydrido, acetamido, haloacetamido, amidino, guanidino, alkyl,
alkoxy, alkoxyamino, aminoalkyl, hydroxy, amino, lower alkylamino,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, hydroxyalkyl, aminoalkyl, halo, haloalkyl,
carboalkoxy, carboxy, carboxyamido, carboxyalkyl, and cyano;
Y.sup.0 is formula (IV): 142 wherein D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 are independently selected from the group consisting of C,
N, O, S and a covalent bond with the provisos that no more than one
is a covalent bond, K.sup.2 is C, no more than one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 is O, no more than one of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 must be a covalent bond when two of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are O and S, and no more than four of
D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are N; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, amidino, guanidino, carboxy, haloalkylthio,
alkoxy, hydroxy, amino, lower alkylamino, alkylthio, alkylsulfinyl,
alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo, haloalkyl,
haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; Q.sup.b is selected from the group consisting
of NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido, and
C(NR.sup.25)NR.sup.23R.sup.24; R.sup.20, R.sup.21, R.sup.23,
R.sup.24, and R.sup.25 are independently selected from the group
consisting of hydrido and alkyl; Q.sup.s is CH.sub.2.
29. The compound as recited in claim 28 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclo[2,2,1]-heptyl,
1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl,
azetidin-3-yl, bicyclo[3,1,0]hexan-6-yl, 2-morpholinyl,
3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl,
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,
1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl,
2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl,
3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and
3-tetrahydrothienyl, wherein each ring carbon is optionally
substituted with R.sup.33, ring carbons and a nitrogen adjacent to
the carbon atom at the point of attachment are optionally
substituted with R.sup.9 or R.sup.13, a ring carbon or nitrogen
adjacent to the R.sup.9 position and two atoms from the point of
attachment are optionally substituted with R.sup.10, and a ring
carbon or nitrogen atom adjacent to the R.sup.13 position and two
atoms from the point of attachment is optionally substituted with
R.sup.12; R.sup.9, R.sup.11, and R.sup.13 are independently
selected from the group consisting of hydrido, methyl, ethyl,
methoxy, ethoxy, hydroxy, amino, N-methylamino, N,N-dimethylamino,
methylthio, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl
1-hydroxyethyl, amidocarbonyl, N-methylamidocarbonyl, carboxy, and
cyano; R.sup.10 and R.sup.12 are independently selected from the
group consisting of hydrido, amidino, amidocarbonyl,
N-methylamidocarbonyl, guanidino, methyl, ethyl, methoxy, ethoxy,
hydroxy, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, carboxy,
carboxymethyl, amino, acetamido, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, trifluoroacetamido, aminomethyl,
N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo,
and cyano; R.sup.33 is selected from the group consisting of
hydrido, amidino, guanidino, methyl, ethyl, methoxy, ethoxy,
hydroxy, carboxy, amino, N-methylamino, dimethylamino, methylthio,
ethylthio, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
fluoro, chloro, bromo, amidosulfonyl, N-methylamidosulfonyl,
hydroxymethyl, amidocarbonyl, cyano, and Q.sup.b; A is selected
from the group consisting of single covalent bond, NH, N(CH.sub.3),
CH.sub.2, CH.sub.3CH, CH.sub.2CH.sub.2, and
CH.sub.2CH.sub.2CH.sub.2; R.sup.1 is selected from the group
consisting of hydrido, trifluoromethyl, pentafluoroethyl, fluoro,
and chloro; R.sup.2 is selected from the group consisting of
phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl,
3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent
to the carbon at the point of attachment is optionally substituted
by R.sup.9, the other carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.13, a carbon adjacent
to R.sup.9 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.10, a carbon adjacent to
R.sup.13 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.12, and any carbon adjacent to
both R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
Y.sup.0 is selected from the group consisting of:
1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-R.sup.18-6-R.sup.19benzene,
2-Q.sup.b-5-Q.sup.s-6-R.sup.17-4-R.sup.18-2-R.sup.19pyridine,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene,
3-Q.sup.b-6-Q.sup.s-2-R.sup.16-5-R.sup.18-4-R.sup.19pyridine,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thiophene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19furan,
2-Q.sup.b-5-Q.sup.s-3-R.s- up.16-4-R.sup.17furan,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R9pyrrole,
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17pyrrole,
4-Q.sup.b-2-Q.sup.s-5-R- .sup.19thiazole, and
2-Q.sup.b-5-Q.sup.s-4-R.sup.17thiazole; R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are independently selected from the group
consisting of hydrido, methyl, ethyl, amidino, guanidino, methoxy,
hydroxy, amino, aminomethyl, 1-aminoethyl, 2-aminoethyl,
N-methylamino, dimethylamino, methylthio, ethylthio,
trifluoromethylthio, methylsulfinyl, methylsulfonyl,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
trifluoromethoxy, fluoro, chloro, amidosulfonyl,
N-methylamidosulfonyl, hydroxymethyl, carboxy, and cyano, Q.sup.b
is selected from the group consisting of NR.sup.20R.sup.21 and
C(NR.sup.25)NR.sup.23R.sup.24, with the proviso that said Q.sup.b
group is bonded directly to a carbon atom; R.sup.20, R.sup.21,
R.sup.23, R.sup.24, and R.sup.25 are independently selected from
the group consisting of hydrido, methyl, and ethyl; Q.sup.s is
CH.sub.2.
30. The compound as recited in claim 29 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
oxalan-2-yl, 2-(2R)-bicyclo[2,2,1]-heptyl, 1,1-dioxothiolan-3-yl,
oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl,
1-pyrrolidinyl and 1-piperidinyl; A is selected from the group
consisting of a single covalent bond, CH.sub.2, NHC(O),
CH.sub.2CH.sub.2 and CH.sub.2CH.sub.2CH.sub.2; R.sup.1 is selected
from the group consisting of hydrido, 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: 1-Q.sup.b-4-Q.sup.s-2-R.sup.16-3-R.sup.17-5-
-R.sup.18-6-R.sup.19benzene,
3-Q.sup.b-5-Q.sup.s-4-R.sup.16-2-R.sup.19thio- phene, and
2-Q.sup.b-5-Q.sup.s-3-R.sup.16-4-R.sup.17thiophene; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.16 and
R.sup.19 are optionally Q.sup.b with the proviso that no more than
one of R.sup.16 and R.sup.19 is Q.sup.b at the same time and that
Q.sup.b is Q.sup.be; R.sup.17 and R.sup.18 are independently
selected from the group consisting of hydrido, fluoro, chloro,
hydroxy, hydroxymethyl, amino, carboxy, and cyano; Q.sup.b is
selected from the group consisting of Q.sup.be wherein Q.sup.be is
hydrido and C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23, R.sup.24, and
R.sup.25 are independently selected from the group consisting of
hydrido and methyl; Q.sup.s is CH.sub.2.
31. The compound as recited in claim 30 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
oxalan-2-yl, 2-(2R)-bicyclo[2,2,1]-heptyl, 1,1-dioxothiolan-3-yl,
oxetan-3-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and
1-piperidinyl; A is selected from the group consisting of a single
covalent bond, CH.sub.2, CH.sub.2CH.sub.2 and
CH.sub.2CH.sub.2CH.sub.2; R.sup.1 is selected from the group
consisting of hydrido and chloro; R.sup.2 is selected from the
group consisting of 3-aminophenyl, 2,6-dichlorophenyl,
2-hydroxyphenyl, phenyl, 5-amino-2-thienyl, and 3-thienyl; 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. A compound as recited in claim 25 where said compound is
selected from the group having the Formula: 143or a
pharmaceutically acceptable salt thereof, wherein: R.sup.2 is
3-aminophenyl, B is cycylopropyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B
is cyclobutyl, A is single bond, Y.sup.0 is
4-amidino-2-fluorobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-aminophenyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B
is cyclopropyl, A is single bond, Y.sup.0 is
4-amidino-2-fluorobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-aminophenyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is hydrido; R.sup.2 is 3-aminophenyl,
B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidino-3-fluorobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-aminophenyl, B is cyclopentyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is
5-amino-2-thienyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B
is cyclopropyl, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and
R.sup.1 is chloro; 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 R.sup.1 is chloro; R.sup.2 is 3-aminophenyl, B
is cyclopentyl, A is single bond, Y.sup.0 is
4-amidino-2-fluorobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-aminophenyl, B is cyclohexyl, A is CH.sub.2CH.sub.2, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is hydrido; R.sup.2 is 3-aminophenyl,
B is oxalan-2-yl, A is CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and
R.sup.1 is chloro; R.sup.2 is phenyl, B is 1-pyrrolidinyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is
chloro; R.sup.2 is 3-aminophenyl, B is 1-piperidinyl, A is
CH.sub.2CH.sub.2, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is
chloro; R.sup.2 is 3-aminophenyl, B is 1,1-dioxothiolan-3-yl, A is
single bond, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is chloro;
R.sup.2 is 2-hydroxyphenyl, B is cyclobutyl, A is single bond,
Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is
3-aminophenyl, B is 1-pyrrolidinyl, A is CH.sub.2CH.sub.2CH.sub.2,
Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is
phenyl, B is cyclobutyl, A is single bond, Y.sup.0 is
4-amidinobenzyl, and R.sup.1 is chloro; R.sup.2 is 3-thienyl, B is
cyclobutyl, A is single bond, Y.sup.0 is 4-amidinobenzyl, and
R.sup.1 is hydrido; R.sup.2 is 2,6-dichlorophenyl, B is cyclobutyl,
A is single bond, Y.sup.0 is 4-amidinobenzyl, and R.sup.1 is
chloro.
33. The compound having the Formula: 144or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of aryl and heteroaryl wherein a carbon adjacent to the
carbon at the point of attachment is optionally substituted by
R.sup.32, the other carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.36, a carbon adjacent
to R.sup.32 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.33, a carbon adjacent
to R.sup.36 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.35, and any carbon
adjacent to both R.sup.33 and R.sup.35 is substituted by R.sup.34;
R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkylenedioxy,
haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino,
haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl, aralkyl,
cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl,
haloalkoxy, hydroxyalkyl, alkylamino, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b; B is optionally selected from the
croup 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 croup consisting of R.sup.32,
R.sup.33, R.sup.34, R.sup.35, and R.sup.36; B is optionally
selected from the group consisting of C3-C12 cycloalkyl and C4-C9
saturated heterocyclyl, wherein each ring carbon is optionally
substituted with R.sup.33, a ring carbon other than the ring carbon
at the point of attachment of B to A is optionally substituted with
oxo provided that no more than one ring carbon is substituted by
oxo at the same time, ring carbons and a nitrogen adjacent to the
carbon atom at the point of attachment are optionally substituted
with R.sup.9 or R.sup.13, a ring carbon or nitrogen adjacent to the
R.sup.9 position and two atoms from the point of attachment is
optionally substituted with R.sup.10, a ring carbon or nitrogen
adjacent to the R.sup.13 position and two atoms from the point of
attachment is optionally substituted with R.sup.12, a ring carbon
or nitrogen three atoms from the point of attachment and adjacent
to the R.sup.10 position is optionally substituted with R.sup.11, a
ring carbon or nitrogen three atoms from the point of attachment
and adjacent to the R.sup.12 position is optionally substituted
with R.sup.33, and a ring carbon or nitrogen four atoms from the
point of attachment and adjacent to the R.sup.11 and R.sup.33
positions is optionally substituted with R.sup.34; R.sup.9,
R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are independently
selected from the group consisting of hydrido, acetamido,
haloacetamido, alkoxyamino, alkanoyl, haloalkanoyl, amidino,
guanidino, alkylenedioxy, haloalkylthio, alkoxy, hydroxy, amino,
lower alkylamino, alkylthio, alkylsulfinyl, alkylsulfamido,
alkylsulfonyl, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, halo, haloalkyl, haloalkoxy, hydroxyalkyl,
aminoalkyl, carboalkoxy, carboxy, carboxyalkyl, carboxamido, and
cyano; A is selected from the group consisting of single covalent
bond and (CH(R.sup.15)).sub.pa--(W.sup.7).sub.rr wherein rr is an
integer selected from 0 through 1, pa is an integer selected from 0
through 3, and W.sup.7 is selected from the group consisting of O,
S, C(O), (R.sup.7)NC(O), (R.sup.7)NC(S), and N(R.sup.7); R.sup.7 is
selected from the group consisting of hydrido, hydroxy and alkyl;
R.sup.15 is selected from the group consisting of hydrido, hydroxy,
halo, alkyl, and haloalkyl; R.sup.1 is selected from the group
consisting of hydrido, alkyl, cyano, halo, haloalkyl, haloalkoxy,
amino, aminoalkyl, alkylamino, amidino, hydroxy, hydroxyamino,
alkoxy, hydroxyalkyl, alkoxyamino, thiol, and alkylthio; R.sup.2 is
Z.sup.0--Q; Z.sup.0 is selected from the group consisting of
covalent single bond and (CR.sup.41R.sup.42).sub.q wherein q is an
integer selected from 1 through 2,
(CH(R.sup.41)).sub.g--W.sup.0--(CH(R.s- up.42)).sub.p wherein g and
p are integers independently selected from 0 through 3 and W.sup.0
is selected from the group consisting of O, S, and N(R.sup.41), and
(CH(R.sup.41)).sub.e--W.sup.22--(CH(R.sup.42)).sub.h wherein e and
h are integers independently selected from 0 through 1 and W.sup.22
is selected from the group consisting of CR.sup.41.dbd.CR.sup.42- ,
1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl,
1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,
2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl,
1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl,
1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl,
3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,
2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl,
3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso
that Z.sup.0 is directly bonded to the pyrazinone ring; R.sup.41
and R.sup.42 are independently selected from the group consisting
of hydrido, hydroxy, and amino; Q is selected from the group
consisting of hydrido with the proviso that Z.sup.0 is other than a
covalent single bond, aryl and heteroaryl, wherein a carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.9, the other carbon adjacent to the carbon at
the point of attachment is optionally substituted by R.sup.13, a
carbon adjacent to R.sup.9 and two atoms from the carbon at the
point of attachment is optionally substituted by R.sup.10, a carbon
adjacent to R.sup.13 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.12, and any carbon
adjacent to both R.sup.10 and R.sup.12 is optionally substituted by
R.sup.11; K is CHR.sup.4a wherein R.sup.4a is selected from the
group consisting of hydrido, hydroxyalkyl, alkyl alkoxyalkyl,
alkylthioalkyl, and haloalkyl; E.sup.0 is selected from the group
consisting of a covalent single bond, C(O)N(H), (H)NC(O),
(R.sup.7)NS(O).sub.2, and S(O).sub.2N(R.sup.7); Y.sup.AT is
Q.sup.b--Q.sup.s; Q.sup.s is (CR.sup.37R.sup.38).sub.b wherein b is
an integer selected from 1 through 4, R.sup.37 is selected from the
group consisting of hydrido, alkyl, and haloalkyl, and R.sup.38 is
selected from the group consisting of hydrido, alkyl, haloalkyl,
aroyl, and heteroaroyl with the provisos that there is at least one
aroyl or heteroaroyl substituent, that no more than one aroyl or
heteroaroyl is bonded to (CR.sup.37R.sup.38).sub.b at the same
time, that said aroyl and said heteroaroyl are optionally
substituted at from one through three of the ring carbons with a
substituent selected from the group consisting of R.sup.16,
R.sup.17, R.sup.18, and R.sup.19, that said aroyl and said
heteroaroyl are bonded to the CR.sup.37R.sup.38 that is directly
bonded to E.sup.0, that is no more than one alkyl or one haloalkyl
is bonded to a CR.sup.37R.sup.38 at the same time, and that said
alkyl and haloalkyl are bonded to a carbon other than the one
bonding the aroyl or heteroaroyl; R.sup.16, R.sup.17, R.sup.18, and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, guanidino, carboxy, haloalkylthio, alkoxy,
hydroxy, amino, alkoxyamino, lower alkylamino, alkylthio,
alkylsulfinyl, alkylsulfonyl, alkanoyl, haloalkanoyl, alkyl, halo,
haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl, and cyano;
R.sup.16 and R.sup.19 are optionally Q.sup.b with the proviso that
no more than one of R.sup.16 and R.sup.19 is Q.sup.b at the same
time and that Q.sup.b is Q.sup.be; Q.sup.b is selected from the
group consisting of NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is
hydrido, N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), and
C(NR.sup.25)NR.sup.23R.sup.24, with the provisos that no more than
one of R.sup.20 and R.sup.21 is hydroxy, amino, alkylamino, or
dialkylamino at the same time and that no more than one of R.sup.23
and R.sup.24 is hydroxy, amino, alkylamino, or dialkylamino at the
same time; R.sup.20, R.sup.21, R.sup.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.
34. The compound as recited in claim 33 having the Formula: 145or a
pharmaceutically acceptable salt thereof, wherein; B is selected
from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl,
3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl,
3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 3-isoxazolyl, and
5-isoxazolyl, wherein a carbon adjacent to the carbon at the point
of attachment is optionally substituted by R.sup.32, the other
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.36, a carbon adjacent to R.sup.32
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.33, a carbon adjacent to R.sup.36
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.35, and any carbon adjacent to both
R.sup.33 and R.sup.35 is optionally substituted by R.sup.34;
R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
amidino, guanidino, methyl, ethyl, methoxy, ethoxy, hydroxy, amino,
N-methylamino, dimethylamino, methylthio, ethylthio,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro,
chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl,
amidocarbonyl, carboxy, cyano, and Q.sup.b; B is optionally
selected from the group consisting of hydrido, ethyl, 2-propenyl,
2-propynyl, propyl, isopropyl, butyl, 2-butenyl, 2-butynyl,
sec-butyl, tert-butyl, isobutyl, 2-methylpropenyl, 1-pentyl,
2-pentenyl, 3-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 3-pentyl,
2-methylbutyl, 2-methy-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 3,3,3,3-trifluoropropyl, wherein
each member of group B is optionally substituted at any carbon up
to and including 5 atoms from the point of attachment of B to A
with one or more of the group consisting of R.sup.32, R.sup.33,
R.sup.34, R.sup.35, and R.sup.36; B is optionally selected from the
group consisting of cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, oxalan-2-yl, 2-(2R)-bicyclo[2,2,1]-heptyl,
1,1-dioxothiolan-3-yl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl,
azetidin-3-yl, bicyclo[3,1,0]hexanyl, 2-morpholinyl, 3-morpholinyl,
4-morpholinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,
2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl,
2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl, 2-tetrahydrofuranyl,
3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl,
4-tetrahydropyranyl, 2-tetrahydrothienyl, and 3-tetrahydrothienyl,
wherein each ring carbon is optionally substituted with R.sup.33,
ring carbons and a nitrogen adjacent to the carbon atom at the
point of attachment are optionally substituted with R.sup.9 or
R.sup.13, a ring carbon or nitrogen adjacent to the R.sup.9
position and two atoms from the point of attachment is optionally
substituted with R.sup.10, and a ring carbon or nitrogen adjacent
to the R.sup.13 position and two atoms from the point of attachment
is optionally substituted with R.sup.12; R.sup.9, R.sup.11, and
R.sup.13 are independently selected from the group consisting of
hydrido, methyl, ethyl, methoxy, ethoxy, hydroxy, amino,
N-methylamino, N,N-dimethylamino, methylthio, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, bromo,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
hydroxymethyl, 1-hydroxyethyl, amidocarbonyl,
N-methylamidocarbonyl, carboxy, and cyano; R.sup.10 and R.sup.12
are independently selected from the group consisting of hydrido,
amidino, amidocarbonyl, N-methylamidocarbonyl, guanidino, methyl,
ethyl, methoxy, ethoxy, hydroxy, hydroxymethyl, 1-hydroxyethyl,
2-hydroxyethyl, carboxy, carboxymethyl, amino, acetamido,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
trifluoroacetamido, aminomethyl, N-methylamino, dimethylamino,
amidosulfonyl, N-methylamidosulfonyl, N,N-dimethylamidosulfonyl,
methoxycarbonyl, fluoro, chloro, bromo, and cyano; A is selected
from the group consisting of single covalent bond, NH, N(CH.sub.3),
CH.sub.2, CH.sub.3CH, CH.sub.2CH.sub.2, and
CH.sub.2CH.sub.2CH.sub.2; R.sup.1 is selected from the group
consisting of hydrido, trifluoromethyl, pentafluoroethyl, fluoro,
and chloro; R.sup.2 is selected from the group consisting of
phenyl, 2-thienyl, 2-furyl, 2-pyrrolyl, 2-imidazolyl, 2-thiazolyl,
3-isoxazolyl, 2-pyridyl, and 3-pyridyl, wherein a carbon adjacent
to the carbon at the point of attachment is optionally substituted
by R.sup.9, the other carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.13, a carbon adjacent
to R.sup.9 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.10, a carbon adjacent to
R.sup.13 and two atoms from the carbon at the point of attachment
is optionally substituted by R.sup.12, and any carbon adjacent to
both R.sup.10 and R.sup.12 is optionally substituted by R.sup.11;
Y.sup.0 is Q.sup.b--Q.sup.s; Q.sup.sis selected from the group
consisting of: C[R.sup.37(benzoyl)](CR.sup.37R.sup.38).sub.b],
C[R.sup.37(2-pyridylcarbo- nyl])](CR.sup.37R.sup.38).sub.b],
C[R.sup.37(3-pyridylcarbonyl])](CR.sup.3- 7R.sup.38).sub.b],
C[R.sup.37(4-pyridylcarbonyl])](CR.sup.37R.sup.38).sub.- b],
C[R.sup.37(2-thienylcarbonyl])](CR.sup.37R.sup.38).sub.b],
C[R.sup.37(3-thienylcarbonyl])](CR.sup.37R.sup.38).sub.b],
C[R.sup.37(2-thiazolylcarbonyl])](CR.sup.37R.sup.38).sub.b],
C[R.sup.37(4-thiazolylcarbonyl])](CR.sup.37R.sup.38).sub.b], and
C[R.sup.37(5-thiazolylcarbonyl])](CR.sup.37R.sup.38).sub.b],
wherein b is an integer selected from 1 through 3, R.sup.37 and
R.sup.38 are independently selected from the group consisting of
hydrido, alkyl, and haloalkyl, with the provisos that said aroyl
and said heteroaroyl are optionally substituted at from one through
three of the ring carbons with a substituent selected from the
group consisting of R.sup.16, R.sup.17, R.sup.18, and R.sup.19 with
the proviso that R.sup.17 and R.sup.18 are optionally substituted
at a carbon selected from other than the meta and para carbons
relative to the carbonyl of the benzoyl substituent and the
heteroaroyl substituent, that said benzoyl and said heteroaroyl are
bonded to the carbon directly bonded to amide nitrogen of the
1-(amidocarbonymethylene) group, and that is no more than one alkyl
or one haloalkyl is bonded to a CR.sup.37R.sup.38 at the same time;
R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independently
selected from the group consisting of hydrido, methyl, ethyl,
amidino, guanidino, methoxy, hydroxy, amino, aminomethyl,
1-aminoethyl, 2-aminoethyl, N-methylamino, dimethylamino,
methylthio, ethylthio, trifluoromethylthio, methylsulfinyl,
methylsulfonyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, trifluoromethoxy, fluoro, chloro,
amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl, carboxy, and
cyano; Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21 and C(NR.sup.25)NR.sup.23R.sup.24, with the
proviso that said Q.sup.b group is bonded directly to a carbon
atom; R.sup.20, R.sup.21, R.sup.23, R.sup.24, and R.sup.25 are
independently selected from the group consisting of hydrido,
methyl, and ethyl.
35. The compound as recited in claim 34 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of 2-aminophenyl, 3-aminophenyl, 3-amidinophenyl,
4-amidinophenyl, 3-carboxyphenyl, 3-carboxy-5-hydroxyphenyl,
3-chlorophenyl, 4-chlorophenyl, 3,4-dichloropbenyl, 2-fluorophenyl,
3-fluorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 3-methoxyaminophenyl, 3-methoxyphenyl,
4-methoxyphenyl, 3-methylphenyl, 4-methylphenyl, phenyl,
3-trifluoromethylphenyl, 2-imidazoyl, 2-pyridyl, 3-pyridyl,
5-chloro-3-trifluoromethyl-2-pyridyl, 4-pyridyl, 2-thienyl,
3-thienyl, and 3-trifluoromethyl-2-pyridyl; B is optionally
selected from the group consisting of hydrido,ethyl, 2-propenyl,
2-propynyl, propyl, isopropyl, butyl, 2-butyl, (R)-2-butyl,
(S)-2-butyl, tert-butyl, isobutyl, 1-pentyl, 3-pentyl,
2-methylbutyl, 2,2,2-trifluoroethyl, 6-amidocarbonylhexyl,
4-methyl-2-pentyl, 3-hydroxypropyl, 3-methoxy-2-propyl,
2-methoxyethyl, 2-methyl-2-butyl, 3-methyl-2-butyl,
2-dimethylaminopropyl, 2-cyanoethyl, 6-hydroxyhexyl,
2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl,
3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl,
4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl,
2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and
4-aminobutyl; B is optionally selected from the group consisting of
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl,
2-(2R)-bicyclo[2,2,1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl,
azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, 1-pyrrolidinyl and
1-piperidinyl; A is selected from the group consisting of single
covalent bond, CH.sub.2, CH.sub.3CH, CH.sub.2CH.sub.2, and
CH.sub.2CH.sub.2CH.sub.- 2; R.sup.1 is selected from the group
consisting of hydrido, methyl, ethyl, propyl, trifluoromethyl,
pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro, chloro, and bromo;
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-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.AT is Q.sup.b--Q.sup.s; Q.sup.s is selected from the group
consisting of: [CH(benzoyl)](CH.sub.2).sub.b,
[CH(2-pyridylcarbonyl)](CH.sub.2).sub.b,
[CH(3-pyridylcarbonyl)](CH.sub.2- ).sub.b,
[CH(4-pyridylcarbonyl)](CH.sub.2).sub.b, [CH(2-thienylcarbonyl)](-
CH.sub.2).sub.b, [CH(3-thienylcarbonyl)](CH.sub.2).sub.b,
[CH(2-thiazolylcarbonyl)](CH.sub.2).sub.b,
[CH(4-thiazolylcarbonyl)](CH.s- ub.2).sub.b, and
[CH(5-thiazolylcarbonyl)](CH.sub.2).sub.b, wherein b is an integer
selected from 1 through 3, with the provisos that said aroyl and
said heteroaroyl are optionally substituted at from one through
three of the ring carbons with a substituent selected from the
group consisting of R.sup.16, R.sup.17, R.sup.18, and R.sup.19 with
the proviso that R.sup.17 and R.sup.18 are optionally substituted
at a carbon selected from other than the meta and para carbons
relative to the carbonyl of the benzoyl substituent and the
heteroaroyl substituent, and that said benzoyl and said heteroaroyl
substituent are bonded to the carbon directly bonded to amide
nitrogen of the 1-(amidocarbonymethylene) group; R.sup.16 and
R.sup.19 are independently selected from the group consisting of
hydrido, amidino, amino, aminomethyl, methoxy, methylamino,
hydroxy, hydroxymethyl, fluoro, chloro, and cyano; R.sup.17 and
R.sup.18 are independently selected from the group consisting of
hydrido, fluoro, chloro, hydroxy, hydroxymethyl, amino, carboxy,
and cyano; Q.sup.b is C(NR.sup.25)NR.sup.23R.sup.24; R.sup.23,
R.sup.24, and R.sup.25 are independently selected from the group
consisting of hydrido and methyl.
36. The compound as recited in claim 35 or a pharmaceutically
acceptable salt thereof, wherein; B is selected from the group
consisting of 3-aminophenyl, 3-amidinophenyl, 4-amidinophenyl,
3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl,
4-methylphenyl, phenyl, 2-imidazoyl, 3-pyridyl, 4-pyridyl, and
3-trifluoromethyl-2-pyridy- l; B is optionally selected from the
group consisting of hydrido, ethyl, 2-propenyl, 2-propynyl, propyl,
isopropyl, butyl, 2-butyl, (R)-2-butyl, (S)-2-butyl, tert-butyl,
isobutyl, 1-pentyl, 3-pentyl, 2-methylbutyl, 2,2,2-trifluoroethyl,
6-amidocarbonylhexyl, 4-methyl-2-pentyl, 3-hydroxypropyl,
3-methoxy-2-propyl, 2-methoxyethyl, 2-methyl-2-butyl,
3-methyl-2-butyl, 2-dimethylaminopropyl, 2-cyanoethyl,
6-hydroxyhexyl, 2-hydroxyethyl, 2-amidinoethyl, 2-guanidinoethyl,
3-guanidinopropyl, 4-guanidinobutyl, 3-hydroxypropyl,
4-hydroxybutyl, 6-cyanohexyl, 2-dimethylaminoethyl, 3-methylbutyl,
2-methylbutyl, (S)-2-methylbutyl, 3-aminopropyl, 2-hexyl, and
4-aminobutyl; B is optionally selected from the group consisting of
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxalan-2-yl,
2-(2R)-bicyclo[2,2,1]-heptyl, 1,1-dioxothiolan-3-yl, oxetan-3-yl,
azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, and 1-piperidinyl; A
is selected from the group consisting of a single covalent bond,
CH.sub.2, CH.sub.2CH.sub.2 and CH.sub.2CH.sub.2CH.sub.2; R.sup.1 is
selected from the group consisting of hydrido and chloro; R.sup.2
is selected from the group consisting of 3-aminophenyl, benzyl,
2,6-dichlorophenyl, 5-amino-2-thienyl, 5-amino-2-fluorophenyl,
3-amino-2-methylphenyl, 5-amino-2-methylthiophenyl,
3-carboxyphenyl, 3-cyanophenyl, 3-chlorophenyl, 2-hydroxyhenyl,
3-hydroxyphenyl, 3-methanesulfonylaminophenyl,
3-methoxycarbonylphenyl, 3-dimethylaminophenyl,
3-methylaminophenyl, 2-methylphenyl, 3-methylphenyl, phenyl,
3-pyridyl, 3-trifluoroacetamidophenyl, 3-bromo-2-thienyl,
2-thienyl, and 3-thienyl; Y.sup.AT is selected from the group
consisting of 5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl,
5-guanidino-1-oxo-1-(4-thiazolyl)-2-pentyl,
5-guanidino-1-oxo-1-(5-thiazo- lyl)-2-pentyl,
5-guanidino-1-oxo-1-(4-amino-2-thiazolyl)-2-pentyl, and
5-guanidino-1-oxo-1-phenyl-2-pentyl.
37. A compound as recited in claim 33 where said compound is
selected from the group having the Formula: 146or a
pharmaceutically acceptable salt thereof, wherein; R.sup.2 is
3-aminophenyl, B is phenyl, A is CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and R.sup.1 is chloro;
R.sup.2 is phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and R.sup.1 is hydrido;
R.sup.2 is benzyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and R.sup.1 is hydrido;
R.sup.2 is phenyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and R.sup.1 is chloro;
R.sup.2 is benzyl, B is phenyl, A is CH.sub.2CH.sub.2, Y.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and R.sup.1 is chloro;
R.sup.2 is phenyl, B is phenyl, A is CH.sub.2CH.sub.2, T.sup.AT is
5-guanidino-1-oxo-1-(2-thiazolyl)-2-pentyl, and R.sup.1 is
hydrido.
38. A composition for inhibiting thrombotic conditions in blood
comprising a compound of any one of claims 8, 16, 24, 32, and 37
and a pharmaceutically acceptable carrier.
39. A composition for inhibiting thrombotic conditions in blood
comprising a compound of any one of claims 1 through 7, claims 9
through 15, claims 17 through 23, claims 25 through 31, and claims
33 through 36 and a pharmaceutically acceptable carrier.
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 38 and 39.
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 38 and 39.
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 38 and 39.
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 38 and 39.
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 of any one of claims 38 and
39.
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 38 and 39.
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 38 and 39.
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 38 and 39.
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 38 and 39.
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 1 through 37 with a therapeutically effective
amount of fibrinogen receptor antagonist.
50. The use of a compound of any one of claims 1 through 37, or a
pharmaceutically acceptable salt thereof, in the manufacture of
medicament for inhibiting thrombus formation, treating thrombus
formation, or preventing thrombus formation in a mammal.
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
pyrazinone 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
Antipiplatelet 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
compounds that act as an inhibitor of a coagulation factor present
in the coagulation cascade or clotting process. In PCT Patent
Application WO 97/40024, Sanderson et al. describe alkyl,
cycloalkyl, and trifluoromethyl substituted pyrazinones reported to
inhibit thrombin activity. In PCT Patent Application WO 98/08840,
Duggan et al. describe 2-heterocyclylacetyl derivatives of
.beta.-alanine esters reported to inhibit .alpha.v.beta.3 and
.alpha.v.beta.5 receptors and possess utility in atheriosclerosis.
In PCT Patent Application WO 98/09949, Suzuki et al. describe
2-heterocyclylacetaraido derivatives of 1,2-diketones and report
that they inhibit proteases, especially chymase inhibitors. In PCT
Patent Application WO 98/42342, Isaacs et al. describe additional
alkyl, cycloalkyl, and trifluoromethyl substituted pyrazinones
reported to inhibit human thrombin. In PCT Patent Application WO
99/61442, Sanderson and Naylor-Olsen describe
1-(5-methylenecarboxamidomethyleneimidazo-[1,2-- a]pyridinyl)
pyrazinones without substitution in the imidazolyl portion and
reported that the compounds inhibit thrombin activity. In PCT
Patent Application WO 99/59591, Sanderson et al. describe
1-((N-substitutedazninopyridyl and
N-substitutedphenyl)amidocarbonylmethy- lene)pyrazinones reported
to inhibit thrombin. In PCT Patent Application WO 99/64446, Lu et
al. describe 1-((N-amidinoarninooxyalkylene and
N-amidinohydrazinoalkylene) amidocarbonylmethylene)pyrazinones
reported to inhibit trypsin-like serine proteases and thrombin. In
Japanese Patent Application 99/229491, Black et al. describe
thrombin inhibiting halo and alkyl substituted pyrazinone
acetarides in which the amide nitrogen is substituted by a group
containing a benzimidazole or indole ring.
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 Pyrazinones,
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 heterocycyl 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, hetemaralkoxy,
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,
beteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,
haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,
alkylaminosulfonyl, amidosulfonyl, monoalkyl, amidosulfonyl,
dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,
diarylamidosulfonyl, monoalkylmonoarylamidosulfonyl, 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 w
herein 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 )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.7 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, beteroaryl, 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,
beteroaryl, 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.39 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, monocarboxamino, 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] R.sup.2 and R.sup.1 are independently selected from the
group consisting of Z.sup.0--Q, hydrido, alkyl, alkenyl, and halo
with the provisos that R.sup.2 is selected from other than the
group consisting of hydrido, alkyl, cycloalkyl, and trifluoromethyl
and R.sup.1 is selected from other than the group consisting of
hydrido and halo unless E.sup.1 is other than C(O)NH, or unless
E.sup.0 is selected from the group consisting of E.sup.2 and
E.sup.3, or unless K is other than (CR.sup.4aR.sup.4b).sub.n
wherein n is 1 unless one of R.sup.4a and R.sup.4b are
independently selected from other than hydrido, or unless .PSI. is
selected from other than NR.sup.5, or unless R.sup.5 is selected
from other than hydrido, or unless Y.sup.0 is selected from other
than wherein Q.sup.s is C.sub.1-4 alkyl, C.sub.3-4 alkenyl or
C.sub.3-4 alkynyl where the C.sub.1-4 alkyl, C.sub.3-4 alkenyl or
C.sub.3-4 alkynyl group is bonded concurrently to E.sup.1 wherein
E.sup.1 is C(O)NH and to the 4-position of an imidazole, the
4-position of a thiazole or the 5-position of a thiazole, or unless
a spacer pair is present selected from the group of spacer pairs
consisting of R.sup.2 and R.sup.4a, R.sup.2 and R.sup.4b, R.sup.2
together with both R.sup.4a and R.sup.4b, R.sup.2 and R.sup.14,
R.sup.2 and R.sup.15, and R.sup.6 with another group selected from
the group consisting of R.sup.4a, R.sup.4b, R.sup.4a and R.sup.4b
together, R.sup.39, R.sup.40, R.sup.39 and R.sup.40 together,
R.sup.14, R.sup.15, and R.sup.5, that R.sup.2 is selected from
other than the group consisting of alkyl, aryl, and heteroaryl and
R.sup.1 is selected from other than the group consisting of hydrido
unless E.sup.1 is other than C(O)NH, or unless E.sup.0 is selected
from the group consisting of E.sup.2 and E.sup.3, or unless K is
other than (CR.sup.4aR.sup.4b).sub.n wherein n is 1 unless one of
R.sup.4a and R.sup.4b are independently selected from other than
hydrido, or unless .PSI. is selected from other than NR.sup.5, or
unless R.sup.5 is selected from other than hydrido, or unless
R.sup.37 and R.sup.38 are independently selected from other than
formyl and 2-oxoacyl, that R.sup.2 is selected from other than the
group consisting of hydroxymethyl, methyl, methoxymethyl,
methylthiomethyl, phenylthiomethyl, methylsulfinyl, methylthio,
alkoxy, cycloalkoxy, alkylthio, alkylsulfinyl, alkysulfonyl,
cycloalkylthio, cycloalkylsulfinyl, and cycloalkysulfonyl, when
Y.sup.0 is other than phenyl, mono-substituted phenyl,
di-substituted phenyl, 5-(2-amino)pyridindyl, or
4-(2-amino)pyridindyl, and that R.sup.2 is selected from other than
the group consisting of hydrido, halo, alkyl, cycloalkyl when
Y.sup.0 is methyleneimidazo(1,2-a)pyridinyl, 4,5-benzimidazol-5-yl,
or indol-5-yl unless R.sup.1 is selected from other than the group
consisting of hydrido or halo, or unless E.sup.1 is other than
C(O)NH, or unless E.sup.0 is selected from the group consisting of
E.sup.2 and E.sup.3, or unless K is other than
(CR.sup.4aR.sup.4b).sub.n wherein n is 1 unless one of R.sup.4a and
R.sup.4b are independently selected from other than hydrido, or
unless .PSI. is selected from other than NR.sup.5 wherein R.sup.5
is hydrido;
[0035] R.sup.1is 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;
[0036] 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;
[0037] R.sup.2 and R.sup.1 are optionally taken together to form a
spacer pair wherein the spacer pair forms 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 from 5 through 8
contiguous members and a partially saturated heterocyclyl ring
having from 5 through 8 contiguous members;
[0038] R.sup.2 and R.sup.1 spacer pairs are optionally selected to
be --W.dbd.X--Y.dbd.Z-- forming a ring selected from the group
consisting of a heteroaryl ring having from 5 through 6 contiguous
members and an aryl, wherein W, X, Y, and Z are independently
selected from the group consisting of C(R.sup.9), N, N(R.sup.10),
O, S and a covalent bond with the provisos that one of W, X, Y, and
Z is independently selected to be a covalent bond when one of W, X,
Y, and Z is selected from the group consisting of O and S, no more
than one of W, X, Y, and Z is selected from the group consisting of
O and S, no more than three of W, X, Y, and Z are selected from the
group consisting of N and N(R.sup.10), and C(R.sup.9), N,
N(R.sup.10), O, and S are independently selected to maintain the
tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, the divalent nature of oxygen, and the
aromaticity of the ring;
[0039] R.sup.2, and R.sup.4a, R.sup.2 and R.sup.4b, R.sup.2 and
R.sup.14 and R.sup.2 and R.sup.15 are optionally independently
selected to form spacer pairs wherein a spacer pair is taken
together to form a linear moiety having from 2 through 5 contiguous
atoms connecting the points of bonding of said spacer pair members
to form a heterocyclyl ring having from 5 through 8 contiguous
members with the proviso that no more than one of the group of
spacer pairs consisting of R.sup.2 and R.sup.4a, R.sup.2 and
R.sup.4b, R.sup.2 and R.sup.14, and R.sup.2 and R.sup.15 is used at
the same time;
[0040] R.sup.2 is optionally independently selected to form a
linear moiety having from 2 through 5 contiguous atoms linked to
the points of bonding of both R.sup.4a and R.sup.4b to form a
heterocyclyl ring having from 5 through 8 contiguous members;
[0041] Z.sup.0 is selected from the group consisting of covalent
single bond, (CR.sup.41R.sup.42).sub.q wherein q is an integer
selected from 1 through 6,
(CH(R.sup.41)).sub.g--W.sup.0--(CH(R.sup.42)).sub.p wherein g and p
are integers independently selected from 0 through 3 and W.sup.0 is
selected from the group consisting of O, S, C(O), C(S), C(O)O,
C(S)O, C(O)S, C(S)S, C(O)N(R.sup.41), (R.sup.41)NC(O),
C(S)N(R.sup.41), (R.sup.41)NC(S), OC(O)N(R.sup.41),
(R.sup.41)NC(O)O, SC(S)N(R.sup.41), (R.sup.41)NC(S)S,
SC(O)N(R.sup.41), (R.sup.41)NC(O)S, OC(S)N(R.sup.41),
(R.sup.41)NC(S)O, N(R.sup.42)C(O)N(R.sup.41),
(R.sup.41)NC(O)N(R.sup.42), N(R.sup.42)C(S)N(R.sup.41),
(R.sup.41)NC(S)N(R.sup.42), S(O), S(O).sub.2,
S(O).sub.2N(R.sup.41), N(R.sup.41)S(O).sub.2, Se, Se(O),
Se(O).sub.2, Se(O).sub.2N(R.sup.41), N(R.sup.41)Se(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
N(R.sup.41), ON(R.sup.41), and SiR.sup.28R.sup.29, and
(CH(R.sup.41)).sub.e--W.sup.22-- -(CH(R.sup.42)).sub.h wherein e
and h are integers independently selected from 0 through 2 and
W.sup.22 is selected from the group consisting of
CR.sup.41.dbd.CR.sup.42, CR.sup.41R.sup.42.dbd.C; vinylidene),
ethynylidene (C.dbd.C, 1,2-ethynyl), 1,2-cyclopropyl,
1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl,
1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,4-morpholinyl,
3,4-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 pyrazinone ring;
[0042] R.sup.28 and R.sup.29 are independently selected from the
group consisting of hydrido, hydroxyalkyl, alkyl, alkenyl, alkynyl,
aryl, aralkyl, aryloxyalkyl, acyl, aroyl, aralkanoyl, heteroaroyl,
aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,
aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl,
heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl,
cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,
cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,
halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl,
halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,
perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,
heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,
cyanoalkyl, dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl,
cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl,
cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl,
dicarboxamidocycloalkyl, carboalkoxycyanocycloalky- l,
carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl,
acylalkyl, arylsulfinylalkyl, arylsulfonylalkyl, aralkylsulfinyl,
cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,
heteroarylsulfonylalkyl, heteroarylsulfinylalkyl,
aralkylsulfinylalkyl, aralkylsulfonylalkyl, carboxy,
dialkoxyphosphono, diaralkoxyphosphono, dialkoxyphosphonoalkyl and
diaralkoxyphosphonoalkyl;
[0043] R.sup.28 and R.sup.29 are optionally taken together to form
a linear moiety spacer having from 2 through 7 contiguous atoms and
forming a ring selected from the group consisting of a cycloalkyl
ring having from 3 through 8 contiguous members, a cycloalkenyl
ring having from 3 through 8 contiguous members, and a heterocyclyl
ring having from 3 through 8 contiguous members;
[0044] Q is formula (II): 5
[0045] wherein D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one can be a
covalent bond, no more than one of D.sup.1, D.sup.2, J.sup.1,
J.sup.2 and K.sup.1 can be O, no more than one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 can be S, one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 must be a covalent bond when two of
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are O and S, and no
more than four of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1
can be N, with the proviso that R.sup.9, R.sup.10, R.sup.11,
R.sup.12, and R.sup.13 are each independently selected to maintain
the tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, and the divalent nature of oxygen;
[0046] Q is optionally selected from formula (III): 6
[0047] wherein D.sup.3, D.sup.4, J.sup.3, and J.sup.4 are
independently selected from the group consisting of C, N, O, and S,
no more than one of D.sup.3, D.sup.4, J.sup.3, and J.sup.4 is O, no
more than one of D.sup.3, D.sup.4, J.sup.3, and J.sup.4 is S, and
no more than three of D.sup.1, D.sup.2, J.sup.1, and J.sup.2 are N
with the proviso that R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are
each independently selected to maintain the tetravalent nature of
carbon, trivalent nature of nitrogen, the divalent nature of
sulfur, and the divalent nature of oxygen;
[0048] Q is optionally selected from the group consisting of
hydrido, alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio,
alkenyl, alkynyl, saturated heterocyclyl, partially saturated
heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,
cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl,
halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl,
haloalkenyloxyalkyl, halocycloalkoxyalkyl, and
halocycloalkenyloxyalkyl with the proviso that Z.sup.0 is selected
from other than a single covalent bond when Q is hydrido;
[0049] K is (CR.sup.4aR.sup.4b).sub.n wherein n is an integer
selected from 1 through 4;
[0050] R.sup.4a and R.sup.4b are independently selected from the
group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl,
alkyl, alkenyl, aryl, aralkyl, aralkoxyalkyl, aryloxyalkyl,
alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,
aralkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl,
haloalkyl, haloalkenyl, heteroaryl, heteroarylalkyl,
heteroarylthioalkyl, heteroaralkylthioalkyl, cyanoalkyl,
alkylsulfinylalkyl, alkylsulfonylalkyl, haloalkylsulfinyl,
arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfonylalkyl,
heteroarylsulfinylalkyl, aralkylsulfinylalkyl, and
aralkylsulfonylalkyl with the provisos that halo, hydroxy, and
cyano are bonded to different carbons when simultaneously present
and that R.sup.4a and R.sup.4b are other than hydroxy or cyano when
bonded to the carbon directly bonded to the pyrazinone
nitrogen;
[0051] R.sup.4a and R.sup.4b, when bonded to the same carbon, are
optionally taken together to form a group selected from the group
consisting of oxo, thiono, and a linear spacer moiety having from 2
through 7 contiguous atoms connected to form a ring selected from
the group consisting of a cycloalkyl ring having 3 through 8
contiguous members, a cycloalkenyl ring having 5 through 8
contiguous members, and a heterocyclyl ring having 5 through 8
contiguous members with the proviso that R.sup.4a and R.sup.4b
taken together is other than oxo or thiono when the common carbon
is directly bonded to the pyrazinone nitrogen;
[0052] E.sup.0 is E.sup.1, when K is (CR.sup.4aR.sup.4b).sub.n,
wherein E.sup.1 is selected from the group consisting of a covalent
single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,
C(O)N(R.sup.7), (R.sup.7)NC(O), C(S)N(R.sup.7), (R.sup.7)NC(S),
OC(O)N(R.sup.7), (R.sup.7)NC(O)O, SC(S)N(R.sup.7), (R.sup.7)NC(S)S,
SC(O)N(R.sup.7), (R.sup.7)NC(O)S, OC(S)N(R.sup.7), (R.sup.7)NC(S)O,
N(R.sup.8)C(O)N(R.sup.7), (R.sup.7)NC(O)N(R.sup.8),
N(R.sup.8)C(S)N(R.sup.7), (R.sup.7)NC(S)N(R.sup.8), S(O),
S(O).sub.2, S(O).sub.2N(R.sup.7), N(R.sup.7)S(O).sub.2,
S(O).sub.2N(R.sup.7)C(O), C(O)N(R.sup.7)S(O).sub.2, Se, Se(O),
Se(O).sub.2, Se(O).sub.2N(R.sup.7), N(R.sup.7)Se(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
N(R.sup.7), ON(R.sup.7), SiR.sup.28R.sup.29,
CR.sup.4a.dbd.CR.sup.4b, ethynylidene (C.dbd.C; 1,2-ethynyl), and
C.dbd.CR.sup.4aR.sup.4b;
[0053] K is optionally selected to be (CH(R.sup.14)).sub.j--T
wherein j is selected from a integer from 0 through 3 and T is
selected from the group consisting of single covalent bond, O, S,
and N(R.sup.7) with the provisos that R.sup.14 is other than
hydroxy, cyano, halo, amino, alkylamino, dialkylamino, and
sulfhydryl when j is 1 and that (CH(R.sup.14)).sub.j is bonded to
the pyrazinone ring;
[0054] E.sup.0 is optionally E.sup.2, when K is
(CH(R.sup.14)).sub.j--T, wherein E.sup.2 is selected from the group
consisting of a covalent single bond, C(O), C(S), C(O)O, C(S)O,
C(O)S, C(S)S, C(O)N(R.sup.7), (R.sup.7)NC(O), C(S)N(R.sup.7),
(R.sup.7)NC(S), (R.sup.7)NC(O)O, (R.sup.7)NC(S)S, (R.sup.7)NC(O)S,
(R.sup.7)NC(S)O, N(R.sup.8)C(O)N(R.sup.7),
(R.sup.7)NC(O)N(R.sup.8), N(R.sup.8)C(S)N(R.sup.7),
(R.sup.7)NC(S)N(R.sup.8), S(O), S(O).sub.2, S(O).sub.2N(R.sup.7),
N(R.sup.7)S(O).sub.2, S(O).sub.2N(H)C(O), C(O)N(H)S(O).sub.2,
Se(O), Se(O).sub.2, Se(O).sub.2N(R.sup.7), N(R.sup.7)Se(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
and N(R.sup.7);
[0055] K is optionally selected to be G--(CH(R.sup.15)).sub.k
wherein k is selected from an integer from 1 through 3 and G is
selected from the group consisting of O, S, and N(R.sup.7) with the
proviso that R.sup.15 is other than hydroxy, cyano, halo, amino,
alkylamino, dialkylamino, and sulfhydryl when k is 1;
[0056] E.sup.0 is optionally E.sup.3 when K is
G--(CH(R.sup.15)).sub.k wherein E.sup.3 is selected from the group
consisting of a covalent single bond, O, S, C(O), C(S), C(O)O,
C(S)O, C(O)S, C(S)S, C(O)N(R.sup.7), (R.sup.7)NC(O),
C(S)N(R.sup.7), (R.sup.7)NC(S), OC(O)N(R.sup.7), (R.sup.7)NC(O)O,
SC(S)N(R.sup.7), (R.sup.7)NC(S)S, SC(O)N(R.sup.7), (R.sup.7)NC(O)S,
OC(S)N(R.sup.7), (R.sup.7)NC(S)O, N(R.sup.8)C(O)N(R.sup.7),
(R.sup.7)NC(O)N(R.sup.8), N(R.sup.8)C(S)N(R.sup.7),
(R.sup.7)NC(S)N(R.sup.8), S(O), S(O).sub.2, S(O).sub.2N(R.sup.7),
N(R.sup.7)S(O).sub.2, Se, Se(O), Se(O).sub.2,
Se(O).sub.2N(R.sup.7), N(R.sup.7)Se(O).sub.2, P(O)(R.sup.8),
N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7), N(R.sup.7),
ON(R.sup.7, SiR.sup.28R.sup.29, CR.sup.4a.dbd.CR.sup.4b,
ethynylidene (C.ident.C; 1,2-ethynyl), and
C.dbd.CR.sup.4aR.sup.4b;
[0057] Y.sup.0 is formula (IV): 7
[0058] wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the group consisting of C, N, O, S and
a covalent bond with the provisos that no more than one is a
covalent bond, K.sup.2 is independently selected from the group
consisting of C and N.sup.+, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is O, no more than one of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 is S, one of D.sup.5, D.sup.6, J.sup.5, and
J.sup.6 must be a covalent bond when two of D.sup.5, D.sup.6,
J.sup.5, and J.sup.6 are O and S, no more than three of D.sup.5,
D.sup.6, J.sup.5, and J.sup.6 are N when K is N.sup.+, and no more
than four of D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are N when
K.sup.2 is carbon with the provisos that R.sup.16, R.sup.17,
R.sup.18, and R.sup.19 are each independently selected to maintain
the tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, and the divalent nature of oxygen;
[0059] R.sup.16 and R.sup.17 are independently optionally taken
together to form a linear moiety spacer having from 3 through 6
contiguous atoms connected to form a ring selected from the group
consisting of a cycloalkenyl ring having from 5 through 8
contiguous members, a partially saturated heterocyclyl ring having
from 5 through 8 contiguous members, a heteroaryl having from 5
through 6 contiguous members, and an aryl;
[0060] R.sup.18 and R.sup.19 are independently optionally taken
together to form a linear moiety spacer having from 3 through 6
contiguous atoms connected to form a ring selected from the group
consisting of a cycloalkenyl ring having from 5 through 8
contiguous members, a partially saturated heterocyclyl ring having
from 5 through 8 contiguous members, a heteroaryl having from 5
through 6 contiguous members, and an aryl;
[0061] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, .sup.+NR.sup.20R.sup.21R.sup.22, oxy, alkyl
aminoalkylenyl, alkylamino, dialkylamino, dialkylsulfoniumalkyl,
acylamino and Q.sup.be wherein Q.sup.be is hydrido and R.sup.20,
R.sup.21, and R.sup.22 are independently selected from the group
consisting of hydrido, amino, alkyl, hydroxy, alkoxy,
aminoalkylenyl, alkylamino, dialkylamino, and hydroxyalkyl with the
provisos that no more than one of R.sup.20, R.sup.21, and R.sup.22
is hydroxy, alkoxy, alkylamino, amino, and dialkylamino at the same
time and that R.sup.20, R.sup.21, and R.sup.22 must be other than
be hydroxy, alkoxy, alkylamino, amino, and dialkylamino when
K.sup.2 is N.sup.+;
[0062] R.sup.20 and R.sup.21, R.sup.20 and R.sup.22, and R.sup.21
and R.sup.22 are independently optionally selected to form a spacer
pair wherein a spacer pair is taken together to form a linear
moiety having from 4 through 7 contiguous atoms connecting the
points of bonding of said spacer pair members to form a
heterocyclyl ring having 5 through 8 contiguous members with the
proviso that no more than one of the group consisting of spacer
pairs R.sup.20 and R.sup.21, R.sup.20 and R.sup.22, and R.sup.21
and R.sup.22 is used at the same time;
[0063] Q.sup.b is optionally selected from the group consisting of
N(R.sup.26)SO.sub.2N(R.sup.23)(R.sup.24), N(R.sup.26)C(O)OR.sup.5,
N(R.sup.26)C(O)SR.sup.5, N(R.sup.26)C(S)OR.sup.5 and
N(R.sup.26)C(S)SR.sup.5 with the proviso that no more than one of
R.sup.23, R.sup.24, and R.sup.26 can be hydroxy, alkoxy,
alkyleneamino, alkylamino, amino, or dialkylamino when two of the
group consisting of R.sup.23, R.sup.24, and R.sup.26 are bonded to
the same atom;
[0064] Q.sup.b is optionally selected from the group consisting of
dialkylsulfonium, trialkylphosphonium,
C(NR.sup.25)NR.sup.23R.sup.24,
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24),
N(R.sup.26)C(O)N(R.sup.23)(- R.sup.24),
N(R.sup.26)C(S)N(R.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(R.sup.23)R.sup.24),
N(R.sup.26)N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.su- p.24),
ON(R.sup.26)C(NR.sup.25)N(R.sup.23)CR.sup.24),
N(R.sup.26)N(R.sup.26)SO.sub.2N(R.sup.23)(R.sup.24),
C(NR.sup.25)SR.sup.5, C(O)NR.sup.23R.sup.24, and
C(O)NR.sup.23R.sup.24 with the provisos that no more than one of
R.sup.23, R.sup.24, and R.sup.26 can be hydroxy, alkoxy,
alkylamino, amino, or dialkylamino when any two of the group
consisting of R.sup.23, R.sup.24, and R.sup.26 are bonded to the
same atom and that said Q.sup.b group is bonded directly to a
carbon atom;
[0065] R.sup.23, R.sup.24, R.sup.25, and R.sup.26 are independently
selected from the group consisting of hydrido, alkyl, hydroxy,
alkoxy, alkylenylamino, amino, alkylamino, dialkylamino, and
hydroxyalkyl;
[0066] R.sup.23 and R.sup.24 are optionally taken together to form
a linear spacer moiety having from 4 through 7 contiguous atoms
connecting the points of bonding to form a heterocyclyl ring having
5 through 8 contiguous members;
[0067] R.sup.23 and R.sup.25, R.sup.24 and R.sup.25, R.sup.25 and
R.sup.26, R.sup.24 and R.sup.26, and R.sup.23 and R.sup.26 are
independently optionally selected to form a spacer pair wherein a
spacer pair is taken together from the points of bonding of
selected spacer pair members to form the group L--U--V wherein L,
U, and V are independently selected from the group consisting of O,
S, C(O), C(S), C(J.sub.H).sub.2 S(O), SO.sub.2,
OP(OR.sup.31)R.sup.30, P(O)R.sup.30, P(S)R.sup.30,
C(R.sup.30)R.sup.31, C.dbd.C(R.sup.30)R.sup.31,
(O).sub.2POP(O).sub.2, R.sup.30(O)POP(O)R.sup.30,
Si(R.sup.29)R.sup.28, Si(R.sup.29)R.sup.28Si(R- .sup.29)R.sup.28,
Si(R.sup.29)R.sup.28OSi(R.sup.29)R.sup.28,
(R.sup.28)R.sup.29COC(R.sup.28)R.sup.29,
(R.sup.28)R.sup.29CSC(R.sup.28)R- .sup.29,
C(O)C(R.sup.30).dbd.C(R.sup.31), C(S)C(R.sup.30).dbd.C(R.sup.31),
S(O)C(R.sup.30).dbd.C(R.sup.31),
SO.sub.2C(R.sup.30).dbd.C(R.sup.31),
PR.sup.30C(R.sup.30).dbd.C(R.sup.31),
P(O)R.sup.30C(R.sup.30).dbd.C(R.sup- .31),
P(S)R.sup.30C(R.sup.30).dbd.C(R.sup.31), DC(R.sup.30)(R.sup.31)D,
OP(OR.sup.31)R.sup.30, P(O)R.sup.30, P(S)R.sup.30,
Si(R.sup.28)R.sup.29 and N(R.sup.30), and a covalent bond with the
proviso that no more than any two of L, U and V are simultaneously
covalent bonds and the heterocyclyl comprised of by L, U, and V has
from 5 through 10 contiguous member;
[0068] D is selected from the group consisting of oxygen, C.dbd.O,
C.dbd.S, S(O).sub.m wherein m is an integer selected from 0 through
2;
[0069] J.sub.H is independently selected from the group consisting
of OR.sup.27, SR.sup.27 and N(R.sup.20)R.sup.21;
[0070] R.sup.27 is selected from the group consisting of hydrido,
alkyl, alkenyl, alkynyl, aralkyl, aryloxyalkyl, aralkoxyalkyl,
alkylsulfinylalkyl, alkylsulfonylalkyl, aralkylthioalkyl,
heteroaralkylthioalkyl, alkoxyalkyl, heteroaryloxyalkyl,
alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,
cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,
cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,
halocycloalkenyl, haloalkoxyalkyl, haloalkenyloxyalkyl,
halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,
perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,
heteroarylthioalkyl, heteroaralkylthioalkyl, arylsulfinylalkyl,
arylsulfonylalkyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,
heteroarylsulfonylalkyl, heteroarylsulfinylalkyl,
aralkylsulfinylalkyl and aralkylsulfonylalkyl;
[0071] R.sup.30 and R.sup.31 are independently selected from the
group consisting of hydrido, hydroxy, thiol, aryloxy, amino,
alkylamino, dialkylamino, hydroxyalkyl, heteroaryloxyalkyl, alkoxy,
alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,
aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl,
alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl,
alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,
arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,
cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl,
haloaralkylsulfinylalkyl, aralkylsulfonylalkyl, cyanoalkyl,
dicyanoalkyl, carboxamidoalkyl, dicarboxamidoalkyl,
cyanocarboalkoxyalkyl, carboalkoxyalkyl, dicarboalkoxyalkyl,
cyanocycloalkyl, dicyanocycloalkyl, carboxamidocycloalkyl,
dicarboxamidocycloalkyl, carboalkoxycyanocycloalkyl,
carboalkoxycycloalkyl, dicarboalkoxycycloalkyl, formylalkyl,
acylalkyl, dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl,
phosphonoalkyl, dialkoxyphosphonoalkoxy, diaralkoxyphosphonoalkoxy,
phosphonoalkoxy, dialkoxyphosphonoalkylamino,
diaralkoxyphosphonoalkylamino, phosphonoalkylamino,
dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, sulfonylalkyl,
alkoxysulfonylalkyl, aralkoxysulfonylalkyl, alkoxysulfonylalkoxy,
aralkoxysulfonylalkoxy, sulfonylalkoxy, alkoxysulfonylalkylamino,
aralkoxysulfonylalkylamino, and sulfonylalkylamino;
[0072] R.sup.30 and R.sup.31 are optionally taken to form a linear
moiety spacer group having from 2 through 7 contiguous atoms to
form a ring selected from the group consisting of a cycloalkyl ring
having from 3 through 8 contiguous members, a cycloalkenyl ring
having from 3 through 8 contiguous members, and a heterocyclyl ring
having from 3 through 8 contiguous members;
[0073] R.sup.23 and R.sup.25, R.sup.24and R.sup.25, R.sup.25 and
R.sup.26, R.sup.24 and R.sup.26, and R.sup.23 and R.sup.26 are
independently optionally selected to form a spacer pair wherein a
spacer pair is taken together from the points of bonding of
selected spacer pair members to form the group L--U--V wherein L,
U, and V are independently selected from the group of
1,2-disubstituted radicals consisting of a cycloalkyl radical, a
cycloalkenyl radical wherein cycloalkyl and cycloalkenyl radicals
are substituted with one or more groups selected from R.sup.30 and
R.sup.31, an aryl radical, an heteroaryl radical, a saturated
heterocyclic radical and a partially saturated heterocyclic radical
wherein said 1,2-substitutents are independently selected from
C.dbd.O, C.dbd.S, C(R.sup.28)R.sup.32, S(O), S(O).sub.2,
OP(OR.sup.31)R.sup.30, P(O)R.sup.30,P(S)R.sup.30 and
Si(R.sup.28)R.sup.29;
[0074] R.sup.23 and R.sup.25, R.sup.24 and R.sup.25, R.sup.25 and
R.sup.26, R.sup.24 and R.sup.26, and R.sup.23 and R.sup.26 are
independently optionally selected to form a spacer pair wherein a
spacer pair is taken together from the points of bonding of
selected spacer pair members to form the group L--U--V wherein L,
U, and V are independently selected from the up of radicals
consisting of 1,2-disubstituted alkylene radicals and
1,2-disubstituted alkenylene radical wherein said 1,2-substitutents
are independently selected from C.dbd.O, C.dbd.S,
C(R.sup.28)R.sup.29, S(O), S(O).sub.2, OP(OR.sup.31)R.sup.30,
P(O)R.sup.30, P(S)R.sup.30, and Si(R.sup.28)R.sup.29 and said
alkylene and alkenylene radical are substituted with one or more
R.sup.30 or R.sup.31 substituents;
[0075] Q.sup.s is selected from the group consisting of a single
covalent bond, (CR.sup.37R.sup.38).sub.b--(W.sup.0).sub.az wherein
az is an integer selected from 0 through 1, b is an integer
selected from 1 through 4, and W.sup.0 is selected from the group
consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,
C(O)N(R.sup.14), (R.sup.14)NC(O), C(S)N(R.sup.14), (R.sup.14)NC(S),
OC(O)N(R.sup.14), SC(S)N(R.sup.14), SC(O)N(R.sup.14),
OC(S)N(R.sup.14), N(R.sup.15)C(O)N(R.sup.14),
(R.sup.14)NC(O)N(R.sup.15), N(R.sup.15)C(S)N(R.sup.14),
(R.sup.14)NC(S)N(R.sup.15), S(O), S(O).sub.2,
S(O).sub.2N(R.sup.14), N(R.sup.14)S(O).sub.2, Se, Se(O),
Se(O).sub.2, Se(O).sub.2N(R.sup.17), N(R.sup.14)Se(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
N(R.sup.14) ON(R.sup.14), and SiR.sup.28R.sup.29,
(CH(R.sup.14)).sub.c--W.sup.1--(CH(R.sup.15)).sub.d wherein c and d
are integers independently selected from 1 through 4, and W.sup.1
is selected from the group consisting of O, S, C(O), C(S), C(O)O,
C(S)O, C(O)S, C(S)S, C(O)N(R.sup.14), (R.sup.14)NC(O),
C(S)N(R.sup.14), (R.sup.14)NC(S), OC(O)N(R.sup.14),
(R.sup.14)NC(O)O, SC(S)N(R.sup.14), (R.sup.14)NC(S)S,
SC(O)N(R.sup.14), (R.sup.14)NC(O)S, OC(S)N(R.sup.14),
(R.sup.14)NC(S)O, N(R.sup.15)C(O)N(R.sup.14),
(R.sup.14)NC(O)N(R.sup.15), N(R.sup.15)C(S)N(R.sup.14),
(R.sup.14)NC(S)N(R.sup.15), S(O), S(O).sub.2,
S(O).sub.2N(R.sup.14), N(R.sup.14)S(O).sub.2, Se, Se(O),
Se(O).sub.2, Se(O).sub.2N(R.sup.14), N(R.sup.14)Se(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
N(R.sup.14), ON(R.sup.14), SiR.sup.28R.sup.29, and
(CH(R.sup.14)).sub.e--W.sup.22--(CH- (R.sup.15)).sub.h wherein e
and h are integers independently selected from 0 through 2 and
W.sup.22 is selected from the group consisting of
CR.sup.41.dbd.CR.sup.42, CR.sup.41R.sup.42.dbd.C; vinylidene),
ethynylidene (C.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;
[0076] R.sup.37 and R.sup.37, when bonded to different carbons, are
optionally taken together to form a linear moiety spacer having
from 1 through 7 contiguous atoms to form a ring selected from the
group consisting of a cycloalkyl ring having from 3 through 8
contiguous members, a cycloalkenyl ring having from 3 through 8
contiguous members, and a heterocyclyl ring having from 3 through 8
contiguous members;
[0077] R.sup.37 and R.sup.38, when bonded to different carbons, are
taken together to form a linear moiety spacer having from 1 through
7 contiguous atoms to form a ring selected from the group
consisting of a cycloalkyl ring having from 3 through 8 contiguous
members, a cycloalkenyl ring having from 3 through 8 contiguous
members, and a heterocyclyl ring having from 3 through 8 contiguous
members;
[0078] R.sup.38 and R.sup.38, when bonded to different carbons, are
taken together to form a linear moiety spacer having from 1 through
7 contiguous atoms to form a ring selected from the group
consisting of a cycloalkyl ring having from 3 through 8 contiguous
members, a cycloalkenyl ring having from 3 through 8 contiguous
members, and a heterocyclyl ring having from 3 through 8 contiguous
members;
[0079] R.sup.37 and R.sup.38, when bonded to the same carbon, are
taken together to form a group selected from a group consisting of
oxo, thiono, alkylene, haloalkylene, and a linear moiety spacer
having from 2 through 7 contiguous atoms to form a ring selected
from the group consisting of a cycloalkyl ring having from 3
through 8 contiguous members, a cycloalkenyl ring having from 3
through 8 contiguous members, and a heterocyclyl ring having from 3
through 8 contiguous members;
[0080] Y.sup.0 is optionally Q.sup.b--Q.sup.ss wherein Q.sup.ss is
selected from the group consisting of (CR.sup.37R.sup.38).sub.f
wherein f is an integer selected from 1 through 6,
(CH(R.sup.14)).sub.c--W.sup.1--(- CH(R.sup.15)).sub.d wherein c and
d are integers independently selected from 1 through 4, and W.sup.1
is selected from the group consisting of W.sup.1 is selected from
the group consisting of O, S, C(O), C(S), C(O)O, C(S)O, C(O)S,
C(S)S, C(O)N(R.sup.14), (R.sup.14)NC(O), C(S)N(R.sup.14),
(R.sup.14)NC(S), OC(O)N(R.sup.14), (R.sup.14)NC(O)O,
SC(S)N(R.sup.14), (R.sup.14)NC(S)S, SC(O)N(R.sup.14),
(R.sup.14)NC(O)S, OC(S)N(R.sup.14), (R.sup.14)NC(S)O,
N(R.sup.15)C(O)N(R.sup.14), (R.sup.14)NC(O)N(R.sup.15),
N(R.sup.15)C(S)N(R.sup.14), (R.sup.14)NC(S)N(R.sup.15), S(O),
S(O).sub.2, S(O).sub.2N(R.sup.14), N(R.sup.14)S(O).sub.2, Se,
Se(O), Se(O).sub.2, Se(O).sub.2N(R.sup.14), N(R.sup.14)Se(O).sub.2,
P(O)(R.sup.8), N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7),
N(R.sup.14), ON(R.sup.14), SiR.sup.28R.sup.29, and
(CH(R.sup.14)).sub.e--W.sup.2--(CH(- R.sup.15)).sub.h wherein e and
h are integers independently selected from 0 through 2 and W.sup.2
is selected from the group consisting of CR.sup.4a.dbd.CR.sup.4b,
ethynylidene (C.ident.C; 1,2-ethynyl), and C.dbd.CR.sup.4aR.sup.4b
with the provisos that R.sup.14 and R.sup.15 are selected from
other than halo and cyano when directly bonded to N, that
(CR.sup.37R.sup.38).sub.f, (CH(R.sup.15)).sub.c, and
(CH(R.sup.15)).sub.e are bonded to E.sup.0, and Q.sup.b is selected
from other than
N(R.sup.26)N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24) or
ON(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24) when Q.sup.ss is
(CR.sup.37R.sup.38).sub.f wherein f is other than the integer
1;
[0081] Y.sup.0 is optionally Q.sup.b--Q.sup.sss wherein Q.sup.sss
is (CH(R.sup.38)).sub.r--W.sup.3, r is an integer selected from 1
through 3, W.sup.3 is selected from the group consisting of
1,1-cyclopropyl, 1,2-cyclopropyl, 1,1-cyclobutyl, 1,2-cyclobutyl,
1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cyclopentyl,
1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl, 2,5-morpholinyl,
2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl,
1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl,
2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl,
2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl, 2,6-piperidinyl,
3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl,
1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,
2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl,
4H-2,4-pyranyl, 4H-2,5-pyran, 2H-pyranyl-2-one-3,4-yl,
2H-pyran-2-one-4,5-yl, 4H-pyran-4-one-2,3-yl, 23-tetrahydrofuranyl,
2,4-tetrahydrofuranyl, 2,5-tetrahydrofuranyl,
3,4-tetrahydrofuranyl, 2,3-tetrahydropyranyl,
2,4-tetrahydropyranyl, 2,5-tetrahydropyranyl,
2,6-tetrahydropyranyl, 3,4-tetrahydropyranyl, and
3,5-tetrahydropyranyl, and each carbon and hyrido containing
nitrogen member of the ring of the W.sup.3 other than the points of
attachment is optionally substituted with one or more of the group
consisting of R.sup.9, R.sup.10, R.sup.11, and R.sup.12, with the
proviso that (CH(R.sup.38)).sub.r is bonded to E.sup.0 and Q.sup.b
is bonded to lowest numbered substituent position of each
W.sup.3;
[0082] Y.sup.0 is optionally Q.sup.b--Q.sup.sssr wherein Q.sup.sssr
is (CH(R.sup.38)).sub.r--W.sup.4, r is an integer selected from 1
through 3, W.sup.4 is selected from the group consisting of
1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl,
1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,
2,5-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl,
1,2-piperazinyl, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl,
2,5-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl,
1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,5-piperidinyl,
2,6-piperidinyl, 3,4-piperidinyl, 3,5-piperidinyl, 3,6-piperidinyl,
1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,
2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
2H-2,3-pyranyl, 2H-2,4-pyranyl, 2H-2,5-pyranyl, 4H-2,3-pyranyl,
4H-2,4-pyranyl, 4H-2,5-pyranyl, 2H-pyranyl-2-one-3,4-yl,
2H-pyranl-2-one-4,5-yl, 4H-pyranl-4-one-2,3-yl
2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, 3,4-tetrahydrofuranyl,
2,3-tetrahydropyranyl, 2,4-tetrahydropyranyl,
2,5-tetrahydropyranyl, 2,6-tetrahydropyranyl,
3,4-tetrahydropyranyl, and 3,5-tetrahydropyranyl, and each carbon
and hydrido containing nitrogen member of the ring of the W.sup.4
other than the points of attachment is optionally substituted with
one or more of the group consisting of R.sup.9, R.sup.10, R.sup.11,
and R.sup.12, with the provisos that (CH(R.sup.38)).sub.r is bonded
to E.sup.0 and Q.sup.b is bonded to highest number substituent
position of each W.sup.4;
[0083] Y.sup.0 is optionally Q.sup.b--Q.sup.ssss wherein Q.sup.ssss
is (CH(R.sup.38)).sub.r--W.sup.5, r is an integer selected from 1
through 3, W.sup.5 is selected from the group consisting of
1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl, 2,7-indenyl,
2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl, 3,5-indenyl,
3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl, 2,5-benzofuranyl,
2,6-benzofuranyl, 2,7-benzofuranyl, 3,4-benzofuranyl,
3,5-benzofuranyl, 3,6-benzofuranyl, 3,7-benzofuranyl,
2,4-benzothiophenyl, 2,5-benzothiophenyl, 2,6-benzothiophenyl,
2,7-benzothiophenyl, 3,4-benzothiophenyl, 3,5-benzothiophenyl,
3,6-benzothiophenyl, 3,7-benzothiophenyl,
2,4-imidazo(1,2-a)pyridinyl, 2,5-imidazo(1,2-a)pyridinyl,
2,6-imidazo(1,2-a)pyridinyl, 2,7-imidazo(1,2-a)pyridinyl,
3,4-imidazo(1,2-a)pyridinyl, 3,5-imidazo(1,2-a)pyridinyl,
3,6-imidazo((1,2-a)pyridinyl, 3,7-imidazo(1,2-a)pyridinyl,
2,4-indolyl, 2,5-indolyl, 2,6-indolyl, 2,7-indolyl, 3,4-indolyl,
3,5-indolyl, 3,6-indolyl, 3,7-indolyl, 1,4-isoindolyl,
1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl, 2,5-isoindolyl,
2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl, 3,4-indazolyl,
3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl, 2,4-benzoxazolyl,
2,5-benzoxazolyl, 2,6-benzoxazolyl, 2,7-benzoxazolyl,
3,4-benzisoxazolyl, 3,5-benzisoxazolyl, 3,6-benzisoxazolyl,
3,7-benzisoxazolyl, 1,4-naphthyl, 1,5-naphthyl, 1,6-naphthyl,
1,7-naphthyl, 1,8-naphthyl, 2,4-naphthyl, 2,5-naphthyl,
2,6-naphthyl, 2,7-naphthyl, 2,8-naphthyl, 2,4-quinolinyl,
2,5-quinolinyl, 2,6-quinolinyl, 2,7-quinolinyl, 2,8-quinolinyl,
3,4-quinolinyl, 3,5quinolinyl, 3,6-quinolinyl, 3,7-quinolinyl,
3,8-quinolinyl, 4,5-quinolinyl, 4,6-quinolinyl, 4,7-quinolinyl,
4,8-quinolinyl, 1,4-isoquinolinyl, 1,5-isoquinolinyl,
1,6-isoquinolinyl, 1,7-isoquinolinyl, 1,8-isoquinolinyl,
3,4-isoquinolinyl, 3,5-isoquinolinyl, 3,6-isoquinolinyl,
3,7-isoquinolinyl, 3,8-isoquinolinyl, 4,5-isoquinolinyl,
4,6-isoquinolinyl, 4,7-isoquinolinyl, 4,8-isoquinolinyl,
3,4-cinnolinyl, 3,5-cinnolinyl, 3,6-cinnolinyl, 3,7-cinnolinyl,
3,8-cinnolinyl, 4,5-cinnolinyl, 4,6-cinnolinyl, 4,7-cinnolinyl, and
4,8-cinnolinyl, and each carbon and hydrido containing nitrogen
member of the ring of the W.sup.5 other than the points of
attachment is optionally substituted with one or more of the group
consisting of R.sup.9, R.sup.10, R.sup.11, and R.sup.12, with the
proviso that Q.sup.b is bonded to lowest number substituent
position of each W.sup.5 and that (CH(R.sup.38)).sub.r is bonded to
E.sup.0;
[0084] Y.sup.0 is optionally Q.sup.b--Q.sup.ssssr wherein
Q.sup.ssssr is (CH(R.sup.38)).sub.r--W.sup.6, r is an integer
selected from 1 through 3, W.sup.6 is selected from the group
consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl, 1,7-indenyl,
2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl, 3,4-indenyl,
3,5-indenyl, 3,6-indenyl, 3,7-indenyl, 2,4-benzofuranyl,
2,5-benzofuranyl, 2,6-benzofuranyl, 2,7-benzofuranyl,
3,4-benzofuranyl, 3,5-benzofuranyl, 3,6-benzofuranyl,
3,7-benzofuranyl, 2,4-benzothiophenyl, 2,5-benzothiophenyl,
2,6-benzothiophenyl, 2,7-benzothiophenyl, 3,4-benzothiophenyl,
3,5-benzothiophenyl, 3,6-benzothiophenyl, 3,7-benzothiophenyl,
2,4-imidazo(1,2-a)pyridinyl, 2,5imidazo(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.
[0085] In an embodiment of compounds of Formula I or a
pharmaceutically acceptable salt thereof,
[0086] J is selected from the group consisting of O and S;
[0087] 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;
[0088] B is formula (V): 8
[0089] 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;
[0090] 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,
cycloalkylisulfonylalkyl, 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, heteroarylsulfinyl alkyl,
heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,
haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,
alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl,
dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,
diarylamidosulfonyl, monoalkylmonoarylamidosulfonyl, 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;
[0091] 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;
[0092] 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;
[0093] 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;
[0094] B is optionally selected from the group consisting of
hydrido trialkylsilyl, C2-C8 alkyl C3-C8 alkylenl, 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;
[0095] B is optionally selected from the group consisting of C3-C15
cycloalkyl, C5-C10cycloalkenyl, 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;
[0096] 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.8)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;
[0097] R.sup.7 and R.sup.8 are independently selected from the
group consisting of hydrido, hydroxy, alkyl, acyl, aroyl,
heteroaroyl, and alkoxyalkyl;
[0098] 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,
halcocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,
carboxy, carboxyalkyl, carboalkoxy, carboxamide, and
carboxamidoalkyl;
[0099] 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;
[0100] .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;
[0101] R.sup.5is selected from the group consisting of hydrido,
hydroxy, amino, alkyl, alkoxy, alkoxyalkyl, haloalkyl, acyl, aroyl,
and heteroaroyl;
[0102] 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;
[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
with the provisos that R.sup.2 is selected from other than the
group consisting of hydrido, alkyl, cycloalkyl, and trifluoromethyl
and R.sup.1 is selected from other than the group consisting of
hydrido and halo unless E.sup.1 is other than C(O)NH, or unless
E.sup.0 is selected from the group consisting of E.sup.2 and
E.sup.3, or unless K is other than (CR.sup.4aR.sup.4b).sub.n
wherein n is 1 unless one of R.sup.4a and R.sup.4b are
independently selected from other than hydrido, or unless .PSI. is
selected from other than NR.sup.5, or unless R.sup.5 is selected
from other than hydrido, or unless Y.sup.0 is selected from other
than wherein Q.sup.sis C.sub.1-4 alkyl, C.sub.3-4 alkenyl or
C.sub.3-4 alkynyl where the C.sub.1-4 alkyl, C.sub.3-4 alkenyl or
C.sub.3-4 alkynyl group is bonded concurrently to E.sup.1 wherein
E.sup.1 is C(O)NH and to the 4-position of an imidazole, the
4-position of a thiazole or the 5-position of a thiazole, or unless
a spacer pair is present selected from the group of spacer pairs
consisting of R.sup.2 and R.sup.4a, R.sup.2 and R.sup.4b, R.sup.2
together with both R.sup.4a and R.sup.4b, R.sup.2 and R.sup.14,
R.sup.2 and R.sup.15, and R.sup.6 with another group selected from
the group consisting of R.sup.4a, R.sup.4b, R.sup.4a and R.sup.4b
together, R.sup.39, R.sup.40, R.sup.39 and R.sup.40 together,
R.sup.14, R.sup.15, and R.sup.5, that R.sup.2 is selected from
other than the group consisting of hydroxymethyl, methyl,
methoxymethyl, methylthiomethyl, phenylthiomethyl, methylsulfinyl,
methylthio, alkoxy, cycloalkoxy, alkylthio, alkylsulfinyl,
alkysulfonyl, cycloalkylthio, cycloalkylsulfinyl, and
cycloalkysulfonyl, when Y.sup.0 is other than phenyl,
mono-substituted phenyl, and di-substituted phenyl
5-(2-amino)pyridindyl, or 4-(2-amino)pyridindyl, and that R.sup.2
is selected from other than the group consisting of hydrido, halo,
alkyl, cycloalkyl when Y.sup.0 is methyleneimidazo(1,2-a)pyridinyl,
4,5-benzimidazol-5-yl, or indol-5-yl unless R.sup.1is selected from
other than the group consisting of hydrido or halo, or unless
E.sup.1 is other than C(O)NH, or unless E.sup.0 is selected from
the group consisting of E.sup.2 and E.sup.3, or unless K is other
than (CR.sup.4aR.sup.4b).sub.n wherein n is 1 unless one of
R.sup.4a and R.sup.4b are independently selected from other than
hydrido, or unless .PSI. is selected from other than NR.sup.5
wherein R.sup.5 is hydrido;
[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 pyrazinone ring;
[0106] R.sup.41and 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.2 is O, no more than one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 is S, one of D.sup.1, D.sup.2,
J.sup.1, J.sup.2 and K.sup.1 must be a covalent bond when two of
D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1 are O and S, and no
more than four of D.sup.1, D.sup.2, J.sup.1, J.sup.2 and K.sup.1
are N, with the proviso that R.sup.9, R.sup.10, R.sup.11, R.sup.12,
and R.sup.13 are each independently selected to maintain the
tetravalent nature of carbon, trivalent nature of nitrogen, the
divalent nature of sulfur, and the divalent nature of oxygen;
[0109] Q is optionally selected from formula (III): 10
[0110] wherein D.sup.3, D.sup.4, J.sup.3, and J.sup.4 are
independently selected from the group consisting of C, N, O, and S,
no more than one of D.sup.3, D.sup.4, J.sup.3, and J.sup.4 is O, no
more than one of D.sup.3, D.sup.4, J.sup.3, and J.sup.4 is S, and
no more than three of D.sup.1, D.sup.2, J.sup.1, and J.sup.2 are N
with the proviso that R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are
each independently selected to maintain the tetravalent nature of
carbon, trivalent nature of nitrogen, the divalent nature of
sulfur, and the divalent nature of oxygen;
[0111] Q is optionally selected from the group consisting of
hydrido, alkyl, alkoxy, alkylamino, alkylthio, haloalkylthio,
alkenyl, alkynyl, saturated heterocyclyl, partially saturated
heterocyclyl, acyl, aroyl, heteroaroyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl,
cycloalkylalkenyl, haloalkyl, haloalkoxy, haloalkenyl,
halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl,
haloalkenyloxyalkyl, halocycloalkoxyalkyl, and
halocycloalkenyloxyalkyl with the proviso that Z.sup.0 is selected
from other than a single covalent bond when Q is hydrido;
[0112] K is (CR.sup.4aR.sup.4b).sub.n wherein n is an integer
selected from 1 through 2;
[0113] R.sup.4a and R.sup.4b are independently selected from the
group consisting of halo, hydrido, hydroxy, cyano, hydroxyalkyl,
alkyl, alkenyl, alkoxyalkyl, aralkyl, heteroaralkyl,
alkylthioalkyl, haloalkyl, haloalkenyl, and cyanoalkyl;
[0114] E.sup.0 is E.sup.1, when K is (CR.sup.4aR.sup.4b).sub.n,
wherein E.sup.1 is selected from the group consisting of a covalent
single bond, O, S, C(O), C(S), C(O)O, C(S)O, C(O)S, C(S)S,
C(O)N(R.sup.7), (R.sup.7)NC(O), C(S)N(R.sup.7), (R.sup.7)NC(S),
OC(O)N(R.sup.7), (R.sup.7)NC(O)O, SC(S)N(R.sup.7), (R.sup.7)NC(S)S,
SC(O)N(R.sup.7), (R.sup.7)NC(O)S, OC(S)N(R.sup.7), (R.sup.7)NC(S)O,
N(R.sup.8)C(O)N(R.sup.7), (R.sup.7)NC(O)N(R.sup.8)
N(R.sup.8)C(S)N(R.sup.7), (R.sup.7)NC(S)N(R.sup.8) , S(O),
S(O).sub.2, S(O).sub.2N(R.sup.7), N(R.sup.7)S(O).sub.2,
S(O).sub.2N(R.sup.7)C(O), C(O)N(R.sup.7)S(O).sub.2, P(O)(R.sup.8),
N(R.sup.7)P(O)(R.sup.8), P(O)(R.sup.8)N(R.sup.7), N(R.sup.7),
ON(R.sup.7), CR.sup.4a.dbd.CR.sup.4b- , ethynylidene (C.ident.C;
1,2-ethynyl), and C.dbd.CR.sup.4aR.sup.4b;
[0115] K is optionally (CH(R.sup.14)).sub.j--T wherein j is
selected from a integer from 0 through 2 and T is selected from the
group consisting of single covalent bond, O, S and N(R.sup.7) with
the proviso that (CH(R.sup.14)).sub.j is bonded to the pyrazinone
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.7N(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
moiet) 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 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.26C(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)(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
connection 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-ethynl), 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.37 R.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,
2,5-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-pyranyl-2-one-3,4-yl,
2H-pyranyl-2-one-4,5-yl, 4H-pyranyl-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.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-isoindoyl, 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, 3,5-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, 3,5-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, 1,4-naphthyl,
1,5-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-C
12 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 croup 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] 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;
[0150] R.sup.2 is Z.sup.0--Q;
[0151] Z.sup.0 is selected from the group consisting of covalent
single bond, (CR.sup.41R.sup.42).sub.q wherein q is an integer
selected from 1 through 3,
(CH(R.sup.41)).sub.g--W.sup.0--(CH(R.sup.42)).sub.p wherein g and p
are integers independently selected from 0 through 3 and W.sup.0 is
selected from the group consisting of O, S, C(O), S(O), S(O).sub.2,
N(R.sup.41), and ON(R.sup.41), and
(CH(R.sup.41)).sub.e--W.sup.22--(CH(R.- sup.42)).sub.h wherein e
and h are integers independently selected from 0 through 2 and
W.sub.22 is selected from the group consisting of
CR.sup.41.dbd.CR.sup.42, 1,2-cyclopropyl, 1,2-cyclobutyl,
1,2-cyclohexyl, 1,3-cyclohexyl, 1,2-cyclopentyl, 1,3-cyclopentyl,
2,3-morpholinyl, 2,4-morpholinyl, 2,6-morpholinyl, 3,4-morpholinyl,
3,5-morpholinyl, 1,2-piperazinyl, 1,3-piperazinyl, 2,3-piperazinyl,
2,6-piperazinyl, 1,2-piperidinyl, 1,3-piperidinyl, 2,3-piperidinyl,
2,4-piperidinyl, 2,6-piperidinyl, 3,4-piperidinyl,
1,2-pyrrolidinyl, 1,3-pyrrolidinyl, 2,3-pyrrolidinyl,
2,4-pyrrolidinyl, 2,5-pyrrolidinyl, 3,4-pyrrolidinyl,
2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso
that Z.sup.0 is directly bonded to the pyrazinone ring;
[0152] R.sup.41 and R.sup.42 are independently selected from the
group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino,
and alkyl;
[0153] 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
[0154] 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;
[0155] K is (CR.sup.4aR.sup.4b).sub.n wherein n is an integer
selected from 1 through 2;
[0156] R.sup.4a and R.sup.4b are independently selected from the
group consisting of halo, hydrido, hydroxyalkyl, alkyl,
alkoxyalkyl, alkylthioalkyl, and haloalkyl;
[0157] 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);
[0158] Y.sup.0 is formula (IV): 14
[0159] 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;
[0160] 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.20 is hydroxy, amino, alkylamino, or
dialkylamino at the same time;
[0161] 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;
[0162] 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;
[0163] 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
3,4tetrahydrofuranyl, 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;
[0164] Y.sup.0is 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.s- up.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.1- 5)).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.ident.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;
[0165] 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, 3,4pyrrolidinyl,
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, 2,4tetrahydrofuranyl, 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;
[0166] 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-4one-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;
[0167] 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, 2,5-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,-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 croup 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;
[0168] 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,
3,5imidazo(1,2-a)pyridinyl, 3,6-imidazo(1,2-a)pyridinyl,
3,7-imidazo(1,2-a)pyridinyl, 2,4-indolyl, 2,5-indolyl, 2,6-indolyl,
2,7-indolyl, 3,4-indolyl, 3,5-indolyl, 3,6-indolyl, 3,7-indolyl,
1,4-isoindolyl, 1,5-isoindolyl, 1,6-isoindolyl, 2,4-isoindolyl,
2,5-isoindolyl, 2,6-isoindolyl, 2,7-isoindolyl, 1,3-isoindolyl,
3,4-indazolyl, 3,5-indazolyl, 3,6-indazolyl, 3,7-indazolyl,
2,4-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,
2,5-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,
1,5-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 croup 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.
[0169] In a preferred embodiment of compounds of Formula I or a
pharmaceutically acceptable salt thereof,
[0170] J is O;
[0171] B is formula (V): 15
[0172] 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;
[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, heteroaryl, heterocyclyl,
alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkyl
amidosulfonyl, dialkyl amidosulfonyl, alkanoyl, haloalkanoyl,
alkyl, alkenyl, halo, haloalkyl, haloalkenyl, haloalkoxy,
hydroxyhaloalkyl, hydroxyalkyl, aminoalkyl, haloalkoxyalkyl
carboxyalkyl, carboalkoxy, carboxy, carboxamido, carboxamidoalkyl,
and cyano,
[0174] 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;
[0175] 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;
[0176] B is optionally selected from the group consisting of C3-C12
cycloalkyl and C4-C9 saturated heterocyclyl, wherein each ring
carbon may be optionally substituted with R.sup.33, a ring carbon
other than the ring carbon at the point of attachment of B to A may
be 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 may be 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 may be 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 may be
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 may be 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 may be 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 may
be substituted with R.sup.34;
[0177] 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;
[0178] R.sup.7 is selected from the group consisting of hydrido,
hydroxy, and alkyl;
[0179] R.sup.15 is selected from the group consisting of hydrido,
hydroxy, halo, alkyl, and haloalkyl;
[0180] .PSI. is selected from the group consisting of NH and
NOH;
[0181] 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;
[0182] R.sup.2 is Z.sup.0--Q;
[0183] 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, 2,4pyrrolidinyl, 2,5pyrrolidinyl,
3,4pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso
that Z.sup.0 is directly bonded to the pyrazinone ring;
[0184] R.sup.41 and R.sup.41 are independently selected from the
group consisting of amidino, hydroxyamino, hydrido, hydroxy, amino,
and alkyl;
[0185] 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
[0186] 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;
[0187] K is (CR.sup.4aR.sup.4b).sub.n wherein n is an integer
selected from 1 through 2;
[0188] R.sup.4a and R.sup.4b are independently selected from the
croup consisting of halo, hydrido, hydroxyalkyl, alkyl,
alkoxyalkyl, alkylthioalkyl, and haloalkyl;
[0189] 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);
[0190] Y.sup.0 is formula (IV): 17
[0191] 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;
[0192] 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;
[0193] 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;
[0194] 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;
[0195] 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;
[0196] R.sup.14 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0197] R.sup.37 and R.sup.38 are independently selected from the
group consisting of hydrido, alkyl, and haloalkyl;
[0198] R.sup.38 is optionally selected from the group consisting of
aroyl and heteroaroyl;
[0199] 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;
[0200] Y.sup.0 is optionally selected from the group consisting of
Q.sup.b--Q.sup.ssss and Q.sup.b--Q.sup.ssssr wherein Q.sup.ssss is
(CH(R.sup.38)).sub.r--W.sup.5 and Q.sup.ssssr is
(CH(R.sup.38)).sub.r--W.- sup.6, r is an integer selected from 1
through 2, and W.sup.5 and W.sup.6 are independently selected from
the group consisting of 1,4-indenyl, 1,5-indenyl, 1,6-indenyl,
1,7-indenyl, 2,7-indenyl, 2,6-indenyl, 2,5-indenyl, 2,4-indenyl,
3,4-indenyl, 3,5-indenyl, 3,6-indenyl, 3,7-indenyl,
2,4-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.
[0201] In a more preferred embodiment of compounds of Formula I or
a pharmaceutically acceptable salt thereof,
[0202] J is O;
[0203] B is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.32, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.36, a carbon adjacent to R.sup.32 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.33, a carbon adjacent to R.sup.36 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.35, and any carbon adjacent to both R.sup.33
and R.sup.35 is optionally substituted by R.sup.34;
[0204] R.sup.32, R.sup.33, R.sup.34, R.sup.35, and R.sup.36 are
independently selected from the group consisting of hydrido,
acetamido, haloacetamido, amidino, guanidino, alkylenedioxy,
haloalkylthio, alkanoyloxy, alkoxy, hydroxy, amino, alkoxyamino,
alkanoyl, haloalkanoyl, nitro, lower alkylamino, alkylthio, aryl,
aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclyl,
alkylsulfonamido, amidosulfonyl, monoalkyl amidosulfonyl, dialkyl
amidosulfonyl, alkyl, alkenyl, halo, haloalkyl, haloalkenyl,
haloalkoxy, hydroxyalkyl, alkylenylamino, carboalkoxy, carboxy,
carboxamido, cyano, and Q.sup.b;
[0205] 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;
[0206] B is optionally selected from the group consisting of C3-C12
cycloalkyl and C4-C9 saturated heterocyclyl, wherein each ring
carbon is optionally optionally substituted with R.sup.33, a ring
carbon other than the ring carbon at the point of attachment of B
to A is optionally substituted with oxo provided that no more than
one ring carbon is substituted by oxo at the same time, ring 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;
[0207] 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;
[0208] 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);
[0209] R.sup.7 is selected from the croup consisting of hydrido
hydroxy and alkyl;
[0210] R.sup.15 is selected from the group consisting of hydrido,
hydroxy, halo, alkyl, and haloalkyl;
[0211] .PSI. is NH;
[0212] 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;
[0213] R.sup.2 is Z.sup.0--Q;
[0214] Z.sup.0 is selected from the group consisting of covalent
single bond and (CR.sup.41R.sup.42).sub.q wherein q is an integer
selected from 1 through 2,
(CH(R.sup.41)).sub.g--W.sup.0--(CH(R.sup.42).sub.p wherein g and p
are integers independently selected from 0 through 3 and W.sup.0 is
selected from the group consisting of O, S, and N(R.sup.41), and
(CH(R.sup.41)).sub.e--W.sup.22--(CH(R.sup.42)).sub.h wherein e and
h are integers independently selected from 0 through 1 and W.sup.22
is selected from the group consisting of CR.sup.41.dbd.CR.sup.42,
1,2-cyclopropyl, 1,2-cyclobutyl, 1,2-cyclohexyl, 1,3-cyclohexyl,
1,2-cyclopentyl, 1,3-cyclopentyl, 2,3-morpholinyl, 2,4-morpholinyl,
2,6-morpholinyl, 3,4-morpholinyl, 3,5-morpholinyl, 1,2-piperazinyl,
1,3-piperazinyl, 2,3-piperazinyl, 2,6-piperazinyl, 1,2-piperidinyl,
1,3-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl, 2,6-piperidinyl,
3,4-piperidinyl, 1,2-pyrrolidinyl, 1,3-pyrrolidinyl,
2,3-pyrrolidinyl, 2,4-pyrrolidinyl, 2,5-pyrrolidinyl,
3,4-pyrrolidinyl, 2,3-tetrahydrofuranyl, 2,4-tetrahydrofuranyl,
2,5-tetrahydrofuranyl, and 3,4-tetrahydrofuranyl, with the proviso
that Z.sup.0 is directly bonded to the pyrazinone ring;
[0215] R.sup.41 and R.sup.42 are independently selected from the
group consisting of hydrido, hydroxy, and amino;
[0216] 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;
[0217] K is CHR.sup.4a wherein R.sup.4a is selected from the group
consisting of hydrido, hydroxyalkyl, alkyl, alkoxyalkyl,
alkylthioalkyl, and haloalkyl;
[0218] E.sup.0 is selected from the group consisting of a covalent
single bond, C(O)N(H), (H)NC(O), (R.sup.7)N S(O).sub.2, and
S(O).sub.2N(R.sup.7);
[0219] Y.sup.0 is formula (IV): 18
[0220] 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;
[0221] 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;
[0222] 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;
[0223] 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;
[0224] 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;
[0225] 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;
[0226] R.sup.14 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0227] R.sup.37 and R.sup.38 are independently selected from the
group consisting of hydrido, alkyl, and haloalkyl;
[0228] R.sup.38 is optionally selected from the group consisting of
aroyl and heteroaroyl;
[0229] Y.sup.0 is optionally Q.sup.b--Q.sup.ss wherein Q.sup.ss is
(CH(R.sup.14)).sub.e--W.sup.2--(CH(R.sup.15)).sub.h, wherein e and
h are integers independently selected from 1 through 2 and W.sup.2
is CR.sup.4a.dbd.CH with the proviso that (CH(R.sup.14)).sub.e is
bonded to E.sup.0.
[0230] In an even more preferred embodiment of compounds of Formula
I or a pharmaceutically acceptable salt thereof,
[0231] J is O;
[0232] B is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.32, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.36, a carbon adjacent to R.sup.32 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.33, a carbon adjacent to R.sup.36 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.35, and any carbon adjacent to both R.sup.33
and R.sup.35 is optionally substituted by R.sup.34;
[0233] 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;
[0234] 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);
[0235] R.sup.7 is selected from the group consisting of hydrido,
hydroxy and alkyl;
[0236] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl,
[0237] .PSI. is NH,
[0238] R.sup.1 is selected from the group consisting of hydrido,
alkyl, cyano, haloalkyl, and halo;
[0239] R.sup.2 is Z.sup.0--Q;
[0240] Z.sup.0 is selected from the group consisting of a covalent
single bond and CH.sub.2;
[0241] 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;
[0242] 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;
[0243] 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,
haloalkylyl, and cyano;
[0244] K is CH.sub.2;
[0245] E.sup.0 is C(O)N(H);
[0246] Y.sup.0 is formula (IV): 19
[0247] wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the croup 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;
[0248] 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;
[0249] 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;
[0250] 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;
[0251] 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;
[0252] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0253] In another even more preferred embodiment of compounds of
Formula I or a pharmaceutically acceptable salt thereof,
[0254] J is O;
[0255] 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;
[0256] R.sup.32, R.sup.33, R.sup.34, R.sup.34, 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;
[0257] A is selected from the croup 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);
[0258] R.sup.7 is selected from the group consisting of hydrido,
hydroxy and alkyl,
[0259] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0260] .PSI. is NH;
[0261] R.sup.1 is selected from the group consisting of hydrido,
alkyl, cyano, haloalkyl, and halo;
[0262] R.sup.2 is Z.sup.0--Q;
[0263] Z.sup.0 is selected from the group consisting of covalent
single bond and CH.sub.2;
[0264] 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;
[0265] 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;
[0266] 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;
[0267] K is CH.sub.2;
[0268] E.sup.0 is C(O)N(H);
[0269] Y.sup.0 is formula (IV): 20
[0270] 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;
[0271] 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;
[0272] 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;
[0273] 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;
[0274] 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;
[0275] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0276] In still another even more preferred embodiment of compounds
of Formula I or a pharmaceutically acceptable salt thereof,
[0277] J is O;
[0278] B is optionally selected from the group consisting of C3-C7
cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring
carbon is optionally substituted with R.sup.33, a ring carbon other
than the ring carbon at the point of attachment of B to A is
optionally substituted with oxo provided that no more than one ring
carbon is substituted by oxo at the same time, ring 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;
[0279] 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;
[0280] 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;
[0281] 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;
[0282] 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);
[0283] R.sup.7 is selected from the group consisting of hydrido,
hydroxy and alkyl;
[0284] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0285] .PSI. is NH;
[0286] R.sup.1 is selected from the group consisting of hydrido,
alkyl, cyano, haloalkyl, and halo;
[0287] R.sup.2 is Z.sup.0--Q;
[0288] Z.sup.0 is selected from the group consisting of covalent
single bond and CH.sub.2;
[0289] 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;
[0290] K is CH.sub.2;
[0291] E.sup.0 is C(O)N(H);
[0292] Y.sup.0 is formula (IV): 21
[0293] 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;
[0294] 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;
[0295] 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;
[0296] 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;
[0297] 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;
[0298] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0299] In a most preferred embodiment of compounds of Formula I or
a pharmaceutically acceptable salt thereof,
[0300] J is O;
[0301] B is selected from the group consisting of aryl and
heteroaryl wherein a carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.32, the other carbon
adjacent to the carbon at the point of attachment is optionally
substituted by R.sup.36, a carbon adjacent to R.sup.32 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.33, a carbon adjacent to R.sup.36 and two
atoms from the carbon at the point of attachment is optionally
substituted by R.sup.35, and any carbon adjacent to both R.sup.33
and R.sup.35 is optionally substituted by R.sup.34;
[0302] 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;
[0303] 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.7is N(R.sup.7);
[0304] R.sup.7 is selected from the group consisting of hydrido and
alkyl;
[0305] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0306] .PSI. is NH;
[0307] R.sup.1 is selected from the group consisting of hydrido,
cyano, haloalkyl, and halo;
[0308] R.sup.2 is Z.sup.0--Q;
[0309] Z.sup.0 is a covalent single bond;
[0310] 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;
[0311] 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;
[0312] 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;
[0313] K is CH.sub.2;
[0314] E.sup.0 is C(O)N(H);
[0315] Y.sup.0 is formula (IV): 22
[0316] 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;
[0317] 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;
[0318] 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;
[0319] 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;
[0320] 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;
[0321] Q.sup.s is CH.sub.2.
[0322] In another most preferred embodiment of compounds of Formula
I or a pharmaceutically acceptable salt thereof,
[0323] J is O;
[0324] 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;
[0325] 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;
[0326] 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);
[0327] R.sup.7 is selected from the group consisting of hydrido and
alkyl;
[0328] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0329] .PSI. is NH;
[0330] R.sup.1 is selected from the group consisting of hydrido,
cyano, haloalkyl, and halo;
[0331] R.sup.2 is Z.sup.0--Q;
[0332] Z.sup.0 is a covalent single bond;
[0333] 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;
[0334] 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;
[0335] 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;
[0336] K is CH.sub.2;
[0337] E.sup.0 is C(O)N(H);
[0338] Y.sup.0 is formula (IV): 23
[0339] wherein D.sup.5, D.sup.6, J.sup.5, and J.sup.6 are
independently selected from the Croup 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;
[0340] 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;
[0341] 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;
[0342] 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;
[0343] 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;
[0344] Q.sup.s is CH.sub.2.
[0345] In still another most preferred embodiment of compounds of
Formula I or a pharmaceutically acceptable salt thereof,
[0346] J is O;
[0347] B is optionally selected from the group consisting of C3-C7
cycloalkyl and C4-C6 saturated heterocyclyl, wherein each ring
carbon is optionally substituted with R.sup.33, a ring carbon other
than the ring carbon at the point of attachment of B to A is
optionally substituted with oxo provided that no more than one ring
carbon is substituted by oxo at the same time, ring 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;
[0348] 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;
[0349] 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;
[0350] 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;
[0351] R.sup.33 is optionally Q.sup.b;
[0352] 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);
[0353] R.sup.7 is selected from the group consisting of hydrido,
hydroxy and alkyl;
[0354] R.sup.15 is selected from the group consisting of hydrido,
halo, alkyl, and haloalkyl;
[0355] .PSI. is NH;
[0356] R.sup.1 is selected from the group consisting of hydrido,
cyano, haloalkyl, and halo;
[0357] R.sup.2 is Z.sup.0--Q;
[0358] Z.sup.0 is a covalent single bond;
[0359] 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;
[0360] K is CH.sub.2;
[0361] E.sup.0 is C(O)N(H);
[0362] Y.sup.0 is formula (IV): 24
[0363] 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;
[0364] 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;
[0365] 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;
[0366] 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;
[0367] 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;
[0368] Q.sup.s is CH.sub.2.
[0369] In a preferred specific embodiment of Formula I, compounds
have the Formula I-S: 25
[0370] or a pharmaceutically acceptable salt thereof, wherein;
[0371] B is selected from the group consisting of phenyl,
2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,
2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,
1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,4-oxadiazol3-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-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.32, the
other carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.36, a carbon adjacent to R.sup.32
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.33, a carbon adjacent to R.sup.36
and two atoms from the carbon at the point of attachment is
optionally substituted by R.sup.35, and any carbon adjacent to both
R.sup.33 and R.sup.35 is optionally substituted by R.sup.34;
[0372] 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;
[0373] B is selected from the group consisting of hydrido,
trimethylsilyl, ethyl, 2-propenyl, 2-propynyl, propyl, isopropyl,
butyl, 2-butenyl, 3-butenyl, 2-butynyl, sec-butyl, tert-butyl,
isobutyl, 2-methylpropenyl, 1-pentyl, 2-pentenyl, 3-pentenyl,
4-pentenyl, 2-pentynyl, 3-pentynyl, 2-pentyl, 1-methyl-2-butenyl,
1-methyl-3-butenyl, 1-methyl-2-butynyl, 3-pentyl,
1-ethyl-2-propenyl, 2-methylbutyl, 2-methyl-2-butenyl,
2-methyl-3-butenyl, 2-methyl-3-butynyl, 3-methylbutyl,
3-methyl-2-butenyl, 3-methyl-3-butenyl, 1-hexyl, 2-hexenyl,
3-hexenyl, 4-hexenyl, 5-hexenyl, 2-hexynyl, 3-hexynyl, 4-hexynyl,
2-hexyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl,
1-methyl-4-pentenyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl,
3-hexyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 1-propyl-2-propenyl,
1-ethyl-2-butynyl, 1-heptyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,
5-heptenyl, 6-heptenyl, 2-heptynyl, 3-heptynyl, 4-heptynyl,
5-heptynyl, 2-heptyl, 1-methyl-2-hexenyl, 1-methyl-3-hexenyl,
1-methyl-4-hexenyl, 1-methyl-5-hexenyl, 1-methyl-2-hexynyl,
1-methyl-3-hexynyl, 1-methyl-4-hexynyl, 3-heptyl,
1-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 1-ethyl-4-pentenyl,
1-butyl-2-propenyl, 1-ethyl-2-pentynyl, 1-ethyl-3-pentynyl,
1-octyl, 2-octenyl, 3-octenyl, 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-5-heptenyl, 1-methyl-6-heptenyl, 1-methyl-2-heptenyl,
1-methyl-3-heptynyl, 1-methyl-4-heptynyl, 1-methyl-5-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,-trifluor- opentyl,
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;
[0374] 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-trinfluoromethylnorbornyl, 7-oxabicyclo[2,2,1]heptan-2-yl,
bicyclo[3,1,0]hexan-6-yl, cycloheptyl, cyclooctyl, 2-morpholinyl,
3-morpholinyl, 4-morpholinyl, 1-piperazinyl, 2-piperazinyl,
1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,
1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-dioxanyl,
4H-2-pyranyl, 4H-3-pyranyl, 4H -4-pyranyl, 4H-pyran-4one-2-yl,
4H-pyran-4-one-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,
2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl,
2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring
carbon is optionally substituted with R.sup.33, a ring carbon and
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, and a ring carbon or nitrogen atom adjacent to the
R.sup.13 position and two atoms from the point of attachment is
optionally substituted with R.sup.12;
[0375] 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;
[0376] 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;
[0377] 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;
[0378] R.sup.1 is selected from the group consisting of hydrido,
cyano, methyl, ethyl, propyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl,
trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy, fluoro, chloro, and
bromo;
[0379] R.sup.2 is Z.sup.0--Q;
[0380] Z.sup.0 is selected from the group consisting of covalent
single bond, 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;
[0381] 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;
[0382] 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;
[0383] E.sup.0 is a covalent single bond, C(O)N(H), (H)NC(O), and
S(O).sub.2N(H);
[0384] Y.sup.0 is selected from the group of formulas consisting
of: 2627
[0385] 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;
[0386] 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;
[0387] Q.sup.b is selected from the group consisting of
NR.sup.20R.sup.21, Q.sup.be wherein Q.sup.be is hydrido,
C(NR.sup.25)NR.sup.23R.sup.24 and
N(R.sup.26)C(NR.sup.25)N(R.sup.23)(R.sup.24), with the proviso that
no more than one of R.sup.20 and R.sup.21 is hydroxy,
N-methylamino, and N,N-dimethylamino at the same time and that no
more than one of R.sup.23 and R.sup.24 is hydroxy, N-methylamino,
and N,N-dimethylamino at the same time;
[0388] 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;
[0389] 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.
[0390] In a more preferred specific embodiment of Formula I,
compounds have the Formula I-MPS wherein B is an aromatic; 28
[0391] (I-MPS Wherein B is Aromatic)
[0392] or a pharmaceutically acceptable salt thereof, wherein;
[0393] B is selected from the group consisting of phenyl,
2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,
2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl,
3-isoxazolyl, 5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,
3-pyridazinyl, 4-pyridazinyl, and 1,3,5-triazin-2-yl, wherein a
carbon adjacent to the carbon at the point of attachment is
optionally substituted by R.sup.32, the other carbon adjacent to
the carbon at the point of attachment is optionally substituted by
R.sup.36, a carbon adjacent to R.sup.32 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.33, a carbon adjacent to R.sup.36 and two atoms from the
carbon at the point of attachment is optionally substituted by
R.sup.35, and any carbon adjacent to both R.sup.33 and R.sup.35 is
optionally substituted by R.sup.34;
[0394] 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, dimethylamiino, 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-hidroxyethyl, 2,2,2-trifluoro-1-hydroxyethyl,
methoxycarbonyl, ethoxycarbonyl, amidocarbonyl,
N-methylamidocarbonyl. N,N-dimethylamidocarbonyl, cyano, and
Q.sup.b;
[0395] 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;
[0396] 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.25, 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;
[0397] 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;
[0398] Q.sup.s is selected from the group consisting of a single
covalent bond, CH.sub.2, and CH.sub.2CH.sub.2.
[0399] In another more preferred specific embodiment of Formula I,
compounds have the Formula I-MPS wherein B is a non-cyclic
substituent: 29
[0400] wherein B is a non-cyclic substituent)
[0401] or a pharmaceutically acceptable salt thereof, wherein;
[0402] 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-methyl butyl,
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;
[0403] 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;
[0404] A is selected from the group consisting of single covalent
bond, NH, (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;
[0405] 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;
[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,
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;
[0407] 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;
[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 still another more preferred specific embodiment of
Formula I, compounds have the Formula I-MPS wherein B is a
non-aromatic cyclic substituent: 30
[0410] wherein B is a non-aromatic cyclic substituent)
[0411] or a pharmaceutically acceptable salt thereof, wherein;
[0412] B is optionally selected from the group consisting of
cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-1-yl, azetidin-2-yl,
azetidin-3-yl, thiaetan-3-yl, cyclopentyl, cyclohexyl, norbornyl,
7-oxabicyclo[2.2.1]heptan-2-yl, bicyclo[3.1.0]hexan-6-yl,
cycloheptyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl,
1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl,
3-piperidinyl, 4-piperidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,
3-pyrrolidinyl, 2-dioxanyl, 4H-2-pyranyl, 4H-3-pyranyl,
4H-4-pyranyl, 4H-pyran-4-one-2-yl, 4H-pyran-4-one-3-yl,
2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrabydropyranyl,
3-tetrahydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, and
3-tetrahydrothienyl, wherein each ring carbon is optionally
substituted with R.sup.33, a rin 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, and a ring
carbon or nitrogen atom adjacent to the R.sup.13 position and two
atoms from the point of attachment is optionally substituted with
R.sup.12;
[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] R.sup.33 and R.sup.34 are independently selected from the
group consisting of hydrido, amidino, guanidino, carboxy, methoxy,
ethoxy, isopropoxy, propoxy, hydroxy, amino, methoxyamino,
etboxyamino, acetamido, trifluoroacetamido, N-methylamino,
dimethylamino, N-ethylamino, methylthio, ethylthio, isopropylthio,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl,
2,2,3,3,3-pentafluoropropyl, trifluoromethoxy,
1,1,2,2-tetrafluoroethoxy, fluoro, chloro, bromo, amidosulfonyl,
N-methylamidosulfonyl, N,N-dimethylamidosulfonyl, hydroxymethyl,
1-hydroxyethyl, 2-hydroxyethyl, 2,2,2-trifluoro-1-hydroxye- thyl,
methoxycarbonyl, ethoxycarbonyl, amidocarbonyl,
N-methylamidocarbonyl, N,N-dimethylamidocarbonyl, cyano, and
Q.sup.b;
[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, and
C(NR.sup.25)NR.sup.23R.sup.25, 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, and R.sup.25 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] The more preferred specific embodiment (I-MPS) compounds of
the present invention having the Formula: 31
[0419] or a pharmaceutically acceptable salt thereof, have common
structural units, wherein;
[0420] R.sup.1 is selected from the group consisting of hydrido,
methyl, ethyl, propyl, trifluoromethyl, pentafluoroethyl,
2,2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl, fluoro, chloro,
and bromo;
[0421] R.sup.2 is Z.sup.0--Q;
[0422] Z.sup.0 is selected from the group consisting of covalent
single bond and CH.sub.2;
[0423] 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-pyrazoly, 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;
[0424] 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;
[0425] R.sup.10 and R.sup.12 are independently selected from the
oroup 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;
[0426] Y.sup.0 is selected from the group of formulas consisting
of: 3233
[0427] 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-arzinoethyl, 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;
[0428] 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.
[0429] In a most preferred specific embodiment of Formula I,
compounds have the Formula I-ElPS wherein B is an aromatic: 34
[0430] (I-EMPS Wherein B is Aromatic)
[0431] or a pharmnaceutically acceptable salt thereof, wherein;
[0432] B is selected from the group consisting of phenyl,
2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,
2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl,
3-isoxazolyl, and 5-isoxazolyl, wherein a carbon adjacent to the
carbon at the point of attachment is optionally substituted by
R.sup.32, the other carbon adjacent to the carbon at the point of
attachment is optionally substituted by R.sup.36, a carbon adjacent
to R.sup.32 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.33, a carbon adjacent
to R.sup.36 and two atoms from the carbon at the point of
attachment is optionally substituted by R.sup.35, and any carbon
adjacent to both R.sup.33 and R.sup.35 is optionally substituted by
R.sup.34;
[0433] 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, ethyltthio,
trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, fluoro,
chloro, bromo, amidosulfonyl, N-methylamidosulfonyl, hydroxymethyl,
amidocarbonyl, carboxy, cyano, and Q.sup.b;
[0434] 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;
[0435] 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;
[0436] 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;
[0437] Q.sup.s is CH.sub.2.
[0438] In another most preferred specific embodiment of Formula I,
compounds have the Formula I-EMPS wherein B is a non-cyclic
substituent: 35
[0439] wherein B is a non-cyclic substituent)
[0440] or a pharmaceutically acceptable salt thereof, wherein;
[0441] 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-methylburyl,
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;
[0442] 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;
[0443] A is selected from the oroup consisting of single covalent
bond, NH, N(CH.sub.3), CH.sub.2, CH.sub.3CH, and
CH.sub.2CH.sub.2;
[0444] 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;
[0445] Q.sup.b is selected from the group consisting of NR.sup.20
R.sup.21, C(NR.sup.25)NR.sup.23R.sup.24, and
N(R.sup.26)C(NR.sup.25)N(R.s- up.23)(R.sup.24), with the proviso
that said Q.sup.b group is bonded directly to a carbon atom;
[0446] 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;
[0447] Q.sup.s is CH.sub.2.
[0448] In still another most preferred specific embodiment of
Formnula I. compounds have the Formula I-EMPS wherein B is a
non-aromatic cyclic substituent: 36
[0449] (I-EMPS Wherein B is a Non-aromatic Cyclic Substituent)
[0450] or a pharmaceutically acceptable salt thereof, wherein;
[0451] B is optionally selected from the group consisting of
cyclopropyl, cyclobutyl, oxetan-3-yl, azetidin-3-yl, thiaetan-3-yl,
cyclopentyl, cyclohexyl, 1-pyrrolidinyl, 2-pyrrolidinyl,
3-pyrrolidinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,
2-tetrahydrothienyl, and 3-tetrahydrothienyl, wherein each ring
carbon is optionally substituted with R.sup.33, a 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, and a ring carbon or nitrogen atom adjacent to the
R.sup.13 position and two atoms from the point of attachment is
optionally substituted with R.sup.12;
[0452] R.sup.33 are independently selected from the group
consisting of hydrindo, 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:
[0453] 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;
[0454] 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;
[0455] 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;
[0456] Q.sup.s is CH.sub.2.
[0457] The most preferred specific embodiment (I-EMPS) compounds of
the present invention having the Formula: 37
[0458] or a pharmaceutically acceptable salt thereof, have common
structural units, wherein;
[0459] R.sup.1 is selected from the group consisting of hydrido,
trifluoromethyl, pentafluoroethyl, fluoro, and chloro;
[0460] R.sup.2 is Z.sup.0--Q;
[0461] Z.sup.0 is a covalent single bond;
[0462] 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;
[0463] 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-methylaminocarbonyl, carboxy, and
cyano;
[0464] 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, trifluoroacetamino, aminomethyl,
N-methylamino, dimethylamino, amidosulfonyl, N-methylamidosulfonyl,
N,N-dimethylamidosulfonyl, methoxycarbonyl, fluoro, chloro, bromo,
and cyano;
[0465] Y.sup.0 is selected from the group of formulas consisting
of: 38
[0466] R.sup.16, R.sup.17, R.sup.18, and R.sup.19 are independendty
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.
[0467] 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.
[0468] 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.
[0469] In yet another embodiment of the present invention, the
novel compounds are selected from the compounds set forth in
Examples 1 through Example 109 and Tables 1 through Table 7.
[0470] The use of generic terms in the description of the compounds
are herein defined for clarity.
[0471] Standard single letter elemental symbols are used to
represent specific types of atoms unless otherwise defined. The
symbol "C" represents a carbon atom.
[0472] The symbol "O" represents an oxygen atom. The svmbol "N"
represents a nitrogen atom. The symbol "P" represents a phosphorus
atom. The svmbol "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.).
[0473] 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.
[0474] 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.
[0475] 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.
[0476] The term "hydrido" denotes a single hydrogen atom (H). This
hydrido radical may be attached, for example, to an oxyoen atom to
form a "hydroxyl" radical, one hydrido radical may be attached to a
carbon atom to form a "methine" radical 13 CH.dbd., or two hydrido
radicals may be attached to a carbon atom to form a "methylene"
(--CH.sub.2--) radical.
[0477] The term "carbon" radical denotes a carbon atom without any
covalent bonds and capable of forming four covalent bonds.
[0478] The term "cyano" radical denotes a carbon radical havino
three of four covalent bonds shared by a nitrogen atom.
[0479] 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.
[0480] 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.
[0481] The term "alkylene" radical denotes linear or branched
radicals havino 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.
[0482] 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.CH13 ), and
1,4-butadienyl (--CH.dbd.CH--CH.dbd.CH--).
[0483] The term "halo" means halooens such as fluorine, chlorine,
bromine or iodine atoms.
[0484] 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,
heptafuoropropyl, difluorochloromethyl, dichlorofluoromethyl,
difluoroethyl, difluoropropyl, dichloroethyl and
dichloropropyl.
[0485] 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.
[0486] 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.
[0487] 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.
[0488] 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 metboxy, 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 fluorometboxy, chloromethoxy, trifluoromethoxy,
difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy,
pentafluoroethoxy, and fluoropropoxy. Examples of such
haloalkoxyalkyl radicals include fluoromethoxymethyl,
chloromethoxyethyl, trifluoromethoxymethyl, difluoromethoxyethyl,
and trifluoroethoxymethyl,
[0489] 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.
[0490] 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.
[0491] 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.
[0492] 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.
[0493] 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.
[0494] 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 irng 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.
[0495] The term "heteroaryl" embraces fully unsaturated
heteroatom-containing ring-shaped aromatic radicals having from 4
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, 4pyridyl, 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-limniting 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, 1,3,4thiadiazolyl, pyrazinyl, piperazinyl,
1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl,
benzimidazoyl, quinolinyl, tetraazolyl, and the like.
[0496] 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.
[0497] The term "sulfinyl", whether used alone or linked to other
terms such as alkylsulfinyl, denotes respectively divalent radicals
--S(O)13 . "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.
[0498] 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.
[0499] 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.
[0500] 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.
[0501] 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.
[0502] The term "cycloalkyl" embraces radicals having three to 15
carbon atoms. More preferred cycloalkyl radicals are "lower
cycloalkyl" radicals having three to seven carbon atoms. Examples
include radicals such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl and cycloheptyl. The term cycloalkyl embraces radicals
having seven to 15 carbon atoms and having two to four rings.
Examples incude radicals such as norbornyl (i.e.,
bicyclo[2.2.]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, cyclobexenyl 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.
[0503] 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.
[0504] The term "cycloalkylalkoxy" embraces cycloalkyl radicals
attached to an alkoxy radical. Examples of such radicals includes
cyclohexylmethoxy and cyclopentylmethoxy.
[0505] 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.
[0506] 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.
[0507] 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.
[0508] The term "cycloalkylalkaoyl" 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.
[0509] 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 alkyltblio radicals are
"lower alkylthio" radicals having one to six carbon atoms. An
example of "lower alkylthio" is methylthio (CH.sub.3--S--). The
"alkylthio" radicals may be further substituted with one or more
halo atoms, such as fluoro, chloro or bromo, to provide
"haloalkylthio" radicals. Examples of such radicals include
fluoromethylthio, chloromethylthio, trifluoromethylthio,
difluoromethylthio, trifluoroethylthio, fluoroethylthio,
tetrafluoroethylthio, pentafluoroethylthio, and
fluoropropylthio.
[0510] 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.
[0511] The terms alkylamino denotes "monoalkylamino" and
"dialkylamino" ontaining one or two alkyl radicals, respectively,
attached to an amino radical.
[0512] The terms arylamino denotes "monoarylamino" and
"diarylaminno" containing one or two aryl radicals, respectively,
attached to an amino radical. Examples of such radicals include
N-phenylamino and N-naphthylamino.
[0513] The term "aralkylamino", embraces arlkyl 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.
[0514] 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.
[0515] 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.
[0516] 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-chloro-4-ethylphenoxy, 3,4-dichlorophenoxy, 4-methylphenoxy,
3-trifluoromethoxyphenoxy, 3-trifluoromethylphenoxy,
4-fluorophenoxy, 3,4-dimethylpheuoxy, 5-bromo-2-fluorophenoxy,
4-bromo-3-fluorophenoxy, 4-fluoro-3-methylphenoxy,
5,6,7,8-tetrahydronaphthyloxy, 3-isopropylphenoxy,
3-cyclopropylphenoxy, 3-ethylphenoxy, 3-pentafluoroethylphenoxy,
3-(1,1,2,2-tetrafluoroethoxy)-phenoxy, and 4-tert-butylphenoxy.
[0517] 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.
[0518] The term "aralkanoyl" embraces aralkalyl radicals, as
defined herein, attached to an carbonyl radical as defined above.
Examples of such radicals include, for example, phenylaceryl.
[0519] 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-trifluoromethyl benzyloxy,
3,5-difluorobenyloxy, 3-bromobenzyloxy, 4-propylbenzyloxy,
2-fluoro-3-trifluoromethylbenzyloxy, and 2-phenylethoxy.
[0520] The term "aryloxyalkyl" embraces aryloxy radicals, as
defined above, attached to an alkyl group. Examples of such
radicals include phenoxymethyl.
[0521] The term "haloaryloxyalkyl" embraces aryloxyalkyl radicals,
as defined above, wherein one to five halo radicals are attached to
an aryloxy group.
[0522] 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.
[0523] The term "heteroaralkanoyl" embraces heteroaralkyl radicals,
as defined herein, attached to an carbonyl radical as defined
above. Examples of such radicals include, for exanple,
pyridylacetyl and furylbutyryl.
[0524] 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.
[0525] The term "haloheteroaryloxyalkyl" embraces
heteroaryloxyalkyl radicals, as defined above, wherein one to four
halo radicals are attached to an heteroaryloxy group.
[0526] The term "heteroarylamino" embraces heterocyclyl radicals,
as defined above, attached to an amino group. Examples of such
radicals include pyridylamino.
[0527] The term "heteroarylaminoalkyl" embraces heteroarylamino
radicals, as defined above, attached to an alkyl group. Examples of
such radicals include pyridylmethylamino.
[0528] The term "heteroaryloxy" embraces heterocyclyl radicals, as
defined above, attached to an oxy group. Examples of such radicals
include 2-thiophenyloxy, 2-pyrmidyloxly, 2-pyridyloxy,
3-pyridyloxy, and 4-pyridyloxy.
[0529] 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.
[0530] The term "arylthio" embraces aryl radicals, as defined
above, attached to an sulfur atom. Examples of such radicals
include phenylthio.
[0531] The term "arylthioalkyl" embraces arylthio radicals, as
defined above. attached to an alkyl group. Examples of such
radicals include phenylthiomethyl.
[0532] 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.
[0533] 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.
[0534] 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 alikylthioalkyl.
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.
[0535] 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.
[0536] 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--.
[0537] 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--.
[0538] 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.+--.
[0539] 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", "cycloalkylal koxy", "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, hidroxy, amino, thio, nitro, lower
alkylamino, alkylthio, alkylthioalkyl, arylamino, aralkylamino,
arylthio, arylthioalkyl, heteroaralkoxyalkyl, alkylsulfinyl,
alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,
heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,
alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,
alkylsulfonamido, alkylaminrnosulfonyl, 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.
[0540] 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 )--, --N.dbd., --CH(OH)--, .dbd.C(OH)--, --CH(OR )--,
.dbd.C(OR )--, 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-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, aryvlthioalkyl, 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.
[0541] 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.
[0542] 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").
[0543] Some of the compounds described contain alkenyl groups, and
are meant to include both cis and trans or "E" and "Z" geometric
forms.
[0544] 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.
[0545] 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.
[0546] 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.
[0547] 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.
[0548] 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):
39
[0549] or a phartaceutically-acceptable salt thereof.
[0550] 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.
[0551] 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.
[0552] 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.
[0553] 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, cyclobexylaminosulfonic, 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, ethylenediarine, 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).
[0554] 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.
[0555] 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.
[0556] 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 ingredienL
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.
[0557] 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.
[0558] The compounds may also be delivered by the use of monoclonal
antibodies as individual carriers to which the compound molecules
are coupled. The compounds may also be coupled with soluble
polymers as targetable drug carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer,
polyhydroxy-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.
[0559] 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.
[0560] 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 varietv of factors, including the age, weight, sex and
medical condition of the subject, the seventy of the disease, the
route and frequency of administration, and the particular compound
employed, and thus may vary widely.
[0561] 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.
[0562] 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.
[0563] 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.
[0564] 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 w hich 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.
[0565] 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 diusoadipate, 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.
[0566] 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 knowd in the pharmaceutical
art.
[0567] 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.
[0568] 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 coadrministration of additional
anti-platelet agents, anticoagulation agents. cardiovascular
therapeutic agents, or thrombolvtic agents, depending on a
patient's therapeutic needs.
[0569] All mentioned references are incorporated by reference as if
here written.
[0570] 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.
[0571] 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.
[0572] The following general synthetic sequences are useful in
making the present invention. Abbreviations used in the schemes and
tables include: "AA" represents amino acids, "AcCN" represents
acetonitrile, "AcOH" represents acetic acid, "BINAP" represents
2,2'-bis(diphenylphosphino)-1,- 1'-binaphthyl, "BnOH" represents
benzyl alcohol, "BnCHO" represents 2-phenylethanal, "BnSO.sub.2Cl"
represents benzylsulfonyl chloride, "Boc" represents
tert-butyloxycarbonyl, "BOP" represents
benzotriazol-1-yl-oxy-tris-(dimethylamino), "bu" represents butyl,
"dba" represents dibenzylidene-acetone, "DCC" represents
1,3-dicyclohexylcarbodiimide, "DCM" represents dichloromethane or
methylene chloride, "DIBAH" or "DIBAL" represents
diisobutylaluminum hydride, "DMF" represents dimethylformamide,
"DMSO" represents dimethylsulfoxide, "DPPA" represents
diphenylphosphorvl azide", "EDC" represents
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, "Ex.
No." represents Example Number, "Fmoc" represents
9-fluorenylmethoxycarbonyl, "HOBt" represents
hydroxybenzoltriazole", "LDA" represents lithium diisopropylamide,
"MW" represents molecular weight, "NMM" represents
N-methylmorpholine, "Ph" represents phenyl or aryl, "PHTH"
represents a phthaloyl group, "pnZ" represents
4-nitrobenzyloxy-carbonyl, "PTC" represents a phase transfer
catalyst, "py" represents pyridine, "RNH.sub.2" represents a
primary organic amine, "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
[0573] The compounds of the present invention can be synthesized,
for example, according to the following procedures and Schemes
given below.
[0574] The general synthetic approach to substituted pyrazinones is
shown in Schemes 1 and 2 below. Treatment of benzyl glycine under
Strecker reaction conditions followed by cyclocondensation with
oxalyl chloride provides the pyrazinone heterocyclic core with an
acetic acid ester at N-1. Heating a solution of the pyrazinone in
ethyl acetate in the presence of excess amine results in the
nucleophilic displacement of the C-3 chlorine atom by the amine.
Stirring the substituted pyrazinone in the presence of lithium
hydroxide results in the unmasking of the acid functional group.
Alternatively, treatment of the pyrazinone with potassium hydroxide
and catalytic palladium on carbon under an atmosphere of hydrogen
results in the reductive dechlorination of the C-5 chlorine atom as
well as the unmasking of the acid functional group. These acids are
then coupled under standard peptide coupling conditions with
various amines. These amines are typically multi-functional, and
are introduced in a protected form. Removal of these protecting
groups in any of several ways provides the compounds for screening.
These synthetic schemes are exemplified in specific examples
disclosed herein. 40 41
Example 1
[0575] 42
[0576] A solution of benzyl glycine hydrochloride (78.00 g, 386.8
mmol) in 1.2 L ethyl acetate was washed with brine and saturated
Na.sub.2CO.sub.3 (1:1, 3.times.1 L). The organic solution was dried
(MgSO.sub.4), filtered, and concentrated. The resulting light
yellow oil was placed on the high vacuum for approximately 15
minutes to remove residual solvent. The yellow oil was then diluted
with 137.0 mL dichloromethane (2.82 M) and added benzaldehyde
(39.30 mL, 386.6 mmol) slowly by syringe at room temperature. The
reaction becomes sliohtly exothermic and turbid. The mixture was
then added trimethylsilyl nitrile (51.60 mL, 386.9 mmnol) drop wise
via syringe over a 10 minute period, upon which a slight exotherm
occurs and the reaction becomes clear and golden brown in color.
The reaction was stirred for 4 hours at room temperature. The
reaction mixture was then concentrated under reduced pressure . The
resulting brown oil was diluted with ethyl acetate (500.0 mL),
washed with brine (3.times.150 mL), dried (MgSO.sub.4), and
concentrated to leave a yellow oil. The oil was diluted ethyl
acetate (80 mL) and added 9.9 M HCl (406.4 mmnol) in ethanol
(prepared by addition of 28.90 mL acetyl chloride to 41.0 mL cold
ethanol). Upon which a white precipitate forms exothermically. The
precipitate was collected by filtration, washed with ethyl ether,
and dried which gave pure benzyl-N-(1-cyanobenzyl)glycine
hydrochloride (EX-1A) in 35% yield: .sup.1H NMR (300 MHz, DMSO)
.delta. 9.13-9.00 (br s, 1H) 7.68-7.60 (m, 2H), 7.55-7.32 (m, 8H)
5.70 (s, 1H), 5.19 (s, 2H), 3.81 (d, J=5.4 Hz, 1H); .sup.13C NMR
(75 MHz, DMSO) d 168.6, 136.1, 130.7, 129.78, 129.49, 129.17,
128.99, 128.92, 127.10, 67.3, 51.7, 47.1; HRMS (ES) calcd for
C.sub.17H.sub.17N.sub.2O.sub.2 281.1290, found 281.1311.
[0577] A suspension of benzyl-N-(1-cyanobenzyl)glycine
hydrochloride (EX-1A) (42.90 g, 135.4 mmol) in 135.0 mL dry
1,2-dicklorobenzene (1.0 M) was added to oxalyl chloride (47.50 mL,
544.5 mmol) with stirring at room temperature. The resulting light
brown suspension was heated to 100.degree. C. for approximately 18
hours. Upon heating to mixture 100.degree. C. the mixture became
homogeneous and dark brown in color with gaseous HCl being evolved.
The reaction was allowed to cool to room temperature and the
volatiles were removed under reduced pressure. The remaining
solution was passed through a silica gel column (1 L hexane flush,
followed by 2 L 50% ethyl acetate/hexanes). Concentration of the
solution gave a dark brown solid. The crude product was purified by
MPLC (2 L hexane flush to 25% ethyl acetate/hexanes) to gave pure
1-Benzyloxycarbonylmethyl-3,5-dichloro-6-phenylpyrazinone (EX-1B)
in 60% yield as a yellow solid: .sup.1H NMR (300 MHz, CDCl.sub.3,)
.delta. 7.58-7.37 (m, 6H), 7.31-7.26 (m, 4H), 5.18 (s, 2H), 4.53
(s, 2H) .sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 166.4, 152.4,
146.0, 138.3, 134.9, 131.1, 130.0, 129.8, 129.1, 129.0, 128.8,
124.3, 68.2, 49.5; HRMS (ES) calcd for
C.sub.19H.sub.15Cl.sub.2N.sub.2O.sub.3 389.0460, found
389.0475.
[0578] A solution of
1-benzyloxycarbonylmethyl-3,5-dichloro-6-phenylpyrazi- none (EX-1B)
(10.19 g, 26.19 mmol) in 103.0 mL ethyl acetate (0.255M) was added
9.90 mL phenethyl amine in one portion at room temperature. The
resulting solution was heated to reflux for 18 hours. The solution
was allowed to cool to room temperature which resulted in a thick
precipitate forming. The reaction mixture was diluted with ethyl
acetate (750.0 mL) and was washed with 0.5 N HCl (1.times.250 mL),
saturated NaHCO.sub.3 (1.times.250 mL) and brine (1.times.250 mL).
The organic solution was dried (MgSO.sub.4), filtered and
concentrated to give the crude product. Recrystallization from
ethyl acetate and hexanes afforded pure
3-(2-phenylethylamino)-5-chloro-6-phenyl-1-benzyloxycarbonylmethylpyrazin-
one (EX-1C) as light yellow crystals in 96% yield: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.46-7.28 (m, 15H), 6.39 (br s, 1H), 5.25
(s, 2H), 4.54 (s, 2H), 3.81-3.79 (m, 2H), 3.04-3.00 (m, 2H);
.sup.13C NMR (75 MHz, CDCl.sub.3) .delta. 167.2, 151.3, 149.2,
138.9, 135.2, 131.9, 130.7, 129.9, 129.3, 129.0, 128.95, 128.86,
128.83, 128.7, 126.9, 123.3, 67.7, 47.9, 42.5, 35.4; HRMS (EI)
calcd for C.sub.27H.sub.25ClN.sub.3O.sub.3 474.1584, found
474.1591.
[0579] A suspension of
3-(2-phenylethylamino)-5-chloro-6-phenyl-1-benzylox-
ycarbonylmethylpyrazinone (EX-1C) (1.26 g. 2.66 mmol) in 27.0 mL
tetrahydrofuran and ethanol (1:1, 0.12 M) was added potassium
hydroxide (463.1 mg, 8.25 mmol) in 4.0 mL water. The resulting
solution was degassed (via high vacuum) three times. The solution
was then added 421.1 mg 5 % Pd/C in one portion. The resulting
mixture was then stirred under an atmosphere of hydrogen overnight.
The reaction mixture was filtered through a pad of Celite 545 then
concentrated under reduced pressure to half of the original volume.
The solution was then diluted with brine and acidified with 20%
(w/w) KHSO.sub.4 to a pH of 1. The resulting turbid solution was
extracted with ethyl acetate (4.times.25 mL). The combined organic
solutions were washed with brine (1.times.25 mL), dried
(MgSO.sub.4). filtered, concentrated to give pure
3-(2-phenethylamino)-6-- phenyl-1-methylenecarboxypyrazinone
(EX-1D) in 97% yield as a white solid: .sup.1H NMR (300 MHz, DMSO)
.delta. 7.49-7.48 (m, 3H), 7.40-7.23 (m, 7H), 6.77 (s, 1H), 4.52
(s, 1H), 4.40 (s, 2H), 3.64-3.57 (m, 2H), 2.93 (t, J=7.4 Hz, 2H);
.sup.13C NMR (75 MHz, DMSO) .delta. 169.6, 151.8, 150.6, 150.5,
143.2, 140.3, 133.2, 130.2, 129.6, 129.4, 129.3, 129.1, 128.8,
128.7, 127.3, 127.1, 126.8, 122.3, 63.6, 47.5, 42.5, 35.2; HRMS
(EI) calcd for C.sub.20H.sub.20N.sub.3O.sub.3 350.1505, found
350.1502.
[0580] p-Cyanobenzaldehyde (38.13 mmoles, 5 g) was stirred in 50 mL
of tetrahydrofuran at O.degree. C. under nitrogen while lithium
bis(trimethylsilyl)amide (83.89 mmoles, 84 mL of a 1.0M solution in
tetrahydrofuran) was added dropwise over 10 min. After addition the
mixture was allowed to warm to room temperature and stirred for 3
hr. Water (50 mL) was then added and stirring continued for 30 min.
Then 2.5N sodium hydroxide (763 mmoles, 305 mL) and di-tert-butyl
dicarbonate (83.89 mmoles, 18.309 g) were added along with
tetrahydrofuran (100 mL) and the mixture was allowed to stir for 3
hr. The layers were then separated. The tetrahydrofuran layer was
diluted with ethyl acetate and washed with brine. The water layer
was extracted twice with ethyl acetate. The combined organic layers
were dried over magnesium sulfate, filtered, the solvent removed in
vacuo. The residue was chromatographed medium pressure liquid
chromatography with 30% ethyl acetate/hexanes to give 4.03 g of
desired 4-(t-butoxycarbonylamidino)-benzaldehyde in 43% yield.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 10.03 (s, 1H), 7.97 (d,
2H) 7.89 (d, 2H), 1.53 (s, 9H).
[0581] The 4-(t-butoxycarbonylamidino)benzaldehyde (4.03 mmoles,
1.0 g) was stirred in tetrahydrofuran (20 mL) at room temperature
under nitrogen while allylamine (6.05 mmoles, 453 uL) was added
dropwise. After addition the mixture was allowed to stir for 6 hr.
The mixture was diluted with methanol (20 mL) and cooled to
0.degree. C. Then sodium borohydride (6.04 mmoles, 22.8 mg) added
in small amounts and allowed to warm to room temperature. After 2
hr the reaction was quenched with water and extracted with
dichloromethane. The organic layer was dried over magnesium
sulfate, filtered, and the solvent removed in vacuo. The oily
residue solidified on standing. The
N-allyl-4-(t-butoxycarbonylamidino)-b- enzylamine product was used
without further purification. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.79 (d, 2H), 7.37 (d, 2H), 5.90-6.10 (m, 1H), 5.19 (dd,
2H), 3.81 (s, 2H), 3.24 (d, 2H), 1.53 (s, 9H)
[0582] The N-allyl-4-(t-butoxycarbonylamidino)benzylamine (3.97
mmoles, 1.15g) and chlorotris(triphenylphosphine)-rhodium(I) (0.21
mmoles, 195 mg) was stirred in acetonitrile/water (84:16, 92 mL)
under nitrogen. The mixture was refluxed for 3 hr and allowed to
cool to room temperature. Then the mixture was filtered through a
pad of celite and the solvent removed in vacuo. The residue was
dried on a hioh vacuum pump to yield an orange glassy product.
4-(t-Butoxycarbonylamidino)benzylamine product was verified by
HPLC/MS and used without further purification.
[0583] A solution of
3-(2-phenethylamino)-6-phenyl-1-methylenecarboxypyraz- inone
(EX-1D) (521.1 mg, 1.491 mmol) in 15.0 mL tetrahydrofuran and
dimethylformamide (1:1, 0.1 M) was added N,N-diisopropylethylamine
(130 mL, 7.463 mmol), N-hydroxybenzotriazole (610.5 mg, 4.518
mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (8553 mg, 4.461 mmol). The resulting mixture was
allowed to stir for 30 minutes. The reaction mixture was then added
4-(t-butoxycarbonyl-amidino)benzylami- ne (763.1 mg, 3.061 mmol)
prepared above in one portion. The resulting mixture was allowed to
stir over nighl The reaction mixture was diluted with ethyl acetate
(50 mL) and washed with 5% citric acid (1.times.25 mL), saturated
NaHCO.sub.3 (1.times.25 mL), and brine (1.times.25 mL). The organic
solution was dried (MgSO.sub.4), filtered and concentrated. The
crude reaction was purified by MPLC (75% ethyl acetateihexanes) to
give the product (EX-1E): .sup.1H NMR (300 MHz, DMSO) .delta. 9.06
(br s, 1H), 8.65 (t, J=5.6 Hz, 1H), 7.94 (d, J=8.1 Hz, 2H),
7.47-7.40 (m, 6H), 7.35-7.21 (m, 8H), 6.75 (s, 1H), 4.41 (s, 2H),
4.36-4.34 (m, 2H), 3.63-3.57 (m, 2H), 2.93 (t, J=7.3 Hz, 2H), 1.48
(s, 9H); .sup.13C NMR (75 MHz, DMSO) .delta. 167.3, 151.9, 150.7,
143.7, 140.4, 133.8. 133.4, 130.3, 129.4, 129.34, 129.29, 129.15,
129.10, 128.3, 127.6, 126.8, 122.2, 78.5, 48.7, 42.6, 35.2, 28.7;
HRMS (EI) calcd for C.sub.33H.sub.37N.sub.6- O.sub.4 581.2876,
found 581.2871.
[0584] A flask of protected pyrazinone (260.7 mg, 0.449 mmol) was
added 5.0 mL of 4 M HCl in dioxane. The resulting solution was
allowed to stir overnight (approximately 18 hours). The solution
was concentrated and the crude product was triturated from ethyl
ether. The resulting white solid was collected by filtration,
washed with ethyl ether and dried to give pure product: .sup.1H NMR
(300 MHz, DMSO) .delta. 9.57 (br s, 2H), 9.38 (br s, 2H), 9.06 (br
s, 1H), 7.88 (d, J=7.9 Hz, 2H), 7.55-7.52 (m, 3H), 7.42-7.24 (m,
9H), 6.66 (s, 1H), 4.43 (s, 2H), 4.38-4.37 (m, 2H), 3.83 (br s,
2H), 3.03-2.98 (m, 2H); HRMS (EI) calcd for
C.sub.28H.sub.29N.sub.6O.sub.2 481.2352, found 481.2348.
Example 2
[0585] 43
[0586] By following the method of Example 1 and substituting
phenylacetaldehyde for benzaldehyde, the compound was prepared:
.sup.1H NMR (400 MHz, DMSO) .delta. 9.43 (s, 2H), 9.25 (s, 2H),
8.84 (br s, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.40-7.16 (m, 12H), 6.61
(s, 1H), 4.47 (s, 2H), 4.27 (s, 2H), 3.86 (s, 2H), 3.75 (br s, 2H),
2.94-2.90 (m, 2H); HRMS (EI) calcd for
C.sub.29H.sub.30N.sub.6O.sub.2 494.2430, found 494.2438.
Example 3
[0587] 44
[0588] A suspension of
3-(2-phenylethylamino)-5-chloro-6-phenyl-1-benzylox-
ycarbonylmethylpyrazinone (135 g, 2.85 mmol) in 28.0 mL
tetrahydrofuran, methanol and water (3:3:1, 0.10 M) was added
potassium hydroxide (0.50 g, 8.93 mmol). The mixture was then
stirred 3 hours. The reaction mixture was concentrated under
reduced pressure to half of the original volume. The solution was
then diluted with brine and acidified with 20% (w/w) KHSO.sub.4 to
a pH of 1. The resulting turbid solution was extracted with ethyl
acetate (4.times.25 mL). The combined organic solutions were washed
with brine (1.times.25 mL), dried (MgSO.sub.4), filtered,
concentrated to give pure EX-3A
(3-(2-phenethylamino)-5-chloro-6-phenyl-1-methylenecarbox-
ypyrazinone) in 88% yield as a white solid: .sup.1H NMR (300 MHz,
DMSO) .delta. 13.15 (br s, 1H), 7.84 (br s, 1H), 7.51-7.50 (br m,
3H), 7.33-7.24 (m, 7H), 4.24 (s, 2H), 3.58 (br s, 2H), 2.94 (br s,
2H); .sup.13C NMR (75 MHz, DMSO) .delta. 169.2, 151.0, 149.6,
140.1, 132.4, 131.1, 130.2, 129.6, 129.3, 129.1, 126.9, 125.4,
123.4, 48.1, 42.8, 34.8; HRMS (EI) calcd for
C.sub.20H.sub.19ClN.sub.3O.sub.3 384.1115, found 384.1118.
[0589] A solution of
(S)-N-[[[4-amino-5-oxo-5-(thiazolyl)pentyl]amino]imin-
omethyl]-4-methoxy-2,3,6-trimethylbenzenesulfonamide
dihydrochioride (1.664 g, 3.161 mmol) in 29.0 mL tetrahydrofuran
and dimethylformamide (1:1, 0.10 M) was added
N,N-diisopropylethylamine (5.00 mL, 28.70 mmol). The resulting
mixture was allowed to stir for 10 minutes at room temperature. The
solution was then added 3-(2-Phenylethylamino)-5-chloro--
6-phenyl-1-methylenecarboxypyrazinone (1.104 g, 2.877 mmol),
N-hydroxybenzotriazole (466.8 mg, 3.454 mmol), and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
(673.1 mg, 3.511 mmol). After the addition was complete the
solution was allowed to stir over night. 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 by MPLC (75% ethyl acetate/bexanes)
to give pure product EX-3B:
[0590] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.04 (d, J=3.0 Hz,
1H), 7.75 (d, J=2.8 Hz, 1H), 7.57 (br s, 1H), 7.42-7.21 (m, 11H),
6.54 (s, 2H), 6.31 (s, 2H), 5.63 (br s, 1H), 4.60 (d, J=16.2 Hz,
1H), 4.21 (d, J=16.5 Hz, 1H), 3.84 (s, 3H), 3.77-3.66 (m, 2H), 3.17
(br s, 1H), 2.96 (d, J=7.2 Hz, 2H), 2.68 (s, 3H), 2.60 (s, 3H),
2.14 (s, 3H), 1.79-1.66 (m, 3H); HRMS (EI) calcd for
C.sub.39H.sub.44ClN.sub.8O.sub.6S.sub.2 819.2514, found
819.2512.
[0591] A solution of material EX-3B (928.1 mg, 1.133 mmol) in 11.3
mL trifluoroacetic acid (0.1 M) was added to thioanisole (0.400 mL,
3.407 mmol) at room temperature with stirring. The resulting
mixture was allowed to stir 6 hours. The reaction mixture was
concentrated under reduced pressure. The crude product was purified
by trituration from ethyl ether. A yellow powder was collected by
filtration, washed with ethyl ether to give the pure product:
.sup.1H NMR (300 MHz, DMF) .delta. 8.76 (d, J=7.2 Hz, 1H),
8.51-8.50 (m, 1H), 8.42-8.41 (m, 1H), 8.17 (br s, 1H), 7.92-7.45
(m, 10H), 5.74 (br s, 1H), 4.67-4.65 (m, 2H), 3.89-3.87 (m, 2H),
3.52 (br s, 2H), 3.23-3.20 (m, 2H), 2.73 (s, 2H), 2.19 (br s, 1H),
1.88 (br s, 3H); HRMS (EI) calcd for
C.sub.29H.sub.32ClN.sub.8O.sub.- 3S 607.2007, found 607.2000.
Example 4
[0592] 45
[0593] By following the method of Example 3 and substituting
3-(2-phenethylamino)-5-chloro-6-benzyl-1-methylenecarboxypyrazinone
for
3-(2-phenethylamino)-5-chloro-6-phenyl-1-methylenecarboxypyrazinone,
the title compound was prepared: HRMS (EI) calcd for
C.sub.30H.sub.34ClN.sub.- 8O.sub.3S 621.2163, found 621.2171.
Example 5
[0594] 46
[0595] By following the method of Example 3 and substituting
3-(2-phenethylamino)-5-chloro-6-(2-phenylethyl)-1-methylenecarboxypyrazin-
one for
3-(2-phenethylamino)-5-choro-6-phenyl-1-methylenecarboxypyrazinone-
, the title compound was prepared: HRMS (EI) calcd for
C.sub.31H.sub.36ClN.sub.8O.sub.3S 635.2320, found 635.2330.
Example 6
[0596] 47
[0597] By following the method of Example 3 and substituting
3-(2-phenethylamino)-6-phenyl-1-methylenecarboxypyrazinone for
3-(2phenethylamino)-5-chlorophenyl-1-methylenecarboxypyrazinone,
the title compound was prepared: HRMS (EI) calcd for
C.sub.29H.sub.33N.sub.6O- .sub.3S 573.2396, found 573.2399.
Example 7
[0598] 48
[0599] By following the method of Example 3 and substituting
3-(2-phenethylamino)-6-benzyl-1-methylenecarboxypyrazinone for
3-(2-phenethylamino)-5-chloro-6-phenyl-1-methylenecarboxypyrazinone,
the title compound was prepared: HRMS (EI) calcd for
C.sub.30H.sub.35N.sub.8O- .sub.3S 587.2553, found 587.2564.
Example 8
[0600] 49
[0601] By following the method of Example 3 and substituting
3-(2-phenethylamino)-6-(2-phenylethyl)-1-methylenecarboxypyrazinone
for
3-(2-phenethylamino)-5-chlorophenyl-1-methylenecarboxypyrazinone,
the title compound was prepared: HRMS (EI) calcd for C.sub.31
H.sub.37N.sub.8O.sub.3S 601.2709, found 601.2714.
Example 9
[0602] 50
[0603] A solution of 2-amino-5-aminomethylpyridine in 1.60 mL
tetrahydrofuran (0.13 M) was added to N,N-diisopropylethylamine
(0.145 mL, 0.832 mmol). The resulting mixture was allowed to stir
for 10 minutes at room temperature. The solution was then added to
3-(2-Phenylethylamino)-6-benzyl-5-chloro-1-methylenecarboxypyrazinone
(81.6 mg, 0.2051 mmol), N-hydroxybenzotriazole (38.1 mg, 0.2819
mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (49.6 mg, 3.511 mmol). The reaction mixture was then
allowed to stir over night. 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 by MPLC (ethyl acetate) to give pure product: .sup.1H
NMR (300 MHz, DMSO) .delta. 8.50 (br s, 1H), 7.83 (s, 1H), 7.68 (br
s, 1H), 7.34-7.19 (m, 13H), 6.46-6.43 (m, 1H), 5.90 (br s, 1H),
4.42 (s, 2H), 4.09 (br s, 2H), 3.98 (br s, 2H), 3.56 (br s, 3H),
2.94 (br s, 3H); HRMS (EI) calcd for
C.sub.27H.sub.28ClN.sub.6O.sub.2 503.1962, found 503.1968.
Example 10
3-(2-Phenylethylamino)-5-chloro-6-phenethyl-1-(2-amino-5-methylcarboxamido-
methylpyridinyl)pyrazinone
[0604] 51
[0605] By following the method of Example 9 and substituting
3-(2-phenethylamino)-5-chloro-6-(2-phenylethyl)-1-methylenecarboxypyrazin-
one for
3(2-phenethylamino)-5-chloro-6-benzyl-1-methylenecarboxypyrazinone-
, the title compound was prepared: HRMS (EI) calcd for
C.sub.28H.sub.30N.sub.6O.sub.2 517.2119, found 517.2127.
Example 11
[0606] 52
[0607] A solution of
3-(2-phenethylamino)-6-phenyl-1-methylenecarboxy-pyra- zinone
(217.6 mg, 0.6228 mmol) in 63 mL tetrahydrofuran and
dimethylformamide (1:1, 0.1 M) was added N,N-diisopropylethylamine
(1.00 mL, 5.741 mmol), N-hydroxybenzotriazole (171.1 mg, 1.266
mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (240.0 mg, 1.252 mmol). The resulting mixture was
allowed to stir for 30 minutes. The reaction mixture was then added
to the 3-(di-Boc-guanidino)propanamin- e (1.30 mg, 3.684 mmol) in
one portion. The resulting mixture was allowed to stir over night.
The reaction mixture was diluted with ethyl acetate (50 mL) and
washed with 5% citric acid (1.times.25 mL), saturated NaHCO.sub.3
(1.times.25 mL), and brine (1.times.25 mL). The organic solution
was dried (MgSO.sub.4), filtered and concentrated. The crude
reaction was purified by MPLC (75% ethyl acetate/hexanes) to give
the product EX-11A:
[0608] .sup.1H NMR (300 MHz, DMSO) .delta. 11.42 (s, 1H), 8.46 (t,
J=6.3 Hz, 1H), 7.92 (t, J=6.0 Hz, 1H), 7.46-7.41 (m, 5H), 7.37-7.23
(m, 5H), 6.86 (s, 1H), 6.24 (br s, 1H), 4.49 (s, 2H), 3.79-3.72 (m,
2H), 3.48-3.42 (m, 2H), 3.31-3.25 (m, 2H), 3.00 (t, J=7.1 Hz, 2H),
1.53 (s, 9H), 1.40 (s, 9H); HRMS (EI) calcd for
C.sub.34H.sub.45N.sub.7O.sub.6 648.3510, found 648.3498.
[0609] A flask of protected guanidine EX-11A (260.7 mg, 0.449 mmol)
was added to 5.0 mL of 4 M HCl in dioxane. The resulting solution
was allowed to stir for 4 hours. The solution was concentrated and
the crude product was triturated from ethyl ether. The resulting
white solid was collected by filtration, washed with ethyl ether
and dried to give pure product: .sup.1H NMR (300 MHz, DMSO) .delta.
9.65 (br s, 1H), 8.48 (t, J=5.1 Hz, 1H), 7.96 (t, J=5.4 Hz, 1H),
7.60-7.22 (m, 13H), 6.66 (s, 1H), 4.32 (s, 2H), 3.82 (br s, 2H),
3.13-3.09 (m, 2H), 3.03-2.98 (m, 2H), 1.59-1.54 (m, 2H); HRMS (EI)
calcd for C.sub.24H.sub.29N.sub.7O.sub.2 448.2461, found
448.2425.
Example 12
[0610] 53
[0611] By following the method of Example 11 and using the
appropriate butanamine, the title compound was prepared: HRMS (EI)
calcd for C.sub.25H.sub.31, N.sub.7O.sub.2 462.2617, found
462.2575.
Example 13
[0612] 54
[0613] By following the method of Example 11 and using the
appropriate pentanamine, the title compound was prepared: HRMS (EI)
calcd for C.sub.26H.sub.33N.sub.7O.sub.2 476.2774, found
476.2783.
Example 14
[0614] 55
[0615] By following the method of Example 11 and using the
appropriate butanamine with
3-(2-phenethylamino)-6-(4methoxyphenyl)-1-methylenecarbox-
ypyrazinone, title compound was prepared: HRMS (EI) calcd for
C.sub.26H.sub.34N.sub.7O.sub.3 492.2723, found 492.2693.
Example 15
[0616] 56
[0617] By following the method of Example 11 and using the
appropriate butanamine with
3-(2-phenethylamino)-6-(4-biphenyl)-1-methylenecarboxypyr- azinone,
the title compound was prepared: HRMS (EI) calcd for
C.sub.31H.sub.36N.sub.7O.sub.2 538.2930, found 538.2918.
Example 16
[0618] 57
[0619] By following the method of Example 11 and using the
appropriate butanamine with
3-(2-phenethylamino)-6-(3,4-methylenedioxyphenyl)-1-methy-
lenecarboxypyrazinone, the title compound was prepared: HRMS (EI)
calcd for C.sub.26H.sub.32N.sub.7O.sub.4 506.2516, found
506.2506.
Example 17
[0620] 58
[0621] Using the procedures of Schemes 1 and 2 and Example 1,
2-{5-chloro-6-(3-bromophenyl)-3-[(methylethyl)amino]-2-oxohydropyrazinyl}-
acetic acid was prepared.
[0622] A solution of
2-{5-chloro-6-(3-bromophenyl)-3-[(methylethyl)amino]--
2-oxohydropyrazinyl}acetic acid (7.4 g, 18.47 mmol) and copper (I)
cyanide (1.75 g, 19.55 mmol) in 75.0 mL dimethylsulfoxide was
heated at 150.degree. C. for 20 hours. The flask was then cooled
and the contents were poured into a solution of 500 mL water and
100 mL 1M HCl. The mixture was then extracted with ethyl acetate
(2.times.1 L). The ethyl acetate layers were separated combined,
dried over magnesium sulfate, filtered, and stripped of solvent
under reduced pressure. Purification by HPLC (25% ethyl acetate in
hexanes) provided 2-{5-chloro-6-(3-cyanophenyl-
)-3-[(methylethyl)amino]-2-oxohydropyrazinyl}acid (EX-17A) of
adequate purity: .sup.1H NMR (400 MHz, CDCl.sub.3) d 7.8-7.4 (br,
4H), 4.4 (br, 2H), 2.2 (br, 1H), 1.3 (br d, 6H); MS (ES) calcd for
C.sub.15H.sub.15ClN.sub.4O.sub.3 346, found 347 (M+H).
2-{5-chloro-6-(3-cyanophenyl)-3-[(methylethyl)amino]-2-oxohydropyrazinyl}-
acetic acid (EX-17A) was converted to the product as described in
Example 1. Mass spectral analysis gave an m/z+1 of 478.
Example 18
[0623] 59
[0624] A solution of 3.90 g (10 mmol) of EX-1B in 50 mL of
CH.sub.3NO.sub.2 was treated with 4.5 mL of
1,8-diazabicyclo[5.4.0]undec-- 7-ene (DBU). After 30 minutes, the
reaction was poured into 300 mL of ethyl acetate and washed with
2.times.25 mL 1 N HCl (aq). The excess organic solvent was removed
under reduced pressure. The resulting oil was treated with 25 mL
H.sub.2O and 25 mL CH.sub.3OH. The solution was treated with 2.8 g
of KOH. After 60 minutes, the reaction was diluted with 300 mL of
acetonitrile. The resulting solid was washed with 100 mL of
acetonitrile. The solid was dissolved in 50 mL 1N HCl (aq) and
extracted with 2.times.100 mL CH.sub.2Cl.sub.2. The organic layer
was dried with MgSO.sub.4, and the excess solvent removed under
reduced pressure. The resulting solid was washed with diethyl ether
and dried in ambient conditions to give 2.1 g (6.4 mmol: 64% yield)
of desired product (EX-18A). LC/MS showed a single peak at 254 nm
and a M+Na at 346. .sup.1H-NMR (dmso-d.sub.6): 4.4 ppm (2H, s); 5.6
ppm (2H, s); 7.3-7.5 ppm (5H, m)
[0625] The product was obtained using standard coupling conditions
and deprotection methods under reducing conditions of Example 1 to
give the desired product after purification by HPLC. LC/MS showed a
single peak at 254 nm and a M+H at 425. .sup.1H-NMR (dmso-d.sub.6):
4.2 ppm (2H, s); 4.4 ppm (2H, m); 4.6 ppm (2H, m); 7.4 ppm (5H, m)
7.6-7.8 ppm (4H, m); 8.4 ppm (2H, bs); 8.7 (1H, m); 9.1 ppm (2H,
bs); 9.3 ppm (2H, bs).
[0626] Using the procedures of Scheme 1, Scheme 2, and Example 1
through Example 18 with suitable reagents, starting materials,
intermediates, and additional pyrazinones of the present invention
were prepared by one skilled in the art using similar methods and
these pryazinones summarized in Table 1.
1TABLE 1 Additional Substituted Pyrazinones Prepared by Procedures
of Scheme 1. Scheme 2, and Examples 1 through 18 60 Ex. MW No.
R.sup.2 B-A Y.sup.0 (m/z + 1) 19 phenyl 2-(4-pyridyl)ethyl
4-amidinobenzyl 516.3 20 benzyl 2-phenylethyl 4-amidinobenzyl 528.9
21 biphenyl 2-(3-pyridyl)ethyl 4-amidinobenzyl 591.9 22 biphenyl
2-(4- 4-amidinobenzyl 625.5 chlorophenyl)ethyl 23 3- benzyl
4-amidinobenzyl 535.3 chlorophenyl 24 biphenyl 2-phenylethyl
4-amidinobenzyl 591.5
Example 25
[0627] 61
[0628] To a solution of 2-iodo-5-methyl benzoic acid (10.0 g, 0.038
mol) in toluene (200 mL) was added trimethylorthoacetate (25 mL) at
room temperature. The reaction action mixture was refluxed for 12
hours. The reaction mixture was cooled to room temperature and
diluted with saturated sodium bicarbonate and ethyl acetate. The
layers were separated and the organic layer washed with brine. The
organic layer was dried (MgSO.sub.4) and solvent removed to give
10.35 g of methyl 2-iodo-5-methylbenzoate (EX-25A) as a yellow oil
with an m/z+1=277.
[0629] A degasssed mixture of ester EX-25A (10.35 g, 0.037 mol)),
Pd(dba).sub.3 (0.017 g, 0.018 mmol)), dppf (0.025 g, 0.045 mmol))
and Zn(CN).sub.2 (2.6 g, 0.02 mol) in DMF (100 mL) was heated to
120.degree. C. for 2 hours. The reaction mixture was poured into
water and ethyl acetate. The organic layer was washed with water
(2.times.) and brine (1.times.). The organic layer was collected,
dried (MgSO.sub.4) and the solvent removed in vacuo to give 5.28 g
methyl 2-cyano-5-methylbenzoate (EX25-B) as a brownish oil with
m/z+1=176
[0630] To a solution of EX-25B (5.28 g, 0.03 mol) in CCl.sub.4 (100
mL) was added NBS (5.37 g, 0.03 mol) and benzoyl peroxide (0.36 g,
0.0015 mol) at room temperature. The reaction mixture was heated to
reflux for 15 hours. The reaction was cooled and the precipitate
filtered away. The organic filtrate was diluted with ether and
washed with saturated sodium bicarbonate. The organic layer was
dried (MgSO.sub.4) and the solvent removed in vacuo to give an oil,
which after chromatography (silica, hexanes to 30% ether/hexanes)
gave 1.57 g methyl 2-cyano-5-bromomethylben- zoate (EX-25C) as a
tan solid with m/z+1=255.
[0631] To a solution of di-tert-butyl iminodicarboxylate (1.48 g,
7.5 mmol) in THF at 0.degree. C. was added NaH (0.31 g, 7.8 mmol).
After stirring at room temperature for 30 minutes, EX-25C (1.57 g,
6.0 mmol) was added as a solution in THF via canula. The reaction
was complete after 2.5 hours at room temperature. The reaction was
quenched by addition of water and ether. The layers were separated
and the organic layer washed with brine (2.times.), dried
(MgSO.sub.4) and the solvent removed in vacuo to give 2.36 g methyl
2-cyano-5-(N,N-bis-Bocaminomethylb- enzoate (EX-25D) as a yellowish
solidwith m/z+1=391.
[0632] To a solution of EX-25D (0.20 g, 0.5 mmol) in anhydrous
methanol (10 mL) was added anhydrous hydrazine (1 mL, 32 mmol)) at
room temperature. The reaction was heated to 70.degree. C.
overnight. The solvent was removed in vacuo to give a solid, which
was suspended in ether and filtered to give 0.11 g of the product
EX-25E as a white solid with an m/z+1=291.
[0633] To a solution of EX-25E (0.22 g, 0.78 mmol) in
dichloromethane (5 mL) at room temperature was added
trifluoroacetic acid (5 mL). After 30 min, the solvent was removed
in vacuo to give a clear residue, which upon drying on high vacuum
became a white solid EX-25F (0.39 g) with m/z+1=191.
[0634] To a solution of
2-{5-chloro-6-(3-aminophenyl)-3-cyclobutylamino-2--
oxohydropyrazinyl}acetic acid (0.93 go 2.6 mmol) in DMF (20 mL) was
added EDC (0.64 g, 3.3 mmol) and HOBt (0.44 g, 3.2 mmol) at room
temperature. After 30 min, the amine EX-25F in a solution of DMF
and triethylamine (1.76 mL, 0.01 mol) was added to the acid. The
reaction mixture was stirred for 1 hour and then poured into
NaHCO.sub.3 (.sub.aq) and ethyl acetate. The layers were separated
and the aqueous layer extracted with ethyl acetate (2.times.) The
organic layer was washed with brine (1.times.), dried (MgSO.sub.4),
and the solvent removed in vacuo to give a brown oil, which after
chromatography (silica, dicholoromethane to 10%
methanol/dichloromethane) gave the product EX-25G (0.29 g) with
m/z+1=521.
[0635] To a suspension of EX-25G (0.29 g, 5.6 mmol) in ether (5 mL)
was added 25 mL of 2.0 M HCl in ether. The reaction was stirred for
30 min to give a fine precipitate which was filtered and dried to
give the product (0.37 g) with m/z+1=521. Analysis
C.sub.25H.sub.25Cl.sub.25N.sub.8O.sub.3- +1.8 HCl+2.15 H.sub.2O
gave C, 47.78%; H, 5.22%; N, 16.29%; O, 12.59%; Cl, 15.43%.
Example 26
[0636] 62
[0637] To a solution of 2-Amino-4-methylpyrimidine (1.0 g, 9.0
mmol) in THF (100 mL) at 0.degree. C. was added TMEDA (4.15 mL,
27.0 mmol) and n-butyl lithium (17.2 mL, 27.0 mmol). After stirring
at 0.degree. C. for 30 min,
(2-bromoethoxy)-tert-butyldimethylsilane (2.16 mL, 10 mmol) was
added in a solution of THF (20 mL) dropwise via canula. The
reaction was allowed to warm to room temperature overnight. The
reaction was diluted with water and ether. The aqueous layer was
extracted (2.times.) with ether. The organic layer was washed with
brine, dried (MgSO.sub.4), and solvent removed in vacuo to give a
brown oil, which after chromatography (silica, dichloromethane to
10% methanol/dicholoromethane) gave EX-26A (1.26 g) with
m/z+1=268.
[0638] To a solution of EX-26A (436 g, 16.0 mmol) in
dichloromethane (100 mL) was added triethylamine (3.4 mL, 24 mmol),
di-tert-butyl dicarbonate (4.53 g, 24 mmol) and DMAP (0.2 g, 0.16
mmol). After stirring at room temperature for 24 hours the reaction
was poured into aqueous sodium bicarbonate and ether. The layers
were separated and the aqueous layer extracted (2.times.) with
ether. The organic layer was washed with brine, and the solvent
removed in vacuo to give a red oil (4.4 g). The oil was purified by
chromatography (silica, 60% ethyl acetate/hexanes) to give a yellow
oil EX-26B (2.77 g) with m/z+1=468.
[0639] To a solution of EX-26B (2.77 g, 6.0 mmol) in THF (100 mL)
was added TBAF (7.1 mL, 1 M in THF) dropwise. After 4 hours at room
temperature the reaction was complete. The reaction mixture was
poured into ethyl acetate and brine. The aqueous layer was
extracted 2.times. with ethyl acetate. The organic layer was dried
(MgSO.sub.4) and the solvent removed to give a yellow oil, which
after chromatography (silica, 70% ethyl acetate/hexanes to 100%
ethyl acetate) gave 1.51 of the alcohol
2-(bis-Boc-amino)-4-(3-hydroxypropyl)pyrimidine (EX-26C) as a
yellow oil with an m/z+1=354.
[0640] To a solution of EX-26C (1.38 g, 4.0 mmol) in toluene (20
mL) was added triethylamine (0.54 mL, 4.0 mmol) and methanesulfonyl
chloride (030 mL, 4.0 mmol). After 10 min, no starting material was
observed by TLC. The reaction mixture was poured into
dichloromethane and water. The layers were separated and the
organic layer was washed with brine and dried (Na.sub.2SO.sub.4).
The solvent was removed to give a yellow oil EX-26D which was used
without further purification. To the crude mesylate EX-26D (1.73 g,
4.0 mmol) in DMF (10 mL) was added NaN.sub.3 (2.6 g, 40 mmol) and
water (1 mL). The reaction mixture was stirred at room temperature
for 18 hours. The reaction was diluted with ether and water. The
layers were separated and the organic layer washed with brine and
dried (Na.sub.2SO.sub.4). The solvent was removed to give an oil,
which after chromatography (silica, 60% ethyl acetateihexanes) gave
the azide EX-26E (0.91 g) with a m/z+1=379.
[0641] To a solution of
2-(bis-Boc-amino)-4-(3-azidopropyl)pyrimidine (EX-26E) (0.39 g, 1.0
mmol) in ethanol at room temperature was added 10% Pd/C and a
hydrogen balloon. After stirring at room temperature for 3 hours
the reaction was complete by TLC. The reaction mixture was filtered
through a pad of celite and washed with ethanol. The solvent was
removed in vacuo to give an oil (0.35 g) which was a mixture of Boc
derivatives EX-26F. To a solution of EX-26F (0.32 g) in
dichloromethane (7 mL) was added trifluoroacetic acid (3 mL)
dropwise. After 30 min, the solvent was removed in vacuo to give
0.34 g of the free amine 2-amino-4-(3-aminopropy- l)pyrimidine
(EX-26G) as an oil with an m/z+1=353.
[0642] To a solution of anilino-acid
2-{(5-chloro-6-(3-aminophenyl)-3-cycl-
obutylamino-2-oxobydropyrazinyl}acetic acid (1.46 g, 4.2 mmol) in
DMF (30 mL) was added HOBt (0.91 g. 6.7 mmol) and EDAC (1.29 g, 6.7
mmol) at room temperature. After stirring for 30 min, EX-26G (1.59
g, 4.2 mmol) in DMF (8 mL) and triethylamine (3.5 mL, 25.2 mmol)
was added. After 30 min, the reaction was diluted with aqueous
sodium bicarbonate and ethyl acetate. The layers were separated and
aqueous layer extracted (2.times.) with ethyl acetate. The organic
layer was washed with brine and dried (MoSO.sub.4). The solvent was
removed in vacuo to give an oil, which after chromatography
(dichloromethane to 15% methanol dichloromethane) gave the product
EX-26H (1.20 g) as a yellow foam with an m/z+1=483.
[0643] To a solution of EX-26H (0.32 g, 0.67 mmol) in 5 mL of ether
was added 20 mL of 3.0 M HCl in ether at room temperature. The
reaction mixture was stirred at room temperature for 20 minutes to
give a precipitate which was filtered to give a yellow solid (034
g) of the di-hydrochloride salt. The solid was purified by RP-HPLC
to give (0.22 ) with an m/z+1=483.
Example 27
[0644] 63
[0645] To a solution of the mixture N-Boc and N,N-bis-Boc
4-(N'-Z-amidino)benzylamines (3.0 g, 6.2 mmol) in 50 mL of EtOH and
20 mL THF was added 300 mg of 5% Pd(C). The solution was
hydrogenated at 40 psi H.sub.2 in a Parr shaker for 18 hrs. The
catalyst was filtered off, and the filtrate concentrated in-vacuo
to afford the mixture EX-27A (2.1 g, 6.0 mmol) of N-Boc and
N,N-bis-Boc 4-amidinobenzylamines as a brownish oil with M+H of 250
(monoBoc) and M+H of 350 (diBoc).
[0646] A solution of EX-27A (2.1 g, 6.0 mmol) in MeOH was treated
with ethylenediamine (1.13 g, 18.9 mmol). The mixture was heated to
reflux for 18 hrs, cooled to room temperature and concentrated in
vacuo. 50 mL of H.sub.2O was added and extracted 3.times. with
CH.sub.2Cl.sub.2. The organic extracts were dried over MgSO.sub.4,
filtered and condensed in vacuo to afford the mixture EX-27B (2.2
g, 5.9 mmol) as a tan solid with M+H of 276 (monoBoc) and M+H of
376 (diBoc).
[0647] A solution of the mixture EX-27B (2.2 g, 5.9 mmol) in 20 mL
methylene chloride and 5 mL pyridine was treated with benzyl
chloroformate (13 g, 7.7 mmol). The mixture was stirred for 1.5 hrs
and then was added 100 mL methylene chloride and 100 mL 0.5 N HCl.
The layers were seperated, and the aqueous extracted 2.times. with
methylene chloride The organics were combined, washed 1.times. with
brine, dried over MgSO.sub.4, filtered and condensed in vacuo.
Purification by column chromatography (silica gel 200-400 mesh)
using 50% ethyl acetate as elutant afforded the mixture EX-27C (1.1
g, 2.2 mmol) as a tan oil with M+H 410 (monoBoc) and M+H 510
(diBoc).
[0648] A solution of the mixture EX-27C (800 mg, 1.6mmol) in 10 mL
of methylene chloride was treated with 5 mL of 4N HCl in dioxane.
The mixture was stirred for 1.5 hrs, and then diethyl ether was
added to precipitate the product. The precipitate was filtered off
and washed extensively with diethyl ether to afford the HCl salt
EX-27D (520 mg, 1.7 mmol) as a tan soild with an M+H of 310.
[0649] A solution of
2-{5-chloro-6-(3-nitrophenyl)-3-cyclobutylamino-2-oxo-
hydropyrazinyl}acetic acid (329 mg, 0.86 mmol) in 10 mL of
methylene chloride was treated with HOBt (127 mg, 0.94 mmol) for 20
min. Then was added EDC (180 mg, 0.94 mmol), DIEA (335 mg, 2.6
mmol), and EX-27D (300 mg, 0.86 mmol), and the reaction was allowed
to stir for 1 hr. Water was then added, and the reaction mixture
extracted 3.times. with methylene chloride. The organics were then
washed 1.times. with brine, dried over MgSO.sub.4, filtered and
condensed in vacuo. Purification by column chromatography (silica
gel 200-400 mesh) eluting with 90% ethyl acetate/hexane and then
100% ethyl acetate afforded EX-27E (325 mg, 0.48 mmol) as a yellow
solid which gave an M+H of 670.
[0650] A solution of EX-27E (325 mg, 0.48 mmol) in 10 mL of MeOH
was treated with 0.7 mL of 3N HCl in MeOH and 5% Pd(C) (50 mg). The
mixture was hydrogenated at 45 psi on a Parr shaker apparatus for 2
hrs. The catalyst was then filtered off and washed extensively with
MeOH. The filtrate was concentrated in vacuo. The residue was
dissolved in EtOH and triturated with diethyl ether. The solid
formed was filtered and extensively washed with diethyl ether to
afford the HCl salt product (220 mg , 0.43 mmol) as an off-white
solid which gave M+H's of 506 (100%) and 508 (60%).
Example 28
[0651] 64
[0652] Using the procedures of Scheme 1, Scheme 2, and Example 1
through Example 18 with suitable reagents, starting materials,
2-{5-chloro-6-(3-nitrophenyl)-3-cyclobutylamino-2-oxohydropyrazinyl}aceti-
c acid and 4-(N-Boc-aminomethyl)benzylamine prepared according to
the literature reference (Callahan. J. F., Ashton-Shue, D., et al.,
J. Med. Chem. 1989, 32, 391-396), the product was obtained and gave
an m/z(M+H).sup.+ of 467.
Example 29
[0653] 65
[0654] Using the procedures of Scheme 1, Scheme 2, and Example 1
through Example 18 with suitable reagents, starling materials,
2-{5-chloro-6-(3-nitrophenyl)-3-cyclobutylamino-2-oxohydropyrazinyl}aceti-
c acid, and 2-(4-imidazoyl)ethanamine commercially available form
Fluka, the product was obtained and gave an m/z(M+H).sup.+ of
442.
Example 30
[0655] 66
[0656] Using the procedures of Scheme 1, Scheme 2, and Example 1
through Example 18 with suitable reagents, starting materials,
2-{5-chloro-(3-nitrophenyl)-3-cyclobutylamino-2-oxohydropyrazinyl}acetic
acid and 2-(4-(2-aminoirnidazoyl))ethanamine prepared according to
the literature reference (Nagai, W. Kirk, K. L., Cohen, L. A., J.
Org. Chem. 1973, 33, 1971-1974), the product was obtained and gave
an m/z(M+H).sup.+ of 457.
Example 31
[0657] 67
[0658] 2-Amino-4-picoline (5.00 g, 46.2 mmol) and 11.20 g of
di-tert-butyl dicarbonate (50.8 mmol) were stirred in 100 mL of
tert-butanol at 30.degree. C. overnight. The reaction mixture was
concentrated in vacuo and chromatographed on silica gel with 25%
EtOAc/Hexane to give 8.20 g (85% yield) of the product EX-31A.
[0659] To a solution of 3.00 g of N-Boc-2-amino-4-picoline (EX-31A,
14.4 mmol) in 150 mL of THF at -78.degree. C. was added 14.4 mL of
2.5 M n-BuLi/Hexanes solution. The reaction mixture was allowed to
warm up to room temperature and stirred for 40 min. The reaction
mixture was cooled down to -78.degree. C. and
1-bromo-2-chloroethane was added. The mixture was stirred at
-78.degree. C. for overnight. The reaction mixture was quenched
with HOAc at -78.degree. C. and concentrated in vacuo. The crude
was dissolved in EtOAc and washed with brine. The EtOAc layer was
dried over MgSO.sub.4 and concentrated in vacuo. The crude product
was purified by silica gel chromatography with 20% EtOAc/Hexane to
give 2.00 g (50%) of the product EX -31B.
[0660] To a solution of 2.00 g of the chloride EX-31B (6.91 mmol)
and 0.50 g of sodium azide (7.69 mmol) in 80 mL of DMF was added 10
mL of water and 0.52 g of sodium iodide. The reaction mixture was
stirred at 55.degree. C. overnight. The mixture was washed with
brine and extracted with EtOAc. The EtOAc layer was dried over
MgSO.sub.4 and concentrated in vacuo. The crude product was
chromatographed on silica gel with 20% EtOAc/Hexane to give 1.80 g
(94%) of the product EX-31C.
[0661] To a solution of 1.74 g of the azide EX-31C (6.27 mmol) in
30 mL of THF was added 1.64 g of triphenylphosphine (6.27 mmol) and
1 mL of water. The reaction mixture was stirred at room temperature
overnight. The reaction mixture was concentrated in vacuo and
chromatographed on silica gel with 10% CH.sub.3OH/CH.sub.2Cl.sub.2
to give 1.26 g (80%) of the amine product EX-31D.
[0662] To a solution of 0.77 g of
2-{5chloro-6-(3-aminophenyl)-3-cyclobuty-
lamino-2-oxohydropyrazinyl}acetic acid (2.21 mmol) in 50 mL of DMF
was added 0.47 g of EDC.HCl and 0.33 g of HOBt. The mixture was
stirred at room temperature for 30 min. After the addition of 0.61
g of the amine EX-31D (2.43 mmol) and 0.50 g of triethylamine the
reaction mixture was stirred at room temperature overnight. The
mixture was washed with water and extracted with EtOAc. The EtOAc
layer was washed with brine and concentrated in vacuo. The crude
product was chromatographed on silica gel with 3%
CH.sub.3OH/CH.sub.2Cl.sub.2 to afford 1.10 g (86%) of the Boc
protected product EX-31E.
[0663] The Boc protected product EX-31E (0.50 g) was treated with
2.0 M of HCl/ether solution for overnight. The mixture was
concentrated in vacuo and chromatographed by DeltaPrep with 10%
CH.sub.3CN/H.sub.2O to give 0.32 g of the product (78%) as a TFA
salt. The TFA salt was converted to the HCl salt by ion exchange
chromatography with BioRad AG 2-X8 resin and 10%
CH.sub.3CN/H.sub.2O and analyzed by mass spectrometer to give an
(M+H) of 482.16.
Example 32
[0664] 68
[0665] A mixture of 26.5 mmol of 4-bromo-3-fluorotoluene, 29 mmol
of copper cyanide and 25 ml of dry DMF is refluxed for 12 hr, then
150 ml water was added and the reaction mixture filtered. The
precipitate was triturated with 100 ml of concentrated ammonium
hydroxide, extracted twice with 50 ml of dichloromethane. The
organic layer was washed with ammonium hydroxide (100 ml) and water
(100) and then concentrated and recrystallized (hexane) to yield 2
g solid 4-cyano-3-fluorotoluene (EX-32A). NMR and MS confirmed the
structure of EX-32A.
[0666] A mixture of 2-fluoro-4-methylbenzonitrile (EX-32A) (2 g,
14.8 mmol). NBS (2.6g, 14.8 mmol) and benzoyl peroxide (178 mg,
0.74 mmol) in CCl.sub.4 (30 ml) was refluxed for 16 hr, then cooled
and filtered. The mixture was then concentrated and purified with
silica-gel column to yield 1.5 g oil EX-32B. NMR and MS confirmed
the structure of EX-32B.
[0667] N,N-(Boc).sub.2NH (1.1 g, 5.17 mmol) in THF (20 ml) was
cooled to 0.degree. C. and NaH (60%, 0.25 g, 6.11 mmol) was added.
The mixture was kept stirring for 30 min., then benzylbromide
EX-32B (1 g, 4.7 mmol) in THF (2 ml) was added. The mixture was
stirred for 3 hr. Then water was added and extracted with EtOAc
(3.times.15 ml). The combined EtOAc was then concentrated and
recrystalized in hexane to yield 0.6 g white solid EX-32C. NMR and
MS all confirmed the structure of EX-32C.
[0668] To the compound EX-32C (200 mg) in CH.sub.2Cl.sub.2 (3 ml)
was added TFA (1.5 ml). The reaction mixture was stirred at RT for
3 h and concentrated to afford oil EX-32D which was directly used
for next amide coupling reaction.
[0669] To
2-{5-chloro-6-(3-nitrophenyl)-3-cyclobutylamino-2-oxohydropyrazi-
nyl}acetic acid (227 mg, 0.6 mmol) was added HOBt (106.1 mg, 0.7
mmol) and EDC (126.7 mg, 0.7 mmol) in DMF (3 ml). The mixture was
stirred at RT for 30 min. Then the amine TFA salt EX-32D in DMF (1
ml) and triethyl amine (0.2 ml) was added to the mixture which was
stirred overnight The mixture was concentrated, purified to yield
200 mg solid EX-32E, confirmed by NMR and MS.
[0670] EX-32E(0.2 g) in THF (5 ml) was added with Pd/C (10%, 20
mg). The mixture was stirred at RT under N.sub.2, and then H.sub.2
gas balloon was connected to the flask. The reaction was stirred
for 24 hr to complete reaction. The mixture was filtered, washed
with ethanol, and then dried to yield 0.16 g white solid EX-32F
which was directly used for next cyclization reaction.
[0671] To acetohydroxamic acid (37 mg, 0.5 mmol) in DMF (2 ml) was
added potassium t-butoxide (1M, 0.5 ml, 0.5 mmol) at room
temperature. After stirring for 30 min, benzonitrile EX-32F (160
mg, 0.33 mmol) in DMF (2 ml) was added. The reaction mixture was
stirred overnight, and then poured into a mixture of brine and
ethyl acetate. The aqueous layer was extracted with EtOAc
(3.times.2 ml), and the combined EtOAc was washed with brine,
dried, concentrated and purified on reverse-phase HPLC to yield 60
mg of the HCl salt. NMR and MS both confirmed the structure of
product.
Example 33
[0672] 69
[0673] By substituting 2-fluoro-4-methylbenzonitrile for
4-methylbenzonitrile, 2-fluoro-4-methylbenzonitrile (EX-32A) was
converted to the protected amidine,
4-(N-benzyloxycarbonylamidino)-3-fluo- robenzylamine hydrogen
chloride salt (EX-33A), using the procedure outlined in Synthetic
Communications, 28(23), 4419-4429 (1998) for preparing
4-(N-benzyloxycarbonylamidino)benzylamine hydrogen chloride salt.
EX-33A was characterized by: MS (LR-ESI) m/z 302 (M+H).sup.+;
.sup.1HNMR (DMSO, 300 MHz) .delta. 8.75 (bs, 3H, CH.sub.2NH.sub.2),
.delta. 7.79-7.02 (m, 8H, aromatic CH), .delta. 5.31-5.07 (m, 2H,
C.sub.H.sub.5CH.sub.2), .delta. 4.10 (s, 2H,
CGH.sub.2NH.sub.3).
[0674] Using the procedure of Example 44 by substituting
2-[3-(N-{2-phenylethyl}amino)-2-oxo-6-phenylhydropyrazinyl]acetic
acid (EX-1D) for
2-[3-({2-[(tert-butoxy)carbonylamino]ethyl}amino)-5-chloro-2--
oxo-6-phenylhydropyrazinyl]acetic acid, EX-33A was converted to the
product which gave an m/z+1 of 499.
Example 34
[0675] 70
[0676] By substituting 3-fluoro-4-methylbenzonitrile for
4-methylbenzonitrile, 3-fluoro-4-methylbenzonitrile was converted
to the protected amidine,
4-(N-benzyloxycarbonylamidino)-2-fluorobenzylamine hydrogen
chloride salt (EX-34A), using the procedure outlined in Synthetic
Communications, 28(23), 4419-4429 (1998) for preparing
4-(N-benzyloxycarbonylamidino)benzylamine hydrogen chloride salt.
EX-34A was characterized by: MS (LR-ESI) m/z 302 (M+H).sup.+;
.sup.1HNMR (DMSO, 300 MHz) .delta. 8.82 (bs, 3H, CH.sub.2NH.sub.3),
.delta. 7.92-7.26 (m, 8H, aromatic CH), .delta. 5.32 (s, 2H,
C.sub.6H.sub.5CH.sub.2), .delta. 4.10 (s, 2H,
CH.sub.2NH.sub.3).
[0677] Using the procedure of Example 44 by substituting
2-[3-(N-{2-phenylethyl}amino)-2-oxo-6-phenylhydropyrazinyl]acetic
acid (EX-1D) for
2-[3-({2-[(tert-butoxy)carbonylamino]ethyl}amino)-5-chloro-2--
oxo-6-phenylhydropyrazinyl]acetic acid, EX-34A was converted to the
product which gave an m/z+1 of 499.
Example 35
[0678] 71
[0679] By substituting 2-methoxy-4-methylbenzonitrile for
4-methylbenzonitrile, 2-methoxy-4-methylbenzonitrile was converted
to the protected amidine,
4-(N-benzyloxycarbonylamidino)-3-methoxybenzylamine hydrogen
chloride salt (EX-35A), using the procedure outlined in Synthetic
Communications, 28(23), 4419-4429 (1998) for preparing
4-(N-benzyloxycarbonylamidino)benzylamine hydrogen chloride salt.
EX-35A was characterized by: MS (LR-ESI) m/z 314 (M+H).sup.+;
.sup.1HNMR (DMSO, 300 MHz) .delta. 7.77-6.95 (m, 8H, aromatic CH),
.delta. 4.74 (bs, 2H, C.sub.6H.sub.5CH.sub.2), .delta. 4.10-3.95
(m, 2H, CH.sub.2NH.sub.3), .delta. 3.80 (s, 3H, OCH.sub.3).
[0680] Using the procedure of Example 44 by substituting
2-[3-(N-{2-phenylethyl}amino)-2-oxo-6-phenylhydropyrazinyl]acetic
acid (EX-1D) for
2-[3-({2-[(tert-butoxy)carbonylamino]ethyl}amino)-5chloro-2-o-
xo-6-phenylhydropyrazinyl]acetic acid, EX-35A was converted to the
product which gave an m/z+1 of 511.
[0681] Using the procedures of Scheme 1, Scheme 2, and the Examples
herein with suitable reagents, starting materials, and
intermediates, additional pyrazinones of the present invention were
prepared and these pryazinones are summarized in Table 2.
2TABLE 2 Additional Substituted Pyrazinones of the Present
Invention Prepared based on the Procedures of Scheme 1, Scheme 2.
and Examples herein. 72 Ex. MW No. R.sup.2 R.sup.1 B-A- Y.sup.0
(m/z + 1) 36 Phenyl H 2- 1-(4-guanidino)-2- 458 phenethyl butynyl
37 Phenyl H 2- 1-(4-guanidino)-cis-2- 460 phenylethyl butenyl 38
Phenyl H 2- (3-aminoindazol-5-yl) 494 phenylethyl methyl 39 Phenyl
H 2- (3-aminoindazol-6-yl) 494 phenylethyl methyl 40 3-amino- Cl
cyclobutyl (4-amidino-3-fluoro)- 498 phenyl benzyl 41 3-amino- Cl
cyclobutyl (4-amidino-2-fluoro)- 511 phenyl benzyl 42 3-amino- Cl
isopropyl (4-amidino-3-fluoro)- 486 phenyl benzyl 43 3-amino- H
isopropyl (4-amidino-3-fluoro)- 452 phenyl benzyl
Example 44
[0682] 73
[0683] To a solution of
2-[3-({2-[(tert-butoxy)carbonylamino]ethyl}amino)--
5-chloro-2-oxo-6-phenylhydropyrazinyl]acetic acid (6.50 g, 15.38
mmol) prepared as described in EX-1C using
2-(tert-butoxycarbonylamino)ethylami- ne in place of
2-phenylethylamine in 100.0 mL dimethylformamide was added
N,N-diisopropylethylamine (21.0 mL, 120.56 mmol),
N-hydroxybenzotriazole (2.73 g, 20.21 mmol), and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.84
g, 20.04 mmol). The resulting mixture was stirred for 30 minutes.
To the reaction mixture was added in one portion (5.9723 g, 18.68
mmol) of the protected amidine,
4-(N-benzyloxycarbonylamidino)benzy- lamine hydrogen chloride salt,
prepared using the procedure outlined Synthetic Communications,
28(23), 4419-4429 (1998). The resulting mixture was stirred over
night. The reaction mixture was diluted with ethyl acetate (2.50
mL) and washed with 5% citric acid (1.times.50 mL), saturated
NaHCO.sub.3 (1.times.50 mL), and brine (1.times.50 mL). The organic
solution was dried (MgSO.sub.4), filtered and concentrated. The
crude reaction was purified by MPLC (80% ethyl acetate/hexanes) to
give pure product EX-44A: .sup.1H NMR (300 MHz, DMSO) .delta.
8.59-8.53 (1H), 7.99-7.96 (m, 2H), 7.81-7.75 (m, 1H), 7.51-7.25 (m,
12H), 6.99 (br m, 1H), 5.14 (s, 2H), 4.32-4.27 (m, 4H), 3.42-3.35
(m, 4H), 3.24-3.20 (m, 2H), 1.41 (s, 9H); .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta. 166.6, 163.0, 156.5, 151.3, 149.9, 143.9,
137.8, 133.5, 132.6, 131.3, 130.1, 129.5, 129.2, 129.1, 128.9,
128.7, 128.4, 127.7, 124.0, 78.5, 66.8, 49.3, 42.6, 36.5, 31.5,
29.0; HRMS (EI) calcd for C.sub.35H.sub.38ClN.sub.7O.su- b.6
688.2650, found 688.2614.
[0684] A solution of pyrazinone EX-44A (334.4 mg, 0.4593 mmol) in
5.0 mL ethanol/4 M HCl in dioxane (3:1, 0.1 M) was flushed with
hydrogen gas. To the solution was then added 113.1 mg 10% Pd/C
(wet), and the resulting suspension was stirred at room temperature
under an atmosphere of hydrooen (balloon pressure) for
approximately 18 hours. The reaction mixture was filtered through a
pad of Celite 545 and rinsed with ethanol. The solvent was removed
under reduced pressure. The resulting oil was triturated with ethyl
ether to provide pure product as a white solid: .sup.1H NMR (400
MHz, DMSO) d 9.50 (s, 2H), 9.29 (s, 2H), 8.8/0 (s, 1H), 8.22 (s,
3H), 7.85-7.80 (m, 3H), 7.44 (br s, 3H), 7.27-7.24 (m, 4H), 4.23
(s, 4H), 3.58-3.54 (m, 4H); HRMS (ES) calcd for
C.sub.22H.sub.25ClN.sub.7- O.sub.2 454.1758, found 454.1741.
Example 45
[0685] 74
[0686] By following the method of Example 45 and substituting
2-[3-({3-[(tert-butoxy)carbonylamino]propyl}amino)-5-chloro-2-oxo-6-pheny-
lhydropyrazinyl]acetic acid for
2-[3-({2-[(tert-butoxy)carbonylamino]ethyl-
}amino)-5-chloro-2-oxo-6-phenylhydropyrazinyl]acetic acid, the
product was prepared: .sup.1H NMR (400 MHz, DMSO) d 9.51 (br s,
2H), 8.28 (br s, 2H), 8.77 (s, 1H), 8.15 (3, 3H), 7.86-7.79 (m,
3H), 7.42 (s, 3H), 7.26-7.24 (m, 4H), 5.37 (br s, 2H), 4.21 (s 4H),
3.39-3.29 (m, 2H), 2.81-2.76 (br s, 2H), 1.86 (br s, 2H); .sup.13C
NMR (100 MHz, DMSO) d 166.7, 166.0, 151.2, 149.7, 146.0, 132.5,
131.1, 129.5, 128.8, 127.9, 126.8, 125.1, 123.9, 65.6, 56.6, 49.2,
42.4, 38.1, 37.3, 34.6, 26.7, 19.2, 15.8; HRMS (EI) calcd for
C.sub.23H.sub.26ClN.sub.3O.sub.6 469.1755, found 469.1725.
Example 46
[0687] 75
[0688] By following the method of Example 44 and substituting
2-[3-({4-[(tertbutoxy)carbonylamino]butyl}amino)-5-chloro-2-oxo-6-phenylh-
ydropyrazinyl]acetic acid for
2-[3-({2-[(tert-butoxy)carbonylamino]ethyl}a-
mino)-5-chloro-2-oxo-6-phenylhydropyrazinyl]acetic acid, the
product was prepared: .sup.1H NMR (400 MHz, DMSO) d 9.49 (br s,
2H), 9.28 (s, 2H), 8.75 (s, 1H), 8.08 (s, 3H), 7.89-7.76 (m, 3H),
7.42 (s, 3H), 7.26-7.24 (m, 4H), 4.70 (br s, 4H), 4.23-4.21 (m,
3H), 2.73 (br s, 2H), 1.57 (br s, 3H), 1.03-0.96 (m, 2H); HRMS (EI)
calcd for C.sub.24H.sub.29ClN.sub.7O.su- b.2 482.2071, found
482.2040.
Example 47
[0689] 76
[0690] A solution of
1-(N-{4-[N-benzyloxycarbonylamidino]benzylamido}carbo-
nylmethyl)-3-({3-[(tert-butoxy)carbonylamino]propyl}amino)-5-chloro-6-phen-
ylpyrazinone hydrochloride (2.0075 g, 2.859 mmol), prepared as an
intermediate in Example 45, in 28.0 mL ethanol/4 M HCl in
dioxane(1:1, 0.1 M) was allowed to stir at room temperature for
approximately 4 hours. The solvent was removed under reduced
pressure. Purification by trituration with ethyl ether gave pure
product EX-47A as a yellow solid: .sup.1H NMR (400 MHz, DMSO) d
11.67 (br s, 1H), 10.53 (br s, 1H), 8.90-8.87 (m, 1H), 8.30-8.25
(m, 3H), 7.89-7.89 (m, 1H), 7.75-7.73 (m, 2H), 7.46-7.23 (m, 13H),
5.532 (s, 2H), 4.26-4.23 (m, 3H), 3.50 (s, 2H), 3.36-3.35 (m, 2H),
2.75 (br m, 2H); HRMS (EI) calcd for C.sub.31
H.sub.32ClN.sub.7O.sub.4 602.2283, found 602.2253.
[0691] To a solution of amino pyrazinone EX-47A (1.9093 g, 2.684
mmol) in 10.0 mL dimethyl formamide (0.25 M) was added
triethylamine (1.90 mL, 13.63 mmol) To the resulting mixture was
then added N,N'-di-BOC-N'-triflylguanidine (1.4021 g, 3.583 mmol,
prepared according to Feichtinger, K., Zapf, C., Sings. H. L., and
Goodman, M., J. Org. Chem., 63, 3804-3805 (1998)) in one portion at
room temperature. The resulting suspension was allowed to stir over
night. The reaction mixture was diluted ethyl acetate (250 mL) and
washed with saturated NaHCO.sub.3 (2.times.100 mL) and brine
(2.times.100 mL). The organic solution was dried (MgSO.sub.4),
filtered and concentrated. Purification by MPLC (75% ethyl
acetate/hexanes) afforded EX-47B: .sup.1H NMR (400 MHz, CDCl.sub.3)
d 11.53 (s, 1H), 8.55-8.48 (m, 2H), 7.97-7.93 (m, 4H), 7.49-7.24
(m, 13H), 5.13 (s, 2H), 4.30-4.25 (m, 4H), 3.90-3.33 (m, 4H),
1.84-1.79 (m, 2H), 1.49 (s, 9H), 1.41 (s, 9H); HRMS (EI) calcd for
C.sub.42H.sub.51ClN.sub.9O.sub.8 844.3549, found 844.3521.
[0692] A solution of pyrazinone EX-47B (1.5450 g, 1.8298 mmol) in
18.0 mL ethanol/4 M HCl in dioxane (3:1, 0.1 M) was flushed with
hydrogen gas. To the solution was then added 157.2 mg 10% Pd/C
(wet), and the resulting suspension was stirred at room temperature
under an atmosphere of hydrogen (balloon pressure) for
approximately 18 hours. The reaction mixture was filtered through a
pad of Celite 545 and rinsed with ethanol. The solvent was removed
under reduced pressure. The resulting oil was triturated with ethyl
ether to provide the pure product in 63% yield: .sup.1H NMR (400
MHz, DMSO) d 9.50 (s, 2H), 9.28 (s, 2H), 8.77 (s, 1H), 7.91 (s,
1H), 7.81-7.79 (m, 3H), 7.42 (br s, 4H), 7.26-7.24 (m, 5H), 6.28
(br s, 2H), 4.23-4.21 (m, 4H), 3.36-3.27 (m, 2H), 3.14-3.13 (br m,
2H), 1.77-1.74 (m, 2H); HRMS (ES) calcd for
C.sub.24H.sub.29ClN.sub.9O.sub.2 510.2133, found 510.2080.
Example 48
[0693] 77
[0694] Using the method of Example 47 and substituting
1-(N-{4-[N-benzyloxycarbonylamidino]benzylamido}carbonylmethyl)-3-({2-[(t-
ert-butoxy)carbonylamino]ethyl}amino)-5-chloro-6-phenylpyrazinone
hydrochloride, prepared as an intermediate in Example 44, for the
propyl analog used in Example 47, the product was prepared: .sup.1H
NMR (400 MHz, DMSO) d 9.51 (s, 2H), 9.29 (s, 2H), 8.80 (s, 1H),
7.90-7.78 (m, 5H), 7.43-7.37 (m, 5H), 7.35-7.23 (m, 5H), 4.23 (s,
4H), 4.03 (s, 2H), 3.40-334 (m, 4H); HRMS (EI) calcd for
C.sub.23H.sub.27ClN.sub.9O.sub.2 496.1976, found 496.1952.
Example 49
[0695] 78
[0696] By following the method of Example 47 and substituting
1-(N-{4-[N-benzyloxycarbonylamidino]benzylamido}carbonylmethyl)-3-({4-[(t-
ert-butoxy)carbonylamino]butyl}amino)-5-chloro-6-phenylpyrazinone
hydrochloride (2.0075 g, 2.859 mmol), prepared as an intermediate
in Example 46, for the propyl analog used in Example 47, the
product was prepared: .sup.1H NMR (400 MHz, DMSO) d 9.47 (s, 2H),
9.28 (s, 2H), 8.74-8.72 (m, 1H), 7.88 (br s, 1H), 7.80-7.73 (m,
3H), 7.43-7.31 (m, 4H), 7.27-7.20 (m, 5H), 5.3-5.32 (m, 3H),
4.25-4.21 (m, 4H), 3.28-3.27 (m, 2H), 3.10-3.08 (m, 2H), 1.58-1.53
(m, 2H), 1.4-1.43 (m, 2H); HRMS (EI) calcd for
C.sub.25H.sub.31ClN.sub.9O.sub.2 524.2289, found 524.2292.
Example 50
[0697] 79
[0698] To a solution of
2-{5-chloro-3-[(2-cyanoethyl)amino]-2-oxo-6-phenyl-
hydropyrazinyl}acetic acid (2.09 g, 6.28 mmol) in 31.0 mL
dimethylformamide/tetrahydrofuran (1:1) was added
N,N-diisopropylethylami- ne (5.50 mL, 31.57 mmol),
N-hydroxybenzotriazole (1.02 g, 7.6 mmol), and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.45
g, 7.51 mmol). The resulting mixture was stirred for 30 minutes. To
the reaction mixture was then added 4-cyanobenzylamine (1.28 g,
7.57 mmol) in one portion. The resulting mixture was allowed to
stir over night. The reaction mixture was diluted with ethyl
acetate (2.50 mL) and washed with 5% citric acid (1.times.50 mL),
saturated NaHCO.sub.3 (1.times.50 mL), and brine (1.times.50 mL).
The organic solution was dried (MgSO.sub.4), filtered and
concentrated. The crude reaction was purified trituration with
ethyl ether to give EX-50A: .sup.1H NMR (300 MHz, DMSO) .delta.
8.59 (t, J=5.6 Hz, 1H), 8.10 (t, J=5.6 Hz, 1H), 7.82 (d, J=8.1 Hz,
2H), 7.53-7.46 (m, 3H), 7.35-7.32 (m, 4H) 4.33-4.29 (m, 4H),
3.63-3.57 (m, 2H), 2.89 (t, J=6.3 Hz, 2H); .sup.13C NMR (75 MHz,
DMSO) .delta. 166.7, 151.1, 149.6, 145.6, 132.93, 132.45, 131.16,
130.21, 129.55, 128.63, 124.97, 124.72, 120.0, 119.6, 110.4, 49.3,
42.6, 37.3, 17.3; HRMS (EI) calcd for
C.sub.23H.sub.20ClN.sub.6O.sub.2 447.1336, found 447.1330.
[0699] To a suspension of bis-nitrile pyrazinone EX-50A (2.26,
58.07 mmol) in 50 mL ethanol/H.sub.2O (2.6:1, 0.1 M) was added
hydroxyl amine hydrochloride (2.61 g, 37.6 mmol) followed by
potassium carbonate (3.08 g, 223 mmol). The resulting white
suspension was stirred and heated to 60.degree. C. over night. The
reaction mixture was cooled to room temperature and diluted with
water (75.0 mL). The mixture was placed in an ice bath, and the pH
was adjusted to approximately 7 using dilute acid. The precipitate
that formed was collected by filtration, washed with cold water and
dried under vacuum to afford pure EX-50B: .sup.1H NMR (300 MHz,
DMSO) .delta. 9.63 (s, 1H), 8.95 (s, 1H), 8.47 (br s, 1H),
7.66-7.61 (m, 2H), 7.53-7.47 (m, 4H), 7.32 (d, J=5.2 Hz), 7.16-7.13
(m, 2H), 5.83 (s, 2H), 5.47 (s, 2H), 4.25 (s, 4H), 3.61-3.53 (m,
2H), 2.39-2.35 (m, 2H); .sup.13C NMR (75 MHz, DMSO) .delta. 166.5,
151.68, 151.35, 151.23, 149.6, 140.3, 132.70, 132.63, 131.3, 130.1,
129.5, 127.6, 126.0, 125.3, 49.2, 42.6, 38.4, 30.6; HRMS (EI) calcd
for C.sub.23H.sub.26ClN.sub.8O.sub.4 513.1766, found 513.1735.
[0700] To a solution of Bis-hydroxyamidine EX-50B (2.40 g, 4.67
mmol) in 19.0 mL acetic acid (0.25 M) was added acetic anhydride
(1.80 mL, 19.1 mmol). The resulting mixture was stirred for 10
minutes and flushed with hydrogen gas. To the solution was then
added Pd/C (wet) and the resulting mixture was allowed to stir
under an atmosphere of hydrogen (balloon pressure) at room
temperature, over night. The reaction mixture was filtered through
a pad of Celite 545 and concentrated under vacuum. Purification by
HPLC (1% acetonitrile to 60% acetonitrile/H.sub.2O/0.1%
trifluoroacetic acid) afford pure product: .sup.1H NMR (400 MHz,
DMSO) .delta. 9.51 (s, 2H), 9.30 (s, 2H), 9.03 (s, 2H), 8.93 (s,
2H), 8.62-8.59 (m, 1H), 7.89-7.86 (m, 2H), 7.74 (d, J=8.3 Hz, 2H),
7.47-7.40 (m, 3H), 7.28-7.23 (m, 4H), 4.27-4.24 (m, 4H), 3.63-3.59
(m, 2H), 2.70-2.68 (m, 2H); HRMS (EI) calcd for
C.sub.23H.sub.26ClN.sub.8O.sub.2 481.1867, found 481.1836.
Example 51
[0701] 80
[0702] By following the method of Example 50 and substituting
2-{-5-chloro-3-[(4-cyanobenzyl)amino]-2-oxo-6-phenylhydropyrazinl}acetic
acid for the 2-cyanoethylamino analog, the product was prepared:
.sup.1H NMR (400 MHz, DMSO) d 9.44 (d, J=16.9 Hz, 3H), 9.26 (d,
J=17.2 Hz, 8.61 (br s, 1H), 8.47-8.44 (m, 1H), 7.74 (d, J=7.0 Hz,
4H), 7.52 (d, J=Hz, 2H), 7.43-7.42 (m, 3H), 7.28-7.22 (m, 4H),
4.56-4.55 (m, 2H), 4.25 (s, 4H); HRMS (EI) calcd for
C.sub.28H.sub.28ClN.sub.8O.sub.2 543.2024, found 543.1986.
Example 52
[0703] 81
[0704] By following the method of Example 50 and substituting
2-{5-chloro-3-[(3-cyanobenzyl)amino]-2-oxo-6-phenylhydropyrazinyl}acetic
acid for the 2-cyanoethylamino analog, the product was prepared:
.sup.1H NMR (400 MHz, DMSO) d 9.41 (s, 4H), 9.28 (d, J=11.0 Hz,
4H), 8.61-8.58 (m, 1H), 8.35-8.32 (m, 1H), 7.77-7.72 (m, 3H),
7.66-7.64 (m, 2H), 7.55-7.52 (m, 1H), 7.45-7.39 (m, 3H), 7.29-7.23
(m, 4H), 4.57-4.55 (m, 2H), 4.26-4.21 (m, 4H); .sup.13C NMR (100
MHz, DMSO) d 166.7, 166.1, 159.8, 159.4, 151.2, 149.6, 145.9,
140.6, 133.3, 132.4, 131.1, 130.1, 129.6, 129.5, 129.1, 128.7,
127.93, 127.86, 127.3, 124.9, 124.5, 49.1, 44.0, 42.4; HRMS (EI)
calcd for C.sub.28H.sub.28ClN.sub.8O.sub.2 543.2024, found
543.2032.
Example 53
[0705] 82
[0706] To a solution of
2-{5-chloro-3-[(2-cyanoethyl)amino]-2-oxo-6-phenyl-
hydropyrazinyl}acetic acid (1.45 g, 3.25 mmol) in 17.0 mL
dimethylformamide was added N,N-diisopropylethylamine (3.00 mL,
17.2 mmol), N-hydroxybenzotriazole (0.536 mg, 3.96 mmol), and
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
(0.752 mg, 3.923 mmol). The resulting mixture was allowed to stir
for 30 minutes. The reaction mixture was then added the Cbz
protected amidine (1.2631 g, 3.950 mmol) prepared and used in
Example 44 in one portion. The resulting mixture was allowed to
stir over night. The reaction mixture was diluted with ethyl
acetate (250 mL) and washed with 5% citric acid (1.times.50 mL),
saturated NaHCO.sub.3 (1.times.50 mL), and brine (1.times.50 mL).
The organic solution was dried (MgSO.sub.4), filtered and
concentrated. The crude reaction was purified by MPLC (100% ethyl
acetate) to give pure EX-53A in 82% yield: .sup.1H NMR (400 MHz,
DMSO) .delta. 9.06 (br s, 1H), 8.50-8.47 (m, 1H), 8.05-8.02 (m,
1H), 7.89 (d, J=8.2 Hz, 2H) 7.46-7.26 (m, 11H), 7.18 (d, J=8.2 Hz,
2H), 5.07 (s, 2H), 4.24-4.21 (m, 4H), 3.55-3.51 (m, 2H), 2.83-2.80
(m, 2H); HRMS (EI) calcd for C.sub.31H.sub.28ClN.sub.7O.sub.4
598.1970, found 598.1970.
[0707] To a solution of pyrazinone EX-53A (1.497 g, 2.50 mmol) in
25.0 mL ethanol/4 M HCl in dioxane (3:1, 0.1 M) was flushed with
hydrogen gas. To the solution was then added 10% Pd/C (wet) and the
resulting suspension was allowed to stir at room temperature under
an atmosphere of hydrogen (balloon pressure) for approximately 18
hours. The reaction mixture was filtered through a pad of Celite
545 and rinsed with ethanol. The solvent was removed under reduced
pressure. Purification by HPLC (5% acetonitrile to 95%
acetonitrile/H.sub.2O/0.1% trifluoroacetic acid) provided pure
product: .sup.1H NMR (400 MHz, DMSO) d 9.51 (s, 2H), 9.29 (s, 2H),
8.63-8.60 (m, 1H), 8.03-8.00 (m, 1H), 7.74 (d, J=8.3 Hz, 2H),
7.44-7.40 (m, 3H), 7.29-7.27 (m, 4H), 4.27-4.24 (m, 4H), 3.55-3.51
(m, 3H), 2.83-2.80 (m, 3H); HRMS (ES) calcd for
C.sub.23H.sub.23ClN.sub.7O.sub.2 464.1602, found 464.1624.
Example 54
[0708] 83
[0709] A solution of p-bromophenethylamine (40 g, 199.92 mmol) and
phthalic anhydride (29.6 g, 199.84 mmol) in 250 mL of dioxane and
25 mL of dimethylformamide was heated at 120.degree. C. for 24
hours. The flask was then cooled, and the resulting white
precipitate was filtered and washed with methanol (200 mL) to give
EX-54A in exceptional yield and purity: .sup.1H NMR (400 MHz,
CDCl.sub.3) d 7.8 (m, 2H), 7.7 (m, 2H), 7.4 (d, 2H), 7.1 (d, 2H),
3.8 (t, 2H), 2.95 (t, 2H); MS (ES) calcd for
C.sub.16H.sub.12BrNO.sub.2 330, found 331 (M+H).
[0710] A nitrogen purged solution of EX-54A (40 g, 121.15 mmol) and
copper (I) cyanide (16.28 g, 181.72 mmol) in 500 mL of
dimethylformamide was heated at 170.degree. C. for 24 hours. The
solvent was removed under vacuum, and the resulting material was
taken up in ethyl acetate. The ethyl acetate suspension was flashed
through celite and concentrated under vacuum. The resulting white
precipitate EX-54B was of exceptional yield and purity: .sup.1H NMR
(300 MHz, CDCl.sub.3) d 7.82 (m, 2H), 7.75 (m, 2H), 7.6 (d, 2H),
7.35 (d, 2H), 3.95 (t, 2H), 3.05 (t, 2H); MS (ES) calcd for
C.sub.17H.sub.12N.sub.2O.sub.2 276, found 277 (M+H).
[0711] A solution of p-cyanophenethylamine EX-54B (25 g, 90.48
mmol) and hydroxylamine hydrochloride (8 g, 115.12 mmol) in 1 L of
ethanol and 20 ML (114.82 mmol) of diisopropylethylamine was heated
at reflux for 16 hours. The flask was then cooled, and the
resulting white precipitate was filtered and air dried to give
EX-54C in an adequate yield and purity: .sup.1H NMR (300 MHz, DMSO)
d 7.75 (d, 2H), 7.55 (d, 2H), 7.25 (d, 2H), 7.2 (d, 2H), 3.8 (m,
2H), 2.95 (m, 2H); MS (ES) calcd for C.sub.17H.sub.15N.sub.3O.sub.3
309, found 310 (M+H).
[0712] A solution of p-(N-hydroxy)amidinophenethyl phthalimide
(EX-54C) (4.53 g, 14.64 mmol) in 200 mL of chloroform was treated
with hydrazine monohydrate (1 mL, 20.62 mmol). The reaction was
stirred vigorously at 50.degree. C. for 24 hours. The flask was
then cooled and the resulting white precipitate was filtered and
washed with chloroform (200 mL). A 50:50 mixture of product EX-54D
and phthalhydrazide was obtained and used as is: .sup.1H NMR (300
MHz, DMSO) d 7.6 (d, 2H), 7.2 (d, 2H), 2.8 (t, 2H), 2.7 (m, 2H); MS
(ES) calcd for C.sub.17H.sub.15N.sub.3O.sub.3 179, found 180
(M+H).
[0713] Reacting EX-54D containing phthalhydrazide with
2-{5-chloro-6-(3-nitrophenyl)-3-[N-(1-methylethyl)amino]-2-oxohydropyrazi-
nyl}acetic acid in place of
2-{5-chloro-6-(3-nitrophenyl)-3-cyclobutylamin-
o-2-oxohydropyrazinyl}acetic acid and EX-27D and then hydrogenating
the resulting intermediate according to the final two procedures
described in Example 27 gave the product with an m/z+1 of 484.
Example 55
[0714] 84
[0715] A solution of diisopropylamine (35.3 ml, 0.251 moles) in
tetrahydrofuran (500 ml) was cooled to -78.degree. C. under a
nitrogen blanket. To this was added 1.6M n-butyllithium in hexanes
(157 ml, 0.251 moles) and allowed to stir for 5 min. Then slowly
added thiopene-2-carbonitrile (21.33 ml, 0.229 moles) in
tetrahydrofuran (115 ml) and allowed to stir. After 45 min, was
added N,N-dimethylformamide (88.66 ml, 1.145 moles) at -78.degree.
C. Citric acid (40 g) was added after 2 h, followed by water (240
ml) and stirred for 18 h. The reaction was concentrated in vacuo,
transferred to a separatory funnel, diluted with brine, and
extracted twice with ether. The combined ether layers were washed
with brine, dried over magnesium sulfate, filtered, and the solvent
removed in vacuo. Chromatography yielded 15.8 g (50%) of
2-cyano-5-formylthiophene (EX-55A) as a brown solid: .sup.1H NMR
(300 MHZ, CDCl.sub.3) d 10.02 (s, 1H), 7.79 (m, 1H), 7.30 (m,
1H).
[0716] 2-Cyano-5-formylthiophene (EX-55A) (15.8 g, 0.229 moles) was
stirred in ethanol (375 ml), and sodium borohydride (4.36 g, 0.115
moles) added in small portions. After 15 min., the solvent was
removed in vacuo, and residue taken up in ethyl acetate. After the
ethyl acetate was washed with 1N potassium hydrogen sulfate and
brine, the organic layer was dried over magnesium sulfate,
filtered, and solvent removed in vacuo. The residue was dried on
vacuum pump to yield 9.57 g (59%) of the alcohol EX-55B as a
brown-orange oil: .sup.1H NMR (300 MHz, CDCl.sub.3) d 7.53 (m, 1H),
7.00 (m, 1H), 4.88 (s, 2H), 2.84 (br s, 1H).
[0717] To a stirring solution of EX-55B (9.57 g, 0.069 moles) in
tetrahydrofuran (80 ml)was added triphenylphosphine (19.86 g, 0.075
moles) and carbon tetrabromide (25.11 g, 0.075 moles). After 18 h,
the reaction was concentrated in vacuo, and the crude material
chromatographed to yield EX-55C as a brown oil:
[0718] .sup.1H NMR (300 MHz, CDCl.sub.3) d 7.52 (m, 1H), 7.14 (m,
1H), 4.69 (s, 2H).
[0719] 2-Aminomethyl-5-carbobenzyloxyamidinothiophene dihydrogen
chloride salt (EX-55D) was prepared by the method outlined in
Synthetic Communications, 28(23), 4419-4429 (1998) by substituting
5-bromomethyl-2-cyanothiophene (EX-55C) for 4-cyanobenzyl bromide
to give after trituration with acetonitrile EX-55D: .sup.1H NMR
(300 MHz, DMSO) d 9.98 (br s, 1H), 8.83 (br s, 2H), 8.10 (s, 1H),
7.40-7.48 (m, 7H), 5.26 (s, 2H), 4.31 (s, 2H); HRMS calcd for
C.sub.14H.sub.16N.sub.3O.sub.2 290.0963, found 290.0949.
[0720] Reacting EX-55D with
2-{5-chloro-6-(3-nitrophenyl)-3-[N-(1-methylet-
hyl)amino]-2-oxohydropyrazinyl}acetic acid in place of
2-{5-chloro-6-(3-nitrophenyl)-3-cyclobutylamino-2-oxohydropyrazinyl}aceti-
c acid and EX-27D and then hydrogenating the resulting intermediate
according to the final two procedures described in Example 27 cave
the product with an m/z+1 of 474.
Example 56
[0721] 85
[0722] To a stirring solution of 3-cyano-6-methylpyridine (20 g,
0.169 moles) in carbon tetrachloride (850 ml) was added
N-bromosuccinimde (30 g, 0.169 moles) and benzoyl peroxide (4.1 g,
0.0169 moles), and the solution was heated to reflux. After 18 h,
the heat was discontinued, diluted with carbon tetrachloride (1 L)
and washed twice with water (1 L). The solvent was removed in vacou
and the crude material chromatographed to yield 12.05 g (36%) of
dark brown solid EX-56A:
[0723] .sup.1H NMR (300 MHz, CDCl.sub.3) d 8.86 (d, 1H), 7.00 (m,
1H), 7.62 (m, 1H), 4.60 (s, 2H); .sup.13C NMR (300 MHz, CDCl.sub.3)
d 156.38, 147.70, 135.82, 118.98, 111.75, 104.66, 27.82; HRMS (EI)
calcd for C.sub.7H.sub.6BrN.sub.2 196.9714, found 196.9661.
[0724] 2-Aminomethyl-5-carbobenzyloxyamidinopyridine dihydrogen
chloride salt (EX-56B) was prepared by the method outlined in
Synthetic Communications. 28(23), 4419-4429 (1998) by substituting
5-bromomethyl-2-cyanopyridine (EX-55A) for 4-cyanobenzyl bromide to
give EX-56B: HPLC/LRMS; 98%, (M+H).sup.+ 285.
[0725] Reacting EX-56B with
2-{5-chloro-6-phenyl-3-[N-(2-phenylethyl)amino-
]-2-oxohydropyrazinyl}acetic acid in place of
2-{(5-chloro-6-(3-nitropheny-
l)-3-cyclobutylamino-2-oxohydropyrazinyl}acetic acid and EX-27D and
then hydrogenating the resulting intermediate according to the
final two procedures described in Example 27 gave the product with
an m/z+1 of 482.
Example 57
[0726] 86
[0727] 2-Cyano-5-methylpyridine (EX-57A) was prepared following the
procedure outlined in Synthetic Communications, 19(13&14),
2371-2374 (1989); HRMS (EI) calcd for C.sub.7H.sub.7N.sub.2
119.0609, found 119.0587.
[0728] By following the procedure of Example 56 and substituting
2-cyano-5-methylpyridine for 3-cyanomethylpyridine, the
intermediate 5-bromomethyl-2cyanopyridine (EX-57B) was
prepared.
[0729] 2-Aminomethyl-5-carbobenzyloxyamidinopyridne dihydrogen
chloride salt (EX-57C) was prepared by the method outlined in
Example 56 substituting 5-bromomethyl-2-cyanopyridine for
6-bromomethyl-3-cyanopyrid- ine: HPLC/LRMS; 95%, (M+H).sup.+
285.
[0730] Reacting 2-Aminomethyl-5-carbobenzyloxyamidinopyridne
dihydrogen chloride salt (EX-57C) with
2-{5-chloro-6-phenyl-3-[N-(2-phenylethyl)amin-
o]-2-oxohydropyraznyl}acetic acid as described in Example 56 gave
the product with an m/z+1 of 482.
Example 58
[0731] 87
[0732] 2-Aminomethyl-5-cyanopyridine hydrochloride (EX-58A) was
prepared by the deprotection with 4N HCl Dioxane of the
intermediate
2-{N,N-bis-(tert-butoxycarbonyl)aminomethyl}-5-cyanopyridine used
to prepare 2-aminomethyl-5-carbobenzyloxyamidinopyridine dihydrogen
chloride salt in Example 56: .sup.1H NMR (400 MHz, DMSO) d 9.04 (s,
1H), 8.64 (br s, 2H), 8.34 (m, 1H), 7.69 (m, 1H), 4.25 (s, 2H);
HRMS (EI) calcd for C.sub.7H.sub.8N.sub.3 134.0718, found
134.0699.
[0733] Using the procedure of Example 44 by substituting
2-[5-chloro-3-(N-{1-methylethyl}amino)-2-oxo-6-phenylhydropyrazinyl]aceti-
c acid (EX-1D) for
2-[3-({2-[(tert-butoxy)carbonylamino]ethyl}amino)-5-chl-
oro-2-oxo-6-phenylhydropyrazinyl]acetic acid, EX-58A was converted
to the product which gave an m/z+1 of 482.
Example 59
[0734] 88
[0735] 4-cyanobenzylamine hydrochloride (EX-59A) was prepared from
10 g (0.030 moles) of
4-{N,N-bis-(tert-butoxycarbonyl)aminomethyl}benzonitrile- ,
prepared following Synthetic Communication, 28(23), 4419-4429
(1998), by stirring it in 4N HCl Dioxane (75 ml). After 3 h, the
solution was concentraed in vacuo and triturated with ether. The
solid was collected by filtration and vacuum dried to yield 5 g
(98%) of EX-59A as a white solid: .sup.1H NMR (DMSO) d 8.68 (br s,
2H), 7.84 (m, 2H), 7.67 (m, 2H), 4.06 (s, 2H); HRMS (EI) calcd for
C.sub.8H.sub.8N.sub.2 133.0766, found 133.0807
[0736] Using the procedure of Example 58, EX-59A was converted to
the product which gave an m/z+1 of 481.
[0737] Using the procedures of Scheme 1, Scheme 2, and the Examples
herein with suitable reagents, starting materials, and
intermediates, additional pyrazinones of the present invention were
prepared and these pryazinones are summarized in Table 3.
3TABLE 3 Additional Substituted Pyrazinones of the Present
Invention Prepared based on the Procedures of Scheme 1, Scheme 2,
and Examples herein. 89 Ex. MW No. R.sup.2 B-A- Y.sup.0 (m/z + 1)
60 Phenyl 2-phenyl- 4-amidinobenzyl 487 ethyl 61 3-Nitrophenyl
isopropyl 4-(N-hydroxyamidino) 514 benzyl 62 3-Aminophenyl
isopropyl 2-(4-amidinophenyl) 482 ethyl 63 Phenyl 2-phenyl-
2-(4-amidinophenyl) 495 ethyl ethyl 64 3-Carbomethoxy isopropyl
4-amidinobenzyl 511 phenyl 65 3-Carboxyphenyl isopropyl
4-amidinobenzyl 497 66 2-bydroxyphenyl cyclobutyl 4-amidinobenzyl
481 67 3-hydroxyphenyl cyclobutyl 4-amidinobenzyl 481 68
3-acetamido isopropyl 2-(4-amidinophenyl) 524 phenyl ethyl
Example 69
[0738] 90
[0739]
1-Benzyloxycarbonylmethyl-6-(5-bromothiophen-2-yl)-3,5-dichloro
pyrazinone (EX-69A) was synthesized as described in the general
schemes of the patent and as described, for example, specifically
for EX-1B substituting 5-bromothiophenecarbaldehyde for
benzaldehyde. EX-69A is a yellow crystalline solid: HPLC-MS (5 to
95% AcCN/6 min @ 1.0 mL/Min @ 254 nm @ 50.degree. C.): retention
time 4.38 min, M+Na.sup.+=494.9 for formula
C.sub.17H.sub.11BrCl.sub.2N.sub.2O.sub.3SNa; .sup.1H NMR (400 MHz,
CDCl.sub.3): d 4.62 (s, 2H), 5.19 (s, 2H), 6.79 (d, J=4.0 Hz, 1H),
7.00 (d, J=4.0 Hz, 1H) 7.32 (m, 2H), 7.37 (m, 3H); .sup.13C NMR
(101 MHz, CDCl.sub.3): d 49.0, 68.1, 117.8, 126.5, 128.6, 128.7,
128.8, 130.1, 130.7, 132.0, 134.5, 147.8, 151.9, 166.2.
[0740] EX-69A (12.15 g, 25.75 mmol) was treated with
cyclobutylamine (3.80 g, 53.52 mmol) in 250 ml toluene at room
temperature for 4 hours. The toluene solution was washed with
saturated ammonium chloride solution and dried over anhydrous
MgSO.sub.4. After removing the toluene, the pure product EX-69B was
obtained as a yellow solid (13.05 g, 99%): HPLC-MS (5 to 95% AcCN/6
min @ 1.0 mL/Min @ 254 nm @ 50.degree. C.): retention time 4.90
min, M+H.sup.30 =508.0 for formula
C.sub.21H.sub.20BrClN.sub.3O.sub.- 3S.
[0741] Potassium phthalimide (4.56 g, 24.6 mmol) and CuI (18.0 g.
94.7 mmol) were mixed in 200 ml dimethylacetamide. The mixture was
stirred at room temperature for 10 minutes. To this mixture was
added compound EX-69B (12.0 g, 23.7 mmol). The resulting mixture
was heated to 160.degree. C. and stirred for 5 hours at an open air
atmosphere. The reaction solution was filtered to remove all the
insoluble solid and was concentrated via high vacuum distillation
at a rotavapor. Aqueous work-up and silica gel flush chromatography
yielded the pure product EX-69C as light yellow solid (6.8 g, 50%)
with the des-bromo side product formation the reason for the low
yield: HPLC-MS (5 to 95% AcCN/6 min @ 1.0 mL/Min @ 254 nm @
50.degree. C.): retention time 3.82 min, M+H.sup.+=575.5 for
formula C.sub.29H.sub.24ClN.sub.4O.sub.5S; .sup.1H NMR (400 MHz,
CDCl.sub.3): d 1.69 (m, 2H), 1.92 (m, 2H), 2.36 (m, 2H), 4.45 (m,
1H), 4.49 (s, 2H), 5.07 (s, 2H), 6.54 (d, J=8.0 Hz, 1H), 6.75 (d,
J=3.6 Hz, 1H), 7.17-7.25 (m, 7H), 7.50 (d, J=4.0 Hz, 1H), 7.71 (dd,
J=2.8, 5.2 Hz, 2H), 7.85 (dd, J=2.8, 5.2 Hz, 2H); .sup.13C NMR (101
MHz, CDCl.sub.3): d 15.2, 30.9, 45.8, 47.4, 67.4, 114.7, 118.2.
123.9, 126.5, 128.28, 128.33, 128.36, 128.39, 128.42, 128.45,
129.5, 129.9, 131.1, 134.8, 134.9, 135.7, 148.5, 150.8, 165.2.
166.9.
[0742] EX-69C (0.55 g, 0.96 mmol) was treated with 1 ml hydrazine
in 10 ml methanol and 5 ml dichloromethane for 4 hours. The
reaction solution was acidified with 1N HCl and filtered to remove
the solid by-product. Aqueous work-up yield the crude (9% pure)
product EX-69D (0.49 g): HPLC-MS (5 to 95% AcCN/6 min @ 1.0 mL/Min
@ 254 nm @ 50.degree. C.): retention time 3.29 min, M+H.sup.+=445.3
for formula C.sub.21H.sub.22ClN.sub.4O.sub.3S.
[0743] EX-69D (0.48 g, 1.08 mmol) was mixed with Boc anhydride
(0.28 g, 1.30 mmol), triethylamine (0.22 g, 2.16 mmol) and DMAP (12
mg, 0.1 mmol). The reaction mixture was stirred for 4 hours at room
temperature. After an aqueous work-up, the crude product in 2 ml
CH.sub.3CN and 2 ml THF was treated with 2 ml 1M LiOH for 3 hours.
Aqueous work-up yield the crude carboxylic acid EX-69E: HPLC-MS (5
to 95% AcCN/6 min @ 1.0 mL/Min @ 2.54 nm @ 50.degree. C.):
retention time 3.18 min, M+H.sup.+=455.4 for formula
C.sub.19H.sub.24ClN.sub.4O.sub.5S.
[0744] EX-69E was coupled with the protected amidine,
4-(N-benzyloxycarbonylamidino)benzylamine hydrogen chloride salt,
prepared using the procedure outlined Synthetic Communications,
28(23), 4419-4429 (1998) in the same way as described before using
EDC, HOBt and DIEA in DMF to give the protected product EX-69F.
EX-69F was purified by reverse phase HPLC using C18 column to give
an off-white amorphous solid: HPLC-MS (5 to 95% AcCN/6 min @ 1.0
mL/Min @ 254 nm (50.degree. C.): retention time 3.28 min,
M+H.sup.+=720.9 for formula C.sub.35H.sub.38ClN.sub.7O.sub.6S;
.sup.1H NMR (400 MHz, CDCl.sub.3): d 1.49 (s, 9H), 1.80 (m, 2H),
2.03 (m, 2H), 2.45 (m, 2H), 4.3 (b, 2H), 4.49 (b, 3H), 5.07 (s,
2H), 6.66-6.78 (m, 2H), 7.0-7.18 (m, 2H), 7.33-7.47 (m, 5H).
[0745] EX-69F was converted to the product by hydrogenation as
described before. After the hydrogenation, it was treated with HCl
saturated methanol solution to remove the Boc group. The product
was purified by reverse phase HPLC with a C18 column with amobile
phase was 0.1% TFA in water and acetonitrile to give the product as
a TFA salt and an off-white amorphous solid: HPLC-MS (5 to 95%
AcCN/6 min @ 1.0 mL/Min @ 254 nm @ 50.degree. C.): retention time
1.94 min, M+H.sup.+=486.4 for formula
C.sub.22H.sub.25ClN.sub.7O.sub.2S: .sup.1H NMR (400 MHz,
methanol-d.sub.4): d 1.79 (m, 2H), 2.06 (m, 2H), 2.39 (m, 2H), 4.45
(s, 2H), 4.46 (m, 1H), 4.57 (s, 1H), 4.58 (s, 1H), 6.01 (d, J=4 Hz,
1H), 6.52 (m, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.75 (m, 2H).
[0746] Sulfonyl analogs of pyrazinones wherein a sulfonyl is
present as a replacement for the carbonyl of the acetamide at the
N-1 position of the pyrazinone can be prepared using Scheme 3:
Sulfonyl Pyrazinone detailed below along with the specific Example
70.
Example 70
[0747] 91 92
[0748] Benzaldehyde (1 eq.) is added slowly by syringe to a
solution of aminomethanesulfonic acid (1 eq.) in dichloromethane at
room temperature. Trimethylsilyl cyanide (1 eq.) is added dropwise
via syringe over a 10 minute period. The reaction is stirred for 4
hours at room temperature and then concentrated under reduced
pressure. The residue is diluted with ethyl acetate, washed with
brine, dried (MgSO.sub.4), and concentrated. The residue is diluted
with ethyl acetate (80 mL) and 9.9 M HCl (1.05 eq.) in ethanol is
added (prepared by addition of 28.90 mL acetyl chloride to 41.0 mL
cold ethanol), resulting in precipitation of the intermediate
product EX-70A. The precipitate is collected by filtration, washed
with ethyl ether, and dried to give pure product EX-70A.
[0749] To a suspension of 1 eq. of EX-70A in dry
1,2-dichlorobenzene (1.0 M) is added oxalyl chloride (4 eq.) with
stirring at room temperature. The resulting suspension is heated at
100.degree. C. for approximately 18 hours. The reaction is allowed
to cool to room temperature and the volatiles are removed under
reduced pressure. The remaining solution is passed through a silica
gel column (hexane flush, followed by 50% ethyl acetate/hexanes).
Concentration of the solution gives crude product EX-70B, which is
purified by column chromatography.
[0750] Phenethylamine (3 eq.) is added to a solution of EX-70B (1
eq.) in ethyl acetate at room temperature. The resulting solution
is heated at reflux for 18 hours. The solution is allowed to cool
to room temperature, resulting in formation of a thick precipitate.
The reaction mixture is diluted with ethyl acetate, washed with 0.5
N HCl, saturated NaHCO.sub.3 and brine. The organic solution is
dried (MgSO.sub.4), filtered and concentrated to give the crude
product. Recrystallization from ethyl acetate and hexanes affords
pure product EX-70C.
[0751] A solution of 1 eq. of EX-70C in dichloromethane with
several drops of dimethylformamide added is cooled to 0.degree. C.
Thionyl chloride (1.1 eq.) is added dropwise and the solution is
slowly warmed to room temperature. After completion of the
reaction, the volatile components are removed under reduced
pressure and the product EX-70D is immediately used in the next
step.
[0752] To the sulfonyl chloride EX-70D (1 eq.) in dichloromethane
is added the amine, 4-(N-tert-butoxycarbonylamidino)benzylamine
hydrochloride, in DMF with 5 eq. of N-methylmorpholine. After
completion of the reaciton, polyaldehyde and/or polyamine resin (10
eq.) are added to remove any unreacted starting materials. The
resins are filtered, rinsed with DMF/DCM (1:1) and the solvents are
removed under reduced pressure to give pure product EX-70E.
[0753] To 1 eq. of EX-70E is added 40 eq. of 4 M HCl/dioxane. The
resulting solution is stirred at room temperature overnight. The
solution is concentrated and the crude product is triturated from
solvent to afford pure product.
[0754] Methylene analogs of pyrazinones wherein a methylene is
present as a replacement for the carbonyl of the acetamide at the
N-1 position of the pyrazinone can be prepared using Scheme 4:
Methylene Pyrazinone detailed below along with the specific Example
71. 93 94
[0755] Diisobutylaluminum hydride (1.05 equiv.) is added over a
period of 15 min to a cooled solution (-78.degree. C.) of 1 eq. of
1-benzyloxycarbonylmethyl-5-chloro-6-phenyl-3-(2-phenylethylamino)pyrazin-
one in tetrahydrofuran . After stirring for 1 h at -78.degree. C.
the reaction is slowly quenched at -78.degree. C. with cold
methanol. The mixture is slowly poured into ice-cold 1N HCl and the
aqueous mixture is extracted with ethyl acetate. The combined
organic layers are washed with brine, dried with MgSO.sub.4,
filtered, and the solvents are removed under reduced pressure. The
crude product is purified by column chromatography to afford
purified product EX-71A.
[0756] Sodium triacetoxyborohydride (1.2 eq.) and a catalytic
amount of acetic acid are added to a suspension of 1.0 eq. of
EX-71A and 1.0 eq. of the amine,
4-(N-tert-butoxycarbonylamidino)benzylamine hydrochloride, in
dichloromethane. The suspension quickly clears and becomes
homogeneous. The reaction is stirred for several hours. The
solution is cooled in an ice bath and basified with 1.0 N NaOH. The
reaction mixture is diluted with dichloromethane and washed with
brine. The organic solution is dried (MgSO.sub.4), filtered and
concentrated to give the crude product. The crude product is
purified by silica gel chromatagraphy to afford purified product
EX-71B.
[0757] To 1 eq. of EX-71 B is added 40 eq. of 4 M HCl/dioxane. The
resulting solution is stirred at room temperature overnight. The
solution is concentrated and the crude product is triturated from
ethyl ether to afford pure product.
General Robotics and Experimental Procedure for the Robotic
Parallel Synthesis of a Series of Amides E-i and Z-i from A-i
[0758] Scheme 5 specifically illustrates the derivatization of the
scaffold A-i to afford the desired product D-i in a parallel array
synthesis format. In a parallel array synthesis reaction block,
individual reaction products were prepared in each of multiple
reaction block vessels in a spatially addressed format. A solution
of the desired scaffold A-i (limiting amount) in acetonitrile (ACN)
was added to the reaction vessels followed by a three-fold
stoichiometric excess solution of the primary amine B-i in
acetonitrile. Excess primary amine was used as a base and to effect
complete conversion of scaffold A-i to product C-i. The reaction
mixtures were incubated at 70.degree. C. for 16-20 h. After cooling
to ambient temperature, each reaction vessel was charged with one
mL of methanol and an excess (3-4 fold stoichiometric excess) of
aqueous potassium hydroxide. The reaction block was shaken
vertically for 14-20 h on an orbital shaker at ambient temperature.
The contents of each reaction vessel were then acidified with
aqueous HCl. Each reaction vessel was then opened, and the
solutions were evaporated to dryness under N.sub.2 and/or a Savant
apparatus. Polyamine resin R-1 (10-15 fold stoichiometric excess)
was added to the solid carboxylic acid followed by dichloromethane
and water (10:1). The mixture was shaken laterally for 14-20 h on
an orbital shaker at ambient temperature (rotating the vials at
least once so each side of the vial was agitated for a minimum of 2
h). The desired product D-i was sequestered away from the reaction
by-products and excess reactants as the insoluble adduct D-x.
Simple filtration of the insoluble resin-adduct D-x and rinsing of
the resin cake with DMF, DCM, MeOH, and DCM afforded the desired
resin-bound product. After drying the resin under vacuum for 2 h,
an excess of HCl/dioxane (7-8 fold stoichiometric excess based on
the loading of amine functionality) along with dichloromethane was
added to each reaction vessel to cleave the desired product D-i
from the resin. The reaction block was shaken laterally for 2-20 h
on an orbital shaker at ambient temperature. Simple filtration of
the solution, rinsing of the resin cake with
dimethylformamide/dichloromethane, and evaporation of the solvents
afforded the desired product D-i in purified form.
[0759] Scheme 6 and Scheme 7 illustrate the conversion of the
carboxylic acid-containing scaffold D-i to the desired amide
product E-i in a parallel synthesis format. A unique scaffold D-i
was added as a solution in dichloromethane/dimethylformamide to
each reaction vessel. A solution of hydroxybenzotriazole B-2 in
dichloromethane/dimethylformamide was added to each reaction
vessel, followed by the polymer-bound carbodiimide reagent R-2 (1.5
fold stoichiometric excess). The parallel reaction block was
agitated vertically on an orbital shaker for 30 min to 1 h. A
limiting amount of the same amine B-3 (0.8 equivalents) in DMF,
along with a 3 fold stoichiometric excess of NMM if the amine B-3
was a salt, was added to the unique contents of each vessel. The
parallel reaction block was then agitated vertically on an orbital
shaker for 2-3 h at ambient temperature. An excess of the
amine-functionalized resin R-1 and aldehyde resin R-3, alone with
dichloromethane solvent were added to each reaction vessel. The
resin-charged reaction block was shaken vertically for 2 h on an
orbital shaker at ambient temperature. The amine-containing resin
R-1 sequestered B-2 and any remaining D-i as their resin-bound
adducts. B-4 and D2, respectively. The aldehyde-containing resin
R-3 sequestered any unreacted B-3 as its resin-bound adduct R-5.
Filtration of the insoluble resins and resin adducts R-1, R-2, R-3,
R-4, R-5, B-4, and D-2 and subsequent rinsing of the vessel
resin-bed with dichloromethane/dimethylformamide afforded filtrates
containing the purified products E-i. Concentration of the
filtrates afforded the purified products E-i, which were weighed
and analyzed by LC/MS.
[0760] For those amines B-3 which contain a protecting group, a
final deprotection step was required after the coupling reaction
(Scheme 8). The residues E-i were dissolved in methanol, Pd/C was
added, and the reaction mixtures were stirred under 10 psi of
H.sub.2 for 1-20 h. The mixtures were filtered through Celite,
rinsed with methanol and concentrated to afford pure products Z-i,
which were weighed and analyzed by LC/MS. If necessary, the
products were purified by reverse-phase HPLC. Conversely, the
deprotection step was done, as needed, in the presence of ammonium
formate (5 fold stoichiometric excess) in place of the 10 psi of
H.sub.2.
[0761] A third method of deprotection uses TMSI generated in situ.
The residues E-i were dissolved in acetonitrile. Sodium iodide and
TMSCl (5 fold stoichiometric excess of each) were added, and the
reaction mixtures were agitated vertically at 55.degree. C. for
14-20 h. Methanol and (N,N-dimethyl)aminomethylpolystyrene resin
were added to each vessel, and the mixtures were agitated for
another 3 h. The mixtures were filtered through Celite, rinsed with
acetonitrile and concentrated to afford products Z-i, which were
weighed and analyzed by LC/MS. If necessary, the products were
purified by reverse-phase HPLC. 95 96 97 98
[0762] Although Schemes 5, 6, 7, and 8 describe the use of parallel
array chemical library technology to prepare compounds of general
formulae D-i, E-i and Z-i, it is noted that one with ordinary skill
in the art of classical synthetic organic chemistry would be able
to prepare D-i, E-i, and Z-i by conventional means (one compound
prepared at a time in conventional glassware and purified by
conventional means such as chromatography and/or
crystallization).
[0763] The various functionalized resins utilized to prepare and
purify parallel reaction mixtures, their source commercially or in
the scientific literature, and the three representations (ie, the R
number, an abbreviated functional structure, and the actual
structural unit bound to the resin for each) are summarized below
as follows: 99
[0764] R-1 Reference: Prepared as reported in J. J. Parlow, D. A
Mischke, and S. S. Woodard, J. Organic Chemistry, 62 5908-5919
(1997) 100
[0765] R-2 Reference: Polystyrene bound N-cyclohexylcarbodiimide
(Argonaut Catalog Number 800371 101
[0766] R-3 Reference: Polystyrene bound benzaldehyde Novabiochem
Catalog Number 01-640182
[0767] The specific compounds prepared, by using the General
Robotics and Experimental Procedure, Schemes 5 through 8, and
general synthetic methods and processes disclosed herein, are
listed below in Tables 4 through Table 7. Tables 4 through Table 7
further summarize the mass spectral characterization data that
confirmed the indicated structure for each compound of the present
invention disclosed in these tables.
4TABLE 4 Structures of Pyrazinones Prepared by General Robotic and
Experimental Procedures General Structure 102 Ex. MW No. R.sup.2
B-A- Y.sup.O R.sup.1 (m/z + 1) 73 5-amino-2- isopropyl 4-amidino-2-
Cl 504 fluorophenyl fluorobenzyl 74 2-chloro-5-prindyl isopropyl
4-amidino-2-Cl 506 fluorobenzyl 75 3-pyridyl isopropyl
4-amidinobenzyl Cl 454 76 5-amino-2- isopropyl 4-amidinobenzyl Cl
515 methylthiophenyl 77 3-nitrophenyl 2-phenylethyl 4-amidinobenzyl
Cl 560.2 78 2-methylphenyl 2-phenylethyl 4-amidinobenzyl Cl 529.4
79 4-methylphenyl 2-phenylethyl 4-amidinobenzyl Cl 529.3 80
1-naphthyl 2-phenylethyl 4-amidinobenzyl Cl 565.3 81 3-methylphenyl
2-phenylethyl 4-amidinobenzyl Cl 529.5 82 2-naphthyl 2-phenylethyl
4-amidinobenzyl Cl 564.9 83 3-methylphenyl 2-phenylethvl
4-amidinobenzyl H 495.8 84 3-methylphenyl 2-phenylethyl
4-amidinobenzyl H 495.5 85 3-methylphenyl 2-phenylethyl
4-amidinobenzyl H 495.4 86 3-aminophenyl 2-phenylethyl
4-amidinobenzyl Cl 530.3 87 3-aminophenyl 2-(3-chloro
4-amidinobenzyl Cl 563.9 phenyl)ethyl 88 3-aminophenyl benzyl
4-amidinobenzyl Cl 516.2 89 3-aminopbenyl cyclobutyl 2-phenylethyl
Cl 452.3 90 3-aminophenyl cyclobuzyl 4-amidinobenzyl Cl 480.5 91
3-aminophenyl benzyl 5-guanidino- Cl 608.4 1-oxo-1- (2-thiazolyl)-
2-pentyl 92 3-aminophenyl cyclobutyl 4-amidinobenzyl H 446.2 93
3-aminophenyl t-butyl 4-amidinobenzyl Cl 482 94 3-aminophenyl N,N-
4-amidinobenzyl Cl 469.2 dimethyl amino 95 3-(N- 2-phenylethyl
4-amidinobenzyl Cl 543.9 methylamino)phenyl 96 3-(N- isopropyl
4-amidinobenzyl Cl 481.6 methylamino)phenyl 97 2-methyl-3-
isopropyl 4-amidinobenzyl Cl 482.2 aminophenyl 98 2-methyl-3-
isopropyl 4-amidinobenzyl H 448.8 aminophenyl 99 3-aminophenyl
cyclobutyl benzyl Cl 438.4
[0768]
5TABLE 5 Structures of Pyrazinones Prepared by General Robotic and
Experimental Procedures 103 Ex. MW No. R.sup.2 B-A- Y.sup.0 (m/z +
1) E-0001 methyl benzyl 2-(4-pyridyl)ethyl 412 E-0002 methyl
2-phenylethyl 2-(4-pyridyl)ethyl 426 E-0003 methyl
2-(3-chlorophenyl)ethyl 2-(4-pyridyl)ethyl 460 E-0004 methyl
2-(4-chlorophenyl)ethyl 2-(4-pyridyl)ethyl 460 E-0005 methyl
2-(3-pyridyl)ethyl 2-(4-pyridyl)ethyl 427 E-0006 methyl
2-(4-pyridyl)ethyl 2-(4-pyridyl)ethyl 427 E-0007 methyl
2-(4-morpholinyl)ethyl 2-(4-pyridyl)ethyl 435 E-0008 methyl
4-pyridylmethyl 2-(4-pyridyl)ethyl 413 E-0009 phenyl benzyl
2-(4-pyridyl)ethvl 474 E-0010 phenyl 2-phenylethyl
2-(4-pyridyl)ethyl 488 E-0011 phenyl 2-(3-chlorophenyl)ethyl
2-(4-pyridyl)ethyl 522 E-0012 phenyl 2-(4-chlorophenyl)ethyl
2-(4-pyridyl)ethyl 522 E-0013 phenyl 2-(3-pyridyl)ethyl
2-(4-pyridyl)ethyl 489 E-0014 phenyl 2-(4-pyridyl)ethyl
2-(4-pyridyl)ethyl 489 E-0015 phenyl 2-(4-morpholinyl)ethyl
2-(4-pyridyl)ethyl 497 E-0016 phenyl 4-pyridylmethyl
2-(4-pyridyl)ethyl 475 E-0017 4-chlorophenyl benzyl
2-(4-pyridyl)ethyl 508 E-0018 4-chlorophenyl 2-phenylethyl
2-(4-pyridyl)ethyl 522 E-0019 4-chlorophenyl
2-(3-chlorophenyl)ethyl 2-(4-pyridyl)ethyl 557 E-0020
4-chlorophenyl 2-(4-chlorophenyl)ethyl 2-(4-pyridyl)ethyl 557
E-0021 4-chlorophenyl 2-(3-pyridyl)ethyl 2-(4-pyridyl)ethyl 523
E-0022 4-chlorophenyl 2-(4-pyridyl)ethyl 2-(4-pyridyl)ethyl 523
E-0023 4-chlorophenyl 2-(4-morpholinyl)ethyl 2-(4-pyridyl)ethyl 531
E-0024 4-chlorophenyl 4-pyridylmethyl 2-(4-pyridyl)ethyl 509 E-0025
4-chlorophenyl benzyl 2-(4-pyridyl)ethyl 508 E-0026 4-chlorophenyl
2-phenylethyl 2-(4-pyridyl)ethyl 522 E-0027 4-chlorophenyl
2-(3-chlorophenyl)ethyl 2-(4-pyridyl)ethyl 557 E-0028
4-chlorophenyl 2-(4-chlorophenyl)ethyl 2-(4-pyridyl)ethyl 557
E-0029 4-chlorophenyl 2-(3-pyridyl)ethyl 2-(4-pyridyl)ethyl 523
E-0030 4-chlorophenyl 2-(4-pyridyl)ethyl 2-(4-pyridyl)ethyl 523
E-0031 4-chlorophenyl 2-(4-morpholinyl)ethyl 2-(4-pyridyl)ethyl 531
E-0032 4-chlorophenyl 4-pyridylmethyl 2-(4-pyridyl)ethyl 509 E-0033
4-methoxyphenyl benzyl 2-(4-pyridyl)ethyl 504 E-0034
4-methoxyphenyl 2-phenylethyl 2-(4-pyridyl)ethyl 518 E-0035
4-methoxyphenyl 2-(3-chlorophenyl)ethyl 2-(4-pyridyl)ethyl 552
E-0036 4-methoxyphenyl 2-(4-chlorophenyl)ethyl 2-(4-pyridyl)ethyl
552 E-0037 4-methoxyphenyl 2-(3-pyridyl)ethyl 2-(4-pyridyl)ethyl
519 E-0038 4-methoxyphenyl 2-(4-pyridyl)ethyl 2-(4-pyridyl)ethyl
519 E-0039 4-methoxyphenyl 2-(4-morpholinyl)ethyl
2-(4-pyridyl)ethyl 527 E-0040 4-methoxyphenyl 4-pyridylmethyl
2-(4-pyridyl)ethyl 505 E-0041 3,4-methylenedioxyphenyl benzyl
2-(4-pyridyl)ethyl 518 E-0042 3,4-methylenedioxyphenyl
2-phenylethyl 2-(4-pyridyl)ethyl 532 E-0043
3,4-methylenedioxyphenyl 2-(3-chlorophenyl)ethyl 2-(4-pyridyl)ethyl
566 E-0044 3,4-methylenedioxyphenyl 2-(4-chlorophenyl)ethyl
2-(4-pyridyl)ethyl 566 E-0045 3,4-methylenedioxyphenyl
2-(3-pyridyl)ethyl 2-(4-pyridyl)ethyl 533 E-0046
3,4-methylenedioxyphenyl 2-(4-pyridyl)ethyl 2-(4-pyridyl)ethyl 533
E-0047 3,4-methylenedioxyphenyl 2-(4-morpholinyl)ethyl
2-(4-pyridyl)ethyl 541 E-0048 3,4-methylenedioxyphenyl
4-pyridylmethyl 2-(4-pyridyl)ethyl 519 E-0049 4-biphenyl benzyl
2-(4-pyridyl)ethyl 550 E-0050 4-biphenyl 2-phenylethyl
2-(4-pyridyl)ethyl 564 E-0051 4-biphenyl 2-(3-chlorophenyl)ethyl
2-(4-pyridyl)ethyl 599 E-0052 4-biphenyl 2-(4-chlorophenyl)ethyl
2-(4-pyridyl)ethyl 599 E-0053 4-biphenyl 2-(3-pyridyl)ethyl
2-(4-pyridyl)ethyl 565 E-0054 4-biphenyl 2-(4-pyridyl)ethyl
2-(4-pyridyl)ethyl 565 E-0055 4-biphenyl 2-(4-morpbolinyl)ethyl
2-(4-pyridyl)ethyl 573 E-0056 4-biphenyl 4-pyridylmethyl
2-(4-pyridyl)ethyl 551 E-0057 benzyl benzyl 2-(4-pyridyl)ethyl 488
E-0058 benzyl 2-phenylethyl 2-(4-pyridyl)ethyl 502 E-0059 benzyl
2-(3-chlorophenyl)ethyl 2-(4-pyridyl)ethyl 536 E-0060 benzyl
2-(4-chlorophenyl)ethyl 2-(4-pyridyl)ethyl 536 E-0061 benzyl
2-(3-pyridyl)ethyl 2-(4-pyridyl)ethyl 503 E-0062 benzyl
2-(4-pyridyl)ethyl 2-(4-pyridyl)ethyl 503 E-0063 benzyl
2-(4-morpholinyl)ethyl 2-(4-pyridyl)ethyl 511 E-0064 benzyl
4-pyridylmethyl 2-(4-pyridyl)ethyl 489 E-0065 2-phenylethyl benzyl
2-(4-pyridyl)ethyl 502 E-0066 2-phenylethyl 2-phenylethyl
2-(4-pyridyl)ethyl 516 E-0067 2-phenylethyl 2-(3-chlorophenyl)ethyl
2-(4-pyridyl)ethyl 550 E-0068 2-phenylethyl 2-(4-chlorophenyl)ethyl
2-(4-pyridyl)ethyl 550 E-0069 2-phenylethyl 2-(3-pyridyl)ethyl
2-(4-pyridyl)ethyl 517 E-0070 2-phenylethyl 2-(4-pyridyl)ethyl
2-(4-pyridyl)ethyl 517 E-0071 2-phenylethyl 2-4-morpholinyl)ethyl
2-(4-pyridyl)ethyl 525 E-0072 2-phenylethyl 4-pyridylmethyl
2-(4-pyridyl)ethyl 503 E-0073 3-chlorophenyl benzyl
2-(4-pyridyl)ethyl 508 E-0074 3-chlorophenyl benzyl
2-(3-pyridyl)ethyl 508 E-0075 3-chlorophenyl benzyl
4-piperidinylmethyl 573 E-0076 3-chlorophenyl 2-phenylethyl
2-(4-pyridyl)ethyl 522 E-0077 3-chlorophenyl 2-phenylethyl
2-(3-pyridyl)ethyl 522 E-0078 3-chlorophenyl 2-phenylethyl
4-piperidinylmethyl 587 E-0079 3-chlorophenyl
2-(3-chlorophenyl)ethyl 2-(4-pyridyl)ethyl 557 E-0080
3-chlorophenyl 2-(3-chlorophenyl)ethyl 2-(3-pyridyl)ethyl 557
E-0081 3-chlorophenyl 2-(3-chlorophenyl)ethyl 4-piperidinylmethyl
622 E-0082 3-chlorophenyl 2-(4-chlorophenyl)ethyl
2-(4-pyridyl)ethyl 557 E-0083 3-chlorophenyl
2-(4-chlorophenyl)ethyl 2-(3-pyridyl)ethyl 557 E-0084
3-chlorophenyl 2-(4-chlorophenyl)ethyl 4-piperidinylmethyl 622
E-0085 3-chlorophenyl benzyl 2-(4-pyridyl)ethyl 508 E-0086
3-chlorophenyl benzyl 2-(3-pyridyl)ethyl 508 E-0087 3-chlorophenyl
benzyl 4-piperidinylmethyl 573 E-0088 3-chlorophenyl 2-phenylethyl
2-(4-pyridyl)ethyl 522 E-0089 3-chlorophenyl 2-phenylethyl
2-(3-pyridyl)ethyl 522 E-0090 3-chlorophenyl 2-phenylethyl
4-piperidinylmethyl 587 E-0091 3-chlorophenyl
2-(3-chlorophenyl)ethyl 2-(4-pyridyl)ethyl 557 E-0092
3-chlorophenyl 2-(3-chlorophenyl)ethyl 2-(3-pyridyl)ethyl 557
E-0093 3-chlorophenyl 2-(3-chlorophenyl)ethyl 4-piperidinylmethyl
622 E-0094 3-chlorophenyl 2-(4-chlorophenyl)ethyl
2-(4-pyridyl)ethyl 557 E-0095 3-chlorophenyl
2-(4-chlorophenyl)ethyl 2-(3-pyridyl)ethyl 557 E-0096
3-chlorophenyl 2-(4-chlorophenyl)ethyl 4-piperidinylmethyl 622
E-0097 4-methoxyphenyl benzyl 2-(4-pyridyl)ethyl 504 E-0098
4-methoxyphenyl benzyl 2-(3-pyridyl)ethyl 504 E-0099
4-methoxyphenyl benzyl 4-piperidinylmethyl 569 E-0100
4-methoxypbenyl 2-phenylethyl 2-(4-pyridyl)ethyl 518 E-0101
4-methoxyphenyl 2-phenylethyl 2-(3-pyridyl)ethyl 518 E-0102
4-methoxyphenyl 2-phenylethyl 4-piperidinylmethyl 583 E-0103
4-methoxyphenyl 2-(3-chlorophenyl)ethyl 2-(4-pyridyl)ethyl 552
E-0104 4-methoxyphenyl 2-(3-chlorophenyl)ethyl 2-(3-pyridyl)ethyl
552 E-0105 4-methoxyphenyl 2-(3-chlorophenyl)ethyl
4-piperidinylmethyl 617 E-0106 4-methoxyphenyl
2-(4-chlorophenyl)ethyl 2-(4-pyridyl)ethyl 552 E-0107
4-methoxyphenyl 2-(4-chlorophenyl)ethyl 2-(3-pyridyl)ethyl 552
E-0108 4-methoxyphenyl 2-(4-chlorophenyl)ethyl 4-piperidinylmethyl
617 E-0109 4-biphenyl benzyl 2-(4-pyridyl)ethyl 550 E-0110
4-biphenyl benzyl 2-(3-pyridyl)ethyl 550 E-0111 4-biphenyl benzyl
4-piperidinylmethyl 615 E-0112 4-biphenyl 2-phenylethyl
2-(4-pyridyl)ethyl 564 E-0113 4-biphenyl 2-phenylethyl
2-(3-pyridyl)ethyl 564 E-0114 4-biphenyl 2-phenylethyl
4-piperidinylmethyl 629 E-0115 4-biphenyl 2-(3-chlorophenyl)ethyl
2-(4-pyridyl)ethyl 599 E-0116 4-biphenyl 2-(3-chlorophenyl)ethyl
2-(3-pyridyl)ethyl 599 E-0117 4-biphenyl 2-(3-chlorophenyl)ethyl
4-piperidinylmethyl 663 E-0118 4-biphenyl 2-(4-chlorophenyl)ethyl
2-(4-pyridyl)ethyl 599 E-0119 4-biphenyl 2-(4-chlorophenyl)ethyl
2-(3-pyridyl)ethyl 599 E-0120 4-biphenyl 2-(4-chlorophenyl)ethyl
4-piperidinylmethyl 663 E-0121 methyl benzyl 4-piperidinylmethyl
477 E-0122 methyl 2-phenylethyl 4-piperidinylmethyl 491 E-0123
methyl 2-(3-chlorophenyl)ethyl 4-piperidinylmethyl 525 E-0124
methyl 2-(4-chlorophenyl)ethyl 4-piperidinylmethyl 525 E-0125
methyl 2-(3-pyridyl)ethyl 4-piperidinylmethyl 528 E-0126 methyl
2-(4-pyridyl)ethyl 4-piperidinylmethyl 528 E-0127 methyl
2-(4-morpholinyl)ethyl 4-piperidinylmethyl 536 E-0128 methyl
2-(1-methylimidazol-4-yl)eth- yl 4-piperidinylmethyl 531 E-0129
methyl 2-(1-methylimidazol-5-yl)e- thyl 4-piperidinylmethyl 531
E-0130 methyl 4-pyridylmethyl 4-piperidinylmethyl 514 E-0131 phenyl
benzyl 4-piperidinylmethyl 539 E-0132 phenyl 2-phenylethyl
4-piperidinylmethyl 553 E-0133 phenyl 2-(3-chlorophenyl)ethyl
4-piperidinylmethyl 587 E-0134 phenyl 2-(4-chlorophenyl)ethyl
4-piperidinylmethyl 587 E-0135 phenyl 2-(3-pyridyl)ethyl
4-piperidinylmethyl 590 E-0136 phenyl 2-(4-pyridyl)ethyl
4-piperidinylmethyl 590 E-0137 phenyl 2-(4-morpholinyl)ethyl
4-piperidinylmethyl 598 E-0138 phenyl
2-(1-methylimidazol-4-yl)ethyl 4-piperidinylmethyl 593 E-0139
phenyl 2-(1-methylimidazol-5-yl)ethyl 4-piperidinylmethyl 593
E-0140 phenyl 4-pyridylmethyl 4-piperidinylmethyl 576 E-0141
4-chlorophenyl benzyl 4-piperidinylmethvl 573 E-0142 4-chlorophenyl
2-phenylethyl 4-piperidinylmethyl 587 E-0143 4-chlorophenyl
2-(3-chlorophenyl)ethyl 4-piperidinylmethyl 622 E-0144
4-chlorophenyl 2-(4-chlorophenyl)ethyl 4-piperidinylmethyl 622
E-0145 4-chlorophenyl 2-(3-pyridyl)ethyl 4-piperidinylmethyl 625
E-0146 4-chlorophenyl 2-(4-pyridyl)ethyl 4-piperidinylmethyl 625
E-0147 4-chlorophenyl 2-(4-morpholinyl)ethyl 4-piperidinylmethyl
633 E-0148 4-chlorophenyl 2-(1-methylimidazol-4-yl)ethyl
4-piperidinylmethyl 628 E-0149 4-chlorophenyl
2-(1-methylimidazol-5-yl)ethyl 4-piperidinylmethyl 628 E-0150
4-chlorophenyl 4-pyridylmethyl 4-piperidinylmethyl 611 E-0151
4-chlorophenyl benzyl 4-piperidinylmethyl 573 E-0152 4-chlorophenyl
2-phenylethyl 4-piperidinylmethyl 587 E-0153 4-chlorophenyl
2-(3-chlorophenyl)ethyl 4-piperidinylmethyl 622 E-0154
4-chlorophenyl 2-(4-chlorophenyl)ethyl 4-piperidinylmethyl 622
E-0155 4-chlorophenyl 2-(3-pyridyl)ethyl 4-piperidinylmethyl 625
E-0156 4-chlorophenyl 2-(4-pyridyl)ethyl 4-piperidinylmethyl 625
E-0157 4-chlorophenyl 2-(4-morpholinyl)ethyl 4-piperidinylmethyl
633 E-0158 4-chlorophenyl 2-(1-methylimidazol-4-yl)ethyl
4-piperidinylmethyl 628 E-0159 4-chlorophenyl
2-(1-methylimidazol-5-yl)ethyl 4-piperidinylmethyl 628 E-0160
4-chlorophenyl 4-pyridylmethyl 4-piperidinylmethyl 611 E-0161
4-methoxyphenyl benzyl 4-piperidinylmethyl 569 E-0162
4-methoxyphenyl 2-phenylethyl 4-piperidinylmethyl 583 E-0163
4-metboxyphenyl 2-(3-chlorophenyl)ethyl 4-piperidinylmethyl 617
E-0164 4-methoxyphenyl 2-(4-chlorophenyl)ethyl 4-piperidinylmethyl
617 E-0165 4-methoxyphenyl 2-(3-pyridyl)ethyl 4-piperidinylmethyl
620 E-0166 4-methoxyphenyl 2-(4-pyridyl)ethyl 4-piperidinylmethyl
620 E-0167 4-methoxyphenyl 2-(4-morpholinyl)ethyl
4-piperidinylmethyl 628 E-0168 4-methoxyphenyl
2-(1-methylimidazol-4-yl)ethyl 4-piperidinylmethyl 623 E-0169
4-methoxyphenyl 2-(1-methylimidazol-5-yl)ethyl 4-piperidinylmethyl
623 E-0170 4-methoxyphenyl 4-pyridylmethyl 4-piperidinylmethyl 606
E-0171 3,4-methylenedioxyphenyl benzyl 4-piperidinylmethyl 583
E-0172 3,4-methylenedioxyphenyl 2-phenylethyl 4-piperidinylmethyl
597 E-0173 3,4-methylenedioxyphenyl 2-(3-chlorophenyl)ethyl
4-piperidinylmethyl 631 E-0174 3,4-methylenedioxyphenyl
2-(4-chlorophenyl)ethyl 4-piperidinylmethyl 631 E-0175
3,4-methylenedioxyphenyl 2-(3-pyridyl)ethyl 4-piperidinylmethyl 634
E-0176 3,4-methylenedioxyphenyl 2-(4-pyridyl)ethyl
4-piperidinylmethyl 634 E-0177 3,4-methylenedioxyphenyl
2-(4-morpholinyl)ethyl 4-piperidinylmethyl 642 E-0178
3,4-methylenedioxyphenyl 2-(1-methylimidazol-4-yl)ethyl
4-piperidinylmethyl 637 E-0179 3,4-methylenedioxyphenyl
2-(1-methylimidazol-5-yl)ethyl 4-piperidinylmethyl 637 E-0180
3,4-methylenedioxyphenyl 4-pyridylmethyl 4-piperidinylmethyl 620
E-0181 4-biphenyl benzyl 4-piperidinylmethyl 615 E-0182 4-biphenyl
2-phenylethyl 4-piperidinylmethyl 629 E-0183 4-biphenyl
2-(3-chlorophenyl)ethyl 4-piperidinylmethyl 663 E-0184 4-biphenyl
2-(4-chlorophenyl)ethyl 4-piperidinylmethyl 663 E-0185 4-biphenyl
2-(3-pyridyl)ethyl 4-piperidinylmethyl 666 E-0186 4-biphenyl
2-(4-pyridyl)ethyl 4-piperidinylmethyl 666 E-0187 4-biphenyl
2-(4-morpholinyl)ethyl 4-piperidinylmethyl 675 E-0188 4-biphenyl
2-(1-methylimidazol-4-yl- )ethyl 4-piperidinylmethyl 669 E-0189
4-biphenyl 2-(1-methylimidazol-5-yl)ethyl 4-piperidinylmethyl 669
E-0190 4-biphenyl 4-pyridylmethyl 4-piperidinylmethyl 652 E-0191
benzyl benzyl 4-piperidinylmethyl 553 E-0192 benzyl 2-phenylethyl
4-piperidinylmethyl 567 E-0193 benzyl 2-(3-chlorophenyl)ethyl
4-piperidinylmethyl 601 E-0194 benzyl 2-(4-chlorophenyl)ethyl
4-piperidinylmethyl 601 E-0195 benzyl 2-(3-pyridyl)ethyl
4-piperidinylmethyl 604 E-0196 benzyl 2-(4-pyridyl)ethyl
4-piperidinylmethyl 604 E-0197 benzyl 2-(4-morpholinyl)ethyl
4-piperidinylmethyl 612 E-0198 benzyl 2-(1-methylimidazol-4-yl)eth-
yl 4-piperidinylmethyl 607 E-0199 benzyl
2-(1-methylimidazol-5-yl)e- thyl 4-piperidinylmethyl 607 E-0200
benzyl 4-pyridylmethyl 4-piperidinylmethyl 590 E-0201 2-phenylethyl
benzyl 4-piperidinylmethyl 567 E-0202 2-phenylethyl 2-phenylethyl
4-piperidinylmethyl 581 E-0203 2-phenylethyl
2-(3-chlorophenyl)ethyl 4-piperidinylmethyl 615 E-0204
2-phenylethyl 2-(4-chlorophenyl)ethyl 4-piperidinylmethyl 615
E-0205 2-phenylethyl 2-(3-pyridyl)ethyl 4-piperidinylmethyl 618
E-0206 2-phenylethyl 2-(4-pyridyl)ethyl 4-piperidinylmethyl 618
E-0207 2-phenylethyl 2-(4-morpholinyl)ethyl 4-piperidinylmethyl 626
E-0208 2-phenylethyl 2-(1-methylimidazol-4-yl)ethyl
4-piperidinylmethyl 621 E-0209 2-phenylethyl
2-(1-methylimidazol-5-yl)ethyl 4-piperidinylmethyl 621 E-0210
2-phenylethyl 4-pyridylmethyl 4-piperidinylmethyl 604
[0769]
6TABLE 6 Structures of Pyrazinones Prepared by General Robotic and
Experimental Procedures 104 Ex MW No. R.sup.2 B-A- Y.sup.0 (m/z +
1) 1471-1 methyl benzyl 4-amidinobenzyl 439 1471-2 methyl
2-(4-chlorophenyl)ethyl 4-amidinobenzyl 488 1471-3 methyl
4-pyridylmethyl 4-amidinobenzyl 440 1471-4 methyl
2-(4-morpholinyl)ethyl 4-amidinobenzyl 462 1471-5 methyl
2-(4-pyridyl)ethyl 4-amidinobenzyl 454 1471-6 methyl
2-(3-chlorophenyl)ethyl 4-amidinobenzyl 488 1471-7 methyl
2-phenylethyl 4-amidinobenzyl 453 1471-8 methyl 2-(3-pyridyl)ethyl
4-amidinobenzyl 454 1471-9 phenyl benzyl 4-amidinobenzyl 501
1471-10 phenyl 2-(4-chlorophenyl)ethyl 4-amidinobenzyl 550 1471-11
phenyl 4-pyridylmethyl 4-amidinobenzyl 502 1471-12 phenyl
2-(4-morpholinyl)ethyl 4-amidinobenzyl 525 1471-13 phenyl
2-(4-pyridyl)ethyl 4-amidinobenzyl 517 1471-14 phenyl
2-(3-chlorophenyl)ethyl 4-amidinobenzyl 550 1471-15 phenyl
2-phenylethyl 4-amidinobenzyl 516 1471-16 phenyl 2-(3-pyridyl)ethyl
4-amidinobenzyl 517 1471-17 4-Cl-phenyl benzyl 4-amidinobenzyl 536
1471-18 4-Cl-phenyl 2-(4-chlorophenyl)ethyl 4-amidinobenzyl 584
1471-19 4-Cl-phenyl 4-pyridylmethyl 4-amidinobenzyl 537 1471-20
4-Cl-phenyl 2-(4-morpholinyl)ethyl 4-amidinobenzyl 559 1471-21
4-Cl-phenyl 2-(4-pyridyl)ethyl 4-amidinobenzyl 551 1471-22
4-Cl-phenyl 2-(3-chlorophenyl)ethyl 4-amidinobenzyl 584 1471-23
4-Cl-phenvl 2-phenylethyl 4-amidinobenzyl 550 1471-24 4-Cl-phenyl
2-(3-pyridyl)ethyl 4-amidinobenzyl 551 1471-25 3-Cl-phenyl benzyl
4-amidinobenzyl 536 1471-26 3-Cl-phenyl 2-(4-chlorophenyl)ethyl
4-amidinobenzyl 584 1471-27 3-Cl-phenyl 4-pyridylmethyl
4-amidinobenzyl 537 1471-28 3-Cl-phenyl 2-(4-morpholinyl)ethyl
4-amidinobenzyl 559 1471-29 3-Cl-phenyl 2-(4-pyridyl)ethyl
4-amidinobenzyl 551 1471-30 3-Cl-phenyl 2-(3-chlorophenyl)ethyl
4-amidinobenzyl 584 1471-31 3-Cl-phenyl 2-phenylethyl
4-amidinobenzyl 550 1471-32 3-Cl-phenyl 2-(3-pyridyl)ethyl
4-amidinobenzyl 551 1471-33 4-methoxyphenyl benzyl 4-amidinobenzyl
532 1471-34 4-methoxyphenyl 2-(4-chlorophenyl)ethyl 4-amidinobenzyl
580 1471-35 4-methoxyphenyl 4-pyridylmethyl 4-amidinobenzyl 533
1471-36 4-methoxyphenyl 2-(4-morpholinyl)ethyl 4-amidinobenzyl 555
1471-37 4-methoxyphenyl 2-(4-pyridyl)ethyl 4-amidinobenzyl 547
1471-38 4-methoxyphenyl 2-(3-chlorophenyl)ethyl 4-amidinobenzyl 580
1471-39 4-methoxyphenyl 2-phenylethyl 4-amidinobenzvl 546 1471-40
4-methoxyphenyl 2-(3-pyridyl)ethyl 4-amidinobenzyl 547 1471-41
3,4-methylenedioxyphenyl benzyl 4-amidinobenzyl 545 1471-42
3,4-methylenedioxyphenyl 2-(4-chlorophenyl)ethyl 4-amidinobenzyl
594 1471-43 3,4-methylenedioxyphenyl 4-pyridylmethyl
4-amidinobenzyl 516 1471-44 3,4-methylenedioxyphenyl
2-(4-morpholinyl)ethyl 4-amidinobenzyl 569 1471-45
3,4-methylenedioxyphenyl 2-(4-pyridyl)ethyl 4-amidinobenzyl 561
1471-46 3,4-methylenedioxyphenyl 2-(3-chlorophenyl)ethyl
4-amidinobenzyl 594 1471-47 3,4-methylenedioxyphenyl 2-phenylethyl
4-amidinobenzyl 560 1471-48 3,4-methylenedioxyphenyl
2-(3-pyridyl)ethyl 4-amidinobenzyl 561 1471-57 ethyl benzyl
4-amidinobenzyl 553 1471-58 ethyl 2-(4-chlorophenyl)ethyl
4-amidinobenzyl 502 1471-59 ethyl 4-pyridylmethyl 4-amidinobenzyl
454 1471-60 ethyl 2-(4-morpholinyl)ethyl 4-amidinobenzyl 476
1471-61 ethyl 2-(4-pyridyl)ethyl 4-amidinobenzyl 468 1471-62 ethyl
2-(3-chlorophenyl)ethyl 4-amidinobenzyl 502 1471-63 ethyl
2-phenylethyl 4-amidinobenzyl 467 1471-64 ethyl 2-(3-pyridyl)ethyl
4-amidinobenzyl 468 1471-67 4-biphenyl 4-pyridylmethyl
4-amidinobenzyl 579 1471-70 4-biphenyl 2-(3-chlorophenyl)ethyl
4-amidinobenzyl 626 1471-71 4-biphenyl 2-phenylethyl
4-amidinobenzyl 592 1471-72 4-biphenyl 2-(3-pyridyl)ethyl
4-amidinobenzyl 593 1507-01 phenyl 3-trifluoromethylbenzyl
4-amidinobenzyl 569 1507-02 phenyl 1-indanyl 4-amidinobenzyl 528
1507-03 phenyl 2-Cl-benzyl 4-amidinobenzyl 536 1507-04 phenyl
4-trifluoromethoxybenzyl 4-amidinobenzyl 585 1507-05 phenyl
3-(1-imidazolyl)propyl 4-amidinobenzyl 520 1507-06 phenyl
2-(4-bromophenyl)ethyl 4-amidinobenzyl 594 1507-07 phenyl
1,2-(diphenyl)ethyl 4-amidinobenzyl 592 1507-08 phenyl 2-indanyl
4-amidinobenzyl 528 1507-09 phenyl 2,2-(diphenyl)ethyl
4-amidinobenzyl 592 1507-10 phenyl 3,3-(diphenyl)propyl
4-amidinobenzyl 606 1507-11 phenyl 2-(4-methoxyphenyl)ethyl
4-amidinobenzyl 546 1507-12 phenyl 2-(3-methoxyphenyl)ethyl
4-amidinobenzyl 546 1507-13 phenyl 4-methoxybenzyl 4-amidinobenzyl
532 1507-15 phenyl 2-trifluoromethylbenzyl 4-amidinobenzyl 569
1507-16 phenyl 1,2,3,4-tetrahydro-1-naphthyl 4-amidinobenzyl 542
1507-17 phenyl 2-(cyclohex-1-enyl)ethyl 4-amidinobenzyl 520 1507-18
phenyl 2-(2-thienyl)ethyl 4-amidinobenzyl 522 1507-19 phenyl
3-[1-(pyrrolidinyl-2-one)]propyl 4-amidinobenzyl 537 1507-20 phenyl
1-carboethoxy-piperidin-4-yl 4-amidinobenzyl 567 1507-21 phenyl
cyclobutvl 4-amidinobenzyl 465 1507-22 phenyl 2,4-dichlorobenzyl
4-amidinobenzyl 570 1507-23 phenyl 2-(3-chlorophenyl)ethyl
4-amidinobenzyl 516 1507-24 phenyl 2-pyridylmethyl 4-amidinobenzyl
502 1507-25 phenyl cyclopentyl 4-amidinobenzyl 479 1507-26 phenyl
2,4-difluorobenzyl 4-amidinobenzyl 537 1507-28 phenyl
1-naphthylmethyl 4-amidinobenzyl 552 1507-29 phenyl cycloheptyl
4-amidinobenzyl 508 1507-30 phenyl 4-bromobenzyl 4-amidinobenzyl
580 1507-31 phenyl cyclopropyl 4-amidinobenzyl 451 1507-32 phenyl
2-methylpropyl 4-amidinobenzyl 467 1507-33 phenyl 2-methoxyethyl
4-amidinobenzyl 469 1507-34 phenyl (S)-.alpha.-methylbenzyl
4-amidinobenzyl 516 1507-35 phenyl 1,1-diphenylmethyl
4-amidinobenzyl 578 1507-36 phenyl 3-(2,3,4,5-tetrahydro-1,1-dioxo-
thiophenyl) 4-amidinobenzyl 530 1507-38 phenyl 3-chlorobenzyl
4-amidinobenzyl 536 1507-40 phenyl 3,5-bis-trifluoromethylbenzyl
4-amidinobenzyl 637 1507-41 phenyl 2,2,2-trifluoroethyl
4-amidinobenzyl 493 1507-42 phenyl 3-fluorobenzyl 4-amidinobenzyl
519 1507-43 phenyl 4-phenylbutyl 4-amidinobenzyl 544 1507-44 phenyl
2-(3,4-dichlorophenyl)ethyl 4-amidinobenzyl 584 1507-45 phenyl
2-(4-methylphenyl)ethyl 4-amidinobenzyl 530 1507-46 phenyl
4-chlorobenzyl 4-amidinobenzyl 536 1507-47 phenyl
3-(dimethylamino)propyl 4-amidinobenzyl 497 1507-48 phenyl
3,4-difluorobenzyl 4-amidinobenzyl 537 1512-01 phenyl
2H,3H-benzo[e]1,4-dioxan-2-ylmethyl 4-amidinobenzyl 560 1512-02
phenyl 2,3-dimethoxybenzyl 4-amidinobenzyl 562 1512-04 phenyl
3,4-methylenedioxy-phenyl 4-amidinobenzyl 545 1512-05 phenyl
2-(3,4-dimethoxyphenyl)ethyl 4-amidinobenzyl 576 1512-06 phenyl
3-(phenyl)propyl 4-amidinobenzyl 530 1512-07 phenyl
2-(3-methoxy)propyl 4-amidinobenzyl 483 1512-11 phenyl
2-ethoxybenzyl 4-amidinobenzyl 546 1512-12 phenyl 3-heptyl
4-amidinobenzyl 510 1512-14 phenyl butyl 4-amidinobenzyl 467
1512-15 phenyl 2-(dimethylamino)ethyl 4-amidinobenzyl 482 1512-16
phenyl cycloheptyl 4-amidinobenzyl 508 1512-17 phenyl
4-t-butylcyclohexyl 4-amidinobenzyl 550 1512-19 phenyl
3-(2,3,4,5-tetrahydro-1,1-dioxothiophenyl) 4-amidinobenzyl 530
1512-20 phenyl phenylamino 4-amidinobenzyl 487 1512-23 phenyl
2,3-dimethylcyclohexyl 4-amidinobenzyl 522 1512-26 phenyl
2-fluoro-4-trifluoromethylbenzyl 4-amidinobenzyl 587 1512-27 phenyl
2-fluoro-5-trifluoromethylbenzyl 4-amidinobenzyl 587 1512-29 phenyl
3-fluoro-5-trifluoromethylbenzyl 4-amidinobenzyl 587 1512-31 phenyl
2-chloro-6-methylbenzyl 4-amidinobenzyl 550 1512-32 phenyl
3,4,5-trifluorobenzyl 4-amidinobenzyl 555 1512-35 phenyl
2,5-dichlorobenzyl 4-amidinobenzyl 570 1512-36 phenyl
2,5-difluorobenzyl 4-amidinobenzyl 537 1512-39 phenyl
3,5-difluorobenzyl 4-amidinobenzyl 537 1512-40 phenyl
3-trifluoromethoxybenzyl 4-amidinobenzyl 585 1512-41 phenyl
2-(3-trifluoromethylphenyl)ethyl 4-amidinobenzyl 584 1512-42 phenyl
2-trifluoromethoxybenzyl 4-amidinobenzyl 585 1512-43 phenyl
2,6-difluorobenzyl 4-amidinobenzyl 537 1512-44 phenyl
2-fluoro-6-trifluoromethylbenzyl 4-amidinobenzyl 587 1512-45 phenyl
2,4-dichloro-6-methylbenzyl 4-amidinobenzyl 584 1512-46 phenyl
2-(1-methylpyrrolidin-2-yl)-ethyl 4-amidinobenzyl 523 1512-47
phenyl 2-(pyrid-2-yl)ethyl 4-amidinobenzyl 517 1515-01
3-trifluoromethylphenyl benzyl 4-amidinobenzyl 569 1515-02
2-methoxyphenyl benzyl 4-amidinobenzyl 532 1515-03
1-(2-bromo-thienyl) benzyl 4-amidinobenzyl 586 1515-04
2-chlorophenyl benzyl 4-amidinobenzyl 536 1515-05 3-methoxyphenyl
benzyl 4-amidinobenzyl 532 1515-06 2-thienyl benzyl 4-amidinobenzyl
508 1515-07 4-fluorophenyl benzyl 4-amidinobenzyl 519 1515-08
4-trifluoromethylphenyl benzyl 4-amidinobenzyl 569 1515-09
3-fluorophenyl benzyl 4-amidinobenzyl 519 1515-10 3-bromophenyl
benzyl 4-amidinobenzyl 580 1515-11 2-fluorophenyl benzyl
4-amidinobenzyl 519 1515-12 2-trifluoromethylphenyl benzyl
4-amidinobenzyl 569 1515-13 3-trifluoromethylphenyl cyclobutyl
4-amidinobenzyl 533 1515-14 2-methoxyphenyl cyclobutyl
4-amidinobenzyl 495 1515-15 1-(2-bromothienyl) cyclobutyl
4-amidinobenzyl 550 1515-16 2-chlorophenyl cyclobutyl
4-amidinobenzyl 500 1515-17 3-methoxyphenyl cyclobutyl
4-amidinobenzyl 495 1515-18 2-thienyl cyclobutyl 4-amidinobenzyl
471 1515-19 4-fluorophenyl cvclobutvl 4-amidinobenzyl 483 1515-20
4-trifluoromethylphenyl cyclobutyl 4-amidinobenzyl 533 1515-22
3-bromophenyl cycloburyl 4-amidinobenzyl 544 1515-23 2-fluorophenyl
cyclobutyl 4-amidinobenzyl 483 1515-24 2-trifluoromethylphenyl
cyclobutyl 4-amidinobenzyl 533 1515-25 3-trifluoromethylphenyl
2-phenylethyl 4-amidinobenzyl 584 1515-26 2-methoxyphenyl
2-phenylethyl 4-amidinobenzyl 546 1515-27 3-bromo-2-thienyl)
2-phenylethyl 4-amidinobenzyl 600 1515-28 2-chlorophenyl
2-phenylethyl 4-axmdinobenzyl 550 1515-29 3-methoxyphenyl
2-phenylethyl 4-amidinobenzyl 546 1515-30 2-thienyl 2-phenylethyl
4-amidinobenzyl 522 1515-31 4-fluorophenyl 2-phenylethyl
4-aimdinobenzyl 534 1515-32 4-trifluoromethylphenyl 2-phenylethyl
4-amidinobenzyl 584 1515-33 3-fluorophenyl 2-phenylethyl
4-amidinobenzyl 534 1515-34 3-bromophenyl 2-phenylethyl
4-amidinobenzyl 594 1515-35 2-fluorophenyl 2-phenylethyl
4-amidinobenzyl 534 1515-36 2-trifluoromethylphenyl 2-phenylethyl
4-amidinobenzyl 584 1515-37 3-trifluoromethylphenyl
2-(3,4-dichlorophenyl)ethyl 4-amidinobenzyl 618 1515-38
2-methoxyphenyl 2-(3,4-dichlorophenyl)ethyl 4-amidinobenzyl 580
1515-39 1-(2-bromo-thienyl) 2-(3,4-dichlorophenyl)ethyl
4-amidinobenzyl 635 1515-40 2-chlorophenyl
2-(3,4-dichlorophenyl)ethyl 4-amidinobenzyl 584 1515-41
3-methoxyphenyl 2-(3,4-dichlorophenyl)ethyl 4-amidinobenzyl 580
1515-42 2-thienyl 2-(3,4-dichlorophenyl)ethyl 4-amidinobenzyl 556
1515-43 4-fluorophenyl 2-(3,4-dichlorophenyl)ethyl 4-amidinobenzyl
568 1515-44 4-trifluoromethylphenyl 2-(3,4-dichlorophenyl)ethyl
4-amidinobenzyl 618 1515-45 3-fluorophenyl 2-(3,4-dichlorophenyl)e-
thyl 4-amidinobenzyl 568 1515-46 3-bromophenyl
2-(3,4-dichlorophenyl)ethyl 4-amidinobenzyl 629 1515-47
2-fluorophenyl 2-(3,4-dichlorophenyl)ethyl 4-amidinobenzyl 568
1515-48 2-trifluoromethylphenyl 2-(3,4-dichlorophenyl)ethyl
4-amidinobenzyl 618 1522-02 phenyl 2-hydroxyethyl 4-amidinobenzyl
455 1522-05 phenyl 4-hydroxybutyl 4-amidinobenzyl 484 1522-06
phenyl (R)-2-butyl 4-amidinobenzyl 468 1522-07 phenyl
6-hydroxyhexyl 4-amidinobenzyl 512 1522-08 phenyl 2-(pyrrolidin-
1-yl)-ethyl 4-amidinobenzyl 509 1522-09 phenyl (S)-2-butyl
4-amidinobenzyl 468 1522-11 phenyl 3-pentyl 4-amidinobenzyl 482
1522-12 phenyl (S)-2-methylbutyl 4-amidinobenzyl 482 1522-13 phenyl
2-methylbutyl 4-amidinobenzyl 482 1522-14 phenyl 3-methylbutyl
4-amidinobenzyl 482 1522-15 phenyl 2-(3-methyl)butyl
4-amidinobenzyl 482 1522-17 phenyl 2-(4-methyl)pentyl
4-amidinobenzyl 496 1522-18 phenyl 3,3-dimethylbutyl
4-amidinobenzyl 496 1522-19 phenyl tricyclo[5.3.1.1<3,9>]dod-
ec-3-yl 4-amidinobenzyl 546 1522-20 phenyl
tricyclo[5.3.1.1<3,9&- gt;]dodec-3-ylmethyl 4-amidinobenzyl
560 1522-21 phenyl 2-propynyl 4-amidinobenzyl 449 1522-23 phenyl
2-(dimethylamino)propyl 4-amidinobenzyl 497 1522-27 phenyl
N,N-butano 4-amidinobenzyl 465 1522-28 phenyl N,N-propano
4-amidinobenzyl 451 1522-31 phenyl benzylthio 4-amidinobenzyl 519
1522-33 phenyl 2-methoxyethyl 4-amidinobenzyl 469 1522-34 phenyl
2-methylpropyl 4-amidinobenzyl 468 1522-35 phenyl
1,2-diethylpyrazolidin4-yl 4-amidinobenzyl 538 1522-36 phenyl
cycloheptyl 4-amidinobenzyl 508 1522-37 phenyl
N-(3-chloro-5-trifluoromethyl- 4-amidinobenzyl 634
pyrid-2-yl)-2-aminoethyl 1522-38 phenyl
N-(3-trifluoromethyl-pyrid-2-yl)- 4-amidinobenzyl 600 2-aminoethyl
1522-40 phenyl 6-cyanohexyl 4-amidinobenzyl 507 1522-41 phenyl
3-hydroxypropyl 4-amidinobenzyl 469 1522-42 phenyl
4-(pyrrolidin-1-yl)butyl 4-amidinobenzyl 537 1522-43 phenyl
(S)-1-cyclohexylethyl 4-amidinobenzyl 522 1522-44 phenyl
2-(2R)-bicyclo-[2.2.1]heptyl 4-amidinobenzyl 506 1522-46 phenyl
3-(2,3,4,5-tetrahydro-1,1-dioxothiophenyl) 4-amidinobenzyl 530
1522-47 phenyl 4-t-butylcyclohexyl 4-amidinobenzyl 550 1526-01
3-aminophenyl cyclopropyl 4-amidinobenzyl 466 1526-03 3-aminophenyl
cyclopentyl 4-amidinobenzyl 495 1526-04 3-aminophenyl
2,2,2-trifluoroethyl 4-amidinobenzyl 508 1526-05 3-aminophenyl
2-(3-methoxypropyl) 4-amidinobenzyl 499 1526-06 3-aminophenyl
2-(2-methylbutyl) 4-amidinobenzyl 497 1526-07 3-aminophenyl t-butyl
4-amidinobenzyl 483 1526-09 3-aminophenyl (S)-2-butyl
4-amidinobenzyl 483 1526-11 3-aminophenyl 3-pentyl 4-amidinobenzyl
497 1526-12 3-aminophenyl ethyl 4-amidinobenzyl 454 1526-13
3-aminophenyl propyl 4-amidinobenzyl 469 1526-14 3-aminophenyl
2-buryl 4-amidinobenzyl 483 1526-15 3-aminophenyl 2-(3-methylbutyl)
4-amidinobenzyl 497 1526-16 3-aminophenyl (R)-2-butyl
4-amidinobenzyl 483 1526-17 3-aminophenyl 2-(4-methylpentyl)
4-amidinobenzyl 511 1526-19 3-aminophenyl 2-propenyl
4-amidinobenzyl 466 1526-21 3-aminophenyl 2-propynyl
4-amidinobenzyl 464 1526-23 3-aminophenyl cyclobutyl
4-amidinobenzyl 481 1526-24 3-aminophenyl isopropyl 4-amidinobenzyl
469 1526-25 3-aminophenyl 2-methoxyethyl 4-amidinobenzyl 485
1526-26 3-aminophenyl 2-methylpropyl 4-amidinobenzyl 483 1526-29
3-aminophenyl (1S)-1-cyclohexylethyl 4-amidinobenzyl 537 1526-30
3-aminophenyl 2-(2R)bicyclo[2.2.1]hept- yl 4-amidinobenzyl 521
1526-33 3-aminophenyl (2S)-oxalan-2-ylmethyl 4-amidinobenzyl 511
1526-40 3-aminophenyl butyl 4-amidinobenzyl 483 1526-41
3-aminophenyl cyclopropylmethyl 4-amidinobenzyl 481 1543-03
3-aminophenyl 2-(pyrrolidin-1-yl)ethyl 4-armdinobenzyl 524 1543-05
3-aminophenyl methyl 4-amidinobenzyl 440 1543-07 3-aminophenyl
3-(1-imidazolyl)propyl 4-amidinobenzyl 535 1543-09 3-aminophenyl
2-dimethylaminoethyl 4-amidinobenzyl 498 1543-11 3-aminophenyl
6-amidocarbonylhexyl 4-amidinobenzyl 540 1543-13 3-aminophenyl
3-hydroxypropyl 4-amidinobenzyl 485 1543-15 3-aminophenyl
2-(piperid-1-yl)ethyl 4-amidinobenzyl 538 1543-19 3-aminophenyl
2-dimethylaminopropyl 4-amidinobenzyl 512 1543-21 3-aminophenyl
4-(pyrrolidin-1-yl)butyl 4-amidinobenzyl 552 1543-25 3-aminophenyl
2-(3-diethylamino)propyl 4-amidinobenzyl 540 1543-27 3-aminophenyl
3-(pyrrolidin-1-yl)propyl 4-amidinobenzyl 538 1543-31 3-aminophenyl
ethyl 4-amidino-2-fluorobenzyl 472 1543-33 3-aminophenyl
cyclopropyl 4-amidino-2-fluorobenzyl 484 1543-34 3-aminophenyl
cyclopentyl 4-amidino-2-fluorobenzyl 513 1543-35 3-aminophenyl
propyl 4-amidino-2-fluorobenzyl 486 1543-36 3-aminophenyl butyl
4-amidino-2-fluorobenzyl 501 1543-37 3-aminophenyl
2-(pyrrolidin-1-yl)ethyl 4-amidino-2-fluorobenzyl 542 1543-38
3-aminophenyl 2-methylpropyl 4-amidino-2-fluorobenzyl 501
1543-39 3-aminophenyl cyclobutyl 4-amidino-2-fluorobenzyl 499
1543-40 3-aminophenyl isopropyl 4-amidino-2-fluorobenzyl 486
1543-41 3-aminophenyl cyclobutyl 8-aza-1,4-dioxaspiro[4.5]decyl 474
1543-45 3-aminophenyl cyclobutyl 3,3-diethylpyrrolidin-1-yl 462
1543-46 3-aminophenyl cyclobutyl 4-(4-aminophenyl)pyrazinyl 497
[0770]
7TABLE 7 Structures of Pyrazinones Prepared by General Robotic and
Experimental Procedures 105 MW (m/ Ex. z + No. R.sup.2 B--A--
R.sup.4a 1) 1517-01 3-thienyl benzyl H 508 1517-03 phenyl benzyl
(S)-methyl 516 1517-04 phenyl benzyl methylthiomethyl 562 1517-05
phenyl benzyl (R)-methyl 516 1517-06 2,6- benzyl H 570
dichlorophenyl 1517-07 3-thienyl cyclobutyl H 472 1517-08 phenyl
cyclobutyl benzyl 556 1517-09 phenyl cyclobutyl (S)-methyl 480
1517-10 phenyl cyclobutyl methylthiomethyl 526 1517-11 phenyl
cyciobutvl (R)-methyl 480 1517-12 2,6- cyclobutyl H 534
dichlorophenyl 1517-13 3-thienyl 2-phenylethyl H 522 1517-14 phenyl
2-phenylethvl benzyl 606 1517-15 phenyl 2-phenylethyl (S)-methyl
530 1517-16 phenyl 2-phenylethyl methylthiomethyl 576 1517-17
phenyl 2-phenylethyl (R)-methyl 530 1517-18 2,6- 2-phenylethyl H
584 dichiorophenyl 1517-19 3-thienyl 2-(3-chlorophenyl)- H 556
ethyl 1517-20 phenyl 2-(3-chlorophenyl)- benzyl 640 ethyl 1517-23
phenyl 2-(3-chlorophenyl)- (R)-methyl 564 ethyl 1517-24 2,6-
2-(3-chlorophenyl)- H 619 dichiorophenyl ethyl 1517-25 phenyl
cyclohexyl H 494 1517-26 phenyl 4-heptyl H 510 1517-29 phenyl
2-hexyl H 496 1517-31 phenyl N-methyl N-(1- H 468 methylethyl)
1517-33 phenyl propyl H 453 1517-35 phenyl butyl H 468 1517-36
phenyl trimethylsilylmethyl H 498 1517-37 phenyl 2-butyl H 468
1517-38 phenyl prop-2-enyl H 451 1517-39 phenyl methyl H 425
1517-40 phenyl 3-methylburyl H 482 1517-41 phenyl 3.3-dimethylbutyl
H 496 1517-43 phenyl cyclopropylmethyl H 465 1517-44 phenyl
isopropyl H 453 1517-46 phenyl ethyl H 439 1517-47 phenyl 3-heptyl
H 524 1517-48 phenyl pentyl H 482
[0771] Formula (I) compounds of this invention possessing hydroxyl,
thiol, and amine functional groups can be converted to a wide
variety derivatives. Alternatively, derivatized Formula (I)
compounds can be obtained by first derivatizing one or more
intermediates in the processes of preparation before further
transforming the derivatized intermediate to compounds of Formula
(I). A hydroxyl group in the form of an alcohol or phenol can be
readily converted to esters of carboxylic, sulfonic, carbamic,
phosphonic, and phosphoric acids. Acylation to form a carboxylic
acid ester is readily effected using a suitable acylating reagent
such as an aliphatic acid anhydride or acid chloride. The
corresponding aryl and heteroaryl acid anhydrides and acid
chlorides can also be used. Such reactions are generally carried
out using an amine catalyst such as pyridine in an inert solvent.
Similarly, carbamic acid esters (urethanes) can be obtained by
reacting a hydroxyl group with isocyanates and carbamoyl chlorides.
Sulfonate, phosphonate, and phosphate esters can be prepared using
the corresponding acid chloride and similar reagents. Compounds of
Formula (I) that have at least one thiol group present can be
converted to the corresponding thioesters derivatives analogous to
those of alcohols and phenols using the same reagents and
comparable reaction conditions. Compounds of Formula (I) that have
at least one primary or secondary amine group present can be
converted to the corresponding amide derivatives. Amides of
carboxylic acids can be prepared using the appropriate acid
chloride or anhydrides with reaction conditions analogous to those
used with alcohols and phenols. Ureas of the corresponding primary
or secondary amine can be prepared using isocyanates directly and
carbamoyl chlorides in the presence of an acid scavenger such as
triethylamine or pyridine. Sulfonamides can be prepared from the
corresponding sulfonyl chloride in the presence of aqueous sodium
hydroxide or a tertiary amine. Suitable procedures and methods for
preparing these derivatives can be found in House's Modern
Synthetic Reactions, W. A. Benjamin, Inc., Shriner, Fuson, and
Curtin in The Systematic Identification of Organic Compounds, 5th
Edition, John Wiley & Sons, and Fieser and Fieser in Reagents
for Organic Synthesis, Volume 1, John Wiley & Sons. Reagents of
a wide variety that can be used to derivatize hydroxyl, thiol, and
amines of compounds of Formula (I) are available from commercial
sources or the references cited above, which are incorporated
herein by reference.
[0772] Formula (I) compounds of this invention possessing hydroxyl,
thiol, and amine functional groups can be alkylated to a wide
variety of derivatives. Alternatively, alkylated Formula (I)
compounds can be obtained by first alkylating one or more
intermediates in the processes of preparation before further
transforming the alkylated intermediate to compounds of Formula
(I). A hydroxyl group of compounds of Formula (I) can be readily
converted to ethers. Alkylation to form an ether is readily
effected using a suitable alkylating reagent such as an alkyl
bromide, alkyl iodide or alkyl sulfonate. The corresponding
aralkyl, heteroaralkyl, alkoxyalkyl, aralkyloxyalkyl, and
heteroaralkyloxyalkyl bromides, iodides, and sulfonates can also be
used. Such reactions are generally carried out using an alkoxide
forming reagent such as sodium hydride, potassium t-butoxide,
sodium amide, lithium amide, and n-butyl lithium using an inert
polar solvent such as DMF, DMSO, THF, and similar, comparable
solvents, amine catalyst such as pyridine in an inert solvent.
Compounds of Formula (I) that have at least one thiol group present
can be converted to the corresponding thioether derivatives
analogous to those of alcohols and phenols using the same reagents
and comparable reaction conditions. Compounds of Formula (I) that
have at least one primary, secondary or tertiary amine group
present can be converted to the corresponding secondary, tertiary
or quaternary ammonium derivative. Quaternary ammonium derivatives
can be prepared using the appropriate bromides, iodides, and
sulfonates analogous to those used with alcohols and phenols.
Conditions involve reaction of the amine by warming it with the
alkylating reagent with a stoichiometric amount of the amine (i.e.,
one equivalent with a tertiary amine, two with a secondary, and
three with a primary). With primary and secondary amines, two and
one equivalents, respectively, of an acid scavenger are used
concurrently. Secondary or tertiary amines can be prepared from the
corresponding primary or secondary amine. A primary amine can be
dialkylated by reductive amination using an aldehyde, such as
formaldehyde, and sodium cyanoborohydride in the presence of
glacial acetic acid. A primary amine can be monoalkylated by first
monoprotecting the amine with a ready cleaved protecting group,
such as trifluoroacetyl. An alkylating agent, such as
dimethylsulfate, in the presence of a non-nucleophilic base, such
as Barton's base (2-tert-butyl-1,1,3,3-tetramethylguanidine), gives
the monomethylated protected amine. Removal of the protecting group
using aqueous potassium hydroxide gives the desired monoalkylated
amine. Additional suitable procedures and methods for preparing
these derivatives can be found in House's Modern Synthetic
Reactions, W. A. Benjamin. Inc., Shriner. Fuson, and Curtin in The
Systematic Identification of Organic Compounds. 5th Edition. John
Wiley & Sons, and Fieser and Fieser in Reagents for Organic
Synthesis published by John Wiley & Sons. Perfluoroalkyl
derivatives can be prepared as described by DesMarteau in J. Chem.
Soc. Chem. Commun. 2241 (1998). Reagents of a wide variety that can
be used to derivatize hydroxyl, thiol, and amines of compounds of
Formula (I) are available from commercial sources or the references
cited above, which are incorporated herein by reference.
[0773] The examples of synthetic approaches to the preparation
pyrazinones derivatized in a nucleophilic substituent such as may
be present in B, R.sup.1, R.sup.2 and Y.sup.0 are shown in specific
Examples 100 through 104 below. 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.
Example 100
[0774] 106
[0775] By following the method of Example 1 and substituting
3-nitrobenzaldehyde for benzaldehyde,
1-benzyloxycarbonylmethyl-3,5-dichl-
oro-6-(3-nitrophenyl)pyrazinone (EX-100A) was obtained. The
pyrazinone,
1-benzyloxycarbonylmethyl-3,5-dichloro-6-(3-nitrophenyl)pyrazinone
(EX-100A), (15.01 g, 34.6 mmol) was taken up in 325 mL of 50% EtOH
(w/w) and heated to 75.degree. C. EtOAc was added until the
solution was homogeneous (about 80 mL). Iron powder (9.4 g, 168
mmol) was added, followed by 0.57 mL of 12 M HCl (6.8 mmol) in
about 0.6 mL of 50% EtOH. The reaction was monitored by TLC (80%
EtOAc/hexanes) and was complete within 40 minutes. The reaction
mixture was cooled to room temperature, and the iron was removed by
filtration through Celite. The yellow solution was diluted with 600
mL of EtOAc and 300 mL of water. Saturated NaCl was added to help
separate the layers. The organic phase was washed with saturated
NaHCO.sub.3 (2.times.250 mL), saturated NaCl (1.times.250 mL),
dried over MgSO.sub.4, filtered, and the solvents were removed
under reduced pressure. The residue was taken up in 20-25 mL of 3.4
M HCl in EtOAc. Additional EtOAc (about 25 ml) was added, and the
mixture was heated to dissolve all of the compound. The volatile
components were removed under reduced pressure. The residue (crusty
solid) was taken up in EtOAc and slowly dripped into hexanes. The
pale yellow solid that precipitated was filtered and dried under
vacuum at room temperature to yield 12.19 g (80% yield) of
1-benzyloxycarbonylmethyl-3,5-dichloro-6-(3--
aminophenyl)pyrazinone hydrochloride (EX-100B) as a pale yellow
solid: .sup.1H NMR (300 MHz, CD.sub.3OD) d 4.61 (AB q, 2H, J=17
Hz). 5.20 (AB q, 2H, J=12 Hz), 7.31-7.51 (m, 7H), 7.63-7.67 (m,
2H); HPLC purity (retention time): 91% (3.0 min), LRMS m/z 404
(M.sup.++H).
[0776] The pyrazinone,
1-benzyloxycarbonylmethyl-3,5-dichloro-6-(3-aminoph-
enyl)pyrazinone hydrochloride (EX-100B), (78.2 mg, 0.18 mmol) was
taken up in 5 mL of dichloromethane. Pyridine (32 mL, 0.40 mmol)
was added, followed by acetic chloride (26 mL, 036 mmol) in 1 mL of
dichloromethane. The reaction was stirred at ambient temperature
until the reaction was complete by TLC and LC/MS after 24 hours.
The reaction solution was then washed with saturated NaHCO.sub.3
(4.times.5 mL), saturated NaCl (1.times.5 mL), dried over
MgSO.sub.4 and concentrated to give 68.9 mg (86% yield) of the
product 1-benzyloxycarbonylmethyl-3-dichloro-6-(3-acet-
amidophenyl)pyrazinone (EX-100C): .sup.1H NMR (300 MHz, CDCl.sub.3)
d 2.21 (s, 3H), 4.55 (AB q, 2H, J=16.6 Hz), 5.17 (s, 2H), 6.96 (d,
1H, J=7.7 Hz), 7.26-7.40 (m, 5H), 7.57 (s, 1H), 7.74-7.79 (m, 1H),
8.19-8.24 (br m, 1H), 8.65 (br s, 1H).
[0777] Following the necessary final steps of the procedure of
Example 1, EX-100C was converted to the product: HPLC purity
(retention time): 100% (2.9 min); LRMS m/z 572.5 (M.sup.++H).
Example 101
[0778] 107
[0779] By following the method of Example 100 and substituting
methanesulfonyl chloride for acetyl chloride the product was
prepared: HPLC purity (retention time): 100% (2.9 min); LRMS m/z
608.2 (M.sup.++H).
Example 102
[0780] 108
[0781] By following the method of Example 100 and substituting
trifluoroacetic anhydride for acetyl chloride, the product was
prepared: HPLC purity (retention time): 100% (3.3 min); LRMS m/z
626.3 (M.sup.++H).
Example 103
[0782] 109
[0783] By following the method of Example 1 and substituting
3-nitrobenzaldehyde for benzaldehyde
1-benzyloxycarbonylmethyl-3,5-dichlo-
ro-6-(3-aminophenyl)pyrazinone was obtained.
[0784] The
1-benzyloxycarbonylmethyl-3,5-dichloro-6-(3-aminophenyl)pyrazin-
one (210.6 mg, 0.48 mmol) was taken up in 9 mL of acetonitrile.
Polyamine resin (1.05 g, 4.9 mmol) was added, along with about 10
mL of dichloromethane. After agitating about 10 mins the resin was
filtered, rinsed with acetonitrile, and the solvents concentrated
to about 10 mL. Formaldehyde (37%) (0.4 mL, 4.9 mmol) was added,
followed by NaCNBH.sub.3 (1.0 M in THF, 1.5 mL, 1.5 mmol) and the
dropwise addition of two 50 mL portions of glacial acetic acid
(17.4 M, 1.74 mmol). The reaction was monitored by LC/MS. A third
50 mL portion of glacial acetic acid was added after 3.5 h to force
the reaction to completion. The solution was diluted with about 40
mL of diethyl ether and washed with 1.2 M NaOH (3.times.5 mL),
saturated NaCl (1.times.5 mL), dried over MgSO.sub.4, and the
solvents were removed under reduced pressure to give 0.17 g (82%
yield) of
1-benzyloxycarbonylmethyl-3,5-dichloro-6-(3-[N,N-dimethylamino]-
phenyl)pyrazinone (EX-103A): .sup.1H NMR (300 MHz, CDCl.sub.3): d
2.96 (s, 6H), 4.59 (s, 2H), 5.19 (s, 2H), 6.55 (m, 2H), 6.82 (d,
1H). 7.25-7.40 (m, 6H).
[0785] Following the necessary final steps of the procedure of
Example 1, EX-103A was converted to the product: HPLC purity
(retention time): 94% (2.6 min): LRMS m/z558.4 (M.sup.-+H).
Example 104
[0786] 110
[0787] By following the method of Example 100 and replacing
phenethylamine with isopropylamine,
1-benzyloxycarbonylmethyl-3-isopropylamino-5-chloro--
6-(3-aminophenyl)pyrazinone was obtained.
[0788] The
1-benzyloxycarbonylmethyl-3-isopropylamino-5-chloro-6-(3-aminop-
henyl)pyrazinone (1.01 g, 2.4 mmol) was dissolved in 25 mL of THF.
Pyridine (0.37 mL, 4.6 mmol) was added, followed by
pentafluoropyridine trifluoroacetate (0.79 mL, 4.6 mmol). After 2
h, polyamine resin (3.1 g, 8.7 mmol) and 25 mL of dichloromethane
was added, and the mixture was vigorously stirred for 1-2 h. The
resin was filtered, rinsed with dichloromethane (3.times.5 mL), and
the volatiles were removed under reduced pressure to give the
desired product EX-104A in quantitative yield: .sup.1H NMR (300
MHz, CDCl.sub.3) d 1.30 (d, 3H, J=1.4 Hz), 1.32 (d, 3H, J=1.4 Hz),
4.24 (m, 1H), 4.47 (AB q, 2H, J=16.9 Hz), 5.15 (s, 2H), 6.22 (d,
1H, J=8.2 Hz), 7.12 (d, 1H, J=7.7 Hz), 7.25-7.42 (m, 5H), 7.54 (s,
1H), 7.73-7.81 (m, 1H), 8.62 (d, 1H, J=4.2 Hz), 9.10 (br s,
1H).
[0789] The
1-benzyloxycarbonylmethyl-3-isopropylamino-5-chloro-6-(3-[N-tri-
fluoroacetamido]phenyl)pyrazinone (EX-104A) (0.63 g, 1.2 mmol) was
dissolved in 20 mL of dichloromethane. Barton's base
(2-tert-butyl-1,1,3,3-tetramethylguanidine) (0.5 mL, 2.5 mmol) and
dimethylsulfate (0.66 mL, 7 mmol) wee added, and the reaction was
stirred at ambient temperature overnight. The reaction was
monitored by LC/MS, and after completion the solution was washed
with aqueous NH.sub.4OH (2.times.10 mL) and 5% HCl (1.times.10 mL).
The combined aqueous washes were extracted with dichloromethane
(1.times.10 mL). The combined organic phases were washed with
saturated NaCl (1.times.10 mL), dried over MgSO.sub.4, filtered,
and the volatiles were removed under reduced pressure to give 0.51
g (80% yield) of the desired product (EX-104B): HPLC purity
(retention time): 97% (4.4 min); LRMS m/z 537.5 (M.sup.++H).
[0790] Following the necessary final steps of the procedure of
Example 1, EX104B was converted to the product: .sup.1H NMR (300
MHz, CD.sub.3OD) d 1.31 (s, 3H), 1.33 (s, 3H), 2.94 (s, 3H), 4.22
(m, 1H), 4.40-4.52 (m, 4H), 7.01-7.05 (m, 2H), 7.17-7.19 (m, 1H),
7.42-7.45 (m, 1H), 7.49 (d, 2H, J=8.3 Hz) 7.80 (d, 2H, J=8.3 Hz);
HPLC purity (retention time): 100% (2.1 min); LRMS m/z 481.6
(M.sup.++H).
[0791] Pyrazinones, wherein a B-A substituent is introduced by
reaction of a 3-amino group of an intermediate pyrazinone with an
electrophilic reagent, can be prepared using the general procedures
and processes shown in Scheme 9 and Scheme 10 and as illustrated
below in specific Examples 105-109. 111 112
[0792] The examples of synthetic approaches to the preparation
pyrazinones in which the substituents represented by B-A are
introduced by reaction of a 3-amino group of the pyrazinone with an
electrophilic reagent are shown in specific Examples 105 through
109 below. The specific examples recited below should be considered
a being merely illustrative of the wide variety possible and not
construed as limiting to one of ordinary skill in the art.
[0793] Example 105 113
[0794] 1-Benzyloxycarbonylmethyl-3,5-dichloro-6-phenylpyrazinone
(EX-1B) (0.8 g, 2.06 mmol) was mixed with 20 ml 0.5 M ammonia in
dioxane in a sealed tube. The tube was heated to 100.degree. C. for
12 hours. After removing the dioxane under reduced pressure, the
residue was dissolved in ethyl acetate. The ethyl acetate solution
was washed with water and brine and dried over anhydrous
Na.sub.2SO.sub.4. After removing the solvent, the product was
recrystallized in acetone to yield the pure amino pyrazinone
EX-105A as a white crystal solid (0.76 g, 99%): HPLC-MS (0 to 95%
AcCN/6 min @ 1.0 mL/Min @ 254 nm @ 50.degree. C.): retention time
3.75 min, M+H.sup.+=370.0 for formula
C.sub.19H.sub.17ClN.sub.3O.sub.3. .sup.1H NMR (400 MHz,
CDCl.sub.3): d 4.43 (s, 2H), 5.13 (s, 2H), 5.78 (b, 2H), 7.21-7.27
(m, 5H), 7.35-7.39 (m, 5H).
[0795] EX-105A (4.7 g, 12.73 mmol) was mixed with 1.34 g 10% Pd/C
in 100 ml methanol. The mixture was stirred under hydrogen
atmosphere that was introduced via a balloon for 48 hours. After
filtration and removing the solvent, a white crystal solid was
obtained as the carboxylic acid product EX-105B (3.0 g, 97%):
HPLC-MS (0 to 95% AcCN/6 min @ 1.0 mL/Min @ 254 nm @ 50.degree.
C.): retention time 1.45 min. M+H.sup.-=246.0 for formula
C.sub.12H.sub.12N.sub.3O.sub.3.
[0796] EX-105B (3.0 g, 12.2 mmol) in 100 ml methanol was cooled
down to -50.degree. C. SOCl.sub.2 (1.4 ml, 19.1 mmol) was added to
the solution. After stirring at room temperature for four hours,
the mix was heated to reflux for three hours. After removing the
solvent, the residue was subjected to a silica gel plug using ethyl
acetate to elute. The pure product was obtained by
recrystallization in methanol as a white crystal solid EX-105C
(2.22 g, 68%): HPLC-MS (0 to 95% AcCN/6 min @ 1.0 mL/Min @ 254 nm @
50.degree. C.): retention time 1.94 min, M+H.sup.+=260.0 for
formula C.sub.13H.sub.14N.sub.3O.sub.3.
[0797] EX-105C (0.258 g, 1 mmol) was mixed with benzenesulfonyl
chloride (0.353 g, 2 mmol) in 3 ml pyridine. The reaction mixture
was heated at 90.degree. C. for 2 hours. After removing the
pyridine, the crude product was obtained by an aqueous work-up
procedure. The crude product EX-105D was dissolved in 10 ml
methanol and treated with 10 ml 1M LiOH solution for 15 minutes.
After the solution was acidified with 2 N HCl to a pH of about 2
and the methanol removed under reduced pressure, a yellow
precipitate was obtained via filtration and washing with water. The
pure sulfonamide EX-105E is a yellow crystalline solid (0.267 g,
70%): HPLC-MS (0 to 95% AcCN/6 min @ 1.0 mL/Min @ 254 nm @
50.degree. C.): retention time 2.88 min, M+H.sup.+=386.0 for
formula C.sub.18H.sub.16N.sub.3O.sub.5- S.
[0798] .sup.1H NMR (400 MHz, methanol-d.sub.4): d 4.44 (s, 2H),
6.77 (s, 1H), 7.32 (dd, J=8.0, 1.6 Hz, 2H), 7.42-7.48 (m, 3H), 7.54
(t, J=8.0 Hz, 2H), 7.60-7.64 (m, 1H), 8.09 (d, J=8.0, 2H). .sup.13C
NMR (101 MHz, methanol-d.sub.4): d 48.4, 129.2, 129.9, 130.0,
130.6, 131.0, 132.6, 134.4, 141.4, 146.1, 157.0, 159.0, 160.0,
170.3.
[0799] EX-105E (0.106 g, 0.275 mmol) was mixed with EDC (0.055 g,
0.289 mmol) and HOBt (0.044 g, 0.289 mmol) in 2 ml DMF. The mixture
was stirred for 10 minutes. To this mixture was then added the
protected amidine, 4-(N-benzyloxycarbonylamidino)benzylamine
hydrogen chloride salt (0.289 mmol), and DIEA (0.144 ml, 0.825
mmol) in 1 ml DMF. The reaction solution was stirred for 2 hours at
room temperature. The DMF was removed under reduced pressure. The
remaining residue was triturated in 1 N HCl and washed with water
to yield the product EX-105F as an off-white amorphous solid (0.152
g, 85%): HPLC-MS (0 to 95% AcCN/6 min @ 1.0 mL/Min @ 254 nm @
50.degree. C.): retention time 3.14 min. M+H.sup.+=651.3 for
formula C.sub.34H.sub.30N.sub.5O.sub.7S. .sup.1H NMR (400 MHz,
methanol-d.sub.4): d 4.42 (s, 2H), 4.51 (s, 2H), 5.40 (s, 2H), 6.76
(s, 1H), 7.35-7.62 (m, 15H), 7.75 (d, J=8.0 Hz, 2H), 8.08 (d, J=8.0
Hz, 2H). .sup.13C NMR (101 MHz, methanol-d.sub.4): d 43.6, 49.7,
70.7, 111.6, 118.2, 119.7, 127.3, 128.7, 129.0, 129.1, 129.8,
129.9, 130.0, 130.8, 131.0, 132.6, 134.4, 135.8, 136.2, 141.5,
146.3, 147.6, 153.0, 154.5, 167.9, 169.0.
[0800] EX-105F (0.148 g, 0.228 mmol), p-toluenesulfonic acid mono
hydrate (0.045 g, 0.24 mmol) and 10% Pd on activated carbon (0.012
g, 0.007 mmol) were mixed with 5 ml methanol. The mixture was
stirred for 2 hours under an atmosphere of hydrogen that was
introduced through a rubber balloon. After filtering off the
catalyst and removing the methanol, the remaining residue was
triturated in a solvent of 2:1 ether to methanol to yield a white
amorphous solid as the product (0.105 g, 95%) as the mono-salt of
p-toluenesulfonic acid: HPLC-MS (0 to 95% AcCN/6 min @ 1.0 mL/Min @
254 nm @ 50.degree. C.): retention time 2.64 min, M+H.sup.+=517.5
for formula C.sub.26H.sub.25N.sub.6O.sub.4S. .sup.1H NMR (400 MHz,
methanol-d.sub.4): d 2.35 (s, 3H), 4.40 (s, 2H), 4.52 (s, 2H), 6.77
(s, 1H), 7.21 (d, J=7.6 Hz, 2H), 7.34 (d, J=7.2 Hz, 2H), 7.41-7.51
(m, 3H), 7.55 (t, J=7.6 Hz, 2H), 7.64 (t, J=7.2 Hz, 1H), 7.79 (d,
J=8.0 Hz, 2H), 7.74 (d, J=8.0 Hz, 2H). .sup.13C NMR (101 MHz,
methanol-d.sub.4): d 21.2, 43.5, 70.7, 119.5, 126.8, 128.0, 128.7,
128.9, 129.0, 129.7, 129.8, 129.9, 130.6, 130.9, 132.4, 134.3,
136.0, 141.3, 141.6, 146.2, 146.4, 152.9, 167.9, 168.7.
Example 106
[0801] 114
[0802] Following the method of Example 105, EX-105C (0.0932 g, 0.36
mmol) was treated with phenyl isocyanate (0.128 g, 1.08 mmol) and
0.2 ml pyridine in 2 ml acetonitrile at 80.degree. C. for 3 hours
instead of benzenesulfonyl chloride. After the reaction mixture was
kept in a freezer for two days, a nice crystal solid formed as the
pure pyrazinone urea EX-106A (0.129 g, 95%): HPLC-MS (0 to 95%
AcCN/6 min @ 1.0 mL/Min @ 254 nm @ 50.degree. C.): retention time
3.73 min, M+H.sup.+=379.3 for formula
C.sub.20H.sub.19N.sub.4O.sub.4.
[0803] .sup.1H NMR (400 MHz, CDCl.sub.3): d 3.75 (s, 3H), 4.55 (s,
2H), 6.97 (s, 1H), 7.10 (t, J=7.6 Hz, 1H), 7.32-7.38 (m, 4H),
7.46-7.52 (m, 3H), 7.58 (d, J=8.0 Hz, 2H), 8.28 (s, 1H), 11.1 (s,
1H). .sup.13C NMR (101 MHz, CDCl.sub.3): d 47.4, 52.8, 119.6,
120.2, 123.9, 128.9, 129.1, 129.4, 130.1, 130.9, 133.8, 137.8,
145.7, 150.8, 150.9, 167.3.
[0804] Saponification of compound EX-106A manner similar to the
procedure as described in the synthesis of EX-105D yielded compound
EX-106B. HPLC-MS (0 to 95% AcCN/6 min @ 1.0 mL/Min @ 254 mm @
50.degree. C.): retention time 3.34 min, M+H.sup.+=365.1 for
formula C.sub.19H.sub.16N.sub.4O.sub.4. Compound EX-106B was
coupled with 4-(N-benzyloxycarbonylamidino)benzylamine hydrogen
chloride salt using EDC, HOBt and DIEA as described before to yield
the protected product EX-106C as an off-white solid: HPLC-MS (0 to
95% AcCN/6 min @ 1.0 mL/Min @ 254 nm @ 50.degree. C.): retention
time 3.58 min, M+H.sup.+=630.0 for formula
C.sub.35H.sub.32N.sub.7O.sub.5. .sup.1H NMR (400 MHz,
methanol-d.sub.4): d 4.49 (s, 2H), 4.61 (s, 2H), 5.40 (s, 2H), 7.06
(s, 1H), 7.11 (t, J=7.2 Hz, 1H), 7.32-7.56 (m, 16H), 7.76 (d, J=8
Hz. 2H).
[0805] EX-106C was converted to the HCl salt of the product by
hydrogenation in methanol in the presence of HCl with Pd/C as the
catalyst. The product was an off-white amorphous solid: HPLC-MS (0
to 95% AcCN/6 min @ 1.0 mL/Min @ 254 nm @ 50.degree. C.): retention
time 3.01 min, M+H.sup.+=496.4 for formula
C.sub.27H.sub.26N.sub.7O.sub.3, .sup.1H NMR (400 MHz,
methanol-d.sub.4): d 4.47 (s, 2H), 4.65 (s, 2H), 6.97 (s, 1H), 7.15
(t, J=7.2 Hz, 1H), 7.27-7.54 (m, 9H), 7.57 (d, J=7.2 Hz, 2H) 7.78
(d, J=8.0 Hz, 2H), 8.76 (s, 1H), 9.26 (s, 1H). HRMS m/z MH.sup.+
496.2036, calcd for C.sub.27H.sub.26N.sub.7O.sub.3 496.2097.
Example 107
[0806] 115
[0807] Using the procedure of Example 106 and substituting
3-(benzyloxycarbonylamido)phenyl isocyanate for phenyl isocyanate,
the product was obtained as the HCl salt: HPLC-MS (0 to 95% AcCN/6
min @ 1.0 mL/Min @ 254 nm @ 50.degree. C.): retention time 1.84
min, M+H.sup.+=511.6 for formula C.sub.27H.sub.27N.sub.8O.sub.3.
.sup.1H NMR (400 MHz, methanol-d.sub.4): d 4.46 (s, 2H), 4.65 (s,
2H), 6.97 (s, 1H), 7.17 (d, J=6.8 Hz, 1H), 7.45-7.60 (m, 8H), 7.78
(m, 3H) 7.94 (s, 1H), 8.77 (s, 1H), 9.26 (s, 1H). HRMS m/z MH.sup.+
511.2251, calcd for C.sub.27H.sub.27N.sub.8O.sub.3 511.2206.
Example 108
[0808] 116
[0809] Using the procedure of Example 106 and substituting
3,5-dichlorophenyl isocyanate for phenyl isocyanate, the product
was obtained as the HCl salt: HPLC-MS (0 to 95% AcCN/6 min @ 1.0
mL/Min @ 254 nm @ 50.degree. C.): retention time 3.41 min,
M+H.sup.+=564.4 for formula
C.sub.27H.sub.24Cl.sub.12N.sub.7O.sub.3. .sup.1H NMR (400 MHz,
methanol-d.sub.4): d 4.47 (s, 2H), 4.63 (s, 2H), 7.04 (s, 1H), 7.18
(t, J=1.6 Hz, 1H), 7.45-7.56 (m, 7H), 7.64 (d, J=2 Hz, 2H) 7.78 (d,
J=8.0 Hz, 2H). 8.77 (s, 1H), 9.26 (s, 1H). HRMS m/z MH.sup.+
564.1351, calcd for C.sub.27H.sub.24Cl.sub.2N.sub.7O.sub.3
564.1318.
Example 109
[0810] 117
[0811] Using the procedure of Example 106 and substituting
isopropyl isocyanate for phenyl isocyanate, the product was
obtained as the HCl salt: HPLC-MS (0 to 95% AcCN/6 min @ 1.0 mL/Min
@ 254 nm @ 50.degree. C.): retention time 2.43 min. M+H.sup.+=462.4
for formula C.sub.24H.sub.28N.sub.7O.sub.3. .sup.1H NMR (400 MHz,
methanol-d.sub.4): d 1.25 (d, J=6.4 Hz, 6H), 3.99(m, 1H), 4.45 (s,
2H), 4.64 (s, 2H), 6.82 (s, 1H), 7.43-7.53 (m, 5H), 7.60 (m, 1H)
7.67 (t, J=6.4 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 8.77 (s, 1H), 9.26
(s, 1H). HRMS m/z MH.sup.+ 462.2230, calcd for
C.sub.24H.sub.28N.sub.7O.sub.3 462.2254.
Assays for Biological Activity
TF-VIIa Assay
[0812] 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
[0813] Human factor Xa (0.3 nM) and 0.15 mM
N-.alpha.-Benzyloxycarbonyl-D--
arginyl-L-glycyl-L-arginine-p-nitroaniline-dihydrochloride (S-2765)
are added to a 96-well assay plate containing either inhibitor or
buffer (50 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.1% BSA). The
reaction, in a final volume of 100 ul is measured immediately at
405 nm to determine background absorbance. The plate is incubated
at room temperature for 60 min, at which time the rate of
hydrolysis of the substrate is measured by monitoring the reaction
at 405 nm for the release of p-nitroaniline. Percent inhibition of
Xa activity is calculated from OD.sub.405nm value from the
experimental and control sample.
Thrombin Assay
[0814] Human thrombin (0.28 nM) and 0.06 mM
H-D-Phenylalanyl-L-pipecolyl-L- -arginine-p-nitroaniline
dihydrochloride are added to a swell 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
[0815] Trypsin (5 ug/ml; 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.
[0816] 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.
[0817] Using bioassay procedures described herein, the biological
activity of the compounds of Examples 1 through Example 109 and
Tables 1 through Table 7 are summarized in Table 8 and Table 9.
8TABLE 8 Inhibitory Activity of Pyrazinones toward TF-VIIA,
Thrombin II, Factor Xa, and Trypsin II. 118 IC50 or % IC50 or %
IC50 or % IC50 or % Inhibition Inhibition Inhibition Inhibition Ex.
TF-VIIa Thrombin Factor Xa Trpysin II No. (30 .mu.M) II (30 .mu.M)
(30 .mu.M) (30 .mu.M) 1 1 1 >100 0.2 2 5 0.4 >100 1 3 0.2
<0.04 1 0.4 4 0.3 0.1 3 0.5 5 7 1 4 1 6 0.1 <0.04 1 0.4 7 0.2
0.1 3 0.4 8 3 0.2 1 0.4 9 >30 30 >0 >30 10 >30 >0
>0 >30 11 91 <0.1 >100 1 12 >100 7 >100 1 13
>100 48 >100 14 14 >100 29 >100 0.3 15 >100 >100
>100 1 16 >100 13 >100 1 17 0.71 15.32 41% 0.24 18 47% 20%
0 1.13 19 0.8 0.22 22% @ 30 0.27 20 41% @ 30 4 6% @ 30 7 21 8% @ 30
26.8 21% @ 30 2 22 0% @ 30 47% @ 30 13% @ 30 1.7 23 ta 1.7 17 38% @
30 0.32 24 0% @ 30 46% @ 30 22% @ 30 1.3 25 7% 3% 4% 9% 26 1% 4% 5%
3% 27 12.5 >30 >30 16 28 3 >30 >30 0.23 29 pending
pending pending pending 30 pending pending pending pending 31 22%
4% 4% 20% 32 12 0 0 0 33 4% 30 0 3.6 34 20% 0.59 0 1.3 35 29% 5%
10% 2.88 36 5% 31% 0 30% 37 1.8 1.9 0 0.3 38 0.9 0.58 22% 0.4 39
1.7 0.26 0 0.28 40 0.06 0 0 0.1 41 0.02 8 0 0.1 42 0.5 17% 0 0.53
43 0.25 43% 0 0.15 44 2.1 40% 4% 0.54 45 0.89 13 9% 0.25 46 0.98
18.7 10% 0.23 47 0.66 1.14 10.6 0.20 48 0.57 6.4 20% 0.38 49 0.57
6.4 28.9 0.19 50 0.50 14.2 39% 0.24 51 0.65 2.14 9.68 0.17 52 0.59
7.0 24.0 0.15 53 0.30 11.1 7% 0.15 54 11.3 0% 0% 0% 55 0.15 0.12 0%
0.18 56 16.7 3.13 0% 0.738 57 1.4 0.15 0% 0.22 58 0% 1% 1% 4% 59 0%
0% 2% 7% 60 0.901 <0.04 5.65 0.192 61 1% 0% 0% 10% 62 5.6 4% 10%
2.2 63 28% 6% 0 7 64 0.78 2 19% 0.07 65 0.36 2.8 12% 0.3 66 0.34
40% 0 0.28 67 0.20 4.25 0 0.14 68 32% 0% 6% 4.8 69 0.06 2.6 2.6
0.07 73 0.03 4.4 0 0.1 74 3.25 1.78 13% 0.15 75 0.21 2 9% 0.04 76
0.12 0 0 0.28 77 2.52 0.98 >30 1.13 78 0.43 0.3 16% @ 30 0.23 79
4.14 0.3 30% @ 30 0.15 80 1.29 4.55 29% @ 30 0.16 81 1 0.89 33% @
30 0.22 82 20 4.67 32% @ 30 0.17 83 0.75 0.84 >30 0.36 84 3.03
0.5 >30 0.2 85 0.88 0.92 42% @ 30 0.19 86 0.07 0.9 26% @ 30 78%
@ 1 87 0.07 1.5 >30 0.26 88 0.1 15 >30 0.27 89 5% @ 30 3% @
30 5% @ 30 9% @ 30 90 0.02 8 16% @ 30 0.1 91 0.07 0.4 7 0.5 92
0.053 17.7 18% @ 30 0.25 93 0.07 15.4 >30 0.16 94 0.04 48% @ 30
>30 0.24 95 0.6 0.58 >30 0.21 96 0.26 6.39 >30 0.12 97
0.04 29% @ 30 >30 0.24 98 0.09 20% @ 30 10% @ 30 0.07 99 6% @ 30
0% @ 30 8% @ 30 7% @ 30 100 1.6 0.1 >30 62% @ 1 101 0.6 0.1
>30 83% @ 1 102 1.2 1 43% @ 30 0.39 103 0.3 1.3 11% @ 30 0.45
104 1.2 19 >30 0.7 105 0 17% 5% 0.49 106 1.11 28.8 30% 0.25 107
0.57 48% 35% 0.24 108 4.13 16% 20% 0.5 109 6.17 46% 10% 0.22 1471-1
8.17 2.57 10% 0.79 1471-2 3.62 86% @ .04 10% 0 1471-3 13.59 6.31 0
1.29 1471-4 29.4 18.3 0 3.1 1471-5 8.69 0.09 12% 1.79 1471-6 2.85
63% @ .04 14% 0.68 1471-7 4.28 0.06 4% 0.87 1471-8 3.86 70% @ .04
27% 0.65 1471-9 0.77 7.63 29% 0.24 1471-10 0.6 69% @ .04 45% 0.18
1471-11 1.69 12.03 9% 0.93 1471-12 7.97 37% @ 30 9% 0.93 1471-13
1.47 0.33 0% 0.53 1471-14 0.18 62% @ .04 23 0.05 1471-15 0.63 0.16
10% 0.24 1471-16 0.82 0.1 23% 0.28 1471-17 11.01 3.76 16 0.24
1471-18 11.21 0.15 26% 0.8 1471-19 33% 16.86 26% 1.6 1471-20 42%
9.46 34% 0.57 1471-21 8.18 0.08 30 0.24 1471-22 14.56 0.32 28% 0.5
1471-23 8.88 0.2 36% 0.28 1471-24 10.05 0.05 23 0.27 1471-25 2.45
24.47 31% 0.36 1471-27 4.19 40% 16% 0.59 1471-28 7.22 26.99 8% 0.39
1471-29 2.18 0.67 21% 0.47 1471-30 0.83 0.13 41% 0.08 1471-31 1.98
0.72 17% 0.47 1471-32 1.19 0.17 25% 0.23 1471-33 31% 34% 22% 0.36
1471-34 17.47 0.74 24% 0.25 1471-35 37% 40% 22% 0.27 1471-36 11%
15% 6% 0.74 1471-37 39% 6.02 7% 0.43 1471-38 24.38 3.92 18% 0.34
1471-39 23.45 4.06 11% 0.29 1471-40 40% 4.03 11% 0.47 1471-41 18.33
25.8 34% 0.33 1471-42 10.45 0.55 15% 0.45 1471-43 25.26 34% 18%
0.44 1471-44 34% 25% 13% 0.53 1471-45 13.22 1.19 24% 0.27 1471-46
13.02 1.76 21% 0.37 1471-47 12.59 2.24 22% 0.41 1471-48 15.7 0.92
17% 0.42 1471-57 4.73 0.9 11% 0.67 1471-58 12.44 76% @ .04 0% 4.03
1471-59 7.52 1.95 0% 1.03 1471-60 13.01 2.97 0% 1.52 1471-61 5 0.04
0% 1.2 1471-62 4% 24% 0% >30 1471-63 3.45 56% @ .04 2% 0.84
1471-64 3.02 78% @ .04 2% 0.61 1471-67 12% 27% 16% 0.82 1471-70 10%
33% 12% 1.01 1471-71 6% 24% 0% 2.58 1471-72 15% 12.2 22% 0.72
1507-01 6.3 18.9 16% 0.9 1507-02 9.4 36% 9% 1.1 1507-03 3.6 21 21%
0.8 1507-04 29.5 9.5% >30 9% @ 1 1507-05 4.7 22 10% 1507-06 20
0.5 >30 8% @ 1 1507-07 25% 27 >30 7% @ 1 1507-08 7% 10% 1%
1507-09 22.6 0.97 13% 0.7 1507-10 24% 39.5% >30 7% @ 1 1507-11 3
<0.04 >30 27% @ 1 1507-12 6.7 0.6 >30 12% @ 1 1507-13 26.7
6% >30 8% @ 1 1507-15 12 25% >30 11% @ 1 1507-16 5.8 21.3 18%
1 1507-17 27.4 0.9 16% 2.8 1507-18 10.6 10.6 >30 6% @ 1 1507-19
12.9 45% 4% 1507-20 20.9 10.5% >30 11% @ 1 1507-21 0.4 4.6 23%
0.36 1507-22 45% 1.5% >30 8% @ 1 1~07-23 28.9 11% >30 11% @ 1
1507-24 0% 7.5% 15% 25% @ 30 1507-25 1.6 22.4 >30 60% @ 1
1507-26 20.5 11.5% >30 11% @ 1 1507-28 38% 1.5 >30 1% @ 1
1507-29 5.8 27% 4% 1507-30 13.4 18.5 >30 0% @ 1 1507-31 3.7
21.5% >30 2% @ 1 1507-32 21.3 16.5% >30 0% @ 1 1507-33 28.4
8.5% >30 2% @ 1 1507-34 8.5 20% >30 0% @ 1 1507-35 19.9 15.9
28% 0.49 1507-36 13.8 18% 0% 1507-38 16 34.5% >30 0% @ 1 1507-40
5.7 30 11% 1507-41 48% 10.5% 17% 13.9 1507-42 11.6 23.5% >30 0%
@ 1 1507-43 4.1 7.1 21% 0.97 1507-44 6 0.5 9% 1507-45 7.3 1 >30
0% @ 1 1507-46 4.3 36% 8% 1507-47 17.6 37% 19% 1.6 1507-48 18.3 14%
>30 11% @ 1 1512-01 18 18% 4% 1512-02 19.2 19% 3% 1512-04 10.8
17% 8% 1512-05 16.7 1.7 10% 1512-06 12.6 23.6 4% 1512-07 3.6 30 4%
1512-11 30 22% 5% 1512-12 11.3 10.5 5% 1512-14 3.2 27.9 7% 1512-15
20.9 23% 6% 1512-16 6.5 34% 10% 1512-17 39% 6% 4% 1512-19 14.3 17%
3% 1512-20 11.2 9% 8% 1512-23 14.6 34% 6% 1512-26 26.9 7% 5%
1512-27 16.5 13% 3% 1512-29 47% 8% 4% 1512-31 43% 9% 14% 1512-32
21.9 10% 5% 1512-35 22.5 23% 4% 1512-36 3.8 48% 9% 1512-39 6 47% 4%
1512-40 40% 9% 3% 1512-41 30 4.4 4% 1512-42 25 15% 1% 1512-43 11
27% 9% 1512-44 43% 20% 6% 1512-45 27% 16% 11% 1512-46 11.7 27.2 10%
1512-47 3.5 0.3 13% 1515-01 7 25% >30 2.3 1515-02 3.8 26% >30
1.5 1515-03 1.9 40% >30 2.9 1515-04 5.2 43% >30 2.8 1515-05 4
9.8 >30 0.9 1515-06 1.7 6.2 >30 1.1 1515-07 14.2 3.8 >30
1.2 1515-08 11% 9% >30 2 1515-09 4.1 44% >30 1.1 1515-10 5.7
38% >30 1.1 1515-11 4.3 44% >30 1.9 1515-12 6.3 9% >30 8.2
1515-13 1.4 37% >30 1.3 1515-14 2.9 7% >30 4 1515-15 2.6 1%
>30 11.7 1515-16 8.8 3% >30 17.3 1515-17 4.4 43% >30 3.2
1515-18 0.6 4.4 >30 1.1 1515-19 24.2 9.4 >30 8.4 1515-20 32%
36% >30 1.2 1515-22 4.2 25% >30 2.7 1515-23 6.2 18% >30
8.5 1515-24 1.6 22% >30 6.7 1515-25 2.9 3.5 >30 1.4 1515-26
1.6 3.3 >30 1.3 1515-27 1.1 2 >30 2 1515-28 3 2.1 >30 2.4
1515-29 5.2 1 >30 2.2 1515-30 1.2 0.4 >30 1.2 1515-31 8.1 0.1
>30 1.2 1515-32 25% 6.3 >30 1.4 1515-33 2.3 1.1 >30 1
1515-34 4.4 2.4 >30 1.3 1515-35 1.8 1.2 >30 1.1 1515-36 2.7
8.6 >30 5.4 1515-37 3.6 4 >30 1.6 1515-38 1.8 2.5 >30 1.4
1515-39 1.6 1.7 >30 2.3 1515-40 4.4 1.7 >30 2.4 1515-41 2.6
0.4 >30 1 1515-42 1.8 0.5 >30 1.4 1515-43 6.8 0.1 >30 1.1
1515-44 30% 7.7 >30 1.4 1515-45 2.9 1 >30 1.2 1515-46 4.8 2
>30 1.3 1515-47 3.1 1.6 >30 1.8 1515-48 4.1 6.2 >30 4.1
1517-01 1.2 1.8 0 0.38 1517-03 9 36% 0 2 1517-04 5.7 14.5 0 4.5
1517-05 4.6 29.8 0 1.2 1517-06 2.5 11.9 0 1.6 1517-07 0.4 1.1 0
0.32 1517-08 43% 30% 0 3.8 1517-09 2.6 30% 0 1.5 1517-10 2 38% 0
2.1 1517-11 3 22% 0 1.9 1517-12 0.8 18.1 0 2.1 1517-13 0.6 0.1 0
0.28 1517-14 30% 20% 0 8.4 1517-15 3.1 5.3 0 1.5 1517-16 3.4 26.1 0
5.1 1517-17 1.8 4.1 0 0.85 1517-18 1.3 1 0 0.98 1517-19 0.9 0.1 0
0.4 1517-20 22% 25% 0 7.3 1517-23 2.3 4.3 0 1.4 1517-24 1.8 1 0
0.84 1517-25 1.4 16.5 0 0.72 1517-26 1.8 2.1 0 0.32 1517-29 0.9 1.2
0 0.3 1517-31 9.1 19.9 0 0.69 1517-33 0.4 5.2 0 0.21 1517-35 33% 9%
0 23.6 1517-36 3 28.1 0 0.61 1517-37 0.4 3.7 0 0.28 1517-38 0.7 8.7
0 0.33 1517-39 0.7 20.4 0 0.43 1517-40 1.2 6.4 0 0.37 1517-41 2.2
16.6 0 0.59 1517-43 25% 4% 0 43% 1517-44 0.2 4 0 0.22 1517-46 0.4
11.3 0 0.36 1517-47 9.8 5.2 0 0.65 1517-48 1.2 2.4 0 0.29 1522-02
0. 20 >30 0.2 1522-05 0.6 10 >30 0.2 1522-06 5.5 20 >30
0.3 1522-07 0.47 1 >30 0.15 1522-08 0.27 1 >30 0.1 1522-09
0.2 3 >30 0.2 1522-11 0.43 1 >30 0.2 1522-12 0.81 8 >30
0.3 1522-13 0.75 8 >30 0.2 1522-14 0.84 8 >30 0.2 1522-15
0.54 4 >30 0.2 1522-17 0.62 1 >30 0.35 1522-18 1.7 20 >30
0.2 1522-19 13 >30 >30 0.3 1522-20 5 >30 >30 0.2
1522-21 0.72 3 >30 0.2 1522-23 2.2 20 >30 0.3 1522-27 6.3 20
>30 0.35 1522-28 >30 >30 >30 2 1522-31 6.4 8 >30
0.35 1522-33 0.88 10 >30 0.2 1522-34 0.5 8 >30 0.2 1522-35 4
10 >30 0.35 1522-36 1 10 >30 0.3 1522-37 2 0.08 >30 0.3
1522-38 1 0.1 >30 0.3 1522-40 0.5 0.8 >30 0.2 1522-41 0.5 10
>30 0.2 1522-42 1 2 >30 0.15 1522-43 0.8 20 >30 0.3
1522-44 0.8 10 >30 0.2 1522-46 1 10 >30 0.2 1522-47 3 15
>30 2 1526-01 0.02 13.13 >30 0.15 1526-03 0.06 17.3 >30
0.15 1526-04 0.03 18.08 >30 0.16 1526-05 0.1 15 >30 0.19
1526-06 0.17 12.04 >30 0.21 1526-07 0.08 20.91 >30 0.19
1526-09 0.03 11.23 >30 0.14 1526-11 0.05 3.21 >30 0.15
1526-12 0.04 28.41 >30 0.2 1526-13 0.06 22.42 >30 0.2 1526-14
0.04 7.63 >30 0.14 1526-15 0.06 6.88 >30 0.15 1526-16 0.04
5.6 >30 0.13 1526-17 0.08 2.21 >30 0.17 1526-19 0.04 16.97
>30 0.15 1526-21 0.05 20.03 >30 0.18 1526-23 0.03 9.45 >30
0.15 1526-24 0.04 11.06 >30 0.17 1526-25 0.14 40% >30 0.19
1526-26 0.06 14.27 >30 0.16 1526-29 0.12 50% >30 0.22 1526-30
0.08 21.42 >30 0.2 1526-33 0.26 29% >30 0.24 1526-40 0.1
17.85 >30 0.22 1526-41 0.07 24.04 >30 0.16 1543-03 0.64 26%
34% 0.06 1543-05 0.06 27% 14% 0.07 1543-07 0.21 24.56 19% 0.09
1543-09 0.69 14% 12% 0.18 1543-11 0.07 16.56 24% 0.04 1543-13 0.09
41% 12% 0.06 1543-15 0.95 45% 41% 0.14 1543-19 0.22 37% 11% 0.08
1543-21 0.29 17.12 27% 0.06 1543-25 0.28 8.12 26% 0.05 1543-27 0.38
24.6 27% 0.06 1543-31 0.04 24.26 8% 0.06 1543-33 0.03 19.34 14%
0.05 1543-34 0.08 17.32 20% 0.06 1543-35 0.07 23.61 8% 0.07 1543-36
0.08 12.57 15% 0.05 1543-37 1.23 16% 16% 0.12 1543-38 0.09 18.26
14% 0.06 1543-39 0.04 12.77 14% 0.05 1543-40 0.04 11.45 10% 0.04
1543-41 3% 0% 9% 6% 1543-45 1% 0% 5% 8% 1543-46 22% 0% 11% 18%
[0818]
9TABLE 9 Inhibitory Activity of Pyrazinones toward Factor Xa,
TF-VIIA, Thrombin II, and Trypsin II. % % Inhibition % % Inhibition
Thrombin Inhibition Inhibition Example TF-VIIa II(100 Factor Xa
Trpysin II Number (100 .mu.M) .mu.M) (100 .mu.M) (100 .mu.M) E-0001
0 0 1 0 E-0002 0 0 0 0 E-0003 0 10 0 0 E-0004 0 6 0 0 E-0005 0 0 0
0 E-0006 2 0 0 1 E-0007 0 0 0 0 E-0008 0 -0.2 0 0 E-0009 0 8 1 1
E-0010 0 5 0 0 E-0011 0 0 0 0 E-0012 0 0 0 0 E-0013 0 2 0 1 E-0014
0 6 0 0 E-0015 0 3 0 3 E-0016 0 10 0 4 E-0017 0 10 0 1 E-0018 1 10
0 4 E-0019 0 9 0 2 E-0020 0 13 1 4 E-0021 0 9 1 5 E-0022 0 12 0 2
E-0023 0 5 0 1 E-0024 0 0 0 1 E-0025 0 13 0 3 E-0026 0 13 0 3
E-0027 0 10 0 2 E-0028 0 8 0 3 E-0029 0 8 0 2 E-0030 0 8 0 4 E-0031
0 4 0 1 E-0032 0 6 0 3 E-0033 0 6 0 5 E-0034 0 7 6 3 E-0035 4 12 0
2 E-0036 0 1 0 0 E-0037 0 5 0 2 E-0038 0 9 0 3 E-0039 0 9 1 2
E-0040 0 7 0 4 E-0041 0 8 0 2 E-0042 0 8 0 5 E-0043 0 12 0 3 E-0044
0 9 0 3 E-0045 0 7 0 4 E-0046 0 7 0 4 E-0047 0 9 0 2 E-0048 0 1 0 0
E-0049 2 0 0 0 E-0050 0 0 0 0 E-0051 0 0 0 0 E-0052 0 0 0 0 E-0053
0 0 0 0 E-0054 0 0 0 0 E-0055 0 0 0 0 E-0056 0 0 0 0 E-0057 0 0 6 0
E-0058 0 0 0 0 E-0059 0 0 0 0 E-0060 0 0 0 0 E-0061 0 0 0 0 E-0062
0 0 0 0 E-0063 0 0 0 0 E-0064 0 0 0 0 E-0065 0 0 0 0 E-0066 0 -0.2
0 0 E-0067 0 1 0 0 E-0068 0 3 0 0 E-0069 0 0 0 0 E-0070 0 0 0 0
E-0071 0 0 0 0 E-0072 0 0 0 0 E-0073 0 0 2 6 E-0074 0 0 0 8 E-0075
0 0 0 7 E-0076 0 0 1 10 E-0077 0 0 3 7 E-0078 0 3 1 10 E-0079 0 0 4
11 E-0080 1 0 4 5 E-0081 0 24 5 8 E-0082 4 0 4 3 E-0083 2 53 3 6
E-0084 0 0 0 8 E-0085 0 5 0 9 E-0086 0 0 4 11 E-0087 0 0 0 10
E-0088 0 0 3 9 E-0089 3 0 4 8 E-0090 0 0 2 11 E-0091 1 0 4 8 E-0092
1 0 3 9 E-0093 0 14 0 10 E-0094 2 0 2 7 E-0095 2 0 4 9 E-0096 0 5 0
10 E-0097 0 0 3 11 E-0098 0 0 2 8 E-0099 0 0 1 10 E-0100 7 0 6 12
E-0101 11 2 10 11 E-0102 0.4 0 3 13 E-0103 2 0 3 11 E-0104 3 0 5 9
E-0105 0 0 3 12 E-0106 5 0 3 9 E-0107 4 0 6 12 E-0108 0 0 4 12
E-0109 2 0 3 12 E-0110 0 0 3 14 E-0111 4 0 1 14 E-0112 11 0 1 13
E-0113 14 0 3 11 E-0114 10 0 3 14 E-0115 15 0 3 11 E-0116 13 0 4 10
E-0117 9 0 1 9 E-0118 12 0 3 9 E-0119 13 0 5 10 E-0120 8 0 1 9
E-0121 0 8 0.1 0 E-0122 0 8 0.1 0 E-0123 0 6 0.1 1 E-0124 0 6 0.1 0
E-0125 0 4 0.1 0 E-0126 0 4 0.1 0 E-0127 0 5 0.1 0 E-0128 0 7 0.1 0
E-0129 0 5 0.1 0 E-0130 0 2 0.1 0 E-0131 0 0 0.1 1 E-0132 0 0 0.1 0
E-0133 0 5 0.1 0 E-0134 0 5 0.1 1 E-0135 0 3 0.1 2 E-0136 0 3 0.1 1
E-0137 2 3 0.1 0 E-0138 1 4 0.1 3 E-0139 0 4 0.1 3 E-0140 0 4 0.1 2
E-0141 0 4 0.1 2 E-0142 1 5 0.1 3 E-0143 1 2 0.1 1 E-0144 0 0 0.1 1
E-0145 0 5 0.1 0 E-0146 0 8 0.1 0 E-0147 0 3 0.1 1 E-0148 0 5 0.1 3
E-0149 0 4 0.1 0 E-0150 0 6 0.1 2 E-0151 0 6 0.1 3 E-0152 0 6 0.1 4
E-0153 0 3 0.1 1 E-0154 0 5 0.1 3 E-0155 2 6 0.1 4 E-0156 0 -0.4
0.1 1 E-0157 0 5 0.1 0 E-0158 0 3 0.1 6 E-0159 0 4 0.1 1 E-0160 0 6
0.1 2 E-0161 0 6 0.1 1 E-0162 0 7 0.1 4 E-0163 0 5 0.1 0 E-0164 0 5
0.1 0 E-0165 0 7 0.1 0 E-0166 0 6 0.1 1 E-0167 0 4 0.1 1 E-0168 7 5
0.1 0 E-0169 0 2 0.1 1 E-0170 0 7 0.1 0 E-0171 0 9 0.1 2 E-0172 0 6
0.1 0 E-0173 0 5 0.1 1 E-0174 0 5 0.1 1 E-0175 0 6 0.1 2 E-0176 0 7
0.1 0 E-0177 0 6 0.1 0 E-0178 0 3 0.1 2 E-0179 0 10 0.1 0 E-0180 0
3 0.1 0 E-0181 0 5 0.1 3 E-0182 0 5 0.1 0 E-0183 0 5 0.1 2 E-0184 0
2 0.1 0 E-0185 0 3 0.1 2 E-0186 0 5 0.1 0 E-0187 0 8 0.1 1 E-0188 0
2 0.1 8 E-0189 0 6 0.1 1 E-0190 0 4 0.1 3 E-0191 0 6 0.1 0 E-0192 0
0 0.1 0 E-0193 0 5 0.1 0 E-0194 0 14 0.2 0 E-0195 0 1 0.1 0 E-0196
0 1 0.1 0 E-0197 0 3 0.1 1 E-0198 0 0 0.1 3 E-0199 0 1 0.1 2 E-0200
0 33 0.2 2 E-0201 0 1 0.1 1 E-0202 0 1 0.1 1 E-0203 0 5 0.1 2
E-0204 0 1 0.1 1 E-0205 0 1 0.1 2 E-0206 0 2 0.1 1 E-0207 0 2 0.1 1
E-0208 0 4 0.1 1 E-0209 1 3 0.1 3 E-0210 0 6 0.1 2
* * * * *