U.S. patent application number 10/660052 was filed with the patent office on 2004-03-25 for novel piperazine derivatives.
This patent application is currently assigned to Pfizer Inc.. Invention is credited to Blumberg, Laura C., Brown, Matthew F., Gladue, Ronald P., McGlynn, Molly A., Poss, Christopher S..
Application Number | 20040058932 10/660052 |
Document ID | / |
Family ID | 22715010 |
Filed Date | 2004-03-25 |
United States Patent
Application |
20040058932 |
Kind Code |
A1 |
Blumberg, Laura C. ; et
al. |
March 25, 2004 |
Novel piperazine derivatives
Abstract
A compound of the formula 1 or the pharmaceutically acceptable
salt thereof; wherein a, b, c, d, e, j, R.sup.1, R.sup.2, R.sup.3,
and R.sup.4 are as defined above useful to treat inflammation and
other immune disorders.
Inventors: |
Blumberg, Laura C.;
(Waterford, CT) ; Brown, Matthew F.; (Stonington,
CT) ; Gladue, Ronald P.; (Stonington, CT) ;
McGlynn, Molly A.; (New London, CT) ; Poss,
Christopher S.; (Baltic, CT) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc.
|
Family ID: |
22715010 |
Appl. No.: |
10/660052 |
Filed: |
September 10, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10660052 |
Sep 10, 2003 |
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09821322 |
Mar 29, 2001 |
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6649611 |
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60193789 |
Mar 31, 2000 |
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Current U.S.
Class: |
514/252.12 ;
544/399; 544/400 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
31/04 20180101; A61P 19/02 20180101; A61P 17/06 20180101; A61P
11/00 20180101; A61P 25/00 20180101; A61P 33/06 20180101; A61P
31/10 20180101; C07D 213/40 20130101; C07D 307/14 20130101; A61P
31/18 20180101; C07D 213/56 20130101; C07D 307/52 20130101; C07D
521/00 20130101; A61P 19/08 20180101; C07D 295/185 20130101; C07D
295/215 20130101; A61P 25/10 20180101; A61P 1/04 20180101; C07D
307/20 20130101; C07D 307/68 20130101; A61P 11/06 20180101; A61P
29/00 20180101; A61P 31/22 20180101; A61P 37/08 20180101; C07D
233/64 20130101; C07D 213/38 20130101; A61P 3/10 20180101; A61P
43/00 20180101; C07D 295/192 20130101; A61P 37/00 20180101; C07D
207/16 20130101; C07D 295/30 20130101; A61P 35/00 20180101; C07D
307/24 20130101; A61P 13/10 20180101 |
Class at
Publication: |
514/252.12 ;
544/399; 544/400 |
International
Class: |
A61K 031/495; A61K
031/497; C07D 241/04 |
Claims
1. A compound of the formula 123or the pharmaceutically acceptable
salt thereof; wherein a is 1, 2, 3, 4 or 5; b is 0, 1, 2, 3 or 4; c
is 0 or 1; d is 1, 2, 3, 4 or 5; e is 0 or 1; j is 1, 2, 3, or 4; X
is C(O), C(S) or CH.sub.2; Y is CH.sub.2, or if e is 0, Y is
CHR.sup.8 wherein R.sup.8 is hydrogen, (C.sub.6-C.sub.10)aryl or
NR.sup.9R.sup.10; Z is oxygen, NR.sup.9 or CR.sup.11R.sup.12; each
R.sup.1 is independently selected from hydrogen, hydroxy,
hydroxysulfonyl, halo, (C.sub.1-C.sub.6)alkyl, mercapto,
mercapto(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylthio,
(C.sub.1-C.sub.6)alkylsulfinyl, (C.sub.1-C.sub.6)alkylsufonyl,
(C.sub.1-C.sub.6)alkylthio(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyls- ulfinyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonyl(C.sub.1-C.su- b.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.6-C.sub.10)aryloxy,
halo(C.sub.1-C.sub.6)alkyl, trifluoromethyl, formyl,
formyl(C.sub.1-C.sub.6)alkyl, nitro, nitroso, cyano,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkox- y, trifluoromethoxy,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)cycloal-
kyl(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.su- b.6)alkyl,
(C.sub.3-C.sub.7)cycloalkylamino, (C.sub.3-C.sub.7)cycloalkylam-
ino(C.sub.1-C.sub.6)alkyl,
((C.sub.3-C.sub.7)cycloalkyl)((C.sub.1-C.sub.6)- alkyl)amino,
((C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.6)alkyl)amino(C.su-
b.1-C.sub.6)alkyl, cyano(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.7)alkenyl, (C.sub.2-C.sub.7)alkynyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryl(-
C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.2-C.sub.6)alkenyl,
hydroxy(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.6-C.sub.10)aryl(C.sub.1-C.su- b.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkylthio(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.2-C.sub.6)alkenyl, hydroxy(C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.-
sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryloxy(C.sub- .1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.-
sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).- sub.2amino, (C.sub.6-C.sub.10)arylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.- sub.6)alkylamino,
amino(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylamino-
(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.- 6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.- sub.1-C.sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.s- ub.6)alkyl,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)alkyl)amino(-
C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl)(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbnony)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.s-
ub.6)alkyl, carboxy, (C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkylcarbonyl,
(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.- sub.6)alkyl,
(C.sub.6-C.sub.10)arylcarbonyl, (C.sub.6-C.sub.10)arylcarbony-
l(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbo- nyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkycarbonyl(C.sub.1-C.sub.6)a-
lkyl, carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub- .1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxycarbonyl(C.-
sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkylcarbonyl-
oxy(C.sub.1-C.sub.6)alkyl, aminocarbonyl,
(C.sub.1-C.sub.6)alkylaminocarbo- nyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl,
(C.sub.6-C.sub.10)arylam- inocarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl,
aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl(- C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-
-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkyl, amidino,
guanidino, ureido, (C.sub.1-C.sub.6)alkylureido,
((C.sub.1-C.sub.6)alkyl)- .sub.2ureido,
ureido(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylureido(C-
.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6- )alkyl,
(C.sub.2-C.sub.9)heterocycloalkyl, (C.sub.2-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkyl and
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkyl; each R.sup.2 and
R.sup.3 are independently selected from oxo, halo,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C-.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)a-
lkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.6-C.sub.10)aryl,
(C.sub.6-C.sub.10)aryl(- C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.2-C.sub.6)alkenyl, H--C(O)--,
H--C(O)--(C.sub.1-C.sub.6)alkyl, hydroxy(C.sub.1-C.sub.6)alkyl- ,
hydroxy(C.sub.2-C.sub.6)alkenyl, hydroxy(C.sub.2-C.sub.6)alkynyl,
hydroxy(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
thio(C.sub.1-C.sub.6)alkyl, cyano(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryloxy(- C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxy(C.sub-
.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylthio(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfinyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonyl(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkylthio(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)- alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
azido(C.sub.1-C.sub.6)alkyl,
aminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylaminocarbonylamino(C-
.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6- )alkyl,
hydroxy(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryloxy(C.sub.1-C.sub.6)alkylcarbonyloxy(C.sub.1-C.sub.-
6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkylcarbonyloxy(C.sub.1--
C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub-
.6)alkylcarbonyloxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbonyl,
(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)a- lkoxycarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl,
aminocarbonyl, (C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl,
(C.sub.6-C.sub.10)arylaminoc- arbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl,
carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.- sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-
-C.sub.6)alkyl, aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6-
)alkyl, (C.sub.6-C.sub.10)arylsulfonyl,
(C.sub.2-C.sub.9)heterocycloalkyl, (C.sub.2-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.- sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkyl or
R.sup.14R.sup.15N(C.sub.1-C.sub.6)alkyl wherein R.sup.14 and
R.sup.15 are each independently (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkylcarbon- yl; R.sup.4 is
(R.sup.5).sub.f(R.sup.6).sub.g(C.sub.6-C.sub.10)aryl,
(R.sup.5).sub.f(R.sup.6).sub.g(C.sub.3-C.sub.10)cycloalkyl,
(R.sup.5).sub.f(R.sup.7).sub.h(C.sub.2-C.sub.9)heteroaryl, or
(R.sup.5).sub.f(R.sup.7).sub.h(C.sub.2-C.sub.9)heterocycloalkyl,
wherein f is 1, 2, 3 or 4; g and h are each independently 0, 1, 2
or 3; R.sup.5 is one to three groups independently selected from
(C.sub.2-C.sub.9)heterocycloalkylcarbonyl,
(C.sub.2-C.sub.9)heteroarylcar- bonyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylaminocarbonyl,
ureido(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkylureido(C- .sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.-
sub.1-C.sub.6)alkylaminocarbonyl,
halo(C.sub.1-C.sub.6)alkylaminocarbonyl,
aminosulfonyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkyla-
minosulfonyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkylsul-
fonylamino(C.sub.1-C.sub.6)alkylcarbonylamino,
cyanoguanidino(C.sub.1-C.su- b.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkylcyanoguanidino(C.sub.1-C.sub-
.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino(C.sub.-
1-C.sub.6)alkylcarbonylamino,
aminocarbonyl(C.sub.1-C.sub.6)alkylcarbonyla- mino,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylcarbonylamino,
aminosulfonyl(C.sub.1-C.sub.6)alkylcarbonylamino,
hydroxy(C.sub.1-C.sub.6- )alkylureido,
amino(C.sub.1-C.sub.6)alkylureido, (C.sub.1-C.sub.6)alkylami-
no(C.sub.1-C.sub.6)alkylureido,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.- 1-C.sub.6)alkylureido,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)a- lkylureido,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylureido,
aminosulfonyl(C.sub.1-C.sub.6)alkylureido,
aminocarbonyl(C.sub.1-C.sub.6)- alkylureido,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylurei- do,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkylureid-
o, acetylamino(C.sub.1-C.sub.6)alkylureido,
(acetyl)((C.sub.1-C.sub.6)alky-
l)amino(C.sub.1-C.sub.6)alkylureido,
halo(C.sub.1-C.sub.6)alkylsulfonylami- no,
amino(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylamino(- C.sub.1-C.sub.6)alkylsulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.-
sub.1-C.sub.6)alkylsulfonylamino,
acetylamino(C.sub.1-C.sub.6)alkylsulfony- lamino,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkylsulfony-
lamino, ureido(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylu- reido(C.sub.1-C.sub.6)alkylsulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2ur-
eido(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylami-
no(C.sub.1-C.sub.6)alkylsulfonylamino,
cyanoguanidino(C.sub.1-C.sub.6)alky- lsulfonylamino,
(C.sub.1-C.sub.6)alkylcyanoguanidino(C.sub.1-C.sub.6)alkyl-
sulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino(C.sub.1-C.sub.-
6)alkylsulfonylamino,
aminocarbonyl(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
aminosulfonylamino, (C.sub.1-C.sub.6)alkylaminosulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2aminosulfonylamino,
aminocarbonyl(C.sub.1-C-
.sub.6)alkylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylsu-
lfonylamino,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)a-
lkylsulfonylamino, cyanoguanidino,
(C.sub.1-C.sub.6)alkylcyanoguanidino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino,
(C.sub.2-C.sub.9)heterocycl- oalkylcyanoguanidino,
(C.sub.2-C.sub.9)heteroarylcyanoguanidino,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylcyanoguanidino,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylcyanoguanidino,
amino(C.sub.1-C.sub.6)alkylcyanoguanidino,
(C.sub.1-C.sub.6)alkylamino(C.- sub.1-C.sub.6)alkylcyanoguanidino,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.s-
ub.1-C.sub.6)alkylcyanoguanidino,
aminocarbonyl(C.sub.1-C.sub.6)alkylcyano- guanidino,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylcyanog-
uanidino,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alky-
lcyanoguanidino, aminocarbonyl(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylamino,
aminosulfonyl(C.sub.1-C.sub.6)alkylamino,
(C.sub.2-C.sub.9)heteroaryl(C.s- ub.1-C.sub.6)alkylamino,
acetylamino(C.sub.1-C.sub.6)alkylamino,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.-
6)alkyl, cyano(C.sub.1-C.sub.6)alkylaminoalkyl,
aminocarbonyl(C.sub.1-C.su- b.6)alkylamino(C.sub.1-C.sub.6)alkyl,
acetylamino(C.sub.1-C.sub.6)alkylami- no(C.sub.1-C.sub.6)alkyl,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.-
sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylami-
no(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylam-
ino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.s-
ub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.su- b.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcyanoguanidino-
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl-
).sub.2cyanoguanidino(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.-
sub.6)alkyl,
ureido(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)a-
lkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylamino(C.su-
b.1-C.sub.6)alkyl,
aminocarbonyloxy(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.s-
ub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub-
.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylcarbony-
lamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(-
C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
aminosulfonyl(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkylcarbonylamino(C.sub.1-C.sub.6)alkylcarbo-
nylamino(C.sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.sub.6)alkylcarbon-
ylamino(C.sub.1-C.sub.6)alkyl
cyano(C.sub.1-C.sub.6)alkylcarbonylamino(C.s- ub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1--
C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylaminocarbo-
nylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.-
1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl
hydroxy(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alk-
yl
(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkylaminocarbonyla-
mino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.-
sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylaminocarbonylam-
ino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylami-
no(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)alkylaminocarbonyl-
amino(C.sub.1-C.sub.6)alkyl
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.su-
b.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)hetero-
aryl(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
ureido(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)-
alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylureido(C.-
sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.- sub.6)alkyl
halo(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.-
sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkylsulf-
onylamino(C.sub.1-C.sub.6)alkyl,
acetylamino(C.sub.1-C.sub.6)alkylsulfonyl-
amino(C.sub.1-C.sub.6)alkyl,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-
-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl
ureido(C.sub.1-C.sub.6)a- lkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylureido(C.su-
b.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylsulfonylamino(C-
.sub.1-C.sub.6)alkyl
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)a-
lkylsulfonylamino(C.sub.1-C.sub.6)alkyl
cyanoguanidino(C.sub.1-C.sub.6)alk-
ylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl(cyanoguanidi-
no)(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2(cyanoguanidino)(C.sub.1-C.sub.6)alkylsulfo-
nylamino(C.sub.1-C.sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkylsulfony-
lamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-
-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)hetero-
cycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.su-
b.6)alkyl,
(C2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)alkylsul-
fonylamino(C.sub.1-C.sub.6)alkyl,
aminosulfonylamino(C.sub.1-C.sub.6)alkyl- ,
(C.sub.1-C.sub.6)alkylaminosulfonylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminosulfonylamino(C.sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl(cyanoguanidi- no)(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2(cyanoguanidino)(-
C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyl(cyanoguanidino)(C-
.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)al-
kyl(cyanoguanidino)(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalk- yl(cyanoguanidino)amino,
(C.sub.2-C.sub.9)heteroaryl(cyanoguanidino)(C.sub-
.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkyl(cyanog-
uanidino)(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.6)alkyl(cyanoguanidin-
o)(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alky-
l(cyanoguanidino)(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ami-
no(C.sub.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkyl-
,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkyl(cyanoguanidino-
)(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub-
.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkyl,
aminosulfonyl, (C.sub.1-C.sub.6)alkylaminosulfonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminos- ulfonyl,
(C.sub.2-C.sub.9)heterocycloalkylsulfonyl,
amino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkylamino(C.s- ub.1-C.sub.6)alkylaminosulfonyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub-
.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heteroarylaminosulfonyl,
hydroxy(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkoxy(C.sub- .1-C.sub.6)alkylaminosulfonyl,
ureido(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylaminosulfonyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylam-
inosulfonyl,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)a-
lkylaminosulfonyl,
aminocarbonyl(C.sub.1-C.sub.6)alkylaminosulfonyl,
cyanoguanidino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heterocycloalkylaminosulfonyl, R.sup.6 is one to
three groups independently selected from hydrogen, hydroxy,
hydroxysulfonyl, halo, (C.sub.1-C.sub.6)alkyl, mercapto,
mercapto(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylthio,
(C.sub.1-C.sub.6)alkylsulfinyl, (C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.6-C.sub.10)arylsulfonyl,
(C.sub.1-C.sub.6)alkylthio(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyls- ulfinyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonyl(C.sub.1-C.su- b.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, halo(C.sub.1-C.sub.6)alkyl,
trifluoro(C.sub.1-C.sub.6)alkyl, formyl,
formyl(C.sub.1-C.sub.6)alkyl, nitro, nitroso, cyano,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkoxy, trifluoro(C.sub.1-C.sub.6)alkoxy,
amino(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.3-C.sub.10)cycloalkyl(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.3-C.sub.10)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.10)cycloalkylamino,
(C.sub.3-C.sub.10)cycloalkylamino(C.su- b.1-C.sub.6)alkyl,
cyano(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.6-C.sub.10)aryl,
(C.sub.6-C.sub.10)aryl(- C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.2-C.sub.6)alkenyl,
hydroxy(C.sub.1-C.sub.6)alkyl, (hydroxy)
(C.sub.6-C.sub.10)aryl(C.sub.1-C- .sub.6)alkyl,
((C.sub.1-C.sub.6)alkylamino)(C.sub.6-C.sub.10)aryl(C.sub.1--
C.sub.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkylthio(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.2-C.sub.6)alkenyl, hydroxy(C.sub.2-C.sub.6)alkenyl,
hydroxy(C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)- alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl-
, aryloxy(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)al-
koxy(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino, (C.sub.6-C.sub.10)arylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylamino,
amino(C.sub.1-C.sub.6)alkylamino,
(C.sub.2-C.sub.9)heterocycloalkylamino,
(C.sub.2-C.sub.9)heteroarylamino,
(C.sub.3-C.sub.10)cycloalkyl(C.sub.1-C.- sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.2-C.sub.6)alkenylcarbonylami- no,
(C.sub.3-C.sub.10)cycloalkylcarbonylamino,
(C.sub.6-C.sub.10)arylcarbo- nylamino,
(C.sub.2-C.sub.9)heterocycloalkylcarbonylamino,
halo(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-- C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.-
6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)al- kyl)amino,
((C.sub.1-C.sub.6)alkoxycarbonyl)((C.sub.1-C.sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkylsulfonylamino, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylcarbonylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.s-
ub.6)alkyl,
C.sub.3-C.sub.10)cycloalkyl(C.sub.1-C.sub.6)alkyl)amino(C.sub.-
1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alky- l,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylcarbonylamino(C.su-
b.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkoxycarbonyl)((C.sub.1-C.sub.6)alky-
l)amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1- -C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkylsulfonyl)((C.sub.1-C.sub.6)alkyl)am-
ino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylsulfonylamino(C.sub.1-C.s- ub.6)alkyl,
((C.sub.6-C.sub.10)arylsulfonyl)((C.sub.1-C.sub.6)alkyl)amino(-
C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkylamino(C.sub.1-C.su- b.6)alkyl,
(C.sub.2-C.sub.9)heteroarylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)a- lkoxycarbonyl,
(C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.6-C.sub.10)arylcarbo- nyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl,
hydroxy(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C- .sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxycarbony-
l(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkylcarb-
onyloxy(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl-
oxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.sub.6)- alkyl,
(C.sub.6-C.sub.10)arylcarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.sub.6)alky-
l, aminocarbonyl, (C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl,
(C.sub.6-C.sub.10)arylaminoc- arbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(aminocarbonyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(amino(C.sub.1-C.sub.6)alkyl)aminocarbonyl,
(hydroxy(C.sub.1-C.sub.6)alky- laminocarbonyl,
aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6-
)alkyl, amidino, hydroxyamidino, guanidino, ureido,
(C.sub.1-C.sub.6)alkylureido, (C.sub.6-C.sub.10)arylureido,
((C.sub.6-C.sub.10)aryl).sub.2ureido,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.su- b.6)alkylureido,
halo(C.sub.1-C.sub.6)alkylureido, ((C.sub.1-C.sub.6)alkyl-
)((C.sub.6-C.sub.10)aryl)ureido,
((C.sub.1-C.sub.6)alkyl).sub.2ureido,
halo(C.sub.1-C.sub.6)alkylcarbonylureido,
ureido(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylureido(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl).sub.2ureido(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkyl,
(halo(C.sub.1-C.sub.6)alkyl)((C.sub.1-C.sub.6)alkyl)ureido(C.sub.1-C.sub.-
6)alkyl,
((C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl)ureido(C.s-
ub.1-C.sub.6)alkyl, glycinamido, (C.sub.1-C.sub.6)alkylglycinamido,
aminocarbonylglycinamido,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkylca- rbonylglycinamido,
(aminocarbonyl)((C.sub.1-C.sub.6)alkyl)glycinamido,
((C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1--
C.sub.6)alkyl)glycinamido,
((C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C-
.sub.6)alkylcarbonyl)glycinamido,
(C.sub.6-C.sub.10)arylcarbonylglycinamid- o,
((C.sub.6-C.sub.10)arylcarbonyl)((C.sub.1-C.sub.6)alkyl)glycinamido,
((C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl)glycinamido,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl)((C.sub.1-C.sub-
.6)alkyl)glycinamido,
(C.sub.6-C.sub.10)arylaminocarbonylglycinamido,
((C.sub.6-C.sub.10)arylaminocarbonyl)((C.sub.1-C.sub.6)alkyl)glycinamido,
glycinamido(C.sub.1-C.sub.6)alkyl, alaninamido,
(C.sub.1-C.sub.6)alkylala- ninamido,
alaninamido(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.- sub.6)alkyl and
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkyl; R.sup.7 is
one to three groups independently selected from hydrogen, hydroxy,
halo, (C.sub.1-C.sub.6)alkyl, (C.sub.1-Cr)alkylsulfonyl,
(C.sub.6-C.sub.10)arylsulfonyl, (C.sub.1-C.sub.6)alkoxy,
hydroxy(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkyl, fomyl,
nitro, cyano, halo(C.sub.1-C.sub.6)alkoxy,
(C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryl(-
C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino, (C.sub.6-C.sub.10)arylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino- ,
(C.sub.2-C.sub.6)alkenylcarbonylamino, cycloalkylcarbonylamino,
(C.sub.6-C.sub.10)arylcarbonylamino,
halo(C.sub.1-C.sub.6)alkylcarbonylam- ino,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)alkyl)amino,
((C.sub.1-C.sub.6)alkoxycarbonyl)((C.sub.1-C.sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkylsulfonylamino, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylcarbonylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.s-
ub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)a- lkoxycarbonyl,
(C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.6-C.sub.10)arylcarbo- nyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl,
aminocarbonyl, (C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminoc- arbonyl,
(C.sub.6-C.sub.10)arylaminocarbonyl, aminocarbonyl(C.sub.1-C.sub.-
6)alkyl, (C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
guanidino, ureido, (C.sub.1-C.sub.6)alkylureido,
ureido(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkyl, and
glycinamido; R.sup.9 and R.sup.10 are each independently selected
from the group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbo- nyl,
(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.sub.6)alky-
l, aminocarbonyl, (C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl and
(C.sub.1-C.sub.6)alkoxyca- rbonyl; and R.sup.11 and R.sup.12 are
each independently selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.6-C.sub.10)aryl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, amino,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.3-C.sub.8)cycloalkylcarbonyla- mino,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino- ,
(C.sub.6-C.sub.10)arylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.s-
ub.1-C.sub.6)alkylcarbonylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)al- kylcarbonylamino,
((C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl)((-
C.sub.1-C.sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C- .sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkylcarbonylamino(C.sub.1-C.sub.6)alk- yl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6-
)alkyl,
(C.sub.2-C.sub.9)heteroarylcarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(- C.sub.1-C.sub.6)alkyl,
aminocarbonylamino, (C.sub.1-C.sub.6)alkylaminocarb- onylamino,
halo(C.sub.1-C.sub.6)alkylaminocarbonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonylamino,
aminocarbonylamino(C.su- b.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.- 6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonylamino(C.sub.1-C.sub.6)-
alkyl,
halo(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6ralkylamino(C.sub.1-C.sub.6)- alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl,
carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.- sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkyl.
2. A compound according to claim 1, wherein R.sup.1 is hydrogen,
halo, cyano, nitro, trifluoromethyl, trifluoromethoxy,
(C.sub.1-C.sub.6)alkyl, hydroxy or
(C.sub.1-C.sub.6)alkylcarbonyloxy.
3. A compound according to claim 1, wherein R.sup.2 and R.sup.3 are
each independently selected from (C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkyl, amino(C.sub.1-C.sub.6)alkyl,
amino(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.s- ub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.3-C.sub.8)cycloalkyl,
hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub- .1-C.sub.6)alkyl,
ureido(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyureid-
o(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkyl or
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkyl.
4. A compound according to claim 1, wherein c is 1; X is C(O) of
CH.sub.2; d is 2; Y is ethylene; and e is 0.
5. A compound according to claim 1, wherein c is 1; X is C(O) or
CH.sub.2; d is for 2; Y is CH.sub.2 or ethylene; e is 1; and Z is
oxygen or NR.sup.9 wherein R.sup.9 is hydrogen or
(C.sub.1-C.sub.6)alkyl.
6. A compound according to claim 1, wherein c is 1; X is C(O) or
CH.sub.2; d is 1; Y is CHR.sup.8 wherein R.sup.8 is
NR.sup.9R.sup.10; R.sup.9 and R.sup.10 are each independently
hydrogen, (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkylcarbonyl;
e is 1; and Z is selected from the group consisting of oxygen,
CR.sup.11R.sup.12 wherein R.sup.11 and R.sup.12 are hydrogen, and
NR.sup.9 wherein R.sup.9 is hydrogen or (C.sub.1-C.sub.6)alkyl.
7. A compound according to claim 1, wherein R.sup.4 is
(R.sup.5).sub.f(R.sup.6).sub.g(C.sub.6-C.sub.10)aryl or
(R.sup.5).sub.f(R.sup.7).sub.h(C.sub.2-C.sub.9)heteroaryl wherein
f, g and h are independently 1 or 2.
8. A compound according to claim 1, wherein R.sup.5 is selected
from the group consisting of
(C.sub.2-C.sub.9)heterocycloalkylcarbonyl,
(C.sub.2-C.sub.9)heteroarylcarbonyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-- C.sub.6)alkylaminocarbonyl,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.su-
b.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.-
6)alkylaminocarbonyl, ureido(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylaminocarbonyl,
aminosulfonyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkyla-
minosulfonyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkylsul-
fonylamino(C.sub.1-C.sub.6)alkylcarbonylamino,
cyanoguanidino(C.sub.1-C.su- b.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkylcyanoguanidino(C.sub.1-C.sub-
.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino(C.sub.-
1-C.sub.6)alkylcarbonylamino,
aminocarbonyl(C.sub.1-C.sub.6)alkylcarbonyla- mino,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylcarbonylamino,
aminosulfonyl(C.sub.1-C.sub.6)alkylcarbonylamino,
amino(C.sub.1-C.sub.6)a- lkylureido,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylureido,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkylureido,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylureido,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylureido,
aminosulfonyl(C.sub.1-C.sub.6)alkylureido,
aminocarbonyl(C.sub.1-C.sub.6)- alkylureido,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylurei- do,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkylureid-
o, acetylamino(C.sub.1-C.sub.6)alkylureido,
(acetyl)((C.sub.1-C.sub.6)alky-
l)amino(C.sub.1-C.sub.6)alkylureido,
amino(C.sub.1-C.sub.6)alkylsulfonylam- ino,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkylsulfonylamino,
acetylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
(acetyl)((C.sub.1-C.sub.6-
)alkyl)amino(C.sub.1-C.sub.6)alkylsulfonylamino
ureido(C.sub.1-C.sub.6)alk- ylsulfonylamino,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylsulfony- lamino,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylsulfonyl-
amino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylsulfonylam-
ino, cyanoguanidino(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylcyanoguanidino(C.sub.1-C.sub.6)alkylsulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino(C.sub.1-C.sub.6)alkylsulfony-
lamino, aminocarbonyl(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylsulfonylamino
aminosulfonylamino, (C.sub.1-C.sub.6)alkylaminosulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2aminosulfonylamino,
aminocarbonyl(C.sub.1-C-
.sub.6)alkylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylsu-
lfonylamino
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)al-
kylsulfonylamino,
amino(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.-
sub.6)alkyl
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylaminocarbonyl
amino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1--
C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alk-
yl (C.sub.1-C.sub.6)
alkylcarbonylamino(C.sub.1-C.sub.6)alkylaminocarbonyl-
amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C-
.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl
(C.sub.1-C.sub.6)alkoxycarbonyl
amino(C.sub.1-C.sub.6)alkylaminocarbonyla-
mino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonyl
amino(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl
(C.sub.2-C.sub.9)heteroaryoxycarbonylamino(C.sub.1-C.sub.6)alkylaminocarb-
onylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-
-C.sub.6)alkylaminocarbony lamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub-
.1-C.sub.6)alkyl,
ureido(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkyl- ,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6-
)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylureido(C-
.sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.sub.6)alkylureido(C.sub.1-C- .sub.6)alkyl,
amino(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alk- yl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-
-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyls-
ulfonylamino(C.sub.1-C.sub.6)alkyl
acetylamino(C.sub.1-C.sub.6)alkylsulfon-
ylamino(C.sub.1-C.sub.6)alkyl
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.-
1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
ureido(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C-
.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylsu-
lfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.s-
ub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkylsulfonylamino-
(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2(cyanoguanidino)(C.s-
ub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylsulfonylamino(C-
.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.-
sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)alkylsulfonyl-
amino(C.sub.1-C.sub.6)alkyl,
aminosulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminosulfonylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminosulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkylsulfonyl,
amino(C.sub.1-C.sub.6)alkylami- nosulfonyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylaminosulfonyl- ,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heteroarylaminosulfonyl,
ureido(C.sub.1-C.sub.6)alkylami- nosulfonyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylaminosulfony- l,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylaminosulfonyl-
,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylam-
inosulfonyl,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)a-
lkylaminosulfonyl,
aminocarbonyl(C.sub.1-C.sub.6)alkylaminosulfonyl,
cyanoguanidino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heterocycloalkylaminosulfonyl
halo(C.sub.1-C.sub.6)alkyl- aminocarbonyl,
hydroxy(C.sub.1-C.sub.6)alkylureido,
halo(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl(-
C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.1-C.sub.6)-
alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkyls- ulfonylamino(C.sub.1-C.sub.6)alkyl,
aminosulfonyl, (C.sub.1-C.sub.6)alkyla- minosulfonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminosulfonyl,
hydroxy(C.sub.1-C.sub.6)alkylaminosulfonyl, and
(C.sub.1-C.sub.6)alkoxy(C- .sub.1-C.sub.6)alkylaminosulfonyl.
9. A compound according to claim 1, wherein R.sup.6 and R.sup.7 are
each independently halo, halo(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, trifluoromethyl,
trifluoromethoxy, hydroxy, aminocarbonyl, cyano, ureido,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino or glycinamino.
10. A pharmaceutical composition for treating or preventing a
disorder or condition selected from autoimmune diseases, rheumatoid
arthritis, type I diabetes (recent onset), lupus, inflammatory
bowel disease, optic neuritis, psoriasis, multiple sclerosis,
polymyalgia rheumatica, uveitis, and vasculitis, acute and chronic
inflammatory conditions osteoarthritis, adult Respiratory Distress
Syndrome, Respiratory Distress Syndrome of infancy, ischemia
reperfusion injury, glomerulonephritis, and chronic obstructive
pulmonary disease (COPD) allergic conditions, asthma and atopic
dermatitis, inflammation associated with infection, viral
inflammation, influenza, hepatitis and Guillian-Barre, chronic
bronchitis, chronic or acute tissue, cell, and solid organ
transplant rejection, xeno-transplantation, atherosclerosis,
restenosis, HIV infectivity (co-receptor usage), and granulomatous
diseases, sarcoidosis, leprosy and tuberculosis, and sequelae
associated with cancers, multiple myelomax; limiting the production
of cytokines and/or TNF at inflammatory sites, as a consequence of
decreasing cell infiltration; for treating diseases and/or
congestive heart failure, linked to TNF and IL-1 and for treating
pulmonary emphysema or dyspnea associated therewith, emphysema;
HIV-1, HIV-2, HIV-3; cytomegalovirus (CMV), adenoviruses, Herpes
viruses (Herpes zoster and Herpes simplex), for treating sequelae
associated with infection where such infection induces production
of detrimental inflammatory cytokines and/or TNF, fungal
meningitis, joint tissue damage, hyperplasia, pannus formation and
bone resorption, psoriatic arthritis, hepatic failure, bacterial
meningitis, Kawasaki syndrome, myocardial infarction, acute liver
failure, lyme disease, septic shock, cancer, trauma, and malaria,
in a mammal, comprising an amount of a compound according to claim
1, or a pharmaceutically acceptable salt or pro-drug thereof, that
is effective in treating or preventing such disorder or condition
and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition for treating or preventing a
disorder or condition that can be treated or prevented by
inhibiting chemokine binding to the receptor CCR1 in a mammal,
comprising an amount of a compound according to claim 1, or a
pharmaceutically acceptable salt thereof, effective in treating or
preventing such disorder or condition and a pharmaceutically
acceptable carrier.
12. A method for treating or preventing a disorder or condition
selected from autoimmune diseases, rheumatoid arthritis, type I
diabetes (recent onset), lupus, inflammatory bowel disease, optic
neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica,
uveitis, and vasculitis, acute and chronic inflammatory conditions
osteoarthritis, adult Respiratory Distress Syndrome, Respiratory
Distress Syndrome of infancy, ischemia reperfusion injury,
glomerulonephritis, and chronic obstructive pulmonary disease
(COPD) allergic conditions, asthma and atopic dermatitis,
inflammation associated with infection, viral inflammation,
influenza, hepatitis and Guillian-Barre, chronic bronchitis,
chronic or acute tissue, cell, and solid organ transplant
rejection, xeno-transplantation, atherosclerosis, restenosis, HIV
infectivity (co-receptor usage), and granulomatous diseases,
sarcoidosis, leprosy and tuberculosis, and sequelae associated with
cancers, multiple myelomax; limiting the production of cytokines
and/or TNF at inflammatory sites, as a consequence of decreasing
cell infiltration; for treating diseases and/or congestive heart
failure, linked to TNF and IL-1 and for treating pulmonary
emphysema or dyspnea associated therewith, emphysema; HIV-1, HIV-2,
HIV-3; cytomegalovirus (CMV), adenoviruses, Herpes viruses (Herpes
zoster and Herpes simplex), for treating sequelae associated with
infection where such infection induces production of detrimental
inflammatory cytokines and/or TNF, fungal meningitis, joint tissue
damage, hyperplasia, pannus formation and bone resorption,
psoriatic arthritis, hepatic failure, bacterial meningitis,
Kawasaki syndrome, myocardial infarction, acute liver failure, lyme
disease, septic shock, cancer, trauma, and malaria, in a mammal,
comprising administering to a mammal in need of such treatment or
prevention an amount of a compound according to claim 1, or a
pharmaceutically acceptable salt or pro-drug thereof, that is
effective in treating or preventing such disorder or condition.
13. A method for treating or preventing a disorder or condition
that can be treated or prevented by antagonizing the CCR1 receptor
in a mammal, comprising administering to a mammal in need of such
treatment or prevention an amount of a compound according to claim
1, or a pharmaceutically acceptable salt thereof, that is effective
in treating or preventing such disorder or condition.
Description
[0001] This application claims the benefit of priority of
provisional Patent Application Serial No. 60/193,789 filed Mar. 31,
2000, and nonprovisional patent application Ser. No. 09/821,322
filed Mar. 29, 2001, which is incorporated herein by reference in
their entirety for all purposes.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to novel piperazine
derivatives, methods of use and pharmaceutical compositions
containing them.
[0003] The compounds of the invention are potent and selective
inhibitors of chemokine binding to its receptor CCR1 found on
inflammatory and immunomodulatory cells (preferably leukocytes and
lymphocytes). The CCR1 receptor is also sometimes referred to as
the CC-CKR1 receptor. These compounds also inhibit MIP-1.alpha.
(and the related chemokines shown to interact with CCR1 (eq.,
RANTES and MCP-3)) induced chemotaxis of THP-1 cells and human
leukocytes and are potentially useful for the treatment or
prevention of autoimmune diseases (such as rheumatoid arthritis,
type I diabetes (recent onset), lupus, inflammatory bowel disease,
optic neuritis, psoriasis, multiple sclerosis, polymyalgia
rheumatica, uveitis, and vasculitis), acute and chronic
inflammatory conditions (such as osteoarthritis, adult Respiratory
Distress Syndrome, Respiratory Distress Syndrome of infancy,
ischemia reperfusion injury, and glomerulonephritis), allergic
conditions (such as asthma and atopic dermatitis), infection
associated with inflammation (such as viral inflammation (including
influenza and hepatitis) and Guillian-Barre), chronic bronchitis,
xeno-transplantation, transplantation tissue rejection (chronic and
acute), organ transplant rejection (chronic and acute),
atherosclerosis, restenosis, HIV infectivity (co-receptor usage),
and granulomatous diseases (including sarcoidosis, leprosy and
tuberculosis) and sequelae associated with certain cancers such as
multiple myeloma. Compounds in this series may also limit the
production of cytokines at inflammatory sites, including but not
limited to TNF and IL-1, as a consequence of decreasing cell
infiltration, providing benefit for diseases linked to TNF and
IL-1, including congestive heart failure, pulmonary emphysema or
dyspnea associated therewith, emphysema; HIV-1, HIV-2, HIV-3;
cytomegalovirus (CMV), adenoviruses, Herpes viruses (Herpes zoster
and Herpes simplex). They may also provide benefit for the sequelae
associated with infection where such infection induces production
of detrimental inflammatory cytokines such as TNF e.g, fungal
meningitis, joint tissue damage, hyperplasia, pannus formation and
bone resorption, psoriatic arthritis, hepatic failure, bacterial
meningitis, Kawasaki syndrome, myocardial infarction, acute liver
failure, lyme disease, septic shock, cancer, trauma, and
malaria.
[0004] MIP-1.alpha. and RANTES are soluble chemotactic peptides
(chemokines) which are produced by inflammatory cells, in
particular CD8+ lymphocytes, polymorphonuclear leukocytes (PMNs)
and macrophages, J. Biol. Chem., 270 (30) 29671-29675 (1995). These
chemokines act by inducing the migration and activation of key
inflammatory and immunomodulatory cells. Elevated levels of
chemokines have been found in the synovial fluid of rheumatoid
arthritis patients, chronic and acute rejecting tissue from
transplant patients and in the nasal secretions of allergic
rhinitis patients following allergen exposure (Teran, et al., J.
Immunol., 1806-1812 (1996), and Kuna et al., J. Allergy Clin.
Immunol. 321 (1994)). Antibodies which interfere with the
chemokine/receptor interaction by neutralizing MIP1.alpha. or gene
disruption have provided direct evidence for the role of
MIP-1.alpha. and RANTES in disease by limiting the recruitment of
monocytes and CD8+ lymphocytes (Smith et al., J. Immunol, 153, 4704
(1994) and Cook et al., Science, 269, 1583 (1995)). Together this
data demonstrates that CCR1 receptor antagonists would be an
effective treatment of several immune based diseases. The compounds
described within are potent and selective antagonists of the CCR1
receptor.
SUMMARY OF THE INVENTION
[0005] The present invention also relates to a compound of the
formula 2
[0006] or the pharmaceutically acceptable salt thereof; wherein
[0007] a is 1, 2, 3, 4 or 5;
[0008] b is 0, 1, 2, 3 or 4;
[0009] c is 0 or 1;
[0010] d is 1,2, 3, 4 or 5;
[0011] e is 0 or 1;
[0012] j is 1, 2, 3, or 4;
[0013] X is C(O), C(S) or CH.sub.2;
[0014] Y is CH.sub.2, or if e is 0, Y is CHR.sup.8 wherein R.sup.8
is hydrogen, (C.sub.6-C.sub.10)aryl or NR.sup.9R.sup.10;
[0015] Z is oxygen, NR.sup.9 or CR.sup.11R.sup.12;
[0016] each R.sup.1 is independently selected from hydrogen,
hydroxy, hydroxysulfonyl, halo, (C.sub.1-C.sub.6)alkyl, mercapto,
mercapto(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylthio,
(C.sub.1-C.sub.6)alkylsulfinyl, (C.sub.1-C.sub.6)alkylsufonyl,
(C.sub.1-C.sub.6)alkylthio(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyls- ulfinyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonyl(C.sub.1-C.su- b.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, (C.sub.6-C.sub.10)aryloxy,
halo(C.sub.1-C.sub.6)alkyl, trifluoromethyl, formyl,
formyl(C.sub.1-C.sub.6)alkyl, nitro, nitroso, cyano,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkox- y, trifluoromethoxy,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)cycloal-
kyl(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.su- b.6)alkyl,
(C.sub.3-C.sub.7)cycloalkylamino, (C.sub.3-C.sub.7)cycloalkylam-
ino(C.sub.1-C.sub.6)alkyl,
((C.sub.3-C.sub.7)cycloalkyl)((C.sub.1-C.sub.6)- alkyl)amino,
((C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.6)alkyl)amino(C.su-
b.1-C.sub.6)alkyl, cyano(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.7)alkenyl, (C.sub.2-C.sub.7)alkynyl,
(C.sub.6-C.sub.10)aryl, (C.sub.6-C.sub.10)aryl(-
C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.2-C.sub.6)alkenyl,
hydroxy(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.6-C.sub.10)aryl(C.sub.1-C.su- b.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkylthio(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.2-C.sub.6)alkenyl, hydroxy(C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.-
sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryloxy(C.sub- .1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.-
sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).- sub.2amino, (C.sub.6-C.sub.10)arylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.- sub.6)alkylamino,
amino(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylamino-
(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.- 6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.- sub.1-C.sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.s- ub.6)alkyl,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)alkyl)amino(-
C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl)(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbnony)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.s-
ub.6)alkyl, (C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.- 1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkylcarbonyl,
(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylcarbonyl,
(C.sub.6-C.sub.10)arylcarbonyl(C.sub.1-C.- sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkycarbonyl(C.sub.1-C.sub.6)alkyl-
, carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C- .sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.-
1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkylcarbonyloxy(-
C.sub.1-C.sub.6)alkyl, aminocarbonyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl,
(C.sub.6-C.sub.10)arylaminoc- arbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl,
aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl(- C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-
-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkyl, amidino,
guanidino, ureido, (C.sub.1-C.sub.6)alkylureido,
((C.sub.1-C.sub.6)alkyl)- .sub.2ureido,
ureido(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylureido(C-
.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6- )alkyl,
(C.sub.2-C.sub.9)heterocycloalkyl, (C.sub.2-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkyl and
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkyl;
[0017] each R.sup.2 and R.sup.3 are independently selected from
oxo, halo, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.2-.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.s-
ub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.6-C.sub.10)aryl,
(C.sub.6-C.sub.10)aryl(- C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.2-C.sub.6)alkenyl, H--C(O)--,
H--C(O)--(C.sub.1-C.sub.6)alkyl, hydroxy(C.sub.1-C.sub.6)alkyl- ,
hydroxy(C.sub.2-C.sub.6)alkenyl, hydroxy(C.sub.2-C.sub.6)alkynyl,
hydroxy(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkyl,
thio(C.sub.1-C.sub.6)alkyl, cyano(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryloxy(- C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxy(C.sub-
.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylthio(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfinyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonyl(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkylthio(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)- alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
azido(C.sub.1-C.sub.6)alkyl,
aminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylaminocarbonylamino(C-
.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6- )alkyl,
hydroxy(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryloxy(C.sub.1-C.sub.6)alkylcarbonyloxy(C.sub.1-C.sub.-
6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkylcarbonyloxy(C.sub.1--
C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub-
.6)alkylcarbonyloxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbonyl,
(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.sub.6)alkyl, carboxy,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)a- lkoxycarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl,
aminocarbonyl, (C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl,
(C.sub.6-C.sub.10)arylaminoc- arbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl,
carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.- sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-
-C.sub.6)alkyl, aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6-
)alkyl, (C.sub.6-C.sub.10)arylsulfonyl,
(C.sub.2-C.sub.9)heterocycloalkyl, (C.sub.2-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.- sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkyl or
R.sup.14R.sup.15N(C.sub.1-C.sub.6)alkyl wherein R.sup.14 and
R.sup.15 are each independently (C.sub.1-C.sub.6)alkyl or
(C.sub.1-C.sub.6)alkylcarbon- yl;
[0018] R.sup.4 is
(R.sup.5).sub.f(R.sup.6).sub.g(C.sub.6-C.sub.10)aryl,
(R.sup.5).sub.f(R.sup.6).sub.g(C.sub.3-C.sub.10)cycloalkyl,
(R.sup.5).sub.f(R.sup.7).sub.h(C.sub.2-C.sub.9)heteroaryl, or
(R.sup.5).sub.f(R.sup.7).sub.h(C.sub.2-C.sub.9)heterocycloalkyl,
[0019] wherein f is 1, 2, 3 or 4;
[0020] g and h are each independently 0, 1, 2 or 3;
[0021] R.sup.5 is one to three groups independently selected from
(C.sub.2-C.sub.9)heterocycloalkylcarbonyl,
(C.sub.2-C.sub.9)heteroarylcar- bonyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylaminocarbonyl,
ureido(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkylureido(C- .sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.-
sub.1-C.sub.6)alkylaminocarbonyl,
halo(C.sub.1-C.sub.6)alkylaminocarbonyl,
aminosulfonyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkyla-
minosulfonyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkylsul-
fonylamino(C.sub.1-C.sub.6)alkylcarbonylamino,
cyanoguanidino(C.sub.1-C.su- b.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkylcyanoguanidino(C.sub.1-C.sub-
.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino(C.sub.-
1-C.sub.6)alkylcarbonylamino,
aminocarbonyl(C.sub.1-C.sub.6)alkylcarbonyla- mino,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylcarbonylamino,
aminosulfonyl(C.sub.1-C.sub.6)alkylcarbonylamino,
hydroxy(C.sub.1-C.sub.6- )alkylureido,
amino(C.sub.1-C.sub.6)alkylureido, (C.sub.1-C.sub.6)alkylami-
no(C.sub.1-C.sub.6)alkylureido,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.- 1-C.sub.6)alkylureido,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)a- lkylureido,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylureido,
aminosulfonyl(C.sub.1-C.sub.6)alkylureido,
aminocarbonyl(C.sub.1-C.sub.6)- alkylureido,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylurei- do,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkylureid-
o, acetylamino(C.sub.1-C.sub.6)alkylureido,
(acetyl)((C.sub.1-C.sub.6)alky-
l)amino(C.sub.1-C.sub.6)alkylureido,
halo(C.sub.1-C.sub.6)alkylsulfonylami- no,
amino(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylamino(- C.sub.1-C.sub.6)alkylsulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.-
sub.1-C.sub.6)alkylsulfonylamino,
acetylamino(C.sub.1-C.sub.6)alkylsulfony- lamino,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkylsulfony-
lamino, ureido(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylu- reido(C.sub.1-C.sub.6)alkylsulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2ur-
eido(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylami-
no(C.sub.1-C.sub.6)alkylsulfonylamino,
cyanoguanidino(C.sub.1-C.sub.6)alky- lsulfonylamino,
(C.sub.1-C.sub.6)alkylcyanoguanidino(C.sub.1-C.sub.6)alkyl-
sulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino(C.sub.1-C.sub.-
6)alkylsulfonylamino,
aminocarbonyl(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
aminosulfonylamino, (C.sub.1-C.sub.6)alkylaminosulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2aminosulfonylamino,
aminocarbonyl(C.sub.1-C-
.sub.6)alkylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylsu-
lfonylamino,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)a-
lkylsulfonylamino, cyanoguanidino,
(C.sub.1-C.sub.6)alkylcyanoguanidino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino,
(C.sub.2-C.sub.9)heterocycl- oalkylcyanoguanidino,
(C.sub.2-C.sub.9)heteroarylcyanoguanidino,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylcyanoguanidino,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylcyanoguanidino,
amino(C.sub.1-C.sub.6)alkylcyanoguanidino,
(C.sub.1-C.sub.6)alkylamino(C.- sub.1-C.sub.6)alkylcyanoguanidino,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.s-
ub.1-C.sub.6)alkylcyanoguanidino,
aminocarbonyl(C.sub.1-C.sub.6)alkylcyano- guanidino,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylcyanog-
uanidino,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alky-
lcyanoguanidino, aminocarbonyl(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylamino,
aminosulfonyl(C.sub.1-C.sub.6)alkylamino,
(C.sub.2-C.sub.9)heteroaryl(C.s- ub.1-C.sub.6)alkylamino,
acetylamino(C.sub.1-C.sub.6)alkylamino,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.-
6)alkyl, cyano(C.sub.1-C.sub.6)alkylaminoalkyl,
aminocarbonyl(C.sub.1-C.su- b.6)alkylamino(C.sub.1-C.sub.6)alkyl,
acetylamino(C.sub.1-C.sub.6)alkylami- no(C.sub.1-C.sub.6)alkyl,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.-
sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylami-
no(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylam-
ino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.s-
ub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.su- b.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcyanoguanidino-
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl-
).sub.2cyanoguanidino(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.-
sub.6)alkyl,
ureido(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)a-
lkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylamino(C.su-
b.1-C.sub.6)alkyl,
aminocarbonyloxy(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.s-
ub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub-
.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylcarbony-
lamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(-
C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
aminosulfonyl(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
cyano(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub-
.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alky-
laminocarbonylamino(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkylam-
inocarbonylamino(C.sub.1-C.sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alky-
laminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbonyla-
mino(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylaminocarbonylami-
no(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.s-
ub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylam-
inocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryloxycarb-
onylamino(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylaminocarbonylamino-
(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkyla-
minocarbonylamino(C.sub.1-C.sub.6)alkyl,
ureido(C.sub.1-C.sub.6)alkylureid- o(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alky-
lureido(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.-
1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.sub.- 6)alkylureido(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkylsulfonylami- no(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1- -C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylsulfonyla-
mino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.-
sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
acetylamino(C.sub.1-C.sub.-
6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(acetyl)((C.sub.1-C.sub.6)alky-
l)amino(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
ureido(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C-
.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylsu-
lfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.s-
ub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkylsulfonylamino-
(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2(cyanoguanidino)(C.s-
ub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylsulfonylamino(C-
.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.-
sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)alkylsulfonylamino-
(C.sub.1-C.sub.6)alkyl, aminosulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminosulfonylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminosulfonylamino(C.sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl(cyanoguanidi- no)(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2(cyanoguanidino)(-
C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyl(cyanoguanidino)(C-
.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)al-
kyl(cyanoguanidino)(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalk- yl(cyanoguanidino)amino,
(C.sub.2-C.sub.9)heteroaryl(cyanoguanidino)(C.sub-
.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkyl(cyanog-
uanidino)(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.6)alkyl(cyanoguanidin-
o)(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alky-
l(cyanoguanidino)(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ami-
no(C.sub.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkyl-
,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkyl(cyanoguanidino-
)(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub-
.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkyl,
aminosulfonyl, (C.sub.1-C.sub.6)alkylaminosulfonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminos- ulfonyl,
(C.sub.2-C.sub.9)heterocycloalkylsulfonyl,
amino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkylamino(C.s- ub.1-C.sub.6)alkylaminosulfonyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub-
.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heteroarylaminosulfonyl,
hydroxy(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkoxy(C.sub- .1-C.sub.6)alkylaminosulfonyl,
ureido(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylaminosulfonyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylam-
inosulfonyl,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)a-
lkylaminosulfonyl,
aminocarbonyl(C.sub.1-C.sub.6)alkylaminosulfonyl,
cyanoguanidino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heterocycloalkylaminosulfonyl, R.sup.6 is one to
three groups independently selected from hydrogen, hydroxy,
hydroxysulfonyl, halo, (C.sub.1-C.sub.6)alkyl, mercapto,
mercapto(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylthio,
(C.sub.1-C.sub.6)alkylsulfinyl, (C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.6-C.sub.10)arylsulfonyl,
(C.sub.1-C.sub.6)alkylthio(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyls- ulfinyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonyl(C.sub.1-C.su- b.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkoxy,
(C.sub.6-C.sub.10)aryloxy, halo(C.sub.1-C.sub.6)alkyl,
trifluoro(C.sub.1-C.sub.6)alkyl, formyl,
formyl(C.sub.1-C.sub.6)alkyl, nitro, nitroso, cyano,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkoxy, trifluoro(C.sub.1-C.sub.6)alkoxy,
amino(C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.10)cycloalkyl,
(C.sub.3-C.sub.10)cycloalkyl(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.3-C.sub.10)cycloalkyl(C.sub.1-C.sub.6)alkyl,
(C.sub.3-C.sub.10)cycloalkylamino,
(C.sub.3-C.sub.10)cycloalkylamino(C.su- b.1-C.sub.6)alkyl,
cyano(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.6-C.sub.10)aryl,
(C.sub.6-C.sub.10)aryl(- C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.2-C.sub.6)alkenyl,
hydroxy(C.sub.1-C.sub.6)alkyl, (hydroxy)
(C.sub.6-C.sub.10)aryl(C.sub.1-C- .sub.6)alkyl,
((C.sub.1-C.sub.6)alkylamino)(C.sub.6-C.sub.10)aryl(C.sub.1--
C.sub.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkylthio(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.2-C.sub.6)alkenyl, hydroxy(C.sub.2-C.sub.6)alkenyl,
hydroxy(C.sub.2-C.sub.6)alkynyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)- alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl-
, aryloxy(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)al-
koxy(C.sub.1-C.sub.6)alkyl, amino, (C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino, (C.sub.6-C.sub.10)arylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylamino,
amino(C.sub.1-C.sub.6)alkylamino,
(C.sub.2-C.sub.9)heterocycloalkylamino,
(C.sub.2-C.sub.9)heteroarylamino,
(C.sub.3-C.sub.10)cycloalkyl(C.sub.1-C.- sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.2-C.sub.6)alkenylcarbonylami- no,
(C.sub.3-C.sub.10)cycloalkylcarbonylamino,
(C.sub.6-C.sub.10)arylcarbo- nylamino,
(C.sub.2-C.sub.9)heterocycloalkylcarbonylamino,
halo(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-- C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.-
6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)al- kyl)amino,
((C.sub.1-C.sub.6)alkoxycarbonyl)((C.sub.1-C.sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkylsulfonylamino, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylcarbonylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.s-
ub.6)alkyl,
C.sub.3-C.sub.10)cycloalkyl(C.sub.1-C.sub.6)alkyl)amino(C.sub.-
1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alky- l,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylcarbonylamino(C.su-
b.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkoxycarbonyl)((C.sub.1-C.sub.6)alky-
l)amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1- -C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkylsulfonyl)((C.sub.1-C.sub.6)alkyl)am-
ino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylsulfonylamino(C.sub.1-C.s- ub.6)alkyl,
((C.sub.6-C.sub.10)arylsulfonyl)((C.sub.1-C.sub.6)alkyl)amino(-
C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkylamino(C.sub.1-C.su- b.6)alkyl,
(C.sub.2-C.sub.9)heteroarylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)a- lkoxycarbonyl,
(C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.6-C.sub.10)arylcarbo- nyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl,
hydroxy(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C- .sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkoxycarbony-
l(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkylcarb-
onyloxy(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl-
oxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.sub.6)- alkyl,
(C.sub.6-C.sub.10)arylcarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.sub.6)alky-
l, aminocarbonyl, (C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl,
(C.sub.6-C.sub.10)arylaminoc- arbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(aminocarbonyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylaminocarbonyl,
(amino(C.sub.1-C.sub.6)alkyl)aminocarbonyl,
(hydroxy(C.sub.1-C.sub.6)alky- laminocarbonyl,
aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6-
)alkyl, amidino, hydroxyamidino, guanidino, ureido,
(C.sub.1-C.sub.6)alkylureido, (C.sub.6-C.sub.10)arylureido,
((C.sub.6-C.sub.10)aryl).sub.2ureido,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.su- b.6)alkylureido,
halo(C.sub.1-C.sub.6)alkylureido, ((C.sub.1-C.sub.6)alkyl-
)((C.sub.6-C.sub.10)aryl)ureido,
((C.sub.1-C.sub.6)alkyl).sub.2ureido,
halo(C.sub.1-C.sub.6)alkylcarbonylureido,
ureido(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylureido(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl).sub.2ureido(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkyl,
(halo(C.sub.1-C.sub.6)alkyl)((C.sub.1-C.sub.6)alkyl)ureido(C.sub.1-C.sub.-
6)alkyl,
((C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl)ureido(C.s-
ub.1-C.sub.6)alkyl, glycinamido, (C.sub.1-C.sub.6)alkylglycinamido,
aminocarbonylglycinamido,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkylca- rbonylglycinamido,
(aminocarbonyl)((C.sub.1-C.sub.6)alkyl)glycinamido,
((C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1--
C.sub.6)alkyl)glycinamido,
((C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C-
.sub.6)alkylcarbonyl)glycinamido,
(C.sub.6-C.sub.10)arylcarbonylglycinamid- o,
((C.sub.6-C.sub.10)arylcarbonyl)((C.sub.1-C.sub.6)alkyl)glycinamido,
((C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl)glycinamido,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl)((C.sub.1-C.sub-
.6)alkyl)glycinamido,
(C.sub.6-C.sub.10)arylaminocarbonylglycinamido,
((C.sub.6-C.sub.10)arylaminocarbonyl)((C.sub.1-C.sub.6)alkyl)glycinamido,
glycinamido(C.sub.1-C.sub.6)alkyl, alaninamido,
(C.sub.1-C.sub.6)alkylala- ninamido,
alaninamido(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.- sub.6)alkyl and
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkyl;
[0022] R.sup.7 is one to three groups independently selected from
hydrogen, hydroxy, halo, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsu- lfonyl, (C.sub.6-C.sub.10)arylsulfonyl,
(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkoxy,
halo(C.sub.1-C.sub.6)alkyl, fomyl, nitro, cyano,
halo(C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.6-C.sub.10)aryl,
(C.sub.6-C.sub.10)aryl(- C.sub.1-C.sub.6)alkyl, amino,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
(C.sub.6-C.sub.10)arylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino- ,
(C.sub.2-C.sub.6)alkenylcarbonylamino, cycloalkylcarbonylamino,
(C.sub.6-C.sub.10)arylcarbonylamino,
halo(C.sub.1-C.sub.6)alkylcarbonylam- ino,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)alkyl)amino,
((C.sub.1-C.sub.6)alkoxycarbonyl)((C.sub.1-C.sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkylsulfonylamino, amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylcarbonylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.s-
ub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)a- lkoxycarbonyl,
(C.sub.1-C.sub.6)alkylcarbonyl, (C.sub.6-C.sub.10)arylcarbo- nyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl,
aminocarbonyl, (C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminoc- arbonyl,
(C.sub.6-C.sub.10)arylaminocarbonyl, aminocarbonyl(C.sub.1-C.sub.-
6)alkyl, (C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylaminocarbonyl(C.sub.1-C.sub.6)alkyl,
guanidino, ureido, (C.sub.1-C.sub.6)alkylureido,
ureido(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkyl, and
glycinamido;
[0023] R.sup.9 and R.sup.10 are each independently selected from
the group consisting of hydrogen, (C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylcarbo- nyl,
(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl(C.sub.1-C.sub.6)alky-
l, aminocarbonyl, (C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl and
(C.sub.1-C.sub.6)alkoxyca- rbonyl; and R.sup.11 and R.sup.12 are
each independently selected from the group consisting of hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.6-C.sub.10)aryl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl, hydroxy,
(C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, amino,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.3-C.sub.8)cycloalkylcarbonyla- mino,
(C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino- ,
(C.sub.6-C.sub.10)arylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.s-
ub.1-C.sub.6)alkylcarbonylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)al- kylcarbonylamino,
((C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonyl)((-
C.sub.1-C.sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C- .sub.6)alkyl,
(C.sub.3-C.sub.8)cycloalkylcarbonylamino(C.sub.1-C.sub.6)alk- yl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6-
)alkyl,
(C.sub.2-C.sub.9)heteroarylcarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.6-C.sub.10)arylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(- C.sub.1-C.sub.6)alkyl,
aminocarbonylamino, (C.sub.1-C.sub.6)alkylaminocarb- onylamino,
halo(C.sub.1-C.sub.6)alkylaminocarbonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonylamino,
aminocarbonylamino(C.su- b.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.- 6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonylamino(C.sub.1-C.sub.6)-
alkyl,
halo(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)- alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl,
carboxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.- sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkyl and
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkyl.
[0024] Preferred compounds of formula I include those wherein
R.sup.1 is hydrogen, halo, cyano, nitro, trifluoromethyl,
trifluoromethoxy, (C.sub.1-C.sub.6)alkyl, hydroxy or
(C.sub.1-C.sub.6)alkylcarbonyloxy.
[0025] Other preferred compounds of formula I include those wherein
R.sup.2 and R.sup.3 are each independently selected from
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.8)cycloalkyl,
amino(C.sub.1-C.sub.6)alkyl, amino(C.sub.3-C.sub.8)cycloalkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.3-C.sub.8)cycloalkyl,
hydroxy(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub- .1-C.sub.6)alkyl,
ureido(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyureid-
o(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkyl or
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkyl.
[0026] Other preferred compounds of formula I include those wherein
c is 1; X is C(O); d is 1; Y is CH.sub.2; e is 1; and Z is
oxygen.
[0027] Other preferred compounds of formula I include those wherein
c is 1; X is C(O); d is 2; Y is ethylene; and e is 0.
[0028] Other preferred compounds of formula I include those wherein
c is 1; X is C(O); d is 1; Y is CH.sub.2; e is 1; and Z is NR.sup.9
wherein R.sup.9 is hydrogen or (C.sub.1-C.sub.6)alkyl.
[0029] Other preferred compounds of formula I include those wherein
c is 1; X is CH.sub.2; d is 1; Y is CH.sub.2; e is 1; and Z is
oxygen.
[0030] Other preferred compounds of formula I include those wherein
c is 1; X is CH.sub.2; d is 2; Y is ethylene; and e is 0.
[0031] Other preferred compounds of formula I include those wherein
c is 1; X is CH.sub.2; d is 1; Y is CH.sub.2; e is 1; and Z is
NR.sup.9 wherein R.sup.9 is hydrogen or (C.sub.1-C.sub.6)alkyl.
[0032] Other preferred compounds of formula I include those wherein
c is 1; X is C(O); d is 1; Y is CHR.sup.8 wherein R.sup.8 is
NR.sup.9R.sup.10; R.sup.9 and R.sup.10 are each independently
hydrogen, (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkylcarbonyl;
e is 1; and Z is oxygen.
[0033] Other preferred compounds of formula I include those wherein
c is 1; X is C(O); d is 1; Y is CHR.sup.8 wherein R.sup.8 is
NR.sup.9R.sup.10; R.sup.9 and R.sup.10 are each independently
hydrogen, (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkylcarbonyl;
e is 1; and Z is CR.sup.11R.sup.12 wherein R.sup.11 and R.sup.12
are hydrogen.
[0034] Other preferred compounds of formula I include those wherein
c is 1; X is C(O); d is 1; Y is CHR.sup.8 wherein R.sup.8 is
NR.sup.9R.sup.10; R.sup.9 and R10 are each independently hydrogen,
(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkylcarbonyl; e is 1;
and Z is NR.sup.9 wherein R.sup.9 is hydrogen or
(C.sub.1-C.sub.6)alkyl.
[0035] Other preferred compounds of formula I include those wherein
c is 1; X is CH.sub.2; d is 1; Y is CHR.sup.8 wherein R.sup.8 is
NR.sup.9R.sup.10; R.sup.9 and R10 are each independently hydrogen,
(C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkylcarbonyl; e is 1;
and Z is oxygen.
[0036] Other preferred compounds of formula I include those wherein
c is 1; X is CH.sub.2; d is 1; Y is CHR.sup.8 wherein R.sup.8 is
NR.sup.9R.sup.10; R.sup.9 and R.sup.10 are each independently
hydrogen, (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkylcarbonyl;
e is 1; and Z is CR.sup.11R.sup.12 wherein R.sup.11 and R.sup.12
are hydrogen.
[0037] Other preferred compounds of formula I include those wherein
c is 1; X is CH.sub.2; d is 1; Y is CHR.sup.8 wherein R.sup.8 is
NR.sup.9R.sup.10; R.sup.9 and R.sup.10 are each independently
hydrogen, (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkylcarbonyl;
e is 1; and Z is NR.sup.9 wherein R.sup.9 is hydrogen or
(C.sub.1-C.sub.6)alkyl.
[0038] Other preferred compounds of formula I include those wherein
R.sup.4 is (R.sup.5).sub.f(R.sup.6).sub.g(C.sub.6-C.sub.10)aryl or
(R.sup.5).sub.f(R.sup.7).sub.h(C.sub.2-C.sub.9)heteroaryl wherein
f, g and h are independently 1 or 2.
[0039] Other preferred compounds of formula I include those wherein
R.sup.5 is (C.sub.2-C.sub.9)heterocycloalkylcarbonyl,
(C.sub.2-C.sub.9)heteroarylcarbonyl,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-- C.sub.6)alkylaminocarbonyl,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.su-
b.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.-
6)alkylaminocarbonyl, ureido(C.sub.1-C.sub.6)alkylaminocarbonyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylaminocarbonyl,
aminosulfonyl(C.sub.1-C.sub.6)alkylaminocarbonyl or
(C.sub.1-C.sub.6)alkylaminosulfonyl(C.sub.1-C.sub.6)alkylaminocarbonyl.
[0040] Other preferred compounds of formula I include those wherein
R.sup.5 is
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylcarbo-
nylamino, cyanoguanidino(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkylcyanoguanidino(C.sub.1-C.sub.6)alkylcarbonylamino,
((C,
--C.sub.6)alkyl).sub.2cyanoguanidino(C.sub.1-C.sub.6)alkylcarbonylam-
ino, aminocarbonyl(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylcarbonylamino,
or aminosulfonyl(C.sub.1-C.sub.6)alkylcarbonylamino.
[0041] Other preferred compounds of formula I include those wherein
R.sup.5 is amino(C.sub.1-C.sub.6)alkylureido,
(C.sub.1-C.sub.6)alkylamino- (C.sub.1-C.sub.6)alkylureido,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-- C.sub.6)alkylureido,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alk- ylureido,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylureido,
aminosulfonyl(C.sub.1-C.sub.6)alkylureido,
aminocarbonyl(C.sub.1-C.sub.6)- alkylureido,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylurei- do,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkylureid-
o, acetylamino(C.sub.1-C.sub.6)alkylureido,
(acetyl)((C.sub.1-C.sub.6)alky-
l)amino(C.sub.1-C.sub.6)alkylureido.
[0042] Other preferred compounds of formula I include those wherein
R.sup.5 is amino(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkylsulfonylamino,
acetylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
(acetyl)((C.sub.1-C.sub.6-
)alkyl)amino(C.sub.1-C.sub.6)alkylsulfonylamino,
ureido(C.sub.1-C.sub.6)al- kylsulfonylamino,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylsulfon- ylamino,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylsulfony-
lamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylsulfonyla-
mino, cyanoguanidino(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylcyanoguanidino(C.sub.1-C.sub.6)alkylsulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino(C.sub.1-C.sub.6)alkylsulfony-
lamino, aminocarbonyl(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
aminosulfonylamino, (C.sub.1-C.sub.6)alkylaminosulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2aminosulfonylamino,
aminocarbonyl(C.sub.1-C-
.sub.6)alkylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylsu-
lfonylamino or
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6-
)alkylsulfonylamino.
[0043] Other preferred compounds of formula I include those wherein
R.sup.5 is cyanoguanidino, (C.sub.1-C.sub.6)alkylcyanoguanidino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino,
(C.sub.2-C.sub.9)heterocycl- oalkylcyanoguanidino,
(C.sub.2-C.sub.9)heteroarylcyanoguanidino,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylcyanoguanidino,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylcyanoguanidino,
amino(C.sub.1-C.sub.6)alkylcyanoguanidino,
(C.sub.1-C.sub.6)alkylamino(C.- sub.1-C.sub.6)alkylcyanoguanidino,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.s-
ub.1-C.sub.6)alkylcyanoguanidino,
aminocarbonyl(C.sub.1-C.sub.6)alkylcyano- guanidino,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylcyanog-
uanidino or
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)al-
kylcyanoguanidino.
[0044] Other preferred compounds of formula I include those wherein
R.sup.5 is aminocarbonyl(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylamino,
aminosulfonyl(C.sub.1-C.sub.6)alkylamino,
(C.sub.2-C.sub.9)heteroaryl(C.s- ub.1-C.sub.6)alkylamino,
acetylamino(C.sub.1-C.sub.6)alkylamino or
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkylamino.
[0045] Other preferred compounds of formula I include those wherein
R.sup.5 is cyano(C.sub.1-C.sub.6)alkylaminoalkyl or
aminocarbonyl(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl.
[0046] Other preferred compounds of formula I include those wherein
R.sup.5 is
acetylamino(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkylamino(C.sub.1--
C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkyla-
mino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylam-
ino(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)alkylamino(C.-
sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.s- ub.6)alkyl,
(C.sub.1-C.sub.6)alkylcyanoguanidino(C.sub.1-C.sub.6)alkylamin-
o(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino(C.su-
b.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfon-
ylamino(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
ureido(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)a-
lkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylamino(C.su-
b.1-C.sub.6)alkyl or
aminocarbonyloxy(C.sub.1-C.sub.6)alkylamino(C.sub.1-C-
.sub.6)alkyl.
[0047] Other preferred compounds of formula I include those wherein
R.sup.5 is
acetylamino(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6-
)alkyl,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkylcarbony-
lamino(C.sub.1-C.sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkylcarbonyla-
mino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.-
sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).s-
ub.2aminocarbonyl(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl-
,
aminosulfonyl(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl
or
cyano(C.sub.1-C.sub.6)alkylcarbonylamino(C.sub.1-C.sub.6)alkyl.
[0048] Other preferred compounds of formula I include those wherein
R.sup.5 is
amino(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)-
alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylaminocarbonyl
amino(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1--
C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alk-
yl, (C.sub.1-C.sub.6)
alkylcarbonylamino(C.sub.1-C.sub.6)alkylaminocarbony-
lamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1--
C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonyl
amino(C.sub.1-C.sub.6)alkylaminocarbonyla-
mino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonyl
amino(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C6)alkylaminocarbonyl-
amino(C.sub.1-C.sub.6)alkyl,
(C2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)- alkylaminocarbony
lamino(C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.9)heteroary-
l(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkyl,
ureido(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkyl, (C,
--C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylureido(C.sub.1--
C.sub.6)alkyl or
cyanoguanidino(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.- 6)alkyl.
Other preferred compounds of formula I include those wherein
R.sup.5 is
amino(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl- ,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C-
.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkylsul-
fonylamino(C.sub.1-C.sub.6)alkyl,
acetylamino(C.sub.1-C.sub.6)alkylsulfony-
lamino(C.sub.1-C.sub.6)alkyl,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.-
1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
ureido(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C-
.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylsu-
lfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.s-
ub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
cyanoguanidino(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkylsulfonylamino-
(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2(cyanoguanidino)(C.s-
ub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylsulfonylamino(C-
.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.-
sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)alkylsulfonyl-
amino(C.sub.1-C.sub.6)alkyl,
aminosulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminosulfonylamino(C.sub.1-C.sub.6)alkyl or
((C.sub.1-C.sub.6)alkyl).sub.2aminosulfonylamino(C.sub.1-C.sub.6)alkyl.
[0049] Other preferred compounds of formula I include those wherein
R.sup.5 is cyanoguanidino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkyl(c- yanoguanidino)(C.sub.1-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2(cyano-
guanidino)(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyl(cyanog-
uanidino)(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryl(cyanoguanidin-
o)(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.-
6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkyl,
(C.sub.2-C.sub.9)heteroaryl-
(C.sub.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkyl,
amino(C.sub.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-
-C.sub.6)alkyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl(-
cyanoguanidino)(C.sub.1-C.sub.6)alkyl,
aminocarbonyl(C.sub.1-C.sub.6)alkyl-
(cyanoguanidino)(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminocarbony-
l(C.sub.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkyl or
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkyl(cyanogu-
anidino)(C.sub.1-C.sub.6)alkyl.
[0050] Other preferred compounds of formula I include those wherein
R.sup.5 is (C.sub.2-C.sub.9)heterocycloalkylsulfonyl,
amino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkylamino(C.s- ub.1-C.sub.6)alkylaminosulfonyl,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub-
.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heteroarylaminosulfonyl,
ureido(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkylureido(C- .sub.1-C.sub.6)alkylaminosulfonyl,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.-
sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.su-
b.1-C.sub.6)alkylaminosulfonyl,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub-
.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbony-
lamino(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heteroaryloxyc-
arbonylamino(C.sub.1-C.sub.6)alkylaminosulfonyl,
aminocarbonyl(C.sub.1-C.s- ub.6)alkylaminosulfonyl,
cyanoguanidino(C.sub.1-C.sub.6)alkylaminosulfonyl- ,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylaminosulfonyl,
(C.sub.2-C.sub.9)heterocycloalkylaminosulfonyl, Other preferred
compounds of formula I include those wherein R.sup.5 is
halo(C.sub.1-C.sub.6)alkyla- minocarbonyl,
hydroxy(C.sub.1-C.sub.6)alkylureido, halo(C.sub.1-C.sub.6)al-
kylsulfonylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylami-
no(C.sub.1-C.sub.6)alkyl,
hydroxy(C.sub.1-C.sub.6)alkylaminocarbonylamino(-
C.sub.1-C.sub.6)alkyl,
halo(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.s- ub.6)alkyl,
aminosulfonyl, (C.sub.1-C.sub.6)alkylaminosulfonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminosulfonyl,
hydroxy(C.sub.1-C.sub.6)alky- laminosulfonyl, and
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkylaminosulf- onyl.
[0051] Other preferred compounds of formula I include those wherein
R.sup.6 and R.sup.7 are each independently halo,
halo(C.sub.1-C.sub.6)alk- yl, (C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkoxy, trifluoromethyl, trifluoromethoxy,
hydroxy, aminocarbonyl, cyano, ureido,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino or glycinamino.
[0052] The present invention also relates to the pharmaceutically
acceptable acid addition salts of compounds of the formula I. The
acids which are used to prepare the pharmaceutically acceptable
acid addition salts of the aforementioned base compounds of this
invention are those which form non-toxic acid addition salts, i.e.,
salts containing pharmacologically acceptable anions, such as the
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,
bisulfate, phosphate, acid phosphate, acetate, lactate, citrate,
acid citrate, tartrate, bitartrate, succinate, maleate, fumarate,
gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate and pamoate [,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
[0053] The invention also relates to base addition salts of formula
I. The chemical bases that may be used as reagents to prepare
pharmaceutically acceptable base salts of those compounds of
formula I that are acidic in nature are those that form non-toxic
base salts with such compounds. Such non-toxic base salts include,
but are not limited to those derived from such pharmacologically
acceptable cations such as alkali metal cations (ea., potassium and
sodium) and alkaline earth metal cations (eq., calcium and
magnesium), ammonium or water-soluble amine addition salts such as
N-methylglucamine-(meglumine), and the lower alkanolammonium and
other base salts of pharmaceutically acceptable organic amines.
[0054] The compounds of this invention may contain olefin-like
double bonds. When such bonds are present, the compounds of the
invention exist as cis and trans configurations and as mixtures
thereof.
[0055] The present invention also relates to compounds of formula I
wherein any of the hydrogens may optionally be replaced by
deuterium.
[0056] Unless otherwise indicated, the alkyl, alkenyl and alkynyl
groups referred to herein, as well as the alkyl moieties of other
groups referred to herein (e.g., alkoxy), may be linear or
branched, and they may also be cyclic (e.g., cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or
branched and contain cyclic moieties. Unless otherwise indicated,
halogen includes fluorine, chlorine, bromine, and iodine.
[0057] (C.sub.3-C.sub.10)Cycloalkyl when used herein refers to
cycloalkyl groups containing zero to two levels of unsaturation
such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl,
cycloheptenyl, bicyclo[3.2.1]octane, norbornanyl etc.
[0058] (C.sub.2-C.sub.9)Heterocycloalkyl when used herein refers to
pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl,
pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl,
chromenyl, barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl,
isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,
1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl,
1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl,
tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl,
1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl,
chromanyl, etc.
[0059] (C.sub.2-C.sub.9)Heteroaryl when used herein refers to
furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl,
isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl,
1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl,
1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl,
1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl,
cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl,
benzo[b]thiophenyl, 5, 6, 7, 8-tetrahydro-quinolin-3-yl,
benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl,
benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl,
isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl,
isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl,
benzoxazinyl; etc.
[0060] Aryl when used herein refers to phenyl or naphthyl.
[0061] The term "ureido", as used herein, refers to an
"amino-carbonyl-amino" moiety.
[0062] The term "acetyl", as used herein, refers to an
"alkyl-carbonyl" moiety wherein alkyl is defined as above.
[0063] The term "cyanoguanidino", as used herein, refers to a
functional group having the following formula 3
[0064] The term
"(C.sub.2-C.sub.9)heterocycloalkyl(C.dbd.N--CN)amino", as used
herein refers to a functional group having the following formula
4
[0065] wherein "HET" refers to a (C.sub.2-C.sub.9)heterocyloalkyl
or (C.sub.2-C.sub.9)heteroaryl group and the nigrogen of said group
is the place of attachment.
[0066] The term "mercapto", as used herein, refers to a "HS-"
moeity.
[0067] The compounds of this invention include all conformational
isomers (e.g., cis and trans isomers) and all optical isomers of
compounds of the formula I (e.g., enantiomers and diastereomers),
as well as racemic, diastereomeric and other mixtures of such
isomers.
[0068] The present invention also relates to a pharmaceutical
composition for treating or preventing a disorder or condition
selected from autoimmune diseases, rheumatoid arthritis, recent
onset type I diabetes, lupus, inflammatory bowel disease, optic
neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica,
uveitis, vasculitis, acute and chronic inflammatory conditions,
osteoarthritis, adult Respiratory Distress Syndrome, Respiratory
Distress Syndrome of infancy, ischemia reperfusion injury,
glomerulonephritis, allergic conditions, asthma, atopic dermatitis,
infection associated with inflammation, viral inflammation,
influenza, hepatitis, Guillian-Barre, chronic bronchitis,
xeno-transplantation, chronic and acute transplantation tissue
rejection, chronic and acute organ transplant rejection,
atherosclerosis, restenosis, HIV infectivity, granulomatous
diseases, sarcoidosis, leprosy and tuberculosis and sequelae
associated with certain cancers such as multiple myeloma. Compounds
in this series may also limit the production of cytokines at
inflammatory sites, including but not limited to TNF and IL-1, as a
consequence of decreasing cell infiltration, providing benefit for
diseases linked to TNF and IL-1, including congestive heart
failure, pulmonary emphysema or dyspnea associated therewith,
emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus (CMV),
adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex).
They may also provide benefit for the sequelae associated with
infection where such infection induces production of detrimental
inflammatory cytokines such as TNF e.g, fungal meningitis, joint
tissue damage, hyperplasia, pannus formation and bone resorption,
psoriatic arthritis, hepatic failure, bacterial meningitis,
Kawasaki syndrome, myocardial infarction, acute liver failure, lyme
disease, septic shock, cancer, trauma, and malaria in a mammal,
preferably a human, comprising an amount of a compound of the
formula I or a pharmaceutically acceptable salt thereof effective
in treating or preventing such disorder or condition and a
pharmaceutically acceptable carrier.
[0069] The present invention also relates to a pharmaceutical
composition for treating or preventing a disorder or condition that
can be treated or prevented by inhibiting chemokine binding to the
receptor CCR1 in a mammal, preferably a human, comprising an amount
of a compound of the formula I, or a pharmaceutically acceptable
salt thereof, effective in treating or preventing such disorder or
condition and a pharmaceutically acceptable carrier. Examples of
such disorders and conditions are those enumerated in the preceding
paragraph.
[0070] The present invention also relates to a method for treating
or preventing a disorder or condition selected from autoimmune
diseases, rheumatoid arthritis, recent onset type I diabetes,
lupus, inflammatory bowel disease, optic neuritis, psoriasis,
multiple sclerosis, polymyalgia rheumatica, uveitis, vasculitis,
acute and chronic inflammatory conditions, osteoarthritis, adult
Respiratory Distress Syndrome, Respiratory Distress Syndrome of
infancy, ischemia reperfusion injury, glomerulonephritis, allergic
conditions, asthma, atopic dermatitis, infection associated with
inflammation, viral inflammation, influenza, hepatitis,
Guillian-Barre, chronic bronchitis, xeno-transplantation, chronic
and acute transplantation tissue rejection, chronic and acute organ
transplant rejection, atherosclerosis, restenosis, HIV infectivity,
granulomatous diseases, sarcoidosis, leprosy and tuberculosis and
sequelae associated with certain cancers such as multiple myeloma.
Compounds in this series may also limit the production of cytokines
at inflammatory sites, including but not limited to TNF and IL-1,
as a consequence of decreasing cell infiltration, providing benefit
for diseases linked to TNF and IL-1, including congestive heart
failure, pulmonary emphysema or dyspnea associated therewith,
emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus (CMV),
adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex).
They may also provide benefit for the sequelae associated with
infection where such infection induces production of detrimental
inflammatory cytokines such as TNF e.g, fungal meningitis, joint
tissue damage, hyperplasia, pannus formation and bone resorption,
psoriatic arthritis, hepatic failure, bacterial meningitis,
Kawasaki syndrome, myocardial infarction, acute liver failure, lyme
disease, septic shock, cancer, trauma, and malaria in a mammal,
preferably a human, comprising administering to a mammal in need of
such treatment or prevention an amount of a compound of the formula
I, or a pharmaceutically acceptable salt thereof, that is effective
in treating or preventing such disorder or condition.
[0071] The present invention also relates to a method for treating
or preventing a disorder or condition that can be treated or
prevented by antagonizing the CCR1 receptor in a mammal, preferably
a human, comprising administering to a mammal in need of such
treatment or prevention an amount of a compound of the formula I,
or a pharmaceutically acceptable salt thereof, that is effective in
treating or preventing such disorder or condition.
[0072] The present invention also relates to a pharmaceutical
composition for treating or preventing a disorder or condition
selected from autoimmune diseases, rheumatoid arthritis, recent
onset type I diabetes, lupus, inflammatory bowel disease, optic
neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica,
uveitis, vasculitis, acute and chronic inflammatory conditions,
osteoarthritis, adult Respiratory Distress Syndrome, Respiratory
Distress Syndrome of infancy, ischemia reperfusion injury,
glomerulonephritis, allergic conditions, asthma, atopic dermatitis,
infection associated with inflammation, viral inflammation,
influenza, hepatitis, Guillian-Barre, chronic bronchitis,
xeno-transplantation, chronic and acute transplantation tissue
rejection, chronic and acute organ transplant rejection,
atherosclerosis, restenosis, HIV infectivity, granulomatous
diseases, sarcoidosis, leprosy and tuberculosis and sequelae
associated with certain cancers such as multiple myeloma. Compounds
in this series may also limit the production of cytokines at
inflammatory sites, including but not limited to TNF and IL-1, as a
consequence of decreasing cell infiltration, providing benefit for
diseases linked to TNF and IL-1, including congestive heart
failure, pulmonary emphysema or dyspnea associated therewith,
emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus (CMV),
adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex).
They may also provide benefit for the sequelae associated with
infection where such infection induces production of detrimental
inflammatory cytokines such as TNF e.g, fungal meningitis, joint
tissue damage, hyperplasia, pannus formation and bone resorption,
psoriatic arthritis, hepatic failure, bacterial meningitis,
Kawasaki syndrome, myocardial infarction, acute liver failure, lyme
disease, septic shock, cancer, trauma, and malaria in a mammal,
preferably a human, comprising a CCR1 receptor antagonizing
effective amount of a compound of the formula I, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
[0073] The present invention also relates to a pharmaceutical
composition for treating or preventing a disorder or condition that
can be treated or prevented by antagonizing the CCR1 receptor in a
mammal, preferably a human, comprising a CCR1 receptor antagonizing
effective amount of a compound of the formula I, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
[0074] The present invention also relates to a method for treating
or preventing a disorder or condition selected from autoimmune
diseases, rheumatoid arthritis, recent onset type I diabetes,
lupus, inflammatory bowel disease, optic neuritis, psoriasis,
multiple sclerosis, polymyalgia rheumatica, uveitis, vasculitis,
acute and chronic inflammatory conditions, osteoarthritis, adult
Respiratory Distress Syndrome, Respiratory Distress Syndrome of
infancy, ischemia reperfusion injury, glomerulonephritis, allergic
conditions, asthma, atopic dermatitis, infection associated with
inflammation, viral inflammation, influenza, hepatitis,
Guillian-Barre, chronic bronchitis, xeno-transplantation, chronic
and acute transplantation tissue rejection, chronic and acute organ
transplant rejection, atherosclerosis, restenosis, HIV infectivity,
granulomatous diseases, sarcoidosis, leprosy and tuberculosis and
sequelae associated with certain cancers such as multiple myeloma.
Compounds in this series may also limit the production of cytokines
at inflammatory sites, including but not limited to TNF and IL-1,
as a consequence of decreasing cell infiltration, providing benefit
for diseases linked to TNF and IL-1, including congestive heart
failure, pulmonary emphysema or dyspnea associated therewith,
emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus (CMV),
adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex).
They may also provide benefit for the sequelae associated with
infection where such infection induces production of detrimental
inflammatory cytokines such as TNF e.g, fungal meningitis, joint
tissue damage, hyperplasia, pannus formation and bone resorption,
psoriatic arthritis, hepatic failure, bacterial meningitis,
Kawasaki syndrome, myocardial infarction, acute liver failure, lyme
disease, septic shock, cancer, trauma, and malaria in a mammal,
preferably a human, comprising administering to a mammal in need of
such treatment or prevention a CCR1 receptor antagonizing effective
amount of a compound of formula I, or a pharmaceutically acceptable
salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0075] The following reaction Schemes illustrate the preparation of
the compounds of the present invention. Unless otherwise indicated
a, b, c, d, e, j, R1, R.sup.2, R.sup.3 and R.sup.4 in the reaction
Schemes and the discussion that follow are defined as above.
[0076] R.sup.16 and R.sup.17 together with the nitrogen to which
they are attached is selected from the group consisting of amino,
amino(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkylamino(C.s- ub.1-C.sub.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub-
.1-C.sub.6)alkylcarbonylamino,
acetylamino(C.sub.1-C.sub.6)alkylcarbonylam- ino,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkylcarbonylam-
ino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylcarbonylamin-
o, cyanoguanidino(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkylcyanoguanidino(C.sub.1-C.sub.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino(C.sub.1-C.sub.6)alkylcarbony-
lamino, aminocarbonyl(C.sub.1-C.sub.6)alkylcarbonylamino,
aminocarbonylamino(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkylaminocarbonylamino(C.sub.1-C.sub.6)alkylcarbonylami-
no,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonylamino(C.sub.1-C.sub.6)alkyl-
carbonylamino,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylcarbonylam- ino,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylcarbonylamino,
aminosulfonyl(C.sub.1-C.sub.6)alkylcarbonylamino,
hydroxy(C.sub.1-C.sub.6- )alkylureido,
(amino(C.sub.1-C.sub.6)alkylureido, (C.sub.1-C.sub.6)alkylam-
ino(C.sub.1-C.sub.6)alkylureido,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub- .1-C.sub.6)alkylureido,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)- alkylureido,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylureido,
aminosulfonyl(C.sub.1-C.sub.6)alkylureido,
aminocarbonyl(C.sub.1-C.sub.6)- alkylureido,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylurei- do,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkylureid-
o, acetylamino(C.sub.1-C.sub.6)alkylureido,
(acetyl)((C.sub.1-C.sub.6)alky-
l)amino(C.sub.1-C.sub.6)alkylureido,
carboxy(C.sub.1-C.sub.6)alkylureido,
halo(C.sub.1-C.sub.6)alkylsulfonylamino,
amino(C.sub.1-C.sub.6)alkylsulfo- nylamino,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkylsulfonylamino,
acetylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
(acetyl)((C.sub.1-C.sub.6-
)alkyl)amino(C.sub.1-C.sub.6)alkylsulfonylamino,
ureido(C.sub.1-C.sub.6)al- kylsulfonylamino,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylsulfon- ylamino,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylsulfony-
lamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylsulfonyla-
mino, cyanoguanidino(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylcyanoguanidino(C.sub.1-C.sub.6)alkylsulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino(C.sub.1-C.sub.6)alkylsulfony-
lamino, aminocarbonyl(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
aminosulfonylamino, (C.sub.1-C.sub.6)alkylaminosulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2aminosulfonylamino,
aminocarbonyl(C.sub.1-C-
.sub.6)alkylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylsu-
lfonylamino
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)al-
kylsulfonylamino, cyanoguanidino,
(C.sub.1-C.sub.6)alkylcyanoguanidino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino,
(C.sub.2-C.sub.9)heterocycl- oalkylcyanoguanidino,
(C.sub.2-C.sub.9)heteroarylcyanoguanidino,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylcyanoguanidino,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylcyanoguanidino,
amino(C.sub.1-C.sub.6)alkylcyanoguanidino,
(C.sub.1-C.sub.6)alkylamino(C.- sub.1-C.sub.6)alkylcyanoguanidino,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.s-
ub.1-C.sub.6)alkylcyanoguanidino,
aminocarbonyl(C.sub.1-C.sub.6)alkylcyano- guanidino,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylcyanog-
uanidino,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alky-
lcyanoguanidino, hydroxy(C.sub.1-C.sub.6)alkylamino,
aminocarbonyl(C.sub.1-C.sub.6)alkylamino,
carboxy(C.sub.1-C.sub.6)alkylam- ino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylamino,
aminosulfonyl(C.sub.1-C.sub.6)alkylamino,
(C.sub.2-C.sub.9)heteroaryl(C.s- ub.1-C.sub.6)alkylamino,
acetylamino(C.sub.1-C.sub.6)alkylamino,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkylamino, ((C.sub.1-C.sub.6)alkyl).sub.2amino,
(C.sub.6-C.sub.10)arylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl- amino,
amino(C.sub.1-C.sub.6)alkylamino,
(C.sub.2-C.sub.9)heterocycloalkyl- amino,
(C.sub.2-C.sub.9)heteroarylamino,
(C.sub.3-C.sub.10)cycloalkyl(C.su- b.1-C.sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.2-C.sub.6)alkenylcarbonylami- no,
(C.sub.3-C.sub.10)cycloalkylcarbonylamino,
(C.sub.6-C.sub.10)arylcarbo- nylamino,
(C.sub.2-C.sub.9)heterocycloalkylcarbonylamino,
halo(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-- C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.-
6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)al- kyl)amino,
((C.sub.1-C.sub.6)alkoxycarbonyl)((C.sub.1-C.sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.3-C.sub.10)cycloalkylamino, ureido,
(C.sub.1-C.sub.6)alkylureido, (C.sub.6-C.sub.10)arylureido,
((C.sub.6-C.sub.10)aryl).sub.2ureido,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.su- b.6)alkylureido,
halo(C.sub.1-C.sub.6)alkylureido, ((C.sub.1-C.sub.6)alkyl-
)((C.sub.6-C.sub.10)aryl)ureido,
((C.sub.1-C.sub.6)alkyl).sub.2ureido,
halo(C.sub.1-C.sub.6)alkylcarbonylureido, glycinamido,
(C.sub.1-C.sub.6)alkylglycinamido, aminocarbonylglycinamido,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkylcarbonylglycinamido,
(aminocarbonyl)((C.sub.1-C.sub.6)alkyl)glycinamido,
((C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1--
C.sub.6)alkyl)glycinamido,
((C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C-
.sub.6)alkylcarbonyl)glycinamido,
(C.sub.6-C.sub.10)arylcarbonylglycinamid- o,
((C.sub.6-C.sub.10)arylcarbonyl)((C.sub.1-C.sub.6)alkyl)glycinamido,
((C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl)glycinamido,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylaminocarbonyl)((C.sub.1-C.sub-
.6)alkyl)glycinamido,
(C.sub.6-C.sub.10)arylaminocarbonylglycinamido and
((C.sub.6-C.sub.10)arylaminocarbonyl)((C.sub.1-C.sub.6)alkyl)glycinamido.
[0077] R.sup.18 and R.sup.19 together with the nitrogen to which
they are attached is selected from the group consisting of
(C.sub.2-C.sub.9)hetero- aryl(C.sub.1-C.sub.6)alkylamino,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1- -C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylamino,
ureido(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C- .sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)al- kylamino,
halo(C.sub.1-C.sub.6)alkylamino, aminosulfonyl(C.sub.1-C.sub.6)a-
lkylamino,
(C.sub.1-C.sub.6)alkylaminosulfonyl(C.sub.1-C.sub.6)alkylamino,
carboxy(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.sub- .1-C.sub.6)alkylamino,
cyano(C.sub.1-C.sub.6)alkylamino,
aminocarbonyl(C.sub.1-C.sub.6)alkylamino,
acetylamino(C.sub.1-C.sub.6)alk- ylamino,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylamino,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylam-
ino,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)alkylamin-
o, cyanoguanidino(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkylcyanog- uanidino(C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2cyanogu-
anidino(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.- sub.1-C.sub.6)alkylamino,
ureido(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylamino,
aminocarbonyloxy(C.sub.1-C.sub.6)alkylamino,
acetylamino(C.sub.1-C.sub.6)- alkylcarbonylamino,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)-
alkylcarbonylamino,
aminocarbonyl(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkylcarbonyl-
amino, ureido(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkylur- eido(C.sub.1-C.sub.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2ure-
ido(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylami-
no(C.sub.1-C.sub.6)alkylcarbonylamino,
aminosulfonyl(C.sub.1-C.sub.6)alkyl- carbonylamino,
hydroxy(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylcar-
bonylamino,
(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.s-
ub.6)alkylcarbonylamino,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino- ,
(C.sub.2-C.sub.9)heteroarylcarbonylamino(C.sub.1-C.sub.6)alkylcarbonylam-
ino,
(C.sub.2-C.sub.9)heterocycloalkylcarbonylamino(C.sub.1-C.sub.6)alkylc-
arbonylamino, cyanoguanidino(C.sub.1-C.sub.6)alkylcarbonylamino,
cyano(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkylcarbonyla-
mino(C.sub.1-C.sub.6)alkylamino-carbonylamino,
amino(C.sub.1-C.sub.6)alkyl- aminocarbonylamino,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylamino- carbonyl
amino, ((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyla-
minocarbonylamino carboxy(C.sub.1-C.sub.6)alkylaminocarbonyl amino,
aminocarbonyl(C.sub.1-C.sub.6)alkylaminocarbonylamino,
(C.sub.1-C.sub.6)
alkylcarbonylamino(C.sub.1-C.sub.6)alkylaminocarbonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylaminocarbonylami-
no, (C.sub.1-C.sub.6)alkoxycarbonyl
amino(C.sub.1-C.sub.6)alkylaminocarbon- ylamino,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonyl
amino(C.sub.1-C.sub.6)alkylaminocarbonylamino,
(C.sub.2-C.sub.9)heteroary-
loxycarbonylamino(C.sub.1-C.sub.6)alkylaminocarbonylamino,
(C.sub.2-C.sub.9)heterocycloalkyl(C.sub.1-C.sub.6)alkylaminocarbonylamino-
,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylaminocarbonylamino,
ureido(C.sub.1-C.sub.6)alkylureido,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-- C.sub.6)alkylureido,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)- alkylureido,
cyanoguanidino(C.sub.1-C.sub.6)alkylureido,
amino(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylamino(C.s- ub.1-C.sub.6)alkylsulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub-
.1-C.sub.6)alkylsulfonylamino,
acetylamino(C.sub.1-C.sub.6)alkylsulfonylam- ino,
(acetyl)((C.sub.1-C.sub.6)alkyl)amino(C.sub.1-C.sub.6)alkylsulfonylam-
ino, ureido(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylurei- do(C.sub.1-C.sub.6)alkylsulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2ureid-
o(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(-
C.sub.1-C.sub.6)alkylsulfonylamino,
cyanoguanidino(C.sub.1-C.sub.6)alkylsu- lfonylamino,
(C.sub.1-C.sub.6)alkyl(cyanoguanidino)(C.sub.1-C.sub.6)alkyls-
ulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2(cyanoguanidino)(C.sub.1-C.sub-
.6)alkylsulfonylamino,
aminocarbonyl(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylsulfonylamino,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylsu-
lfonylamino,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)a-
lkylsulfonylamino, aminosulfonylamino(C.sub.1-C.sub.6)alkyl,
(C.sub.1-C.sub.6)alkylaminosulfonylamino,
((C.sub.1-C.sub.6)alkyl).sub.2a-
minosulfonylamino(C.sub.1-C.sub.6)alkyl, cyanoguanidino,
(C.sub.1-C.sub.6)alkyl(cyanoguanidino),
((C.sub.1-C.sub.6)alkyl).sub.2(cy- anoguanidino),
(C.sub.2-C.sub.9)heterocycloalkyl(cyanoguanidino),
(C.sub.2-C.sub.9)heterocycloalkyl(cyanoguanidino),
(C.sub.2-C.sub.9)heteroaryl(cyanoguanidino),
(C.sub.2-C.sub.9)heterocyclo-
alkyl(C.sub.1-C.sub.6)alkyl(cyanoguanidino),
(C.sub.2-C.sub.9)heteroaryl(C-
.sub.1-C.sub.6)alkyl(cyanoguanidino),
amino(C.sub.1-C.sub.6)alkyl(cyanogua- nidino),
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkyl(cyanoguanidino)-
,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkyl(cyanoguanidino-
), aminocarbonyl(C.sub.1-C.sub.6)alkyl(cyanoguanidino),
(C.sub.1-C.sub.6)alkylaminocarbonyl(C.sub.1-C.sub.6)alkyl(cyanoguanidino)-
,
((C.sub.1-C.sub.6)alkyl).sub.2aminocarbonyl(C.sub.1-C.sub.6)alkyl(cyanog-
uanidino), (C.sub.2-C.sub.9)heterocycloalkyl,
amino(C.sub.1-C.sub.6)alkyla- mino,
(C.sub.1-C.sub.6)alkylamino(C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino(C.sub.1-C.sub.6)alkylamino,
(C.sub.2-C.sub.9)heteroarylamino,
ureido(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkylureido(C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyl).sub.2ureido(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkylsulfonylamino(C.sub.1-C.sub.6)alkylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino(C.sub.1-C.sub.6)alkylamino,
(C.sub.2-C.sub.9)heterocycloalkyloxycarbonylamino(C.sub.1-C.sub.6)alkylam-
ino,
(C.sub.2-C.sub.9)heteroaryloxycarbonylamino(C.sub.1-C.sub.6)alkylamin-
o, aminocarbonyl(C.sub.1-C.sub.6)alkylamino,
cyanoguanidino(C.sub.1-C.sub.- 6)alkylamino,
(C.sub.2-C.sub.9)heteroaryl(C.sub.1-C.sub.6)alkylamino,
(C.sub.2-C.sub.9)heterocycloalkylamino,
(C.sub.1-C.sub.6)alkylcarbonylami- no,
halo(C.sub.1-C.sub.6)alkylcarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbon- ylamino, ureido,
(C.sub.1-C.sub.6)alkylureido, ((C.sub.1-C.sub.6)alkyl).su-
b.2ureido, amino, (C.sub.1-C.sub.6)alkylamino,
(C.sub.3-C.sub.10)cycloalky- lamino,
((C.sub.1-C.sub.6)alkyl).sub.2amino, hydroxy(C.sub.1-C.sub.6)alkyl-
amino, (C.sub.6-C.sub.10)arylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6- )alkylamino,
(C.sub.1-C.sub.6)alkylcarbonylamino, (C.sub.6-C.sub.10)arylca-
rbonylamino,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)alkyl)amino- ,
(C.sub.3-C.sub.10)cycloalkyl(C.sub.1-C.sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkoxycarbonylamino,
(C.sub.1-C.sub.6)alkoxycarbonyl(C.s-
ub.1-C.sub.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkoxycarbonyl)((C.sub.- 1-C.sub.6)alkyl)amino,
(C.sub.1-C.sub.6)alkylsulfonylamino,
((C.sub.1-C.sub.6)alkylsulfonyl)((C.sub.1-C.sub.6)alkyl)amino,
(C.sub.6-C.sub.10)arylsulfonylamino,
((C.sub.6-C.sub.10)arylsulfonyl)((C.- sub.1-C.sub.6)alkyl)amino,
(C.sub.2-C.sub.9)heterocycloalkylamino,
(C.sub.2-C.sub.9)heteroarylamino, halo(C.sub.1-C.sub.6)alkylamino,
(C.sub.6-C.sub.10)arylamino,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkyl- amino,
(aminocarbonyl(C.sub.1-C.sub.6)alkylamino,
((C.sub.1-C.sub.6)alkyla- minocarbonyl(C.sub.1-C.sub.6)alkylamino,
(carboxy(C.sub.1-C.sub.6)alkyl)am- ino,
((C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkylamino,
(amino(C.sub.1-C.sub.6)alkyl)amino,
(hydroxy(C.sub.1-C.sub.6)alkylamino, ureido,
(C.sub.1-C.sub.6)alkylureido, ((C.sub.1-C.sub.6)alkyl).sub.2ureid-
o, (C.sub.6-C.sub.10)arylureido,
(C.sub.6-C.sub.10)aryl).sub.2ureido,
(C.sub.6-C.sub.10)aryl(C.sub.1-C.sub.6)alkylureido,
halo(C.sub.1-C.sub.6)alkylureido,
(halo(C.sub.1-C.sub.6)alkyl)((C.sub.1-C- .sub.6)alkyl)ureido,
((C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alky- l)ureido,
and glycinamido. 5 6 7 8 9 10 11 12 13 14
[0078] In reaction 1 of Preparation A, the compound of formula
XXXV, wherein b is 0, 1 or 2, is converted to the corresponding
compound of formula XXXIV by reacting XXXV with an ethyldiamine
compound of the formula, (R.sup.3).sub.j-ethyldiamine, in the
presence of an aprotic solvent, such as diethylether. The reaction
mixture is heated to reflux for a time period between about 1 hour
to about 12 hours.
[0079] In reaction 2 of Preparation A, the compound of formula
XXXIV is converted to the corresponding compound of formula XXXIII
by reducing XXXIV with a reducing agent, such as sodium
borohydride, in a refluxing protic solvent, such as ethanol. In
reaction 3 of Preparation A, the compound of formula XXXIII is
converted to the corresponding compound of formula XXX by reacting
XXXIII with a benzaldehyde compound of the formula 15
[0080] in the presence of a base, such as triethylamine, and a
reducing agent, such as sodium triacetoxyborohydride, in an aprotic
solvent, such as 1,2-dichloroethane. The reaction mixture is
stirred at room temperature for a time period between about 1 hour
to about 4 hours, preferably about 2 hours.
[0081] In reaction 1 of Preparation B, the compound of formula
XXII, wherein b is 0, 1 or 2, is converted to the corresponding
compound of formula XXI by reacting XXIII with a benzaldehyde
compound of the formula 16
[0082] in the presence of a base, such as triethylamine, a reducing
agent, such as sodium borohydride and an aprotic solvent, such as
1,2-dichloroethane. The reaction is stirred, at room temperature,
for a time period between about 1 hour to about 4 hours, preferably
about 2 hours.
[0083] In reaction 2 of Preparation B, the compound of formula XXI
is converted to the corresponding compound of formula XX by first
reacting a compound of the formula 17
[0084] wherein j is 0, 1 or 2, with 4-methyl morpholine and
isobutylchloroformate in the presence of a polar aprotic solvent,
such as tetrahydrofuran, followed by reacting the intermediate so
formed with the compound of formula XXI. The reaction mixture, so
formed, is stirred overnight at room temperature.
[0085] In reaction 3 of Preparation B, the compound of formula XX
is converted to the corresponding piperizine-2,5-dione compound of
formula XIX by treating XX with trifluoroacetic acid in the
presence of a polar aprotic solvent, such as methylene chloride.
The reaction is stirred, at room temperature, for a time period
between about 1 hour to about 4 hours, preferably about 2
hours.
[0086] In reaction 4 of Preparation B, the compound of formula XIX
is converted to the corresponding compound of formula XVIII by
reducing XIX with a reducing agent, such as lithium aluminum
hydride. The reaction is conducted at a temperature between about
-10C to about 10C, preferably about 0.degree. C., for a time period
between about 10 minutes to about 90 minutes, preferably about 40
minutes.
[0087] In reaction 1 of the Preparation C, the compound of formula
XXV is converted to the corresponding compound of formula XXIV by
reacting XXV with an amine of the formula, NHR.sup.18R.sup.19,
wherein R.sup.18 and R.sup.19 are each independently selected from
hydrogen, a nitrogen containing (C.sub.2-C.sub.9)heterocycloalkyl
or (C.sub.2-C.sub.9)heteroar- yl group, or (C.sub.1-C.sub.6)alkyl
optionally substituted by hydroxy, aminocarbonyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2carbonyl, carboxy,
(C.sub.1-C.sub.6)alkylsu- lfonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino, aminosulfonyl,
(C.sub.1-C.sub.6)alkylaminosulfonyl,
((C.sub.1-C.sub.6)alkyl).sub.2aminos- ulfonyl,
(C.sub.6-C.sub.10)alkoxy, (C.sub.2-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl,
(C.sub.1-C.sub.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)alkyl)amino,
cyano, ureido, (C.sub.1-C.sub.6)alkylureido,
((C.sub.1-C.sub.6)alkyl).sub.2ureid- o, cyanoguanidino,
(C.sub.1-C.sub.6)alkylcyanoguanidino and
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino, or R.sup.18 and
R.sup.19 are taken together with the nitrogen to which they are
attached to form a (C.sub.2-C.sub.9)heteroaryl or
(C.sub.2-C.sub.9)heterocycloalkyl group, in the presence of a polar
aprotic solvent, such as methylene chloride. The reaction mixture
is stirred, at room temperature, for a time period between about 1
hour to about 24 hours, preferably about 12 hours.
[0088] In reaction 2 of Preparation C, the compound of formula XXIV
is converted to the corresponding compound of formula XXIII by
reacting XXIV with thiophenol in the presence of a base, such as
sodium hydride, and a polar aprotic solvent, such as
dimethylformamide. The reaction is heated to reflux for a time
period between about 1 hour to about 10 hours, preferably about 4
hours.
[0089] In reaction 3 of Preparation C, the compound of formula XXV
is converted to the corresponding compound of formula XXXVIII by
reacting XXV with sodium cyanate in the presence of pyridine and a
polar aprotic solvent, such as acetonitrile. The reaction is
stirred, at room temperature, for a time period between about 2
hours to about 18 hours, preferably about 10 hours. An amine of the
formula, H.sub.2N--C(O)--NR.sup.18R.sup.19, is then added and the
reaction mixture so formed is stirred, at room temperature, for a
time period between about 2 hours to about 24 hours, preferably
about 8 hours.
[0090] In reaction 4 of Preparation C, the compound of formula
XXXVIII is converted to the corresponding compound of formula
XXXVII according to the procedure described above in reaction 2 of
Preparation C.
[0091] In reaction 1 of Scheme 1, the compound of formula XXX is
converted to the corresponding compound of formula X by reacting
XXX with a compound of the formula, A-(X).sub.c--(Y).sub.d-A,
wherein A is chloro or bromo, in the presence of a base, such as
triethylamine, and a polar aprotic solvent, such as methylene
chloride. The reaction is stirred at a temperature between about
-10.degree. C. to about 10.degree. C., for a time period between
about 15 minutes to about 90 minutes, preferably about 30
minutes.
[0092] In reaction 2 of Scheme 1, the compound of formula X is
converted to the corresponding compound of formula I by reacting X
with a compound of the formula, H-(Z).sub.e-R.sup.4 wherein e is 1
and Z is oxygen, in the presence of potassium carbonate, potassium
iodide and an aprotic solvent, such as butanone. The reaction is
heated to reflux for a time period between about 4 hours to about 8
hours, preferably about 6 hours.
[0093] In reaction 1 of Scheme 2, the compound of formula XXX is
converted to the corresponding compound of formula I by reacting
XXX with a compound of the formula,
A-(X).sub.c--(Y).sub.d-(Z).sub.e-R.sup.4, wherein A is chloro or
bromo, in the presence of a base, such as triethylamine, and a
polar aprotic solvent, such as methylene chloride. The reaction is
stirred at a temperature between about -10.degree. C. to about
10.degree. C., for a time period between about 15 minutes to about
90 minutes, preferably about 30 minutes.
[0094] In reaction 1 of Scheme 3, the compound of formula X is
converted to the corresponding compound of formula XII according to
the procedure described above in reaction 2 of Scheme 1.
[0095] In reaction 2 of Scheme 3, the compound of formula XII is
converted to the corresponding compound of formula XI by reacting
XlI with lithium hydroxide monohydrate in the presence of methanol,
tetrahydrofuran and water. The reaction mixture is stirred
overnight at room temperature.
[0096] In reaction 3 of Scheme 3, the compound of formula XI is
converted to the corresponding compound of formula II, by reacting
Xl with an amine, in the presence of 4-dimethylaminopyridine,
1-(3-dimethylaminopropyl)-3-ethylcarbodiimine and a polar aprotic
solvent, such as methylene chloride. The resulting reaction mixture
is stirred overnight at room temperature.
[0097] In reaction 1 of Scheme 4, the compound of formula X is
converted to the corresponding compound of formula XV according to
the procedure described above in reaction 2 of Scheme 1.
[0098] In reaction 2 of Scheme 4, the compound of formula XV is
converted to the corresponding compound of formula XIV by
hydrogenating XV in the presence of a catalyst, such as platinum on
carbon, and a polar protic solvent, such as ethanol. The reaction
is carried out under a pressure between about 30 psi to about 40
psi, preferably about 35 psi, for a time period between about 15
minutes to about 1 hour, preferably 30 minutes.
[0099] In reaction 3 of Scheme 4, for urea formation, the compound
of formula XIV is converted to the corresponding compound of
formula V by first reacting XIV with 4-nitrophenyl chloroformate in
the presence of a base, such as pyridine, and a polar aprotic
solvent, such as methlyene chloride, followed by reacting the
intermediate so formed with an amine. The reaction mixture, so
formed, is allowed to stir overnight at room temperature. For
sulfonamide formation, the compound of formula XIV is reacted with
a sulfonyl chloride compound of the formula, R.sup.16--Cl, in the
presence of a base, such as triethylamine, and a polar aprotic
solvent, such as methylene chloride. The reaction is stirred
overnight at ambient temperature. For cyanoguanidine formation, the
compound of formula XIV is first treated with sodium hydride in an
aprotic solvent, such as tetrahydrofuran, followed by reacting, the
intermediate so formed with dimethyl-N-cyanodithio iminocarbonate.
The reaction mixture so formed is heated to reflux overnight. The
N-cyano-S-methyl-isothiourea intermediate is then reacted with an
amine in the presence of a polar protic solvent, such as methanol.
For amide formation, the compound of formula XIV is reacted with an
acid, such as 3-tert-butoxycarbonylaminopr- opionic acid in the
presence of N-methylmorpholine, O-benzotriazole-1-yl-N,N,N,
N-tetramethyluronium hexafluorophosphate and a polar aprotic
solvent, such as methylene chloride.
[0100] In reaction 1 of Scheme 5, the compound of formula X is
converted to the corresponding compound of formula XVI, wherein k
is 0, 1, 2, 3 or 4, according to the procedure described above in
reaction 2 of Scheme 1.
[0101] In reaction 2 of Scheme 5, the compound of formula XVI is
converted to the corresponding compound of formula VII by reacting
XVI with an amine of the formula, R.sup.16 R.sup.17N, wherein
R.sup.16 and R.sup.17 are each indepenently hydrogen, a nitrogen
containing (C.sub.2-C.sub.9)heterocycloalkyl or
(C.sub.2-C.sub.9)heteroaryl group, or (C.sub.1-C.sub.6)alkyl
optionally substituted by hydroxy, aminocarbonyl,
(C.sub.1-C.sub.6)alkylaminocarbonyl,
((C.sub.1-C.sub.6)alkyl).sub.2carbonyl, carboxy,
(C.sub.1-C.sub.6)alkylsu- lfonylamino,
(C.sub.1-C.sub.6)alkoxycarbonylamino, aminosulfonyl,
(C.sub.1-C.sub.6)alkylaminosulfonyl,
[0102] ((C.sub.1-C.sub.6)alkyl).sub.2aminosulfonyl,
(C.sub.6-C.sub.10)alkoxy, (C.sub.2-C.sub.9)heteroaryl,
(C.sub.2-C.sub.9)heterocycloalkyl,
(C.sub.1-C.sub.6)alkylcarbonylamino,
((C.sub.1-C.sub.6)alkylcarbonyl)((C.sub.1-C.sub.6)alkyl)amino,
cyano, ureido, (C.sub.1-C.sub.6)alkylureido,
((C.sub.1-C.sub.6)alkyl).sub.2ureid- o, cyanoguanidino,
(C.sub.1-C.sub.6)alkylcyanoguanidino and
((C.sub.1-C.sub.6)alkyl).sub.2cyanoguanidino, in the presence of a
10:1 ratio solution of dichloroethane/acetic acid. The reaction
mixture is stirred, at room temperature, for a time period between
about 30 minutes to about 2 hours, preferably about 1 hour. A
reducing agent, such as sodium cyanoborohydride is than added to
the mixture and the reaction is allowed to stir overnight at room
temperature. When R.sup.16 and/or R.sup.17 is/are hydrogen, the
compound of formula VII may further be reacted according to the
procedure described above in reaction 3 of Scheme 4, to provide
ureas, sulfonamides, cyanoguanidinos, or amides.
[0103] In reaction 1 of Scheme 6, the compound of formula X is
converted to the corresponding compound of formula XXXIX according
to the procedure described above in reaction 2 of Scheme 1.
[0104] In reaction 2 of Scheme 6, the compound of formua X is
converted to the corresponding compound of formula XXXX according
to the procedure described above in reaction 2 of Scheme 1.
[0105] In reaction 1 of Scheme 7, the acid compound of formula
XXXVI is converted to the corresponding compound of formula XXXII
by treating XXXVI with thionyl chloride neat or in an aprotic
solvent, at room temperature, for a time period between about 1
hour to about 24 hours, preferably 1 hour. The acid chloride so
formed is dissolved in a polar aprotic solvent with a compound of
the formula, (H.sub.3CO)(H.sub.3C)NH.H- Cl, in the presence of an
amine base, such as triethylamine. The reaction mixture is stirred,
at room temperature, for a time period between about 1 hour to
about 48 hours, preferably about 12 hours.
[0106] In reaction 2 of Scheme 7, the amide compound of formula
XXXII is converted to the corresponding compound of formula XXXI by
reacting XXXII with a (C.sub.2-C.sub.9)heteroaryl lithium reagent
in the presence of a polar aprotic solvent at a temperature between
about -100.degree. C. to room temperature, preferably about
-78.degree. C. The resulting reaction mixture is stirred for a time
period between about 1 hour to about 24 hours, preferably about 12
hours, at a temperature between about -78.degree. C. to about
50.degree. C., preferably about 20.degree. C.
[0107] Unless indicated otherwise, the pressure of each of the
above reactions is not critical. Generally, the reactions will be
conducted at a pressure of about one to about three atmospheres,
preferably at ambient pressure (about one atmosphere). The
compounds of the formula I which are basic in nature are capable of
forming a wide variety of different salts with various inorganic
and organic acids. Although such salts must be pharmaceutically
acceptable for administration to animals, it is often desirable in
practice to initially isolate a compound of the formula I from the
reaction mixture as a pharmaceutically unacceptable salt and then
simply convert the latter back to the free base compound by
treatment with an alkaline reagent, and subsequently convert the
free base to a pharmaceutically acceptable acid addition salt. The
acid addition salts of the base compounds of this invention are
readily prepared by treating the base compound with a substantially
equivalent amount of the chosen mineral or organic acid in an
aqueous solvent medium or in a suitable organic solvent such as
methanol or ethanol. Upon careful evaporation of the solvent, the
desired solid salt is obtained.
[0108] The acids which are used to prepare the pharmaceutically
acceptable acid addition salts of the base compounds of this
invention are those which form non-toxic acid addition salts, i.e.,
salts containing pharmacologically acceptable anions, such as
hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or
bisulfate, phosphate or acid phosphate, acetate, lactate, citrate
or acid citrate, tartrate or bitartrate, succinate, maleate,
fumarate, gluconate, saccharate, benzoate, methanesulfonate and
pamoate [1,1'-methylene-bis-(2-hydroxy-3-naphthoate)- ] salts.
[0109] Those compounds of the formula I which are also acidic in
nature, are capable of forming base salts with various
pharmacologically acceptable cations. Examples of such salts
include the alkali metal or alkaline-earth metal salts and
particularly, the sodium and potassium salts. These salts are all
prepared by conventional techniques. The chemical bases which are
used as reagents to prepare the pharmaceutically acceptable base
salts of this invention are those which form non-toxic base salts
with the herein described acidic compounds of formula I. These
non-toxic base salts include those derived from such
pharmacologically acceptable cations as sodium, potassium, calcium
and magnesium, etc. These salts can easily be prepared by treating
the corresponding acidic compounds with an aqueous solution
containing the desired pharmacologically acceptable cations, and
then evaporating the resulting solution to dryness, preferably
under reduced pressure. Alternatively, they may also be prepared by
mixing lower alkanolic solutions of the acidic compounds and the
desired alkali metal alkoxide together, and then evaporating the
resulting solution to dryness in the same manner as before. In
either case, stoichiometric quantities of reagents are preferably
employed in order to ensure completeness of reaction and maximum
product yields.
[0110] Compounds of the formula I and their pharmaceutically
acceptable salts (hereinafter also referred to, collectively, as
"the active compounds") are potent antagonists of the CCR1
receptors. The active compounds are useful in the treatment or
prevention of autoimmune diseases (such as rheumatoid arthritis,
type I diabetes (recent onset), inflammatory bowel disease, optic
neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica,
uveitis, and vasculitis), acute and chronic inflammatory conditions
(such as osteoarthritis, adult respiratory distress syndrome,
Respiratory Distress Syndrome of infancy, ischemia reperfusion
injury, and glomerulonephritis), allergic conditions (such as
asthma and atopic dermatitis), infection associated with
inflammation (such as viral inflammation (including influenza and
hepatitis) and Guillian-Barre), chronic bronchitis,
xeno-transplantation, transplantation tissue rejection,
atherosclerosis, restenosis, HIV infectivity (co-receptor usage),
and granulomatous diseases (including sarcoidosis, leprosy and
tuberculosis).
[0111] The activity of the compounds of the invention can be
assessed according to procedures know to those of ordinary skill in
the art. Examples of recognized methods for determining CCR1
induced migration can be found in Coligan, J. E., Kruisbeek, A. M.,
Margulies, D. H., Shevach, E. M., Strober, W. editors: Current
Protocols In Immunology, 6.12.1-6.12.3. (John Wiley and Sons, NY,
1991). One specific example of how to determine the activity of a
compound for inhibiting migration is described in detail below.
Chemotaxis Assay
[0112] The ability of compounds to inhibit the chemotaxis to
various chemokines can be evaluated using standard 48 or 96 well
Boyden Chambers with a 5 micron polycarbonate filter. All reagents
and cells can be prepared in standard RPMI (BioWhitikker Inc.)
tissue culture medium supplemented with 1 mg/ml of bovine serum
albumin. Briefly, MIP-1 a (Peprotech, Inc., P.O. Box 275, Rocky
Hill N.J.) or other test agonists, were placed into the lower
chambers of the Boyden chamber. A polycarbonate filter was then
applied and the upper chamber fastened. The amount of agonist
chosen is that determined to give the maximal amount of chemotaxis
in this system (e.g., 1 nM for MIP-1.alpha. should be
adequate).
[0113] THP-1 cells (ATCC TIB-202), primary human monocytes, or
primary lymphocytes, isolated by standard techniques can then be
added to the upper chambers in triplicate together with various
concentrations of the test compound. Compound dilutions can be
prepared using standard serological techniques and are mixed with
cells prior to adding to the chamber.
[0114] After a suitable incubation period at 37 degrees centigrade
(e.g. 3.5 hours for THP-1 cells, 90 minutes for primary monocytes),
the chamber is removed, the cells in the upper chamber aspirated,
the upper part of the filter wiped and the number of cells
migrating can be determined according to the following method.
[0115] For THP-1 cells, the chamber (a 96 well variety manufactured
by Neuroprobe) can be centrifuged to push cells off the lower
chamber and the number of cells can be quantitated against a
standard curve by a color change of the dye fluorocein
diacetate.
[0116] For primary human monocytes, or lymphocytes, the filter can
be stained with Dif Quik.RTM. dye (American Scientific Products)
and the number of cells migrating can be determined
microscopically.
[0117] The number of cells migrating in the presence of the
compound are divided by the number of cells migrating in control
wells (without the compound). The quotant is the % inhibition for
the compound which can then be plotted using standard graphics
techniques against the concentration of compound used. The 50%
inhibition point is then determined using a line fit analysis for
all concentrations tested. The line fit for all data points must
have an coefficient of correlation (R squared) of >90% to be
considered a valid assay.
[0118] All of the compounds of the invention that were tested had
IC.sub.50 of less than 25 .mu.M, in the Chemotaxis assay.
[0119] The compositions of the present invention may be formulated
in a conventional manner using one or more pharmaceutically
acceptable carriers. Thus, the active compounds of the invention
may be formulated for oral, buccal, intranasal, parenteral (e.g.,
intravenous, intramuscular or subcutaneous) or rectal
administration or in a form suitable for administration by
inhalation or insufflation. The active compounds of the invention
may also be formulated for sustained delivery.
[0120] For oral administration, the pharmaceutical compositions may
take the form of, for example, tablets or capsules prepared by
conventional means with pharmaceutically acceptable excipients such
as binding agents (e.g., pregelatinized maize starch,
polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers
(e.g., lactose, microcrystalline cellulose or calcium phosphate);
lubricants (e.g., magnesium stearate, talc or silica);
disintegrants (e.g., potato starch or sodium starch glycolate); or
wetting agents (e.g., sodium lauryl sulphate). The tablets may be
coated by methods well known in the art. Liquid preparations for
oral administration may take the form of, for example, solutions,
syrups or suspensions, or they may be presented as a dry product
for constitution with water or other suitable vehicle before use.
Such liquid preparations may be prepared by conventional means with
pharmaceutically acceptable additives such as suspending agents
(e.g., sorbitol syrup, methyl cellulose or hydrogenated edible
fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous
vehicles (e.g., almond oil, oily esters or ethyl alcohol); and
preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic
acid).
[0121] For buccal administration, the composition may take the form
of tablets or lozenges formulated in conventional manner.
[0122] The active compounds of the invention may be formulated for
parenteral administration by injection, including using
conventional catheterization techniques or infusion. Formulations
for injection may be presented in unit dosage form, e.g., in
ampules or in multi-dose containers, with an added preservative.
The compositions may take such forms as suspensions, solutions or
emulsions in oily or aqueous vehicles, and may contain formulating
agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be in powder form for
reconstitution with a suitable vehicle, e.g., sterile pyrogen-free
water, before use.
[0123] The active compounds of the invention may also be formulated
in rectal compositions such as suppositories or retention enemas,
e.g., containing conventional suppository bases such as cocoa
butter or other glycerides.
[0124] For intranasal administration or administration by
inhalation, the active compounds of the invention are conveniently
delivered in the form of a solution or suspension from a pump spray
container that is squeezed or pumped by the patient or as an
aerosol spray presentation from a pressurized container or a
nebulizer, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount. The
pressurized container or nebulizer may contain a solution or
suspension of the active compound. Capsules and cartridges (made,
for example, from gelatin) for use in an inhaler or insufflator may
be formulated containing a powder mix of a compound of the
invention and a suitable powder base such as lactose or starch.
[0125] A proposed dose of the active compounds of the invention for
oral, parenteral or buccal administration to the average adult
human for the treatment of the conditions referred to above (e.g.,
rheumatoid arthritis) is 0.1 to 1000 mg of the active ingredient
per unit dose which could be administered, for example, 1 to 4
times per day.
[0126] Aerosol formulations for treatment of the conditions
referred to above (eq., rheumatoid arthritis) in the average adult
human are preferably arranged so that each metered dose or "puff"
of aerosol contains 20 .mu.g to 1000 .mu.g of the compound of the
invention. The overall daily dose with an aerosol will be within
the range 0.1 mg to 1000 mg. Administration may be several times
daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or
3 doses each time.
[0127] The active agents can be formulated for sustained delivery
according to methods well known to those of ordinary skill in the
art. Examples of such formulations can be found in U.S. Pat. Nos.
3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397.
[0128] The compounds of the invention can also be utilized in
combination therapy with, but not limited to, other therapeutic
agents such as with T-cell immunosuppressant agents such as
rapamycin cyclosporin A and FK-506, with steroid sparing agents
such as Cellcept.RTM., or with classical anti-inflammatory agents
(e.g. cyclooxygenase/lipoxygenase inhibitors) such as tenidap,
aspirin, acetaminophen, naproxen and piroxicam.
[0129] The following Examples illustrate the preparation of the
compounds of the present invention. NMR data are reported in parts
per million (.delta.) and are referenced to the deuterium lock
signal from the sample solvent (deuteriochloroform unless otherwise
specified). Commercial reagents were utilized without further
purification. THF refers to tetrahydrofuran. DMF refers to
N,N-dimethylformamide. Chromatography refers to column
chromatography performed using 32-63 mm silica gel and executed
under nitrogen pressure (flash chromatography) conditions. Low
Resolution Mass Spectra (LRMS) were recorded on either a Hewlett
Packard 5989.RTM., utilizing chemical ionization (ammonium), or a
Fisons (or Micro Mass) Atmospheric Pressure Chemical Ionization
(APCI) platform which uses a 50/50 mixture of acetonitrile/water
with 0.1% formic acid as the ionizing agent. Room or ambient
temperature refers to 20-25.degree. C. All non-aqueous reactions
were run under a nitrogen atmosphere for convenience and to
maximize yields. The names for the compounds of the invention were
created by the Autonom 2.0 PC-batch version from Beilstein
Informationssysteme GmbH (ISBN 3-89536-976-4).
EXAMPLE 1
[0130] 18
(2R,5S)-2-[4-Chloro-2-(piperazine-1-carbonyl)-phenoxy]-1-[4-(4-fluoro-benz-
yl)-2.5-dimethyl-piperazin-1-yl]-ethanone
[0131] (R)-2-(4-Fluoro-benzylamino)-propionic Acid Methyl Ester
[0132] To a solution of (R)-2-amino-propionic acid methyl ester
hydrochloride (25 g, 179 mmol) and 4-fluorobenzaldehyde (23 ml, 215
mmol) in 1,2-dichloroethane (200 ml) was added triethylamine (25
ml, 179 mmol). The resulting mixture was stirred for two hours at
ambient temperature followed by addition of sodium
acetoxyborohydride (57 g, 268 mmol) in four portions. The resulting
mixture was stirred overnight at ambient temperature. The reaction
was neutralized with dilute aqueous sodium hydroxide solution and
extracted with dichloromethane (2.times.). The organic layers were
combined, dried over magnesium sulfate, filtered and concentrated
in vacuo. Chromatography on silica gel gave the title compound
(34.4 g, 91% yield).
[0133]
(2R,5S)-2-[(2-tert-Butoxycarbonylamino-propionyl)-(4-fluoro-benzyl)-
-amino]-propionic Acid Methyl Ester
[0134] To a solution of (R)-2-tert-butoxycarbonylamino-propionic
acid (37 g, 195 mmol) in dry tetrahydrofuran (250 ml) at 0.degree.
C. was added 4-methyl morpholine (21.5 ml, 195 mmol) followed by
isobutylchloroformate (25.3 ml, 195 mmol). The reaction was allowed
to warm to ambient temperature and stirred for two hours. This was
followed by the addition of (S)-2-(4-fluoro-benzylamino)-propionic
acid methyl ester (34.4 g, 162 mmol). The resulting mixture was
stirred overnight at ambient temperature. The reaction mixture was
filtered through a pad of celite and the filter cake was washed
with ethyl acetate. The filtrate was concentrated in vacuo, diluted
with ethyl acetate and washed with water and brine. The organics
were dried over magnesium sulfate, filtered and concentrated in
vacuo. Chromatography on silica gel gave the title compound (43.2
g, 70% yield).
[0135]
(2R,5S)-1-(4-Fluoro-benzyl)-3.6-dimethyl-piperazine-2,5-dione
[0136] To a solution of
(2R,5S)-2-[(2-tert-butoxycarbonylamino-propionyl)--
(4-fluorobenzyl)-amino]-propionic acid methyl ester (43 g, 382
mmol) in dichloromethane (120 ml) at 0.degree. C. was added
trifluoroacetic acid (60 ml). The reaction was allowed to warm to
ambient temperature and stirred for 2 hours. The reaction was
cooled to 0.degree. C. and slowly quenched by addition of 3N
aqueous sodium hydroxide until basic. The resulting mixture was
extracted with dichloromethane (2.times.). The combined organics
were dried over magnesium sulfate, filtered and concentrated in
vacuo to give the title compound (22 g, 78% yield).
[0137] (2R, 5S)-1-(4-Fluoro-benzyl)-2,5-dimethyl-piperazine
[0138] To a solution of (2R,
5S)-1-(4-fluoro-benzyl)-3,6-dimethyl-piperazi- ne-2,5-dione (22 g,
87.9 mmol) in dry tetrahydrofuran (160 ml) at 0.degree. C. was
added a solution of lithium aluminum hydride (1 M in
tetrahydrofuran, 373 ml, 373 mmol) dropwise over 40 minutes. The
reaction mixture was then refluxed for 4 hours, cooled to ambient
temperature and slowly quenched with water. The resulting mixture
was filtered through a pad of celite and the filter cake was washed
with ethyl acetate. The filtrate was then concentrated, diluted
with ethyl acetate and washed with saturated aqueous sodium
hydrogen carbonate. The organic layer was separated, dried over
magnesium sulfate, filtered and concentrated in vacuo to give the
title compound (17.7 g, 91% yield).
[0139] (2R,
5S)-2-Chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-y-
l]-ethanone
[0140] To a solution of (2R,
5S)-1-(4-fluoro-benzyl)-2,5-dimethyl-piperazi- ne (2.5 g, 11.25
mmol) in dry dichloromethane (11 ml) at 0.degree. C. was added
triethylamine (1.57 ml, 11.2 mmol) followed by chloroacetyl
chloride (0.858 ml, 11.2 mmol). The resulting reaction mixture was
stirred for 30 minutes. The reaction was then filtered through a
pad of celite, washed with dichloromethane and the resulting
filtrate was concentrated to give a yellow oil. Chromatography on
silica get gave the title compound (2.84 g, 86% yield).
[0141] (2R.
5S)-5-Chloro-2-[2-[4-(4-fluoro-benzyl)-2.5-dimethyl-pilerazin--
1-yl]-2-oxo-ethoxy]-benzoic Acid Methyl Ester
[0142] To a solution of (2R,
5S)-2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimet-
hyl-piperazin-1-yl]-ethanone (2.75 g, 9.2 mmol) in butanone (50 ml)
was added methyl 5-chloro-2-hydroxybenzoate (1.55 g, 9.2 mmol),
potassium carbonate (2.54 g, 18.4 mmol) and potassium iodide (1.52
g, 9.2 mmol). The resulting mixture was stirred at reflux for 6
hours. The reaction was then cooled, diluted with ethyl acetate,
and washed with brine. The organics were dried over magnesium
sulfate, filtered and concentrated in vacuo to give an orange oil.
Chromatography on silica gel gave the title compound (4.1 g, 100%
yield).
[0143] (2R,
5S)-5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin--
1-yl]-2-oxo-ethoxy}-benzoic Acid
[0144] To a solution of (2R,
5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-di-
methyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoic acid methyl ester
(4.12 g, 9.18 mmol) in tetrahydrofuran (10 ml), methanol (10 ml)
and water (4 ml) was added lithium hydroxide monohydrate (1.93 g,
45.9 mmol). The resulting mixture was stirred overnight at ambient
temperature. The reaction was then concentrated, diluted with 1N
hydrochloric acid and extracted with dichloromethane (2.times.).
The organic layers were combined, dried over magnesium sulfate,
filtered and concentrated to give a white foam. Triteration in
dichloromethane and diethyl ether gave the title compound (1.38 g,
35% yield).
[0145] (2R,
5S)-4-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperaz-
in-1-yl]-2-oxo-ethoxy}-benzoyl)-piperazine-1-carboxylic Acid
Tert-Butyl Ester
[0146] To a solution of (2R,
5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-di-
methyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoic acid (0.10 g, 0.212
mmol) in dichloromethane (4 ml) was added 4-dimethylaminopyridine
(0.039 g, 0.318 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.061
g, 0.318 mmol) and tert-butyl 1-piperazinecarboxylate (0.041 g,
0.222 mmol). The resulting mixture was stirred overnight at ambient
temperature. It was then diluted with dichloromethane and washed
with brine. The organics were dried over magnesium sulfate,
filtered and concentrated to give a clear oil. Chromatography on
silica gel gave the title compound (0.110 g, 85% yield).
[0147] (2R,
5S)-2-[4-Chloro-2-(piperazine-1-carbonyl)-phenoxy]-1-[4-(4-flu-
oro-benzyl)-2.5-dimethyl-piperazin-1-yl]-ethanone
[0148] To a solution of (2R,
5S).sub.4-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-
-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoyl)-piperazine-1-carboxyl-
ic acid tert-butyl ester (0.110 g, 0.182 mmol) in dichloroethane
(10 ml) wass added trifluoroacetic acid (5 ml). The reaction was
stirred for two hours at ambient temperature. The reaction was then
diluted with dichloromethane and washed with 1 N aqueous sodium
hydroxide. The organics were dried over magnesium sulfate, filtered
and concentrated to give the title compound (0.080 g, 87%
yield).
[0149] The title compounds for Examples 2-12 were prepared by a
method analogous to that described in Example 1.
1 19 Example R.sup.20 R.sup.2 2 20 Me 3 21 Me 4 22 H 5 23 H 6 24 H
7 25 H 8 26 H 9 27 H 10 --NHSO.sub.2Me Me 11
--NH--(CH.sub.2).sub.2--NHSO.sub.2CH.sub.3 CH.sub.3 12
--NH--(CH.sub.2).sub.2--NHC(O)NH.sub.2 CH.sub.3
EXAMPLE 13
[0150] 28
(2R)-3-Amino-N-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl-
]-2-oxo-ethoxy}-phenyl)-propionamide
[0151]
[2-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-o-
xo-ethoxy}-phenylcarbanoyl)-ethyl]-carbamic Acid Tert-Butyl
Ester
[0152] To a solution of
2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl-
)-2-methyl-piperazin-1-yl]-ethanone (0.066 g, 0.17 mmol) in
methylene chloride (2 mL) at ambient temperature was added
N-methylmorpholine (0.025 mL, 0.23 mmol),
3-tert-butoxycarbonylamino-propionic acid (0.044 g, 0.23 mmol) and
O-benzotriazole-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (0.076 g, 0.20 mmol). The resulting solution
was stirred at ambient temperature for 60 hours, then concentrated.
Radial chromatography (2 mm plate) gave the title compound (0.114
g)
[0153]
(2R)-3-Amino-N-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperaz-
in-1-yl]-2-oxo-ethoxy}-phenyl)-propionamide
[0154] To a solution of
[2-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-pi-
perazin-1-yl]-2-oxo-ethoxy}-phenylcarbamoyl)-ethyl]-carbamic acid
tert-butyl ester (0.110 g, 0.2 mmol) in methylene chloride (3 mL)
was added trifluoroacetic acid (0.50 mL). The reaction was stirred
for 2 hours at ambient temperature then diluted with saturated
aqueous sodium hydrogen carbonate. The mixture was extracted with
methylene chloride and the combined organics were dried over
magnesium sulfate, filtered and concentrated in vacuo to give the
title compound (0.069 g)
[0155] The title compounds for Examples 14-19 were prepared by a
method analogous to that described in Example 13.
2 29 Example R.sup.20 R.sup.2 14 30 H 15 31 H 16 32 H 17 33 H 18 34
H 19 35 H
EXAMPLE 20
[0156] 36
[0157]
(2R,5S)-1-(2-Amino-ethyl)-3-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-
-dimethyl-piperazin-1-yl]-2-oxo-ethoxy)-phenyl)-urea
[0158] (2R,
5S)-2-(4-Chloro-2-nitro-phenoxy)-1-[4-(4-fluoro-benzyl)-2,5-di-
methyl-piperazin-1-yl]-ethanone
[0159] To a solution of (2R,
5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-di-
methyl-piperazin-1-yl]-2-oxo-ethoxy}-benzoic acid methyl ester (1.0
g, 3.35 mmol) in butanone (35 ml) was added 2-nitro-4-chlorophenol
(0.639 g, 3.69 mmol), potassium carbonate (0.925 g, 6.7 mmol) and
potassium iodide (0.556 g, 3.35 mmol). The reaction mixture was
heated at reflux overnight. The reaction mixture was then cooled,
diluted with water and extracted with ethyl acetate. The combined
organics were dried over magnesium sulfate, filtered and
concentrated to give an orange oil. Chromatography on silica gel
gave the title compound (1.35 g, 93% yield).
[0160] (2R,
5S)-2-(2-Amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2,5-di-
methyl-piperazin-1-yl]-ethanone
[0161] To a solution of (2R,
5S)-2-(4-chloro-2-nitro-phenoxy)-1-[4-(4-fluo-
ro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (2.2 g, 5.05 mmol)
in ethanol (50 ml) in a par bottle was added 5% platinum on carbon
(2.2 g). The reaction mixture was subjected to hydrogen gas (35
psi) for thirty minutes. The reaction mixture was filtered through
celite and washed with ethanol. The filtrate was concentrated to
give a tan foam. Chromatography on silica gel gave the title
compound (1.42 g, 70% yield).
[0162] (2R,
5S)-(5-Chloro-2-[2-[4-(4-fluoro-benzyl)-2.5-dimethyl-piperazin-
-1-yl]-2-oxo-ethoxy}-phenyl)-carbamic acid 4-nitro-phenyl Ester
[0163] To a solution of (2R,
5S)-2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluo-
ro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.150 g, 0.37
mmol) in dichloromethane (7 ml) was added pyridine (0.066 ml, 0.82
mmol) followed by 4-nitrophenyl chloroformate (0.075 g, 0.41 mmol).
The reaction was stirred at ambient temperature for 3 1/2 hours.
The reaction mixture was concentrated followed by chromatography on
silica gel to give the title compound (0.153 g, 74% yield).
[0164]
(2R,5S)-1-(2-Amino-ethyl)-3-(5-chloro-2-[2-[4-(4-fluoro-benzyl)-2,5-
-dimethyl-piperazin-1-yl]-2-oxo-ethoxy]-phenyl)-urea
[0165] To a solution of (2R,
5S)-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-d-
imethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-carbamic acid
4-nitro-phenyl ester (0.206 g, 0.37 mmol) in dry methanol (6 ml)
was added ethyldiamine (0.05 ml, 0.814 mmol). The reaction was
stirred at ambient temperature overnight. The reaction was
concentrated and chromatagraphed on silica gel to give the title
compound (0.115 g, 63% yield).
[0166] The title compounds for Examples 21-27 were prepared by a
method analogous to that described in Example 20.
3 37 Example R.sup.20 R.sup.2 21 38 Me 22 39 H 23 40 Me 24 41 H 25
42 H 26 43 H 27 44 Me
EXAMPLE 28
[0167] 45
(2R)-2-Amino-ethanesulfonic acid
(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-met-
hyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-amide
[0168] 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid
(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy-
}-phenyl)-amide
[0169] To a solution of of
2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-ben-
zyl)-2-methyl-piperazin-1-yl]-ethanone (0.050 g, 0.13 mmol) in
methylene chloride (1 mL) at ambient temperature was added
triethylamine (0.027 mL, 0.19 mmol) and
2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride
(0.045 g, 0.17 mmol). The reaction was stirred overnight at ambient
temperature. Additional triethylamine ((0.027 mL, 0.19 mmol) and
2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride
(0.045 g, 0.17 mmol) was added. The reaction was stirred one hour,
then additional triethylamine (0.055 mL, 0.34 mmol) was added. The
reaction was stirred and hour, then additional
2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanes- ulfonyl chloride
(0.090 g, 0.34 mmol) was added. After stirring an additional 1
hour, the reaction was treated with saturated aqueous sodium
hydrogen carbonate and extracted with methylene chloride
(3.times.). The combined organics were dried over magnesium
sulfate, filtered and concentrated in vacuo. Purification via
radial chromatography (2 mm plate) gave the title compound (0.030
g).
[0170] (2R)-2-Amino-ethanesulfonic acid
(5-chloro-2-{2-[4-(4-fluoro-benzyl-
)-2-methyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-amide
[0171] To a solution of
2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulf- onic acid
(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-o-
xo-ethoxy}-phenyl)-amide (0.030 g, 0.048 mmol) in EtOH (1 mL) at
ambient temperature was added hydrazine hydrate (0.025 mL). The
reaction was stirred overnight at ambient temperature then diluted
with water and extracted with methylene chloride (2.times.). The
combined organics were washed with saturated aqueous brine and
dried over sodium sulfate, filtered and concentrated in vacuo.
Purification via radial chromatography (2 mm plate) gave the title
compound (0.014 g).
[0172] The title compounds for Examples 29-34 were prepared by a
method analogous to that described in Example 28.
4 46 Example R.sup.20 R.sup.2 29 --SO.sub.2CF.sub.3 Me 30 47 H 31
48 H 32 49 H 33 50 H 34 --SO.sub.2N(Me).sub.2 Me
EXAMPLE 35
[0173] 51
(2R)-N-(5-Chloro-242-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-oxo-e-
thoxy]-phenyl)-cyanoguanidine
[0174]
1-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-2-ox-
o-ethoxy}-phenyl)-N-cyano-S-methyl-isothiourea
[0175] To a solution of of
2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-ben-
zyl)-2-methyl-piperazin-1-yl]-ethanone (0.30 g, 0.77 mmol) in
tetrahydrofuran (5 mL) at ambient temperature was added sodium
hydride (0.029 g, 1.22 mmol) and the reaction was stirred for 30
minutes. To this was added S,S1-dimethyl N-cyanodithio
iminocarbonate (0.168, 1.15 mmol) and the mixture was heated at
reflux overnight. The reaction was cooled and quenched with
saturated aqueous ammonium chloride. The mixture was extracted with
EtOAc and the combined organics were dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. Chromatography on silica gel
gave the title compound (0.350 g)
[0176]
(2R)-N-(5-Chloro-2-[2-[4-(4-fluoro-benzyl)-2-methyl-piperazin-1-yl]-
-2-oxo-ethoxy]-phenyl)-cyanoguanidine
[0177] To a solution of
1-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-methyl-pip-
erazin-1-yl]-2-oxo-ethoxy}-phenyl)-N-cyano-S-methyl-isothiourea
(0.045 g, 0.092 mmol) in EtOH (1 mL) was added ammonium hydroxide
(0.100 mL) and the resulting solution was shaken at 60.degree. C.
overnight. The crude reaction mixture was purified directly via
radial chromatography (2 mm plate) to give the title compound
(0.027 g). The title compounds for Examples 36-38 were prepared by
a method analogous to that described in Example 35.
5 52 53 Example R.sup.20 R.sup.2 36 54 H 37 55 H 38 56 H
EXAMPLE 39
[0178] 57
(2R,5S)-2-{4-Chloro-2-[(2-diethylaminothylamino)-methyl]-phenoxy}-1-[4-(4--
fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone
[0179]
(2R,5S)-5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2.5-dimethyl-piperazin-1-
-yl]-2-oxo-ethoxy}-benzaldehyde
[0180] To a solution of
2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piper-
azin-1-yl]-ethanone (2.87 g, 9.6 mmol) in DMF (20 mL) was added
5-chlorosalicylaldehyde (1.65 g, 10.5 mmol), potassium carbonate
(2.64 g, 19.2 mmol) and potassium iodide (1.59 g, 9.6 mmol). The
resulting mixture was heated to 100.degree. C. for 12 hours. The
reaction was cooled, diluted with saturated aqueous brine and
extracted with ethyl acetate (3.times.). The combined organics were
dried over magnesium sulfate and filtered. The filtrate was
concentrated in vacuo to give crude product. Purification via
chromatography on silica gel (15% EtOAc/Hexanes) gave the title
compound 3.40 g, 85% yield.)
[0181]
(2R,5S)-2-{4-Chloro-2-[(2-diethylamino-ethylamino)-methyl]-phenoxy}-
-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone
[0182] To a solution of
(2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dim-
ethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde (0.100 g, 0.25
mmol) in 10:1 dichloroethane acetic acid (2.2 mL) was added
(diethylamino)ethylamine (0.088 mL, 0.625 mmol) and the resulting
solution was stirred for 1 hour at ambient temperature. To this was
added sodium cyanoborohydride (0.0094 g, 0.15 mmol) and the
reaction was stirred overnight at ambient temperature. Upon
completion water was added and the mixture was basified with solid
sodium bicarbonate (pH>10). The product was extracted with
dichloromethane (2.times.) and diethyl ether (2.times.). The
combined organics were dried over magnesium sulfate, filtered and
concentrated in vacuo. Chromatography on silica gel gave the title
compound (0.039 g,.times.30% yield)
[0183] The title compounds for Examples 40-62 were prepared by a
method analogous to that described in Example 39.
6 58 Example R.sup.20 R.sup.2 40 59 Me 41 60 Me 42 61 Me 43 62 Me
44 63 Me 45 64 Me 46 65 Me 47 66 Me 48 67 Me 49 68 Me 50 69 Me 51
70 Me 52 71 Me 53 72 Me 54 73 Me 55 74 Me 56 75 Me 57 76 Me 58 77
Me 59 78 Me 60 79 Me 61 80 Me 62 81 Me
EXAMPLE 63
[0184] 82
N-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-e-
thoxy}-benzyl)-2-diethylamino-acetamide
[0185]
(2R,5S)-2-(2-Aminomethyl-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2-
,5-dimethyl-piperazin-1-yl]-ethanone
[0186] To a solution of
(2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dim-
ethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzaldehyde (1.86 g, 4.44
mmol) in MeOH (20 mL) was added ammonium acetate (3.42 g, 44 mmol)
and sodium cyanoborohydride (0.195 g, 3.1 mmol). The resulting
mixture was stirred overnight at ambient temperature. The reaction
was quenched with concentrated hydrochloric acid and concentrated
in vacuo. The residue was dissolved in water and basified with
aqueous 3N NaOH (pH>10). The product was extracted with
dichloromethane (2.times.) and ethyl acetate (2.times.). The
combined organics were dried over magnesium sulfate, filtered and
concentrated in vacuo. Chromatography on silica gel gave the title
compound (1.29 g, 69% yield)
[0187]
N-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2.5-dimethyl-piperazin-1-yl]--
2-oxo-ethoxy}-benzyl)-2-diethylamino-acetamide
[0188] To a solution of N,N-dimethylglycine (0.014 g, 0.13 mmol)
and
(2R,5S)-2-(2-aminomethyl-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-2,5-dim-
ethyl-piperazin-1-yl]-ethanone (0.063 g, 0.15 mmol) in
dichloromethane (2 mL) was added
1-(3-dimethlaminopropyl)-3-ethylcarbodiimide (0.034 g, 0.18 mmol),
1-hydroxybenzotriazole (0.021 g, 0.15 mmol), and triethylamine
(0.036 mL, 0.36 mmol). After the reaction was stirred for 48 hours,
the solution was diluted with saturated aqueous sodium bicarbonate
and extracted with dichloromethane (3.times.). The combined
organics were dried over magnesium sulfate, filtered and
concentrated in vacuo. Chromatography on silica gel gave the title
compound (0.063 g, 80%).
[0189] The title compounds for Examples 64-85 were prepared by a
method analogous to that described in Example 63.
7 83 Example R.sup.20 R.sup.2 64 84 Me 65 85 Me 66 86 Me 67 87 Me
68 88 Me 69 89 Me 70 90 Me 71 91 Me 72 92 Me 73 93 Me 74 94 Me 75
95 Me 76 96 Me 77 97 Me 78 98 H 79 99 H 80 100 Me 81 101 Me 82 102
Me 83 103 Me 84 104 H 85 105 H
EXAMPLE 86
[0190] 106
(2R,5S)-(N-{2-[3-(5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazi-
n-1-yl]-2-oxo-ethoxy}-benzyl)-ureido]-ethyl}-acetamide
[0191] To a solution of
(2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dim-
ethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylamine (0.200 g, 0.477
mmol) in methylene chloride (10 mL) was added pyridine(0.077 mL,
0.954 mmol) and 4-nitro phenyl chloroformate (0.097 g, 0.525 mmol).
The resulting mixture was stirred for one hour at ambient
temperature and then concentrated in vacuo. The residue (0.055 g,
0.094 mmol) was dissolved in methanol (1 mL).
N-Acetylethylenediamine (0.019 mL, 0.188 mmol) was added and the
reaction was stirred at room temperature over night. The reaction
was concentrated in vacuo and chromatography on silica gel gave the
title compound (0.019 g, 27%).
[0192] The title compounds for Examples 87-90 were prepared by a
method analogous to that described in Example 86.
8 107 Example R.sup.20 R.sup.2 87 108 Me 88 109 Me 89 110 Me 90 111
Me
EXAMPLE 91
[0193] 112
(2R,5S)-2-Amino-ethanesulfonic Acid
5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-
-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylamide
[0194]
(2R,5S)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid
5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-eth-
oxy}-benzylamide
[0195] To a solution of
(2R,5S)-5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dim-
ethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyl amine (0.060 g, 0.143
mmol) in methylene chloride (3 ml) was added
2-(1,3-dioxo-1,3-dihydro-isoindol-2-y- l)-ethanesulfonyl chloride
(0.043 g, 0.150 mmol) and triethylamine (0.060 mL, 0.43 mmol) and
the solution was stirred 1 hr at ambient temperature. The reaction
was diluted with saturated aqueous sodium hydrogen carbonate and
extracted with methylene chloride. The combined organics were dried
over magnesium sulfate, filtered and concentrated in vacuo.
Chromatography on silica gel gave the title compound (0.073 g,
77%).
[0196] (2R,5S)-2-Amino-ethanesulfonic acid
5-chloro-2-{2-[4-(4-fluoro-benz-
yl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-benzylamide
[0197] To a solution of
(2R,5S)-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-et- hanesulfonic
acid 5-chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazi-
n-1-yl]-2-oxo-ethoxy}-benzylamide (0.073 g, 0.111 mmol) in EtOH (1
mL) was added hydrazine (35% aq. 0.25 mL, 2.73 mmol) and the
solution was stirred overnight at ambient temperature. The reaction
was filtered through a glass frit and washed with EtOH. The
filtrate was concentrated in vacuo to give the title compound
(0.056 g, 96%)
[0198] The title compounds for Examples 92-93 were prepared by a
method analogous to that described in Example 91.
9 113 Example R.sup.20 R.sup.2 92 114 H 93 --SO.sub.2NMe.sub.2
Me
EXAMPLE 94
[0199] 115
[0200]
(2R)-N-(2-Amino-ethyl)-N'-(5-chloro-2-{2-[4-(4-fluoro-benzyl)-2-met-
hyl-piperazin-1-yl]-2-oxo-ethoxy}-benzyl)-cyanoguanidine
[0201] A solution of
2-(2-aminomethyl-4-chloro-phenoxy)-1-[4-(4-fluoro-ben-
zyl)-2-methyl-piperazin-1-yl]-ethanone (0.025 g, 0.062 mmol) and
diphenyl cyanocarbonimidate (0.016 g, 0.068 mmol) in ethanol (1 mL)
was heated on a shaker plate at 60.degree. C. After 22 h,
ethylenediamine (0.008 mL, 0.123 mmol) was added and the resulting
solution was heated on a shaker plate at 60.degree. C. for an
additional 21 h. The solution was cooled to ambient temperature,
concentrated and purified using radial chromatography to yield the
title compound (0.021 g, 67%). The title compounds for Examples
95-96 were prepared by a method analogous to that described in
Example 94.
10 116 Example R.sup.20 R.sup.2 95 117 H 96 118 H
EXAMPLE 97
[0202] 119
(2R,
5S)-5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-2-
-oxo-ethoxy}-N-methyl-benzenesulfonamide
[0203] 5-Chloro-2-methoxy-N-methyl-benzenesulfonamide
[0204] To a solution of 5-Chloro-2-methoxy-benzenesulfonyl chloride
(1.0 g, 4.15 mmol) in tetrahydrofuran(8 ml) was bubbled methylamine
gas until saturated. The reaction mixture was sealed with a septa
and stirred overnight at ambient temperature. The reaction mixture
was then concentrated, triterated in dichloromethane and ether,
filtered and dried yielding the above titled compound 1.05 g
(>100%) white solid.
[0205] 5-Chloro-2-hydroxy-N-methyl-benzenesulfonamide
[0206] To a solution of sodium hydride (60% in mineral oil, 90.24
mg, 2.25 mmol) in dry dimethyl formamide was added thiophenol
(0.225 ml, 2.25 mmol) dropwise. To this was then added
5-Chloro-2-methoxy-N-methyl-benzen- esulfonamide (531 mg, 2.25
mmol) followed by refluxing for 4 hours. The reaction mixture was
cooled, diluted with ethyl acetate and washed with a 1N sulfuric
acid solution. The organic layer was separated, dried over
magnesium sulfate, filtered and concentrated in vacuo.
Chromatography on silica gel yielded the above titled compound (320
mg, 53% yield).
[0207] (2R,
5S)-5-Chloro-2-{2-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin--
1-yl]-2-oxo-ethoxy}-N-methyl-benzenesulfonamide
[0208] To a solution of (2R,
5S)-2-Chloro-1-[4-(4-fluoro-benzyl)-2,5-dimet-
hyl-piperazin-1-yl]-ethanone (375 mg, 1.26 mmol) in butanone (12
ml) was added 5-Chloro-2-hydroxy-N-methyl-benzenesulfonamide (280
mg, 1.26 mmol), potassium carbonate (348 mg, 2.52 mmol) and
potassium iodide (209 mg, 1.26 mmol). The resulting reaction
mixture was refluxed for 4 hours. It was allowed to cool, diluted
with ethyl acetate and washed with brine. The organic layer was
separated, dried over magnesium sulfate, filtered and concentrated
in vacuo. Chromatography on silica gel gave the above titled
compound (320 mg, 53% yield).
[0209] The title compounds for Examples 98-100 were prepared by a
method analogous to that described in Example 97.
11 120 Example R.sup.20 R.sup.2 98 --NH.sub.2 Me 99 121 Me 100 122
Me
* * * * *